tbuckley/cabot-search huggingface dataset:
Consensus statement on mandatory measurements in Pancreatic cancer trials for systemic treatment of unresectable disease (COMMPACT)
Authors: L. B. van Rijssen, E. ter Veer, M. G. Besselink, R. M. A. Mali, J. Berlin, S. Boeck, F. Bonnetain, T. Conroy, G. Deplanque, D. Goldstein, Bengt Glimelius, J. P. Neoptolemos, M. Reni, W. Scheithauer, J. van der Meer, J. W. Wilmink, M. J. van der Poel, O. R. Busch, M. G. H. van Oijen, H. W. M. van Laarhoven
Journal: Annals of Oncology (2017)
Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome
Authors: WataruShimizu, CharlesAntzelevitch
Journal: Circulation (1997)

Background This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS). Methods and Results A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291±14 to 354±35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51±15 to 72±17 ms). QT interval increased from 320±13 to 385±37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280±25 to 609±49 ms) and caused a marked delay in the onset of the T wave and...
Abstract 20621: Reduction of Neointimal Hyperplasia With Clopidogrel or Ticagrelor in a Canine Model of Coronary Stent Implantation
Authors: Pierre Voisine, Josep Rodes-Cabau, Marc Ruel, Christian Couture, Marina Urena, Luis Nombela, Henrique Ribeiro, Denis Simard, John Kingma
Journal: Circulation (2016)

Introduction: Ticagrelor is a reversible P2Y12 receptor inhibitor that has emerged to replace clopidogrel for thromboprophylaxis after coronary stent placement, with a quicker onset and more potent...
Abstract 4567: Immunomodulatory action of SGI-110 and combination with γδ T cell immunotherapy in ovarian cancer
Authors: Marina Natoli, Anastasios Karadimitris, Sadaf Ghaem-Maghami
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OC) is regarded as being an immunogenic cancer and strategies to enhance immune function in patients are thought to confer benefit and improve prognosis. Immunotherapy has been shown to be most promising when combined with other therapeutic approaches. Recent evidence in the field and preliminary data from our group suggest that treatment with epigenetic drugs, such as DNA methyltransferase inhibitors (DNMTi), can lead to improved immune activation in several cancers including ovarian. The purpose of this study is to test the hypothesis that treatment with next generation hypomethylating agent SGI-110 can induce the re-expression of immunomodulatory genes and endogenous retroviruses (ERVs), which shifts OC cells towards a more immunogenic expression profile. OC cell lines SKOV3, Kuramochi and OVSAHO were treated with low dose SGI-110 and assessed for increased immunogenicity. Expression of immune biomarkers and ERVs was assessed at different time points at mRNA levels by qPCR and protein levels by Flow Cytometry. Treated cell lines were functionally tested for increased immunogenicity by co-culture with γδ T cells, which were isolated from healthy donors and expanded by zoledronic acid selection. MTT assays were performed to assess cell viability and T cell killing following co-culture. IFNγ and Granzyme B release from T cells and chemokine release from tumor cells were assessed by ELISA. Our results show up-regulation of key immunogenicity biomarkers and ERVs in our panel of OC cell lines, following treatment with SGI-110. Co-culturing SGI-110-treated cell lines with γδ T cells resulted in increased tumor cell killing and T cell activity. We are now analysing RNA-sequencing data of SGI-110-treated OC cell lines in an effort to dissect the immunomodulatory mechanism of action of this novel hypomethylating agent. Moreover, we plan to test the in vivo feasibility of a SGI-110/γδ T cell combination therapy, which if successful might be further optimised for a clinical trial. Citation Format: Marina Natoli, Anastasios Karadimitris, Sadaf Ghaem-Maghami. Immunomodulatory action of SGI-110 and combination with γδ T cell immunotherapy in ovarian 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 4567.
Abstract 1421: Flexible tools for the development and performance verification of customized target enrichment panels
Authors: Cynthia L. Hendrickson, Evan Mauceli, Andrew Barry, Kruti Patel, Catherine Huang, Scott Adams, Bharathi Anekella
Journal: Cancer Research (2018)

