DOCSLIB.ORG

Predicting Response to Standard First-Line Treatment in High-Grade

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Predicting Response to Standard First-Line Treatment in High-Grade ANTICANCER RESEARCH 38 : 5393-5400 (2018) doi:10.21873/anticanres.12869 Predicting Response to Standard First-line Treatment in High-grade Serous Ovarian Carcinoma by Angiogenesis-related Genes MARTA MENDIOLA 1,2 , ANDRÉS REDONDO 3,4,5 , VICTORIA HEREDIA-SOTO 1,2 , JESÚS HERRANZ 6, ALBERTO BERJÓN 1,7 , ALICIA HERNÁNDEZ 5,8 , MARÍA MIGUEL-MARTÍN 1, ROBERTO CRESPO 4, JORGE BARRIUSO 9, PATRICIA CRUZ 3, LAURA YÉBENES 1,7 , ALBERTO PELÁEZ-GARCÍA 1, BEATRIZ CASTELO 3,4 , ANA RAMÍREZ DE MOLINA 10 , JAIME FELIU 2,3,4,5,11 and DAVID HARDISSON 1,5,7 1Molecular Pathology and Therapeutic Targets Group, Departments of 3Medical Oncology, 7Pathology, and 8Gynecology and Obstetrics, and 4Translational Oncology Research Laboratory, La Paz University Hospital (IdiPAZ), Madrid, Spain; 2Center for Biomedical Research in the Cancer Network (Centro de Investigación Biomédica en Red de Cáncer, CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; 5Faculty of Medicine, and 11 UAM-AMGEN Chair, Autonomous University of Madrid (UAM), Madrid, Spain; 6Bioinformatics Unit, and 10 Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, Madrid, Spain; 9Division of Molecular and Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, University of Manchester, Manchester, U.K. Abstract. Background/Aim: Predicting response to treatment Formalin-fixed paraffin-embedded samples from 39 patients in high-grade serous ovarian carcinoma (HGSOC) still with HGSOC who underwent surgical cytoreduction and remains a clinical challenge. The standard-of-care for first- received a first-line chemotherapy with carboplatin and line chemotherapy, based on a combination of carboplatin and paclitaxel were included in this study. Expression levels of 82 paclitaxel, achieves a high response rate. However, the angiogenesis-related genes were measured by quantitative development of drug resistance is one of the major limitations real-time polymerase chain reaction using TaqMan low- to efficacy. Therefore, identification of biomarkers able to density arrays. Results: Univariate analysis identified five predict response to chemotherapy in patients with HGSOC is genes [angiopoietin 1 (ANGPT1), aryl hydrocarbon receptor a critical step for prognosis and treatment of the disease. nuclear translocator (ARNT), CD34, epidermal growth factor Several studies suggest that angiogenesis is an important (EGF) and matrix metallopeptidase 3 (MMP3)] as being process in the development of ovarian carcinoma and statistically associated with response to treatment. chemoresistance. The aim of this study was to identify a profile Multivariable analysis by Lasso-penalized Cox regression of angiogenesis-related genes as a biomarker for response to generated a model with the combined expression of seven first-line chemotherapy in HGSOC. Materials and Methods: genes [angiotensinogen (AGT), CD34, EGF, erythropoietin receptor (EPOR), interleukin 8 (IL8), MMP3 and MMP7)]. The area under the receiver operating characteristics curve (0.679) and cross-validated Kaplan–Meier survival curves Presented in part at the European Medical Oncology Meeting (Madrid, 2014) and American Association for Cancer Research were used to estimate the accuracy of these predictors. (Philadelphia, 2015). Conclusion: An angiogenesis-related gene expression profile useful for response prediction in HGSOC was identified, Correspondence to: David Hardisson, MD, Ph.D., Department of supporting the important role of angiogenesis in HGSOC. Pathology, Hospital Universitario La Paz, IdiPAZ, Paseo de la Castellana, 261, 28046 Madrid, Spain. Tel: +34 917277300, Fax: Advanced ovarian carcinoma is a leading cause of death +34 917277049, e-mail: [email protected] from gynecological cancer in developed countries (1). The Key Words: Ovarian cancer, high-grade serous carcinoma, lethality of this disease is mainly due to the fact that most angiogenesis, gene-expression profile, chemotherapy, response patients are diagnosed with advanced disease (2, 3). prediction. Moreover, despite initial effectiveness of standard treatment, 5393 ANTICANCER RESEARCH 38 : 5393-5400 (2018) involving surgical cytoreduction and a platinum/paclitaxel started. Complete response (CR) was defined as absence of all