The Role of PARP1 in Monocyte and Macrophage
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Genetic Screens in Isogenic Mammalian Cell Lines Without Single Cell Cloning
ARTICLE https://doi.org/10.1038/s41467-020-14620-6 OPEN Genetic screens in isogenic mammalian cell lines without single cell cloning Peter C. DeWeirdt1,2, Annabel K. Sangree1,2, Ruth E. Hanna1,2, Kendall R. Sanson1,2, Mudra Hegde 1, Christine Strand 1, Nicole S. Persky1 & John G. Doench 1* Isogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor- 1234567890():,; intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small- molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts. 1 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA. 2These authors contributed equally: Peter C. DeWeirdt, -
PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide
Published OnlineFirst October 5, 2015; DOI: 10.1158/1535-7163.MCT-15-0587 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway Florian Engert1, Cornelius Schneider1, Lilly Magdalena Weib1,2,3, Marie Probst1,and Simone Fulda1,2,3 Abstract Ewing sarcoma has recently been reported to be sensitive to that subsequent to DNA damage-imposed checkpoint activa- poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for tion and G2 cell-cycle arrest, olaparib/TMZ cotreatment causes synergistic drug combinations, we tested several PARP inhibi- downregulation of the antiapoptotic protein MCL-1, followed by tors (talazoparib, niraparib, olaparib, veliparib) together with activation of the proapoptotic proteins BAX and BAK, mitochon- chemotherapeutics. Here, we report that PARP inhibitors syner- drial outer membrane permeabilization (MOMP), activation of gize with temozolomide (TMZ) or SN-38 to induce apoptosis caspases, and caspase-dependent cell death. Overexpression of a and also somewhat enhance the cytotoxicity of doxorubicin, nondegradable MCL-1 mutant or BCL-2, knockdown of NOXA or etoposide, or ifosfamide, whereas actinomycin D and vincris- BAX and BAK, or the caspase inhibitor N-benzyloxycarbonyl-Val- tine show little synergism. Furthermore, triple therapy of ola- Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce parib, TMZ, and SN-38 is significantly more effective compared olaparib/TMZ-mediated apoptosis. These findings emphasize with double or monotherapy. Mechanistic studies revealed that the role of PARP inhibitors for chemosensitization of Ewing the mitochondrial pathway of apoptosis plays a critical role in sarcoma with important implications for further (pre)clinical mediating the synergy of PARP inhibition and TMZ. -
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. -
R&D Briefing 76
The Impact of Recent Regulatory Developments on the Mexican Therapeutic Landscape Access to innovative medicines is key to El acceso a medicamentos innovadores es clave para improving overall population health, reducing mejorar la salud de toda la población, para reducir los hospitalisation time and decreasing morbidity and tiempos de hospitalización, la morbilidad y la mortalidad mortality. An efficient regulatory process can be de un país. Un proceso regulatorio eficiente tiene un reflected in measurable positive health impacts; impacto positivo medible en la salud, y por el contrario, conversely, activities that slow or impede acciones que retrasan o impiden la eficiencia regulatoria y regulatory efficiency and predictability can be su predictibilidad pueden ser perjudiciales. La parálisis detrimental. Recent developments in the Mexican reciente del Sistema regulatorio mexicano respecto a la regulatory system for the assessments of evaluación de nuevos medicamentos innovadores innovative new products have had a negative conlleva un impacto negativo en la salud de la población impact on Mexican public health. mexicana. This Briefing addresses the impact of suspending Este informe analiza el impacto de la suspensión de las the activities of the New Molecules Committee actividades del Comité de Moléculas Nuevas (NMC, por (NMC) on the Mexican therapeutic landscape. sus siglas en inglés) sobre el horizonte terapéutico de First, we compared the way that “new medicines” México. En primer lugar, comparamos la definición de are defined within the context of the Mexican nuevos medicamentos según el contexto regulatorio regulatory system, with definitions used by mexicano con las definiciones adoptadas por otras comparable regulators and health organisations. agencias reguladoras u organizaciones de salud del We have also investigated the extent to which mundo. -
