DOCSLIB.ORG

Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Published OnlineFirst July 12, 2019; DOI: 10.1158/0008-5472.CAN-19-0214 Cancer Genome and Epigenome Research Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids Saurabh V. Laddha1, Edaise M. da Silva2, Kenneth Robzyk2, Brian R. Untch3, Hua Ke1, Natasha Rekhtman2, John T. Poirier4, William D. Travis2, Laura H. Tang2, and Chang S. Chan1,5 Abstract Lung carcinoids (LC) are rare and slow growing primary predominately found at peripheral and endobronchial lung, lung neuroendocrine tumors. We performed targeted exome respectively. The LC3 subtype was diagnosed at a younger age sequencing, mRNA sequencing, and DNA methylation array than LC1 and LC2 subtypes. IHC staining of two biomarkers, analysis on macro-dissected LCs. Recurrent mutations were ASCL1 and S100, sufficiently stratified the three subtypes. enriched for genes involved in covalent histone modification/ This molecular classification of LCs into three subtypes may chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and facilitate understanding of their molecular mechanisms and KMT2A) as well as DNA repair (17.2%) pathways. Unsuper- improve diagnosis and clinical management. vised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust Significance: Integrative genomic analysis of lung carcinoids molecular subtypes (LC1, LC2, LC3) with distinct clinical identifies three novel molecular subtypes with distinct clinical features. MEN1 gene mutations were found to be exclusively features and provides insight into their distinctive molecular enriched in the LC2 subtype. LC1 and LC3 subtypes were signatures of tumorigenesis, diagnosis, and prognosis. Introduction of Ki67 between ACs and TCs does not enable reliable stratification between well-differentiated LCs (6, 7). It has also been reported that Lung carcinoids (LC) are an indolent and rare type of primary TCs and ACs are overdiagnosed as small cell lung carcinomas lung neoplasms that are, in general, understudied. The 2015 (SCLC) in small crush biopsy specimens (8), a situation where World Health Organization (WHO; ref. 1) classification of LCs artifacts in specimens appear as bluish clusters in which cellular includes atypical carcinoids (AC; 0.2% prevalence) and typical details are not recognizable. As SCLCs are highly malignant, incor- carcinoids (TC; 2% prevalence). TCs are slow growing tumors rect diagnosis of TC and AC tumors as SCLC can subject patients to that rarely spread beyond the lungs whereas ACs are faster growing unnecessary stress and treatment (8). More accurate molecular tumors and have a greater chance of metastasizing to other diagnostic tools and stratification for LCs will help ensure more tissues (2). The WHO classification relies mainly on morphology, appropriate treatment and clinical management. proliferation rate (mitotic index), and necrosis assessment (3). Previous genomic analysis of LC tumors has identified recur- This current method of classification has its drawbacks as studies rent mutations in MEN1, PSIP1, and ARID1A (9), whereas no have shown that the reproducibility of cancer classification and its significant mutations or focal copy alterations were observed in prognostic efficacy have high interobserver variability (3, 4), genes that are frequently mutated in non–small cell lung cancer especially for differentiating between TC and AC (5). Recent WHO (NSCLC), large cell neuroendocrine carcinoma (LCNEC), and classifications highlight use of the Ki67 cell proliferation marker SCLC (e.g., KRAS, TP53, EGFR, and RB1; ref. 10). The different to distinguish ACs from TCs (1).However, overlapping distribution mutation spectrum and low mutation burden (9) of LCs indicate they are distinct from NSCLC and high-grade lung neuroendo- 1Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New crine tumors (NET). It is not known if there are distinct molecular Jersey. 2Department of Pathology, Memorial Sloan-Kettering Cancer Center, subtypes of LCs or their cells of origin. 3 New York, New York. Department of Surgery, Memorial Sloan-Kettering Cancer In this study, we performed genotyping on 29 LCs to detect Center, New York, New York. 4Thoracic Oncology Service, Memorial Sloan- n ¼ 5 mutations in a 354-cancer gene panel, mRNA sequencing ( 30) Kettering Cancer Center, New York, New York. Department of Medicine, Rutgers n ¼ fi Robert Wood Johnson Medical School, New Brunswick, New Jersey. and DNA methylation 450K-array analysis ( 18) and identi ed 3 molecular subtypes with distinct clinical features. We also iden- Note: Supplementary data for this article are available at Cancer Research tified 2 key biomarkers (ASCL1 and S100) to stratify these subtypes. Online (http://cancerres.aacrjournals.org/). Integration of genetic and epigenetic