chemotherapy regime, most women will experience relapse radiographic evidence of disease after finishing surgical resection and eventually die of their disease (4). Recent high- and chemotherapy. Tissue sections stained with hematoxylin and eosin were throughput analysis has demonstrated that high-grade serous reviewed by three gynecological subspecialty pathologists (A.B., ovarian carcinoma (HGSOC) is a different entity in the L.Y., and D.H.). Eligible samples included more than 80% tumor group of ovarian carcinomas (5). However, to date, there are cells, avoiding necrotic areas. no reliable biomarkers ready for the clinic able to identify This study was carried out in accordance with the Helsinki HGSOC tumors resistant to therapy before there is Declaration, and was approved by the Ethics Committee (Comité radiographic or biochemical evidence of progression in the Ético de Investigación Clínica) of the University Hospital La Paz, patient. Madrid, Spain (code HULP: PI-1020). Neoangiogenesis, the formation of new vessels from pre- RNA purification from formalin-fixed paraffin-embedded samples existing vasculature, is one of the hallmarks of cancer (6-8). and real-time quantification of gene expression. Four to eight 4- μm This is a finely regulated process, dynamically changing sections were used for total RNA isolation, with MasterPure RNA between pro-angiogenic and anti-angiogenic states, based on Purification Kit (EPICENTRE Biotechnologies, Madison, WI, USA) the balance of a plethora of regulators. according to the manufacturer’s instructions with minor Specifically, in ovarian cancer it is now well-established modifications. RNA concentrations and RNA quality were measured that vascular endothelial growth factor (VEGF), the main using a Nanodrop 1000A spectrophotometer (Nanodrop Technologies, Wilmington, DE, USA). One microgram of total regulator of this process, is elevated in ascites, suggesting a RNA was used for cDNA synthesis according to the protocol more intense angiogenic activity in the peritoneal cavity, and provided with the High Capacity Archive cDNA Reverse this has also been associated with poor prognosis (9). The Transcription kit (Applied Biosystems, Foster City, CA, USA). inhibition of angiogenesis seems to be a rational approach to Eighty-two angiogenesis-related genes selected from a previous therapy and an antibody to VEGF, bevacizumab, has been study were examined (11). Specific assays for each gene were already approved in Europe for first-line and relapse settings. selected and gene expression was determined by quantitative reverse Additionally, other antiangiogenic drugs were tested, transcription polymerase chain reaction with TaqMan Low Density Arrays (TLDA) in an ABI PRISM 7900 HT Sequence Detection including a VEGF-trap peptide, tyrosine kinase inhibitors, System (Applied Biosystems). Each TLDA was configured with 96 and angiopoietin inhibitors (10). genes in duplicate for two samples. Threshold point expression values We and others previously described prognostic signatures were calculated with SDS 2.2. software (Applied Biosystems). associated with ovarian carcinoma, and our data support the Normalization of gene expression according to the expression of five important role of angiogenesis in ovarian carcinoma (11). In housekeeping genes [ 18S , actin beta ( ACTB ), beta-2 microglobulin this article, we report 82 angiogenesis-related genes and their (B2M ), glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ) and relation with response to treatment as a variable for the glucuronidase beta ( GUSB )] was performed as previously described (12). Best performing genes for normalization of raw data were identification of a favorable versus unfavorable angiogenic selected by GeNorm Analysis software (13). profile. Inmunohistochemical analysis. Two 6-mm in diameter Materials and Methods representative cores for each case were included in the tissue microarray (TMA) using a workstation (Beecher Instruments, Silver Patient samples and clinical records. Thirty-nine non-consecutive Spring, MD, USA). Five-micrometer TMA sections were obtained patients with International Federation of Gynecology and Obstetrics by a semiautomated microtome HM3508 (Microm GmBH, (FIGO) stage III-IV HGOSC treated at the La Paz University Walldorf, Germany), as described elsewhere (14). Tissue sections Hospital, Madrid, Spain, between February 1996 and