tbuckley/cabot-search huggingface dataset:
Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement
Authors: Eric Van Belle, Antoine Rauch, Flavien Vincent, Emmanuel Robin, Marion Kibler, Julien Labreuche, Emmanuelle Jeanpierre, Marie Levade, Christopher Hurt, Natacha Rousse, Jean-Baptiste Dally, Nicolas Debry, Jean Dallongeville, Andre Vincentelli, Cedric Delhaye, Jean-Luc Auffray, Francis Juthier, Guillaume Schurtz, Gilles Lemesle, Thibault Caspar, Olivier Morel, Nicolas Dumonteil, Alain Duhamel, Camille Paris, Annabelle Dupont-Prado, Paulette Legendre, Frederic Mouquet, Berenice Marchant, Sylvie Hermoire, Delphine Corseaux, Karim Moussa, Aurelie Manchuelle, Jean-Jacques Bauchart, Valentin Loobuyck, Claudine Caron, Christophe Zawadzki, Fabrice Leroy, Jean-Christophe Bodart, Bart Staels, Jenny Goudemand, Peter J. Lenting, Sophie Susen
Journal: New England Journal of Medicine (2016)

Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR.We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation.After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year.The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.).
Abstract 3839: Vitamin E delta-tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis
Authors: Kazim Husain, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa
Journal: Cancer Research (2016)

Abstract Background: Colon cancer is the most commonly diagnosed cancer both in men and women and cause of cancer related deaths worldwide. Treatment for the recurrent and metastatic colon cancer remains a center of clinical attention. Cancer stem cells (CSCs) are suggested to be the only cells within tumor with tumorigenic capacity and implicated in metastasis. We have shown that vitamin E delta-tocotrienol (VEDT) is the most bioactive tocotrienols against cancers. This study aimed to evaluate the effect of VEDT on colon cancer growth, metastatic epithelial to mesenchymal transition (EMT), migration/ invasion/angiogenesis and colon CSCs growth and apoptosis. Methods: Human colon cancer cells HCT-116 and metastatic colon cancer cells SW-620 and colon CSCs were treated with VEDT (10-100 μM) for 72 h and cell viability recorded. VEDT (50 μM) was used for malignant transformation; migration/invasion, CSCs spheroid formation, and pluripotency were determined. Azoxymethane treated Fisher 344 rats were used as colon carcinogenesis model. They were treated with 1) vehicle control and 2) VEDT (200 mg/kg, orally twice a day) for 20 weeks. After 20 weeks the polyps and tumor formation were recorded. Results: VEDT significantly inhibited the anchorage-dependent and independent cancer cell growth, migration/invasion and induced apoptosis compared to control. VEDT inhibited the CSC spheroid formation EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) compared to control. Conclusion: Vitamin E delta-tocotrienol inhibited colon cancer growth and metastasis through inhibition of cancer stem cell pluripotency, EMT, migration, invasion, angiogenesis and induction of apoptosis. Citation Format: Kazim Husain, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa. Vitamin E delta-tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3839.
Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia
Authors: L Quotti Tubi, S Canovas Nunes, A Brancalion, E Doriguzzi Breatta, S Manni, E Mandato, F Zaffino, P Macaccaro, M Carrino, K Gianesin, L Trentin, G Binotto, R Zambello, G Semenzato, C Gurrieri, F Piazza
Journal: Leukemia (2016)
Abstract 958: MiR-196b is an epigenetically silenced tumor suppressor for lung cancer
Authors: Carmen S. Tellez, Daniel E. Juri, Kieu Do, Maria A. Picchi, Teresa Wang, Gang Liu, Avrum Spira, Steven A. Belinsky
Journal: Cancer Research (2016)

Abstract Silencing of microRNAs by promoter hypermethylation could play a significant role in lung cancer initiation and progression. A pre-malignancy model using carcinogen transformed human bronchial epithelial cells (HBECs) treated with the demethylating agent 5-aza-2’deoxycytidine followed by next-generation sequencing identified miR-196b and miR-34c-5p as being epigenetically regulated. Bisulfite sequencing confirmed silencing via dense promoter hypermethylation that was commonly replicated in malignant cell lines and primary tumors. Functional studies of miR-196b revealed that it was epigenetically silenced by chromatin modification and DNA methylation during transformation of HBECs and re-expression modulated genes involved in cell cycle regulation. Stable re-expression led to a cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene that was replicated in vivo by a profound reduction in growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibits FOS promoter and AP-1 reporter activity. A case-control study showed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p&amp;lt;0.001). These studies identify miR-196 as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of this microRNA could benefit prevention and therapy for the management of lung cancer. Citation Format: Carmen S. Tellez, Daniel E. Juri, Kieu Do, Maria A. Picchi, Teresa Wang, Gang Liu, Avrum Spira, Steven A. Belinsky. MiR-196b is an epigenetically silenced tumor suppressor for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 958.
Abstract 2813: The synergistic anticancer activity of 1’-acetoxychavicol acetate and sodium butyrate in human hepatocellular carcinoma cells
Authors: Isao Matsui-Yuasa, Akiko Kojima-Yuasa
Journal: Cancer Research (2016)