Abstract Implementation of next generation sequencing for variant identification and discovery presents difficulties both in the selection of genomic loci for inclusion in a panel, as well as the ability to effectively verify the performance of the assay based on the content selected. Balancing the relevance of genomic content with the practical hurdles of developing specific assays necessitates new approaches for the application of next generation sequencing toward precision medicine that are aimed at providing the flexibility of content to efficiently provide data capable of testing fundamental biological hypotheses. NEBNext Direct Custom Ready Panels overcome these obstacles by enabling the rapid development and deployment of customized target enrichment panels. This offering allows researchers to select from a large library of genes for which baits have been developed and optimized to produce sequencing data with extremely high specificity and coverage uniformity. These panels are effective in targeting a wide range of content, from highly focused, single-gene panels, to comprehensive panels comprised of hundreds of genes. In a similar approach for the verification and validation of new panels, SeraCare has developed the VariantFlex™ system, which is comprised of a broad library of mutations to develop custom controls and reference materials for NGS-based assays. These biosynthetic constructs contain variants such as SNVs, indel, frameshift and fusion variants that can be used to formulate controls across a range of variant allele frequencies, providing the necessary content and flexibility to verify assay performance. Here we will present data demonstrating the combined utility of these offerings to assess target enrichment panel performance with a range of genomic content, panel sizes and variant allele frequencies. Citation Format: Cynthia L. Hendrickson, Evan Mauceli, Andrew Barry, Kruti Patel, Catherine Huang, Scott Adams, Bharathi Anekella. Flexible tools for the development and performance verification of customized target enrichment panels [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 1421.
Curcumin-loaded lipid-hybridized cellulose nanofiber film ameliorates imiquimod-induced psoriasis-like dermatitis in mice
Authors: Nae-Won Kang, Min-Hwan Kim, Seo-Yeon Sohn, Ki-Taek Kim, Ju-Hwan Park, Sun-Young Lee, Jae-Young Lee, Dae-Duk Kim
Journal: Biomaterials (2018)
Abstract 5785: EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway
Authors: Bengt Hallberg, Ruth H. Palmer, Ganesh Umapathy, Dan E. Gustafsson, Joachim T. Siaw, Wasi Alam, Jikui Guan, Robert Doebele, Anh T. Le, Andrea Doak
Journal: Cancer Research (2018)

Abstract Background: The protein kinase B (PKB/AKT) and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancer types. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback mechanisms have been described in which inhibition of one pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of targeted monotherapies. Materials and Methods: In order to determine which signalling core should be blocked for combinatorial treatment, we treated a panel of EML4-ALK positive lung cancer cell lines using MEK-ERK inhibitors. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. Results: In this study, we describe a feedback mechanism in which MEK-ERK inhibition leads to increased activation of AKT signaling in EML4-ALK variant (E6a/b;A20) positive NSCLC cell lines. Interestingly, EML4-ALK variant (E13;A20) NSCLC cell lines responds to MEK-ERK inhibitors and shows synergism when combined with ALK tyrosine kinase inhibitors. We found that feedback response in EML4-ALK variant (E6a/b;A20) positive NSCLC cells was mediated by the mammalian target of rapamycin complex 2-associated protein SIN1, resulting in increased survival and proliferation that depended on AKT signaling. Conclusions: Taken together, these results elucidate an important feedback network and contraindicate the use of MEK inhibitors as effective therapeutic strategy in EML4-ALK variant (E6a/b;A20) positive NSCLC. Citation Format: Bengt Hallberg, Ruth H. Palmer, Ganesh Umapathy, Dan E. Gustafsson, Joachim T. Siaw, Wasi Alam, Jikui Guan, Robert Doebele, Anh T. Le, Andrea Doak. EML4-ALK variant E6a/b;A20 positive NSCLC cell lines are associated with growth upon blocking MEK-ERK pathway [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 5785.
Vitamin E Deficiency in Variant Angina
Authors: KunihisaMiwa, YukoMiyagi, AkihikoIgawa, KeikoNakagawa, HiroshiInoue
Journal: Circulation (1996)