December were then incubated for 60 min with the following antibodies: CD34 2003 were included in this study. The main criteria for the selection (#ab8158, 1:50), epidermal growth factor (EGF) (#ab10409, 1:500), of the patients were as follows: Uniform histological type (HGOSC) and matrix metallopeptidase 3 (MMP3) (#ab52915, 1:100) from in order to avoid inter-patient heterogeneity, availability of enough Abcam (Cambridge, UK). Detection was performed with Envision tumoral tissue for the molecular and immunohistochemical studies Plus Detection System (Dako, Agilent Technologies, Glostrup, (avoiding necrotic areas, see below), and adequate follow-up data. Denmark). Optimal conditions for each antibody were set according All patients received at least six cycles of a platinum/taxane-based to distributor recommendations and adjusted with positive and chemotherapy
Load more

Recommended publications
  • Epha4/Tie2 Crosstalk Regulates Leptomeningeal Collateral Remodeling Following Ischemic Stroke
    EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke Benjamin Okyere, … , John B. Matson, Michelle H. Theus J Clin Invest. 2019. https://doi.org/10.1172/JCI131493. Research In-Press Preview Neuroscience Vascular biology Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated that endothelial genetic deletion, using EphA4f/f/Tie2-Cre and EphA4f/f/VeCahderin-CreERT2 mice and vessel painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, CBF and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling is limited by the cross talk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic response. Our findings demonstrate EphA4 is a negative regulator of Tie2 receptor signaling which limits pial collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 represents an attractive new strategy for improving collateral function, neural tissue health and functional recovery following ischemic stroke. Find the latest version: https://jci.me/131493/pdf 1 EphA4/Tie2
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • 4 Transcription and Secretion Novel Regulator of Angiopoietin-Like Protein A
    Acute-Phase Protein α1-Antitrypsin−−A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion This information is current as Eileen Frenzel, Sabine Wrenger, Stephan Immenschuh, of September 28, 2021. Rembert Koczulla, Ravi Mahadeva, H. Joachim Deeg, Charles A. Dinarello, Tobias Welte, A. Mario Q. Marcondes and Sabina Janciauskiene J Immunol 2014; 192:5354-5362; Prepublished online 23 April 2014; Downloaded from doi: 10.4049/jimmunol.1400378 http://www.jimmunol.org/content/192/11/5354 Supplementary http://www.jimmunol.org/content/suppl/2014/04/23/jimmunol.140037 http://www.jimmunol.org/ Material 8.DCSupplemental References This article cites 56 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/192/11/5354.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Acute-Phase Protein a1-Antitrypsin—A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion Eileen Frenzel,* Sabine Wrenger,* Stephan Immenschuh,† Rembert Koczulla,‡ Ravi Mahadeva,x H.
    [Show full text]
  • Angiocrine Endothelium: from Physiology to Cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3
    Pasquier et al. J Transl Med (2020) 18:52 https://doi.org/10.1186/s12967-020-02244-9 Journal of Translational Medicine REVIEW Open Access Angiocrine endothelium: from physiology to cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3 Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The sig- nifcance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogen- esis that is critical for tumor initiation and growth. Nevertheless, the identifcation of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profling studies have demonstrated distinctive expression patterns in tumor- associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identifed which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies. Keywords: Angiocrine, Endothelium, Cancer, Cancer microenvironment, Angiogenesis Introduction of blood vessels in initiation of tumor growth and stated Metastatic disease accounts for about 90% of patient that in the absence of such angiogenesis, tumors can- mortality. Te difculty in controlling and eradicating not expand their mass or display a metastatic phenotype metastasis might be related to the heterotypic interaction [7]. Based on this theory, many investigators assumed of tumor and its microenvironment [1].
