tbuckley/cabot-search huggingface dataset:
Vascular Endothelial Cell Growth–Activated XBP1 Splicing in Endothelial Cells Is Crucial for Angiogenesis
Authors: LingfangZeng, QingzhongXiao, MeiChen, AndrianaMargariti, DanielMartin, AleksandarIvetic, HepingXu, JustinMason, WenWang, GillianCockerill, KazutoshiMori, Julie Yi-shuanLi, ShuChien, YanhuaHu, QingboXu
Journal: Circulation (2013)

Background—Vascular endothelial cell growth factor plays a pivotal role in angiogenesis via regulating endothelial cell proliferation. The X-box binding protein 1 (XBP1) is believed to be a signal transducer in the endoplasmic reticulum stress response. It is unknown whether there is crosstalk between vascular endothelial cell growth factor signaling and XBP1 pathway. Methods and Results—We found that vascular endothelial cell growth factor induced the kinase insert domain receptor internalization and interaction through C-terminal domain with the unspliced XBP1 and the inositol requiring enzyme 1 α in the endoplasmic reticulum, leading to inositol requiring enzyme 1 α phosphorylation and XBP1 mRNA splicing, which was abolished by siRNA-mediated knockdown of kinase insert domain receptor. Spliced XBP1 regulated endothelial cell proliferation in a PI3K/Akt/GSK3β/β-catenin/E2F2–dependent manner and modulated the cell size increase in a PI3K/Akt/GSK3β/β-catenin/E2F2–independent manner. Knockdown of XBP1 or i...
Evidence for Synergy Between α2-Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation
Authors: VéroniqueBruban, VanessaEstato, StephanSchann, Jean-DanielEhrhardt, LaurentMonassier, PierreRenard, ElizabethScalbert, JosianeFeldman, PascalBousquet
Journal: Circulation (2002)

Background— Both α2-adrenergic and non–α2-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Methods and Results— LNP 509, which appeared in this study to be devoid of α2A-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46±4% and 16±2%, respectively. In D79N mice, which lack functional α2A-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17±2%. The hypotension induced by LNP 509 (100 μg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I1-imidazoline binding sites (I1BS). A synergy between LNP 509 and the α2-adrenergic agonist α-methylnoradrenaline (α-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ven...
Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors
Authors: Sergio Gonzalez-Duque, Marie Eliane Azoury, Maikel L. Colli, Georgia Afonso, Jean-Valery Turatsinze, Laura Nigi, Ana Ines Lalanne, Guido Sebastiani, Alexia Carré, Sheena Pinto, Slobodan Culina, Noémie Corcos, Marco Bugliani, Piero Marchetti, Mathieu Armanet, Marc Diedisheim, Bruno Kyewski, Lars M. Steinmetz, Søren Buus, Sylvaine You, Daniele Dubois-Laforgue, Etienne Larger, Jean-Paul Beressi, Graziella Bruno, Francesco Dotta, Raphael Scharfmann, Decio L. Eizirik, Yann Verdier, Joelle Vinh, Roberto Mallone
Journal: Cell Metabolism (2018)
School Level Education to Increase Organ Donation and The Effect Of Deprivation
Authors: M. Byrne, M. Symington, B. Stainer, J. Leighton, H. Jackson, N. Singhal, S. Shiel-Rankin, J. Mayes, J. Mogg, T. Bonham, A. Smit, B. Deutsch, C. Wilson
Journal: International Journal of Surgery (2018)
Abstract 4206: Pretreatment markers of cellular-mediated inflammation and association with survival vary significantly among cancers
Authors: Rachel Howard, Kathleen Egan, Peter Kanetsky
Journal: Cancer Research (2018)