signatures distinguishes each Corresponding Authors: Chang S. Chan, Rutgers Cancer Institute of New Jersey, subtype of carcinoid, providing deeper insight into their distinctive 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-7363; molecular signatures of tumorigenesis as well as cells of origin. E-mail: [email protected]; and Laura H. Tang, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065. Phone: 212-639-5905. E-mail: [email protected] Materials and Methods Cancer Res 2019;79:4339–47 Patient's data doi: 10.1158/0008-5472.CAN-19-0214 Retrospective and prospective reviews of 30 LC neoplasms were Ó2019 American Association for Cancer Research. performed using the pathology files and institutional database at www.aacrjournals.org 4339 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 12, 2019; DOI: 10.1158/0008-5472.CAN-19-0214 Laddha et al. Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY). dataset. The gene expression and mutational data were down- All studies were conducted in accordance with appropriate ethical loaded from supplement data files (https://www.nature.com/ guidelines (following U.S. Common Rule) and with Institutional articles/ncomms4518#supplementary-information) reported in Review Board approval. Written informed consent was obtained ref. 9. This gene expression data were reported as transcript from the patients. All patients were evaluated clinically with con- expression instead of gene expression. We used callapseRows (22) firmed pathologic diagnoses, appropriate radiological and labora- on transcript expression to convert to respective gene expression tory studies, and surgical or oncological management. Fresh-frozen using MaxVariance option. Gene expression for LCs signature (top tumor and paired normal tissues were obtained from MSKCC's 100 variant genes from our 30 LCs dataset) was extracted from this tissue bank under Institutional Review Board protocol. Targeted RNAseq dataset. Unsupervised clustering and PCA analysis on this cancer gene panel DNA sequencing, RNA sequencing (RNA-seq), dataset were performed as previously described for our 30 LCs and DNA methylation array were performed on fresh-frozen sam- dataset. ples. Relevant clinical and pathologic information is presented in Supplementary File S1. DNA methylation and analysis DNA were extracted from LC samples and interrogated for CpG DNA sequencing and analysis DNA methylation using the Illumina 450K array platform (Illu- DNA extraction from microdissected tumor samples and normal mina Inc.). For CpG DNA methylation data analysis, we used adjacent tissues was performed using a commercially available DNA ChAMP (23) package in R with default parameters. Briefly, IDAT Extraction Kit (DNeasy Blood and Tissue Kit, Catalog No. 69504; raw data files were imported in R and filtered to exclude samples Qiagen), according to the manufacturer's protocol. Targeted seq- with detection P-value <0.01 and bead count <3 in at least 5% of uencing on 29 LCs was performed using MSK-IMPACT (11) hybrid samples and normalized using FunctionNormalization (24). capturecancergenepanel(n ¼ 354). Single-nucleotide variants and Additional filtering was performed to remove probes that have short indels (<30 bp) were identified and annotated using MSK- annotated SNPs, present on X and Y chromosome, and have CpG IMPACT pipeline (11). Briefly, raw reads were filtered based on probes mapped to multiple locations. b values for 413,176 probes quality, mapped to NCBI b37 genome using BWA–MEM version were used for all subsequent analysis. Subtype specific differen- 0.7.5a (http://arxiv.org/abs/1303.3997), post-processed using tially methylated CpG probes (DMP) and CpG island were GATK (12), and variant identification using MuTect (13). Variants identified using COHCAP (default parameter; ref. 25). For DMP, were filtered based on its entry in NCBI-dbSNPs (http://www.ncbi. we focused on probes present at TSS1500/200 and first exon for nlm.nih.gov/snp), 1000G project (http://www.1000genomes.org/), subsequent analysis. We integrated gene expression and DNA and COSMIC (http://cancer.sanger.ac.uk/cosmic). Filtered variants methylation to investigate subtype-specific gene expression using were manually reviewed on IGV. We created the mutational Onco- default parameter for COHCAP.integrate.avg.by.island with FDR Print plot for our 29 LCs dataset using the online cBioPortal website P value <0.01. (http://www.cbioportal.org/oncoprinter.jsp). IHC staining RNA-seq and data analysis IHC staining was performed using commercially available Total RNA extraction from microdissected frozen tumor samples antibodies
Recommended publications
  • Mitochondrial Ubiquitin Ligase MITOL Blocks S-Nitrosylated MAP1B-Light Chain 1-Mediated Mitochondrial Dysfunction and Neuronal Cell Death