Background Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm. Methods and Results Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma α-tocopherol levels as well as α-tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma γ-tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels ...
Abstract 2270: Integrating 5hmC and gene expression data infers regulatory mechanisms linked to alternative mRNA splicing in breast cancer
Authors: Cristina Mitrea, Priyanga Wijesinghe, Greg Dyson, Emily Girsch, Bin Bao, Adele Kruger, Aliccia Bollig-Fischer
Journal: Cancer Research (2018)

Abstract Epigenetic mechanisms, such as 5-methylcytosine (5mC), are known to play a major role in breast cancer. However, the role of 5-hydroxymethylcytosine (5hmC) DNA modification remains understudied. We hypothesize that 5hmC mediates redox regulation of gene expression in the triple negative breast cancer (TNBC) subtype. To address this, our objective was to highlight genes that may be the target of this process by identifying redox-regulated, antioxidant-sensitive, gene-localized 5hmC changes associated with mRNA changes in TNBC cells. We proceeded to develop an approach to integrate data sets generated by a methodology called Pvu-sequencing, which measures 5hmC in the genome, and RNA-sequencing. The result of our approach to merge genome-wide, high-throughput TNBC cell line data to identify significant, concordant 5hmC and mRNA changes in response to antioxidant treatment, that perturbs redox signaling, produced a gene set with relevance to alternative mRNA splicing and cancer stem cell function. Key genes identified included TAR DNA binding protein (TARDBP), vimentin (VIM), and splicing factor proline and glutamine rich (SFPQ). Moreover, we have established a method that will be useful for continued research of 5hmC in TNBC cells and tissue samples. Citation Format: Cristina Mitrea, Priyanga Wijesinghe, Greg Dyson, Emily Girsch, Bin Bao, Adele Kruger, Aliccia Bollig-Fischer. Integrating 5hmC and gene expression data infers regulatory mechanisms linked to alternative mRNA splicing in breast 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 2270.
Abstract 15774: Impaired Autophagy Contributes to Toll Like Receptor-4 Induced Osteogenesis in Human Aortic Valve Interstitial Cells
Authors: XinshengDeng, XianzhongMeng, DavidFullerton, JamesJaggers
Journal: Circulation (2014)

Objective: Stimulation of Toll-like receptor 4 (TLR4) induces inflammatory and osteogenic responses in aortic valve interstitial cells (AVICs). Autophagy protects against vascular calcification. We therefore hypothesized that LPS impairs autophagy, and this contributes to osteogenesis in human AVICs via mTOR signaling. Methods: AVICs were isolated from the adult explanted heart transplant recipients without aortic valve abnormalities. Cells were treated with LPS. Autophagy activity was investigated using chemical inhibitors and genetic techniques. The osteogenic markers bone morphogenetic protein 2 (BMP-2) and alkaline phosphatase (ALP), as well as mTOR associated signaling molecules, were analyzed. Results: LPS inhibited autophagy as indicated by changes of protein levels of LC3-II. Suppression of autophagy by 3-methyladenine, bafilomycin, or short hairpin-mediated silencing of Becn1 gene increased the expression of BMP-2 and ALP. Conversely, upregulation of autophagy with rapamycin or overexpression of ...
Nucleotide Receptors Involved in UTP-Induced Rat Arterial Smooth Muscle Cell Migration
Authors: XavierPillois, HervéChaulet, IsabelleBelloc, FrançoiseDupuch, ClaudeDesgranges, Alain-PierreGadeau
Journal: Circulation Research (2002)