Abstract Background. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are established markers of systemic inflammation, and they are believed to have prognostic value in various diseases including many common cancers. These indicators of the cellular-mediated inflammatory response are easily obtained from patient blood samples and hold promise as simple and inexpensive tools for risk stratification. Methods. In the present study, 4509 patients spanning multiple cancer types (breast N=979; colorectal N=1024; esophageal N=594; hepatocellular N=287; melanoma N=349 and pancreatic N=1276) treated at Moffitt Cancer Center and with valid hematology lab values, demographic information, clinical disease characteristics, and outcome data were identified. We compared marker counts and ratios across all cancer types to identify disease-specific patterns in pre-treatment host immune response and evaluated the similarities with other established measures of disease-specific immunogenicity. An initial evaluation of the association between pre-treatment NLR, PLR (and corresponding absolute counts of lymphocytes (L), neutrophils (N) and platelets (P)) and disease-specific survival was conducted, controlling for age, sex, race, disease stage, treatment modality, and additionally for primary site and histological and molecular subtypes as appropriate. Results. Mean levels of N, L, P, NLR, and PLR all demonstrated significant differences across cancer types. Pre-treatment NLR was significantly associated with disease-specific death in four of our six cancer sites (colorectal: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.21-1.79; esophageal: HR = 1.38, 95% CI = 1.05-1.82; melanoma: HR = 1.87, 95% CI = 1.18-2.95; pancreatic: HR = 1.69, 95% CI = 1.43-1.99). Pre-treatment PLR was significantly associated with disease-specific death in two sites (colorectal: HR = 1.34, 95% CI = 1.10-1.64; pancreatic: HR = 1.53, 95% CI = 1.30-1.79). This suggests that the utilization of markers of the cellular-mediated inflammatory response for clinical prognosis and decision-making may require disease-specific risk classification criteria. Citation Format: Rachel Howard, Kathleen Egan, Peter Kanetsky. Pretreatment markers of cellular-mediated inflammation and association with survival vary significantly among cancers [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 4206.
Abstract 4649: Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles
Authors: Christopher M. Baehr, Lei Wang, Kit S. Lam
Journal: Cancer Research (2018)

Abstract Lysosome-mediated cell death has recently become of great interest to the cancer community as several compounds have been shown to preferentially induce cancer cell death via lysosomal membrane permeabilization (LMP) (e.g., oleocanthal, salinomycin, and TiO2 nanoparticles). Further, many cancer cell lines that are resistant to traditional cancer therapeutics are highly susceptible to lysosome-mediated cell death. Here, we develop transformable peptide nanoparticles (NP) designed to traffic to cancer cell lysosomes, form aggregates, and induce LMP. The peptide consists of three motifs: 1) a hydrophilic, cell penetrating, and pH-responsive poly-d-Arg motif, 2) a hydrogen-bonding motif derived from beta amyloid (KLVFF); and 3) hydrophobic bis(pyrene) that fluoresces upon aggregation. The peptides initially self-assemble into NPs (50nm via TEM) in PBS, but when exposed to a lysosomal pH of 4.5, form much larger aggregates. We show that these nanoaggregates colocalize with the lysosome, leading to cell death, suggesting the induction of LMP. Moreover, utilizing bis(pyrene) we show that while these aggregates form in the lung carcinoma cell line, A549, they do not form in 3T3 fibroblasts. Additionally, we demonstrate that these nanoaggregates are highly toxic to A549 cells with IC50 in the low micromolar range (~2μM). This offers a novel organelle-specific strategy to preferentially target and kill cancer cells. Citation Format: Christopher M. Baehr, Lei Wang, Kit S. Lam. Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles [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 4649.
European drug agency loses 30% of staff in planned move to Amsterdam
Authors: Nigel Hawkes
Journal: BMJ (2018)

The European Medicines Agency (EMA) is counting the cost of the UK’s decision to leave the European Union, which is forcing the agency to relocate to Amsterdam.