Poly(ADP-Ribose) Polymerase-1 (PARP1) and P53 Labelling Index Correlates with Tumour Grade in Meningiomas
Original article Poly(ADP-ribose) polymerase-1 (PARP1) and p53 labelling index correlates with tumour grade in meningiomas Tamás Csonka1, Balázs Murnyák1, Rita Szepesi2, Andrea Kurucz1, Álmos Klekner3, Tibor Hortobágyi1 1Division of Neuropathology, Institute of Pathology, 2Department of Neurology, 3Department of Neurosurgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Folia Neuropathol 2014; 52 (2): 111-120 DOI: 10.5114/fn.2014.43782 Abstract Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades accord- ing to the 2007 WHO Classification of Tumours of the Central Nervous System. p53, as one of the most potent tumour suppressor proteins, plays a role in nearly 50% of human tumours. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme with high ATP demand. It plays a role in apoptosis by activating an apoptosis inducing factor, and in necrosis by consuming NAD+ and ATP. Only PARP1 has been investigated in detail in tumours out of the 17 members of the PARP superfamily; however, its role has not been studied in meningiomas yet. The aim of this study was to determine the role of p53 and PARP1 in meningiomas of different grade and to establish whether there is any correlation between the p53 and PARP1 expression. Both PARP1 and p53 have been expressed in all examined meningiomas. PARP1 labelled grade II tumours with a higher intensity as compared to grade I and III neoplasms, respectively. An increased p53 expression was noted in grade III meningiomas. There was no statistical correlation between p53 and PARP1 expression. Our data indicate that both PARP1 and p53 activation is a feature in menin- giomas of higher grade, PARP1 overexpression being an early, whereas p53 overexpression, a late event in tumour progression. -
PARP Inhibitors in Prostate Cancer–The Preclinical Rationale and Current Clinical Development
G C A T T A C G G C A T genes Review PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development Verneri Virtanen 1, Kreetta Paunu 1, Johanna K. Ahlskog 2, Reka Varnai 3,4 , Csilla Sipeky 5 and Maria Sundvall 1,6,* 1 Institute of Biomedicine, and Cancer Research Laboratories, Western Cancer Centre FICAN West, University of Turku, FI-20520 Turku, Finland 2 Faculty of Science and Engineering, Åbo Akademi University, and Turku Bioscience, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland 3 Department of Primary Health Care, University of Pécs, H-7623 Pécs, Hungary 4 Faculty of Health Sciences, Doctoral School of Health Sciences, University of Pécs, H-7621 Pécs, Hungary 5 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland 6 Department of Oncology and Radiotherapy, Turku University Hospital, FI-20521 Turku, Finland * Correspondence: maria.sundvall@utu.fi; Tel.: +358-2-313-0000 Received: 3 June 2019; Accepted: 22 July 2019; Published: 26 July 2019 Abstract: Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. -
Horizon Scanning Status Report June 2019
Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
(12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown Et Al
US 20030082511A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown et al. (43) Pub. Date: May 1, 2003 (54) IDENTIFICATION OF MODULATORY Publication Classification MOLECULES USING INDUCIBLE PROMOTERS (51) Int. Cl." ............................... C12O 1/00; C12O 1/68 (52) U.S. Cl. ..................................................... 435/4; 435/6 (76) Inventors: Steven J. Brown, San Diego, CA (US); Damien J. Dunnington, San Diego, CA (US); Imran Clark, San Diego, CA (57) ABSTRACT (US) Correspondence Address: Methods for identifying an ion channel modulator, a target David B. Waller & Associates membrane receptor modulator molecule, and other modula 5677 Oberlin Drive tory molecules are disclosed, as well as cells and vectors for Suit 214 use in those methods. A polynucleotide encoding target is San Diego, CA 92121 (US) provided in a cell under control of an inducible promoter, and candidate modulatory molecules are contacted with the (21) Appl. No.: 09/965,201 cell after induction of the promoter to ascertain whether a change in a measurable physiological parameter occurs as a (22) Filed: Sep. 25, 2001 result of the candidate modulatory molecule. Patent Application Publication May 1, 2003 Sheet 1 of 8 US 2003/0082511 A1 KCNC1 cDNA F.G. 1 Patent Application Publication May 1, 2003 Sheet 2 of 8 US 2003/0082511 A1 49 - -9 G C EH H EH N t R M h so as se W M M MP N FIG.2 Patent Application Publication May 1, 2003 Sheet 3 of 8 US 2003/0082511 A1 FG. 3 Patent Application Publication May 1, 2003 Sheet 4 of 8 US 2003/0082511 A1 KCNC1 ITREXCHO KC 150 mM KC 2000000 so 100 mM induced Uninduced Steady state O 100 200 300 400 500 600 700 Time (seconds) FIG. -