    [Show full text]
  • Stromal Cell Interactions Mediated by Hypoxia-Inducible Factors Promote Angiogenesis, Lymphangiogenesis, and Metastasis
    Oncogene (2013) 32, 4057–4063 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis GL Semenza Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia- inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins,
    [Show full text]
  • Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance Via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D
    Published OnlineFirst August 18, 2015; DOI: 10.1158/1535-7163.MCT-14-1105 Small Molecule Therapeutics Molecular Cancer Therapeutics Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2 Bryan D. Smith1, Michael D. Kaufman1, Cynthia B. Leary1, Benjamin A. Turner1, Scott C. Wise1, Yu Mi Ahn1, R. John Booth1, Timothy M. Caldwell1, Carol L. Ensinger1, Molly M. Hood1, Wei-Ping Lu1, Tristan W. Patt1, William C. Patt1, Thomas J. Rutkoski1, Thiwanka Samarakoon1, Hanumaiah Telikepalli1, Lakshminarayana Vogeti1, Subha Vogeti1, Karen M. Yates1, Lawrence Chun2, Lance J. Stewart2, Michael Clare1, and Daniel L. Flynn1,3 Abstract Altiratinib (DCC-2701) was designed based on the rationale of wild-type and mutated forms, in vitro and in vivo. Through its engineering a single therapeutic agent able to address multiple balanced inhibitory potency versus MET, TIE2, and VEGFR2, hallmarks of cancer (1). Specifically, altiratinib inhibits not only altiratinib provides an agent that inhibits three major evasive mechanisms of tumor initiation and progression, but also drug (re)vascularization and resistance pathways (HGF, ANG, and resistance mechanisms in the tumor and microenvironment VEGF) and blocks tumor invasion and metastasis. Altiratinib through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 exhibits properties amenable to oral administration and exhibits (KDR) kinases. This profile was achieved by optimizing binding substantial blood–brain barrier penetration, an attribute of into the switch control pocket of all three kinases, inducing type II significance for eventual treatment of brain cancers and brain inactive conformations. Altiratinib durably inhibits MET, both metastases. Mol Cancer Ther; 14(9); 1–12.
    [Show full text]
  • Cardiovascular Disease Products
    Cardiovascular Disease Products For more information, visit: www.bosterbio.com Cardiovascular Disease Research Cardiovascular disease is the leading cause of death in developed nations. Boster Bio aims to supply researchers with high-quality antibodies and ELISA kits so they can make new discoveries and help save lives. In this catalogue you will find a comprehensive list of high-affinity Boster antibodies and high sensitivity Boster ELISA kits targeted at proteins associated with cardiovascular disease. Boster: The Fastest Growing About Bosterbio Antibody Company In 2015 Boster is an antibody manufacturer founded in 1993 by histologist Steven Xia. Over the past two decades, Boster and its products have been cited in over 20,000 publications and counting. The firm specializes in developing antibodies and ELISA kits that feature high affinity, Boster Bio received the CitaAb award for high specificity at affordable the greatest increase in number of prices. citations during 2015 than any other antibody manufacturer. Table of Contents Boster Cardiovascular Disease Related Antibodies…………..………..... 2 Boster Cardiovascular Disease Related ELISA Kits……………………..…. 9 1 High Affinity Boster Antibodies Boster supplies only the highest quality antibodies. Our high-affinity polyclonal and monoclonal antibodies are thoroughly validated by Western Blotting, Immunohistochemistry and ELISA. This is our comprehensive catalog of our antibody products related to cardiovascular disease, sorted in alphabetical order by target gene name. Catalog No Product Name
    [Show full text]
  • High Circulating Angiopoietin-2 Levels Exacerbate Pulmonary