More staff than expected have left the EMA, and Dutch employment rules mean that 135 short term contract staff will no longer be able to work for the agency when it moves in March 2019. Overall, the EMA expects to lose about 30% of its staff, and it is being forced to suspend …
Abstract IA08: Analysis of a histiocytic carcinoma in the dog: The canine's utility in fetching disease genes
Authors: Heidi G. Parker, Edouard Cadieu, Abigail Shearin, Gerard Rutteman, Elaine A. Ostrander
Journal: Clinical Cancer Research (2018)

Abstract Histiocytic sarcoma (HS) is a rare human hematopoietic neoplasm that accounts for less than 1% of hematolymphoid cancers and occurs either concurrently with or subsequently to B- or T-lymphoblastic lymphoma and other B-cell cancers. As such, its genetic etiology has been difficult to establish. HS in dogs, by comparison, shows strong breed specificity with 20% of flat-coated retrievers and 25% of Bernese mountain dogs (BMD) estimated to develop the disease in their lifetime. These two affected breeds share no recent common ancestors and display differences in disease presentation, offering a unique system in which to investigate the genetic predisposition and progression of HS. Our lab has previously undertaken genome wide association study (GWAS) on both BMD and FCR collected in North America and Europe and identified four significantly associated loci, two in BMD and two in FCR. In each breed, only one locus was segregating with disease in the American population while both were present in the European populations. There were no loci in common between the two breeds. Fine mapping of the common BMD HS locus on canine chromosome (CFA) CFA11 revealed a single haplotype spanning the MTAP (methylthioadenosine phosphorylase) gene and part of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which was present in 96% of BMD with HS. The European BMD also showed a significant locus on CFA14 that may be approaching fixation in the American dogs based on allele frequency calculations. We have done targeted resequencing of the CFA14 locus in a subset of European BMD and are in the process of filtering the identified mutations. Promising candidate genes in this region include GRM8, which inhibits the cyclic AMP cascade in the central nervous system and has shown to be involved in several of cancers; POT1, which is involved in telomere length maintenance and protection; and HYAL4, a hyaluronidase potentially involved in extracellular matrix degradation. In addition, the laboratory has generated 30x sequence from two HS cases and a control BMD, two FCR cases, and a control and low pass sequence from 16 dogs (8 cases and controls) in order to identify the likely causative mutations in each of the associated loci as well as breed specific mutations that may predispose the dogs to aggressive cancers. Citation Format: Heidi G. Parker, Edouard Cadieu, Abigail Shearin, Gerard Rutteman, Elaine A. Ostrander. Analysis of a histiocytic carcinoma in the dog: The canine's utility in fetching disease genes [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA08.
Bilateral Versus Unilateral Internal Mammary Revascularization in Patients With Diabetes
Authors: MasahiroEndo, YasukoTomizawa, HiroshiNishida
Journal: Circulation (2003)

Background— This historical cohort study evaluated the benefit of bilateral internal mammary artery (BIMA) grafts in coronary bypass grafting (CABG) for patients with diabetes. Methods and Results— We performed elective, isolated, primary, multiple CABG using skeletonized internal mammary artery (IMA) grafts for multivessel disease in 1131 patients, 467 (41.3%) of whom had type 2 diabetes mellitus. The early and long-term results were compared between 277 patients with diabetes using single IMA (SIMA) grafts and 190 using BIMA grafts (median follow-up, 8.1 years). Hospital mortality was similar in both groups. Early patency rate of all grafts was significantly higher using BIMA than using SIMA (97.7% versus 93.8%, P=0.0012). Survival rates were not significantly different between SIMA and BIMA groups. Late cardiac mortality was significantly higher in patients with low ejection fraction (0.4 or lower) compared with preserved ejection fraction (higher than 0.4) (P=0.0001). In patients with preserved ejecti...
Bleeding Risk in Very Old Patients on Vitamin K Antagonist Treatment
Authors: DanielaPoli, EmiliaAntonucci, SophieTesta, AlbertoTosetto, WalterAgeno, GualtieroPalareti
Journal: Circulation (2011)