Abstract Introduction: It has been suggested that the combined effect of natural products may improve the effect of treatment against the proliferation of cancer cells. We evaluated the combination of 1’-acetoxychavicol acetate (ACA), obtained from Alpinia galangal, and sodium butyrate (NaB), a major short chain fatty acid, on the growth of HepG2 cells. ACA exhibits chemopreventive effects on chemically induced tumors in mouse skin as well as on rat oral, colonic, esophangeal, and pancreatic tumors. ACA also exerts antitumor activity by inducing apoptosis in various tumor cells. On the other hand, sodium butyrate has multiple effects on tumor cells cultured in vitro, including, most notably, inhibition of cell proliferation and induction of apoptosis, as well as initiating the differentiation of various carcinoma cells. The aim of our study was to elucidate the synergistic interaction of ACA and NaB on cell viability in the human hepatocellular carcinoma cell line HepG2 and to examine the mechanism of the anti-cancer effect of combined ACA and NaB treatment. Methods: HepG2 cells or HT-29 cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% FBS. Results: The number of HepG2 cells was synergistically decreased via apoptosis induction with the combined treatment of ACA and NaB. In ACA- and NaB-treated cells, intracellular reactive oxygen species (ROS) levels and NADPH oxidase activities were increased significantly. The decrease in cell number after combined treatment of ACA and NaB was improved with the treatment of catalase. These results suggest that an increase in intracellular ROS levels is involved in cancer cell death. AMP-activated protein kinase (AMPK) plays an essential role in controlling processes related to tumor development. In ACA- and NaB-treated cells, AMPK phosphorylation was induced significantly, and this induction improved when cells were pretreated with catalase. These results suggest that the increase in intracellular ROS is involved in the increase of AMPK phosphorylation. Conclusion: These findings are consistent with the hypothesis that combination treatments can sensitize cancer cells more effectively than individual treatments. We reported that combination treatment of ACA and NaB synergistically induced apoptotic cell death via an increase in intracellular ROS and an increase in pAMPK levels. Our findings may provide new insight into the development of novel combination therapies against hepatocellular carcinoma. Citation Format: Isao Matsui-Yuasa, Akiko Kojima-Yuasa. The synergistic anticancer activity of 1’-acetoxychavicol acetate and sodium butyrate in human hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2813.
Association Between Germline Mutation in<i>VSIG10L</i>and Familial Barrett Neoplasia
Authors: Ryan E. Fecteau, Jianping Kong, Adam Kresak, Wendy Brock, Yeunjoo Song, Hisashi Fujioka, Robert Elston, Joseph E. Willis, John P. Lynch, Sanford D. Markowitz, Kishore Guda, Amitabh Chak
Journal: JAMA Oncology (2016)

Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment.To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family.We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes.Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene.A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes.This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma.
Specific Micro-RNA Expression Profile in Hodgkin Lymphoma.
Authors: Lu Ping Tan, Geert Harms, Tjasso Blokzijl, Rikst Nynke Schakel, Johan Gibcus, Peter Möller, Ralf Küppers, Rogier M. Reijmers, Steven T. Pals, Sibrand Poppema, Bart-Jan Kroesen, Anke van den Berg
Journal: Blood (2007)
Overexpression of Oncogenic KRAS G12V in Human Stem and Progenitor Cells Enhances Proliferation and Initiates Monocytic Differentiation Via Intrinsic and Extrinsic Pathways.
Authors: Szabolcs Fatrai, Djoke van Gosliga, Lina Han, Simon M. G. J. Daenen, Edo Vellenga, Jan Jacob Schuringa
Journal: Blood (2009)
CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice
Authors: Amanda Poissonnier, Doriane Sanséau, Matthieu Le Gallo, Marine Malleter, Nicolas Levoin, Roselyne Viel, Lucie Morere, Aubin Penna, Patrick Blanco, Alain Dupuy, Florence Poizeau, Alain Fautrel, Julien Seneschal, Florence Jouan, Jerome Ritz, Edouard Forcade, Nathalie Rioux, Cécile Contin-Bordes, Thomas Ducret, Anne-Marie Vacher, Paul A. Barrow, Robin J. Flynn, Pierre Vacher, Patrick Legembre
Journal: Immunity (2016)

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.
Abstract 3961: Methodological considerations in the preparation of biomimetic reference materials for ctDNA assays
Authors: Seth B. Harkins, Farol L. Tomson, Bharathi Anekella, Russell Garlick
Journal: Cancer Research (2016)