A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets
biomolecules Review A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets Rubayat Islam Khan †, Saif Shahriar Rahman Nirzhor † and Raushanara Akter * Department of Pharmacy, BRAC University, 1212 Dhaka, Bangladesh; [email protected] (R.I.K.); [email protected] (S.S.R.N.) * Correspondence: [email protected]; Tel.: +880-179-8321-273 † These authors contributed equally to this work. Received: 10 June 2018; Accepted: 26 June 2018; Published: 29 June 2018 Abstract: Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings -
Antiviral Properties of Chalcones and Their Synthetic Derivatives: a Mini Review
Pharmacia 67(4): 325–337 DOI 10.3897/pharmacia.67.e53842 Review Article Antiviral properties of chalcones and their synthetic derivatives: a mini review Radoslav Marinov1, Nadezhda Markova2, Stefka Krumova1, Kamelia Yotovska3, Maya M. Zaharieva4, Petia Genova-Kalou1 1 Department of Virology, National Centre of Infectious and Parasitic Diseases, 44A Gen. Stoletov Blvd., 1233 Sofia, Bulgaria 2 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria 3 Faculty of Biology, Sofia University St. Kliment Ohridski, 8 Dragan Tzankov Blvd., 1164 Sofia, Bulgaria 4 Department of Infectious Microbiology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 25, 1113 Sofia, Bulgaria Corresponding author: Petia Genova-Kalou ([email protected]) Received 2 May 2020 ♦ Accepted 24 May 2020 ♦ Published 27 November 2020 Citation: Marinov R, Markova N, Krumova S, Yotovska K, Zaharieva MM, Genova-Kalou P (2020) Antiviral properties of chalcones and their synthetic derivatives: a mini review. Pharmacia 67(4): 325–337. https://doi.org/10.3897/pharmacia.67.e53842 Abstract Chalcones (natural or synthetic derivatives) are aromatic ketones possessing a central backbone that form a core for variety import- ant compounds with different substitutions. Recent scientific advances show that chalcones exhibit different bio-medical activities, including antiviral, which is related to the variety substitutions. This review provides general information on the origin, sources, virucidal and direct antiviral properties of chalcones in vitro, as well as a brief overview of the possible application and molecular modes of action of these compounds. -
TALZENNA (Talazoparib) RATIONALE for INCLUSION in PA PROGRAM
TALZENNA (talazoparib) RATIONALE FOR INCLUSION IN PA PROGRAM Background Talzenna (talazoparib) is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2 which play a role in DNA repair. Talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer tumor models that expressed mutated or wild-type BRCA 1 and 2 (1). Regulatory Status FDA-approved indication: Talzenna is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA- mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients based on an FDA-approved companion diagnostic for Talzenna (1). Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) can occur in patients treated with Talzenna. Talzenna should not be started until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Complete blood counts should be monitored for cytopenia at baseline and monthly thereafter. If MDS/AML is confirmed, Talzenna should be discontinued (1). Talzenna can also cause myelosuppression, consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia. Talzenna should not be started until patients have adequately recovered from hematological toxicity caused by previous chemotherapy (1). Talzenna can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 7 months following the last dose of Talzenna. Male patients with female partners of reproductive potential or who are pregnant should be advised to use effective contraception during treatment and for at least 4 months following the last dose of Talzenna (1).