Background—Vitamin K antagonist (VKA) therapy is increasingly being used for the prevention of venous thromboembolism and stroke in atrial fibrillation. Bleeds are the major concern for VKA prescription, especially in very old patients who carry many risk factors for bleeding. We performed a large multicenter prospective observational study that enrolled very old patients to evaluate the quality of anticoagulation and the incidence of bleedings. Methods and Results—The study included 4093 patients ≥80 years of age who were naive to VKA for thromboprophylaxis of atrial fibrillation or after venous thromboembolism. Patients' demographic and clinical data were collected, and the quality of anticoagulation and the incidence of bleeding were recorded. The follow-up was 9603 patient-years; median age at the beginning of follow-up was 84 years (range, 80 to 102 years). We recorded 179 major bleedings (rate, 1.87 per 100 patient-years), 26 fatal (rate, 0.27 per 100 patient-years). The rate of bleeding was higher ...
Abstract 5748: Downregulation of glycine decarboxylase renders ovarian cancer cells less proliferative and more chemoresistant
Authors: So-Jin Shin, Hyewon Chung, Jin Young Kim, Hyera Kim, Chi-Heum Cho, Eunyoung Ha
Journal: Cancer Research (2018)

Abstract Glycine decarboxylase (GLDC) is a very recently identified metabolic oncogene that links glycine metabolism with tumorigenesis. We designed this study to determine the role of GLDC in chemoresistance in ovarian cancer cells. First, we found GLDC is downregulated in paclitaxel-resistant ovarian cancer cells (OVCAR3/PTX). Prompted by decreased glucose transport in OVCAR3/PTX cells, we transplanted OVCAR3 and OVCAR3/PTX onto the back of the NOD-scid IL2Rgammanullmice and found that the OVCAR3/PTX tumor grew less rapidly than paclitaxel-sensitive ovarian cancer cells (OVCAR3). We also found that GLDC is downregulated in OVCAR3/PTX tumor. In vitro study revealed that the inhibitory effect of siGLDC on proliferation was significantly greater in OVCAR3 than in OVCAR3/PTX. We also found that knockdown of GLDC in OVCAR3 cells rendered ovarian cancer cells PTX-resistant. Finally, we determined GLDC expressions in patients with chemosensitive and chemoresistant serous-type ovarian cancer and found that GLDC expression was markedly downregulated in chemoresistant cancer patients. In summary, these results suggest that GLDC is associated with ovarian cancer chemoresistance. Citation Format: So-Jin Shin, Hyewon Chung, Jin Young Kim, Hyera Kim, Chi-Heum Cho, Eunyoung Ha. Downregulation of glycine decarboxylase renders ovarian cancer cells less proliferative and more chemoresistant [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 5748.
Abstract 4124: YAP1 fusion proteins mediate oncogenic activity in ependymoma via interaction with TEAD transcription factors
Authors: Kristian W. Pajtler, Konstantin Okonechnikov, Mikaella Vouri, Sebastian Brabetz, David T. Jones, Andrey Korshunov, David Capper, Lukas Chavez, Stefan M. Pfister, Marcel Kool, Daisuke Kawauchi
Journal: Cancer Research (2018)