Abstract Clinical utilization of cell-free DNA (cfDNA) has become commonplace for NIPS testing and has recently been more widely deployed to quantitate cell-free circulating tumor DNA (ctDNA) for use in cancer patient care longitudinally across the treatment spectrum from subclinical, to diagnosis and through treatment. The scarcity and unstable nature of the cfDNA analyte in human plasma is problematic and thus the lack of robust detection methods has limited clinical validation. In this work we sought to avoid the inherent limitations of plasma-based patient reference materials and developed a strategy to prepare a biomimetic reference material which is sufficiently equivalent to the cfDNA found in patients with malignant cancers. Thus far the scarcity and physical form of ctDNA in human plasma has attenuated the validation of assays for clinical utility. To this end, we have generated a biosynthetic construct with short DNA fragments containing relevant cancer mutation sequences, including single-nucleotide variations, insertions and deletions in BRAF, EGFR, KRAS, NRAS, PIK3CA or HER/ERBB2. The mutant fragments were titrated into normal human reference DNA, GM24385, and ultrasonically sheared to ∼160 bp. Precise allele frequency blends were verified by digital PCR (dPCR) prior to encapsulation to enhance stability and compatibility with commutable plasma. The reference material is formulated to 20 ng/mL of extractable DNA in modified Seracare Matribase™ to confer commutability in pre-analytic processes. These materials have been quantitated by dPCR and/or Next Generation Sequencing (NGS). A dilution panel was prepared at 10%, 5%, 2.5%, 1.25%, 0.1% allele frequency (mutant:normal DNA). Linearity (R2 = 0.9997) was observed by dPCR (measured vs. expected) and the NGS detected, Swift Accel-Amplicon 56G Oncology Panel (R2 = 0.997). Due to the low abundance of ctDNA, a characterized reference set is critical to validate assays that are developed with extremely low limit of detection. Data will be presented to show the breadth of this methodology and its utility in validating NGS and dPCR assays. Citation Format: Seth B. Harkins, Farol L. Tomson, Bharathi Anekella, Russell Garlick. Methodological considerations in the preparation of biomimetic reference materials for ctDNA assays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3961.
Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure
Authors: Hendrik B. Sager, Maarten Hulsmans, Kory J. Lavine, Marina B. Moreira, Timo Heidt, Gabriel Courties, Yuan Sun, Yoshiko Iwamoto, Benoit Tricot, Omar F. Khan, James E. Dahlman, Anna Borodovsky, Kevin Fitzgerald, Daniel G. Anderson, Ralph Weissleder, Peter Libby, Filip K. Swirski, Matthias Nahrendorf
Journal: Circulation Research (2016)

Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear.This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05).Myocardial failure is influenced by an altered myeloid cell repertoire.
Abstract 4637: Chk1 inhibition: a promising targeted treatment for head and neck squamous cell carcinoma
Authors: Anne M. van Harten, Marijke Stigter-van Walsum, Marijke Buijze, Boudewijn Jm Braakhuis, Ruud H. Brakenhoff
Journal: Cancer Research (2016)

Abstract Over 90% of all malignant tumors in the head and neck region are squamous cell carcinomas (HNSCC), ranking within the top 10 of most common cancers worldwide. HNSCC arise in the mucosal linings of the upper aerodigestive tract, and known risk factors are tobacco use, excessive alcohol consumption and infection with high risk types of the human papillomavirus (HPV). Despite the application of intensive treatment protocols, the 5-years survival rate of HNSCC patients has hardly increased last decades and remained at approximately 50%. Therefore, new therapeutic possibilities are urgently awaited. Previously, we identified CHEK1 as a candidate therapeutic target for HNSCC in a whole genome siRNA screen (Martens-de Kemp et al, Clin Cancer Res 2013). Additionally, a functional screen using a microRNA expressing library indicated that knockdown of ATM expression may cause a lethal effect in HNSCC cell lines as well (Lindenbergh-van der Plas et al, Clin Cancer Res 2013). The aim of the present study was to investigate whether interference with the ATM/ATR/CHEK1/CHEK2 DNA damage response pathway is indeed a promising therapeutic approach in HNSCC. RNA interference using siRNAs targeting ATM, ATR, CHEK1 and CHEK2 confirmed that particularly CHEK1 is essential for the survival of a subset of HNSCC cell lines, whereas the cell viability of primary oral keratinocytes and fibroblasts was not compromised. This was confirmed in vitro by treatment with a small molecule inhibitor targeting Chk1, and a therapeutic window between cancer and normal oral mucosal cells was observed. Functional assays indicated an S-phase delay in Chk1 inhibited HNSCC cells, followed by DNA damage. The latter was indicated by elevated phosphorylation of ATM Ser1981 and γH2Ax Ser139, as well as the appearance of chromosomal breaks. The DNA damage response initiated caspase-mediated apoptosis, resulting in programmed cell death. In summary, our data show that HNSCC cells appear to depend strongly on a functional Chk1 protein during DNA replication. Therefore, Chk1 inhibition seems an interesting therapeutic strategy for HNSCC, at least in a subset of tumors. Citation Format: Anne M. van Harten, Marijke Stigter-van Walsum, Marijke Buijze, Boudewijn Jm Braakhuis, Ruud H. Brakenhoff. Chk1 inhibition: a promising targeted treatment for head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4637.