    Mitochondrial Ubiquitin Ligase MITOL Blocks S-Nitrosylated MAP1B-Light Chain 1-Mediated Mitochondrial Dysfunction and Neuronal Cell Death

    Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death Ryo Yonashiro, Yuya Kimijima, Takuya Shimura, Kohei Kawaguchi, Toshifumi Fukuda, Ryoko Inatome, and Shigeru Yanagi1 Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan Edited by Ted M. Dawson, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, and accepted by the Editorial Board January 3, 2012 (received for review September 14, 2011) Nitric oxide (NO) is implicated in neuronal cell survival. However, recently been shown to be S-nitrosylated on cysteine 257 and excessive NO production mediates neuronal cell death, in part via translocated to microtubules via a conformational change of LC1 mitochondrial dysfunction. Here, we report that the mitochondrial (12). Additionally, LC1 has been implicated in human neuro- ubiquitin ligase, MITOL, protects neuronal cells from mitochondrial logical disorders, such as giant axonal neuropathy (GAN), frag- damage caused by accumulation of S-nitrosylated microtubule- ile-X syndrome, spinocerebellar ataxia type 1, and Parkinson associated protein 1B-light chain 1 (LC1). S-nitrosylation of LC1 in- disease (10, 13, 14). Therefore, the control of S-nitrosylated LC1 duces a conformational change that serves both to activate LC1 and levels is critical for neuronal cell survival. fi to promote its ubiquination by MITOL, indicating that microtubule We previously identi ed a mitochondrial ubiquitin ligase, MITOL (also known as March5), which is involved in mito- stabilization by LC1 is regulated through its interaction with MITOL. – Excessive NO production can inhibit MITOL, and MITOL inhibition chondrial dynamics and mitochondrial quality control (15 19).
  • Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Co-Regulator in Invasive 6 Lobular Carcinoma of the Breast 7 8 Evelyn K

    Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Co-Regulator in Invasive 6 Lobular Carcinoma of the Breast 7 8 Evelyn K

    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.16.423142; this version posted December 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Running Title: MDC1 co-regulates ER in ILC 2 3 Research article 4 5 Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive 6 lobular carcinoma of the breast 7 8 Evelyn K. Bordeaux1+, Joseph L. Sottnik1+, Sanjana Mehrotra1, Sarah E. Ferrara2, Andrew E. Goodspeed2,3, James 9 C. Costello2,3, Matthew J. Sikora1 10 11 +EKB and JLS contributed equally to this project. 12 13 Affiliations 14 1Dept. of Pathology, University of Colorado Anschutz Medical Campus 15 2Biostatistics and Bioinformatics Shared Resource, University of Colorado Comprehensive Cancer Center 16 3Dept. of Pharmacology, University of Colorado Anschutz Medical Campus 17 18 Corresponding author 19 Matthew J. Sikora, PhD.; Mail Stop 8104, Research Complex 1 South, Room 5117, 12801 E. 17th Ave.; Aurora, 20 CO 80045. Tel: (303)724-4301; Fax: (303)724-3712; email: [email protected]. Twitter: 21 @mjsikora 22 23 Authors' contributions 24 MJS conceived of the project. MJS, EKB, and JLS designed and performed experiments. JLS developed models 25 for the project. EKB, JLS, SM, and AEG contributed to data analysis and interpretation. SEF, AEG, and JCC 26 developed and performed informatics analyses. MJS wrote the draft manuscript; all authors read and revised the 27 manuscript and have read and approved of this version of the manuscript.
  • TERT Promoter Mutations Occur Frequently in Gliomas and a Subset of Tumors Derived from Cells with Low Rates of Self-Renewal