    Thorax Online First, published on September 25, 2017 as 10.1136/thoraxjnl-2017-210413 Pulmonary vasculature Thorax: first published as 10.1136/thoraxjnl-2017-210413 on 25 September 2017. Downloaded from ORIGINAL artiCLE High circulating angiopoietin-2 levels exacerbate pulmonary inflammation but not vascular leak or mortality in endotoxin-induced lung injury in mice Kenny Schlosser,1 Mohamad Taha,1,2 Yupu Deng,1 Lauralyn A McIntyre,3 Shirley H J Mei,1 Duncan J Stewart1,2,4 ► Additional material is ABSTRACT published online only. To view Background Elevated plasma levels of angiopoietin-2 Key messages please visit the journal online (http:// dx. doi. org/ 10. 1136/ (ANGPT2) have been reported in patients with acute thoraxjnl- 2017- 210413). lung injury (ALI); however, it remains unclear whether What is the key question? this increase contributes to, or just marks, the underlying ► Elevated plasma levels of angiopoietin-2 1Regenerative Medicine vasculopathic inflammation and leak associated with (ANGPT2) in acute lung injury (ALI)/acute Program, Ottawa Hospital ALI. Here we investigated the biological consequences respiratory distress syndrome patients are Research Institute , University associated with poor prognosis; however, of Ottawa, Ottawa, Ontario, of inducing high circulating levels of ANGPT2 in a mouse Canada model of endotoxin-induced ALI. it remains unclear whether these elevated 2Department of Cellular and Methods Transgenic mice (ANGPT2OVR) with elevated circulating levels are just a marker or mediator Molecular Medicine, University circulating levels of ANGPT2, achieved through of underlying pulmonary vascular dysfunction. of Ottawa, Ottawa, Ontario, conditional hepatocyte-specific overexpression, Canada What is the bottom line? 3 were examined from 3 to 72 hours following Clinical Epidemiology Program, ► For the first time, this study demonstrates Ottawa Hospital Research lipopolysaccharide (LPS)-induced ALI.
    [Show full text]
  • Role of EFNB2/EPHB4 Signaling in Spiral Artery Development During Pregnancy: an Appraisal
    ESSAY Molecular Reproduction & Development 83:12–18 (2016) Role of EFNB2/EPHB4 Signaling in Spiral Artery Development During Pregnancy: An Appraisal HONGMEI DONG,* CHAORAN YU, JIAO MU, JI ZHANG, AND WEI LIN Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China SUMMARY EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/ EPHB4 signaling plays an important role in physiological and pathological angiogen- esis, and its role in tumor vessel development has been extensively studied. [W]e hypothesize that changing Pregnancy and tumors share similar features, including continuous cell proliferation the distinct spatiotemporal and increased demand for a blood supply. Our previous studies showed that Efnb2 expression of EFNB2/ Ephb4 and were expressed dynamically in the spiral arteries, uterine natural killer EPHB4...contributes to spiral À cells, and trophoblasts during mouse gestation Days 6.5 12.5. Moreover, uterine artery remodeling. natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of ÃCorresponding author: EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its Department of Forensic Medicine Tongji Medical College of dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and Huazhong University of EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this Science and Technology hypothesis will help clarify the mechanisms of pathological pregnancy that may 13 Hangkong Road Wuhan, Hubei 430030, P.
    [Show full text]
  • Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients
    RESEARCH ARTICLE Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients Issam Makhoul1*, Valentina K. Todorova2, Eric R. Siegel3, Stephen W. Erickson3, a1111111111 Ishwori Dhakal3, Vinay R. Raj2, Jeannette Y. Lee3, Mohammed S. Orloff4, Robert J. Griffin5, a1111111111 Ronda S. Henry-Tillman6, Suzanne Klimberg6,7, Laura F. Hutchins1, Susan A. Kadlubar5 a1111111111 a1111111111 1 Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 2 Division of Medical Genetics, University of Arkansas for Medical a1111111111 Sciences, Little Rock, Arkansas, United States of America, 3 Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 4 Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 5 Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 6 Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 7 Department of Pathology, University of OPEN ACCESS Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America Citation: Makhoul I, Todorova VK, Siegel ER, Erickson SW, Dhakal I, Raj VR, et al. (2017) * [email protected] Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Abstract Bevacizumab in Breast Cancer Patients. PLoS ONE 12(1): e0168550. doi:10.1371/journal. pone.0168550 Background Editor: Ratna B. Ray, Saint Louis University, UNITED STATES We previously reported improved pathologic complete response (pCR) in a prospective Received: August 14, 2016 phase II study using neoadjuvant bevacizumab in combination with chemotherapy com- pared to chemotherapy alone in breast cancer patients (41% vs.
    [Show full text]
  • Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
    Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/).
    [Show full text]