Abstract Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of those in children under 3 years. In a previous study we identified two molecular groups of supratentorial (ST) ependymoma in pediatric patients driven by distinct gene fusions involving either the NF-κB effector RELA or the HIPPO signaling regulator YAP1, designated ST-EPN-RELA and ST-EPN-YAP1, respectively. The lack of adequate models for ST-EPN-YAP1, which predominantly occurs in very young children, has so far hindered the development of effective targeted therapies for these tumors. In an attempt to model this group, the most frequent fusion type, YAP1-MAMLD1, was cloned into a Luciferase-carrying transposable vector. Oncogenicity was subsequently tested using an electroporation-based in vivo gene transfer following injection of the vector into the lateral ventricle of E13.5 wildtype mouse embryos. After birth, YAP1-MAMLD1-expressing tumors, monitored using luciferase-based in vivo bioluminescence imaging, developed rapidly with 100% penetrance, indicating that the fusion alone is sufficient to initiate tumors. To further investigate the role of this fusion in human EPNs, we performed YAP1 ChIP-seq analyses on human ST-EPN-YAP1 and ST-EPN-RELA primary tumors. Despite similar gene expression levels of YAP1 in both molecular groups, our comparative analyses found that putative binding sites of TEADs, transcriptional factors interacting with YAP1, were significantly enriched in identified YAP1 peaks in ST-EPN-YAP1. In vivo validation further confirmed that interaction between YAP1-MAMLD1 and TEADs is crucial for oncogenicity of the fusion, since prevention of YAP1-TEAD binding did not result in tumor formation. Thus, targeting the YAP1-TEAD interaction might represent a promising therapeutic approach for this devastating infant disease. Citation Format: Kristian W. Pajtler, Konstantin Okonechnikov, Mikaella Vouri, Sebastian Brabetz, David T. Jones, Andrey Korshunov, David Capper, Lukas Chavez, Stefan M. Pfister, Marcel Kool, Daisuke Kawauchi. YAP1 fusion proteins mediate oncogenic activity in ependymoma via interaction with TEAD transcription factors [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 4124.
Abstract LB-124: Promoting an anti-tumor immune environment with a novel, exquisitely selective CSF1R inhibitor
Authors: Erika Suzuki, Jeffrey J. Kovacs, Nakia D. Spencer, Sonal Sonal, Ningping Feng, Angela L. Harris, Robert A. Mullinax, Andy M. Zuniga, Sarah B. Johnson, Mikhila Mahendra, Tin Oo Khor, Faika Mseeh, Zhen Liu, Jason P. Burke, Keith Mikule, Martin Tremblay, Timothy P. Heffernan, Philip Jones, Barbara Czako, Joseph R. Marszalek
Journal: Cancer Research (2018)

Abstract Tumor-associated macrophages (TAMs) are critical drivers of tumor progression and immunosuppression within the tumor microenvironment. The dominant TAM phenotype is broadly characterized as harboring M2-like macrophage properties, which are anti-inflammatory and pro-tumor, as opposed to M1-like macrophages, which possess tumoricidal and pro-inflammatory characteristics. The dependence of M2 TAMs on CSF1 receptor (CSF1R) kinase signaling has made CSF1R a desirable therapeutic target, and the need for highly selective therapies for use in combinations. Through an extensive medicinal chemistry campaign, we identified a series of orally bioavailable, highly potent, exquisitely selective inhibitors of CSF1R (IC50 &amp;lt; 10 nM) with excellent pharmacologic properties that are appropriate for evaluation as a cancer therapy. The aim of our study was to assess the biological impact of our lead CSF1R inhibitor (CSF1Ri) on macrophage populations and the consequent effect on T effector cells. In vitro biochemical activity was evaluated in various kinase assays comparing our CSF1Ri to BLZ945. The compound was evaluated using syngeneic murine models of colorectal cancer (MC38) and pancreatic adenocarcinoma (PANC02). Tumors were immune profiled using NanoString, immunohistochemistry and flow cytometric analysis establishing that there was a depletion of macrophages and a reduction in the relative amount of M2+ (CD206+MHCII-) cells, with a concomitant increase in M1+ (MHCII+CD206-) cells. Myeloid-derived suppressor cells (MDSCs), CD4, and CD8 cell infiltration were also altered with an elevation of cytotoxic immune cells. In conclusion, we have identified and characterized a novel potent and selective inhibitor of CSF1R with highly favorable PK/PD properties, that compares favorably to BLZ945. We also have clear evidence that our novel CSF1R inhibitors modulates TAM infiltration and phenotype altering the immune cell milieu toward a more favorable anti-tumor environment. Citation Format: Erika Suzuki, Jeffrey J. Kovacs, Nakia D. Spencer, Sonal Sonal, Ningping Feng, Angela L. Harris, Robert A. Mullinax, Andy M. Zuniga, Sarah B. Johnson, Mikhila Mahendra, Tin Oo Khor, Faika Mseeh, Zhen Liu, Jason P. Burke, Keith Mikule, Martin Tremblay, Timothy P. Heffernan, Philip Jones, Barbara Czako, Joseph R. Marszalek. Promoting an anti-tumor immune environment with a novel, exquisitely selective CSF1R inhibitor [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-124.