    TERT Promoter Mutations Occur Frequently in Gliomas and a Subset of Tumors Derived from Cells with Low Rates of Self-Renewal

    TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal Patrick J. Killelaa,1, Zachary J. Reitmana,1, Yuchen Jiaob,1, Chetan Bettegowdab,c,1, Nishant Agrawalb,d, Luis A. Diaz, Jr.b, Allan H. Friedmana, Henry Friedmana, Gary L. Galliac,d, Beppino C. Giovanellae, Arthur P. Grollmanf, Tong-Chuan Heg, Yiping Hea, Ralph H. Hrubanh, George I. Jalloc, Nils Mandahli, Alan K. Meekerh,m, Fredrik Mertensi, George J. Nettoh,l, B. Ahmed Rasheeda, Gregory J. Rigginsc, Thomas A. Rosenquistf, Mark Schiffmanj, Ie-Ming Shihh, Dan Theodorescuk, Michael S. Torbensonh, Victor E. Velculescub, Tian-Li Wangh, Nicolas Wentzensenj, Laura D. Woodh, Ming Zhangb, Roger E. McLendona, Darell D. Bignera, Kenneth W. Kinzlerb, Bert Vogelsteinb,2, Nickolas Papadopoulosb, and Hai Yana,2 aThe Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, NC 27710; bLudwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231; Departments of cNeurosurgery, dOtolaryngology—Head and Neck Surgery, hPathology, lUrology, and mOncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231; eChristus Stehlin Foundation for Cancer Research, Houston, TX 77025; fDepartment of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794; gMolecular Oncology Laboratory, Department of Orthopaedic
  • Multiple Cellular Proteins Interact with LEDGF/P75 Through a Conserved Unstructured Consensus Motif

    Multiple Cellular Proteins Interact with LEDGF/P75 Through a Conserved Unstructured Consensus Motif

    ARTICLE Received 19 Jan 2015 | Accepted 1 Jul 2015 | Published 6 Aug 2015 DOI: 10.1038/ncomms8968 Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif Petr Tesina1,2,3,*, Katerˇina Cˇerma´kova´4,*, Magdalena Horˇejsˇ´ı3, Katerˇina Procha´zkova´1, Milan Fa´bry3, Subhalakshmi Sharma4, Frauke Christ4, Jonas Demeulemeester4, Zeger Debyser4, Jan De Rijck4,**, Va´clav Veverka1,** & Pavlı´na Rˇeza´cˇova´1,3,** Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors. 1 Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic. 2 Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Vinicna 5, 128 44 Prague, Czech Republic.
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming

    Supplemental Materials ZNF281 Enhances Cardiac Reprogramming

    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
  • UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By

    UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By

    UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii
  • FOXA3, a Negative Regulator of Nur77 Expression and Activity in Testicular Steroidogenesis

    FOXA3, a Negative Regulator of Nur77 Expression and Activity in Testicular Steroidogenesis

    Hindawi International Journal of Endocrinology Volume 2021, Article ID 6619447, 8 pages https://doi.org/10.1155/2021/6619447 Research Article FOXA3, a Negative Regulator of Nur77 Expression and Activity in Testicular Steroidogenesis Hansle Kim, Sudeep Kumar, and Keesook Lee School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea Correspondence should be addressed to Keesook Lee; [email protected] Received 30 December 2020; Revised 19 February 2021; Accepted 23 February 2021; Published 3 March 2021 Academic Editor: Vito Angelo Giagulli Copyright © 2021 Hansle Kim et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Biosynthesis of testosterone occurs mainly in the testicular Leydig cells. Nur77, an orphan nuclear receptor that is expressed in response to the luteinizing hormone/cyclic adenosine monophosphate (LH/cAMP) signaling pathway, is one of the key factors that regulate steroidogenesis in Leydig cells. *e function of Nur77 is modulated through interaction with other proteins. FOXA3, a transcription factor that is crucial for male fertility, is also expressed in Leydig cells. Here, we sought to elucidate the role of FOXA3 in testicular steroidogenesis by focusing on its interaction with Nur77. LH/cAMP signaling induces the onset of ste- roidogenesis in Leydig cells but has a repressive effect on the expression of FOXA3. Overexpression of FOXA3 in MA-10 Leydig cells repressed cAMP-induced expression of Nur77 and its target steroidogenic genes (StAR, P450c17, and Hsd3β). Furthermore, FOXA3 suppressed Nur77 transactivation of the promoter of steroidogenic genes.
  • Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms

    Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms

    Neurol Ther DOI 10.1007/s40120-015-0028-y ORIGINAL RESEARCH Latent Class Analysis to Classify Patients with Transthyretin Amyloidosis by Signs and Symptoms Jose Alvir . Michelle Stewart . Isabel Conceic¸a˜o To view enhanced content go to www.neurologytherapy-open.com Received: February 21, 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com ABSTRACT status measures for the latent classes were examined. Introduction: The aim of this study was to Results: A four-class latent class solution was develop an empirical approach to classifying thebestfitforthedata.Thelatentclasseswere patients with transthyretin amyloidosis (ATTR) characterized by the predominant symptoms based on clinical signs and symptoms. as severe neuropathy/severe autonomic, Methods: Data from 971 symptomatic subjects moderate to severe neuropathy/low to enrolled in the Transthyretin Amyloidosis moderate autonomic involvement, severe Outcomes Survey were analyzed using a latent cardiac, and moderate to severe neuropathy. class analysis approach. Differences in health Incorporating disease duration improved the model fit. It was found that measures of health Electronic supplementary material The online status varied by latent class in interpretable version of this article (doi:10.1007/s40120-015-0028-y) contains supplementary material, which is available to patterns. authorized users. Conclusion: This latent class analysis approach On behalf of the THAOS Investigators. offered promise in categorizing patients with ATTR across the spectrum of disease. The four- Trial registration: ClinicalTrials.gov number, class latent class solution included disease NCT00628745. duration and enabled better detection of J. Alvir (&) heterogeneity within and across genotypes Statistical Center for Outcomes, Real-World and than previous approaches, which have tended Aggregate Data, Global Medicines Development, Global Innovative Pharma Business, Pfizer, Inc., to classify patients a priori into neuropathic, New York, NY, USA cardiac, and mixed groups.
  • Annona Coriacea Mart. Fractions Promote Cell Cycle Arrest and Inhibit Autophagic Flux in Human Cervical Cancer Cell Lines

    Annona Coriacea Mart. Fractions Promote Cell Cycle Arrest and Inhibit Autophagic Flux in Human Cervical Cancer Cell Lines

    molecules Article Annona coriacea Mart. Fractions Promote Cell Cycle Arrest and Inhibit Autophagic Flux in Human Cervical Cancer Cell Lines Izabela N. Faria Gomes 1,2, Renato J. Silva-Oliveira 2 , Viviane A. Oliveira Silva 2 , Marcela N. Rosa 2, Patrik S. Vital 1 , Maria Cristina S. Barbosa 3,Fábio Vieira dos Santos 3 , João Gabriel M. Junqueira 4, Vanessa G. P. Severino 4 , Bruno G Oliveira 5, Wanderson Romão 5, Rui Manuel Reis 2,6,7,* and Rosy Iara Maciel de Azambuja Ribeiro 1,* 1 Experimental Pathology Laboratory, Federal University of São João del Rei—CCO/UFSJ, Divinópolis 35501-296, Brazil; [email protected] (I.N.F.G.); [email protected] (P.S.V.) 2 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil; [email protected] (R.J.S.-O.); [email protected] (V.A.O.S.); [email protected] (M.N.R.) 3 Laboratory of Cell Biology and Mutagenesis, Federal University of São João del Rei—CCO/UFSJ, Divinópolis 35501-296, Brazil; [email protected] (M.C.S.B.); [email protected] (F.V.d.S.) 4 Special Academic Unit of Physics and Chemistry, Federal University of Goiás, Catalão 75704-020, Brazil; [email protected] (J.G.M.J.); [email protected] (V.G.P.S.) 5 Petroleomic and forensic chemistry laboratory, Department of Chemistry, Federal Institute of Espirito Santo, Vitória, ES 29075-910, Brazil; [email protected] (B.G.O.); [email protected] (W.R.) 6 Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, 4710-057 Braga, Portugal 7 3ICVS/3B’s-PT Government Associate Laboratory, 4710-057 Braga, Portugal * Correspondence: [email protected] (R.M.R.); [email protected] (R.I.M.d.A.R.); Tel.: +55-173-321-6600 (R.M.R.); +55-3736-904-484 or +55-3799-1619-155 (R.I.M.d.A.R.) Received: 25 September 2019; Accepted: 29 October 2019; Published: 1 November 2019 Abstract: Plant-based compounds are an option to explore and perhaps overcome the limitations of current antitumor treatments.
  • DNV Classification Note 31.2 Strength Analysis of Hull Structure in Roll