Many factors have been shown to be involved in the development of hyperplasic lesions of vessels, but the role of extracellular nucleotides remains largely unknown. The presence of P2Y and P2X nucleotide receptors on arterial endothelial and smooth muscle cells suggests a potential role for nucleotides in the vessel pathophysiology. Although the role of P2X in physiology of vessels is well documented, that of P2Y is not completely understood. We recently demonstrated that extracellular nucleotides, and particularly UTP, induced migration of cultured arterial smooth muscle cells (ASMCs). This migration is dependent on osteopontin expression and involves the Rho and mitogen-activated protein (MAP) kinase pathways. An important question is to determine the specific role of the different P2Y receptors of rat ASMCs in the UTP-induced migration process. Therefore, we first quantified mRNA levels of P2Y2, P2Y4, and P2Y6 nucleotide receptors in cultured rat ASMCs by a competitive RT-PCR approach and demonstrated ...
Acute phase proteins and IP-10 as triage tests for the diagnosis of tuberculosis: systematic review and meta-analysis
Authors: V.S. Santos, D. Goletti, K. Kontogianni, E.R. Adams, B. Molina-Moya, J. Dominguez, V. Crudu, P.R.S. Martins-Filho, M. Ruhwald, L. Lawson, J.S. Bimba, A.L. Garcia-Basteiro, L. Petrone, B.S. Kabeer, K. Reither, L.E. Cuevas
Journal: Clinical Microbiology and Infection (2018)

ObjectivesWe examined the data reported in studies for diagnostic purposes and to discuss whether their intended use could be extended to triage, as rule-in or rule-out tests to select individuals who should undergo further confirmatory tests.MethodsWe searched Scopus, PubMed and Web of Science with the terms 'acute phase proteins,' 'IP-10,' 'tuberculosis,' 'screening' and 'diagnosis,' extracted the sensitivity and specificity of the biomarkers and explored methodologic differences to explain performance variations. Summary estimates were calculated using random-effects models for overall pooled accuracy. The hierarchical summary receiver operating characteristic model was used for meta-analysis.ResultsWe identified 14, four and one studies for C-reactive protein (CRP), interferon γ–induced protein 10 (IP-10) and alpha-1-acid glycoprotein (AGP). The pooled CRP sensitivity/specificity (95% confidence interval) was 89% (80–96) and 57% (36–65). Sensitivity/specificity were higher in high-tuberculosis-burden countries (90%/64%), HIV-infected individuals (91%/61%) and community-based studies (90%/62%). IP-10 sensitivity/specificity in TB vs. non-TB studies was 85%/63% and in TB and HIV coinfected vs. other lung conditions 94%/21%. However, IP-10 studies included diverse populations and a high risk of bias, resulting in very low-quality evidence. AGP had 86%/93% sensitivity/specificity.ConclusionsFew studies have evaluated CRP, IP-10 and AGP for the triage of symptomatic patients. Their high sensitivity and moderate specificity warrant further prospective studies exploring whether their combined use could optimize performance.
Case 24-2018: A 71-Year-Old Man with Acute Renal Failure and Hematuria
Authors: Ronald J. Falk, Jad S. Husseini, Andrew Z. Fenves, Ivy A. Rosales
Journal: New England Journal of Medicine (2018)

A 71-year-old man presented with acute renal failure and hematuria. Examination of the urinary sediment revealed numerous nondysmorphic red cells, a few granular casts, and no cellular casts. Blood cultures grew gram-negative rods. Diagnostic tests were performed.
Abstract LB-294: Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2
Authors: Tary Traore, Mithun Khattar
Journal: Cancer Research (2018)

Abstract Antibody-drug conjugates (ADCs) are a highly potent class of drugs that specifically target cancer cells expressing a tumor associated antigen (TAA). The ADC TAK-522 (XMT-1522) consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR (drug-to-antibody ratio) of twelve AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. We have characterized the ability of both the free payload AF-HPA and the ADC TAK-522 to induce immunogenic cell death (ICD) in vitro in multiple cell lines (NCI-N87, HT-29, SKBR3), as measured by cell surface expression of the ICD marker calreticulin (CRT) using microscopy and flow cytometry. CRT, usually contained in the lumen of the endoplasmic reticulum, translocated to the cell surface within a few hours after treatment with AF-HPA or TAK-522. Furthermore, we developed a novel syngeneic breast cancer (4T1) model expressing human HER2 at a relatively low antigen density. Treatment in this poorly immunogenic tumor model with TAK-522 but not Kadcyla showed significant inhibition of tumor growth in vivo. Importantly, a combination of anti-PD1 mAb and TAK-522 therapy substantially and synergistically enhanced the anti-tumor efficacy, resulting in complete responses in some mice. The frequency of complete responders was further increased when the two drugs were sequentially, rather than concurrently, administered such that TAK-522 administration was followed by anti-PD1 mAb therapy. These results suggest an immunological mechanism involving induction of immunogenic cell death by TAK-522, which in turn may activate the adaptive immune system by releasing tumor specific antigens. TAK-522 is currently being tested in a phase-1b clinical trial in patients with advanced breast, lung and gastric cancer expressing HER2. Based on our data, TAK-522 represents a potential candidate for combination therapies with immune checkpoint modulators in patients with poorly immunogenic HER2 expressing tumors. Citation Format: Tary Traore, Mithun Khattar. Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2 [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 LB-294.
Abstract 1870: The anti-proliferative and pro-apoptotic effect of MDM2-p53 antagonists evaluated in human tumor cells lines and chronic lymphocytic leukemia patient samples
Authors: Elaine Willmore, Yan Zhao, Carmela Ciardullo, Laura Woodhouse, Huw D. Thomas, Maria Ahn, Lynsey Fazal, Martin E. Noble, Ian Hardcastle, Steven Howard, Gianni Chessari, John Lunec, Steve Wedge
Journal: Cancer Research (2018)

Abstract We investigated the cellular response to two MDM2-p53 antagonists (RG7388 and Cpd 1) in a panel of 19 tumor cell lines and in patient-derived chronic lymphocytic leukemia (CLL) cells. RG7388 (Idasanutlin) is an MDM2-p53 antagonist developed by Roche and Cpd1 a novel potent and selective MDM2-p53 antagonist developed as part of an ongoing Alliance between Newcastle University, Cancer Research UK and Astex Pharmaceuticals. RG7388 and Cpd1 potently inhibited the proliferation of many cell lines, with MDM2-amplified SJSA-1 osteosarcoma cells and cells from haematological malignancies being the most sensitive (e.g. GI50 values in the acute myeloid leukemia cell line MOLM13 were 33 + 16 nM for RG7388 and 8 + 1 nM for Cpd 1). We also examined induction of apoptosis by measuring caspase 3/7 activation (24 h treatment). SJSA-1 cells showed a 20-fold increase in caspase activation and Molm13 cells a 6-fold increase (measured at 300nM with RG7388). However, cell lines from solid tumours such as the colorectal carcinoma HCT116 or the hepatocellular carcinoma HepG2 did not show any induction of apoptosis, even at concentrations up to 1µM RG3788. In primary CLL cells, Cpd 1 reduced cell viability (48 h) with an average LC50 of 131 + 46 nM (n = 4), compared to 400 + 55 nM for RG7388 (n =23). We also quantified mRNA levels in 25 primary CLL samples and found that RG7388 induced a predominantly pro-apoptotic gene signature: following 6h treatment, 1µM RG7388 resulted in an average 8-fold induction of PUMA and 3.5-fold increase in BAX compared to a 1.6-fold induction of CDKN1A (p21). Our data confirm that targeting the MDM2-p53 interaction is an effective strategy to inhibit growth and viability of tumor cells, and that some cells, including those expressing high levels of MDM2 or those derived from hematological malignancies, display a striking apoptotic response. Citation Format: Elaine Willmore, Yan Zhao, Carmela Ciardullo, Laura Woodhouse, Huw D. Thomas, Maria Ahn, Lynsey Fazal, Martin E. Noble, Ian Hardcastle, Steven Howard, Gianni Chessari, John Lunec, Steve Wedge. The anti-proliferative and pro-apoptotic effect of MDM2-p53 antagonists evaluated in human tumor cells lines and chronic lymphocytic leukemia patient samples [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 1870.