    DNV Classification Note 31.2 Strength Analysis of Hull Structure in Roll

    CLASSIFICATION NOTES No. 31.2 STRENGTH ANALYSIS OF HULL STRUCTURE IN ROLL ON/ROLL OFF SHIPS AND CAR CARRIERS APRIL 2011 The content of this service document is the subject of intellectual property rights reserved by Det Norske Veritas AS (DNV). The user accepts that it is prohibited by anyone else but DNV and/or its licensees to offer and/or perform classification, certification and/or verification services, including the issuance of certificates and/or declarations of conformity, wholly or partly, on the basis of and/or pursuant to this document whether free of charge or chargeable, without DNV's prior written consent. DNV is not responsible for the consequences arising from any use of this document by others. DET NORSKE VERITAS Veritasveien 1, NO-1322 Høvik, Norway Tel.: +47 67 57 99 00 Fax: +47 67 57 99 11 FOREWORD DET NORSKE VERITAS (DNV) is an autonomous and independent foundation with the objectives of safeguarding life, property and the environment, at sea and onshore. DNV undertakes classification, certification, and other verification and consultancy services relating to quality of ships, offshore units and installations, and onshore industries worldwide, and carries out research in relation to these functions. Classification Notes Classification Notes are publications that give practical information on classification of ships and other objects. Examples of design solutions, calculation methods, specifications of test procedures, as well as acceptable repair methods for some components are given as interpretations of the more general rule requirements. All publications may be downloaded from the Society’s Web site http://www.dnv.com/. The Society reserves the exclusive right to interpret, decide equivalence or make exemptions to this Classification Note.
  • SUPPLEMENTARY NOTE Co-Activation of GR and NFKB

    SUPPLEMENTARY NOTE Co-Activation of GR and NFKB

    SUPPLEMENTARY NOTE Co-activation of GR and NFKB alters the repertoire of their binding sites and target genes. Nagesha A.S. Rao1*, Melysia T. McCalman1,*, Panagiotis Moulos2,4, Kees-Jan Francoijs1, 2 2 3 3,5 Aristotelis Chatziioannou , Fragiskos N. Kolisis , Michael N. Alexis , Dimitra J. Mitsiou and 1,5 Hendrik G. Stunnenberg 1Department of Molecular Biology, Radboud University Nijmegen, the Netherlands 2Metabolic Engineering and Bioinformatics Group, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece 3Molecular Endocrinology Programme, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Greece 4These authors contributed equally to this work 5 Corresponding authors E-MAIL: [email protected] ; TEL: +31-24-3610524; FAX: +31-24-3610520 E-MAIL: [email protected] ; TEL: +30-210-7273741; FAX: +30-210-7273677 Running title: Global GR and NFKB crosstalk Keywords: GR, p65, genome-wide, binding sites, crosstalk SUPPLEMENTARY FIGURES/FIGURE LEGENDS AND SUPPLEMENTARY TABLES 1 Rao118042_Supplementary Fig. 1 A Primary transcript Mature mRNA TNF/DMSO TNF/DMSO 8 12 r=0.74, p< 0.001 r=0.61, p< 0.001 ) 2 ) 10 2 6 8 4 6 4 2 2 0 Fold change (mRNA) (log Fold change (primRNA) (log 0 −2 −2 −2 0 2 4 −2 0 2 4 Fold change (RNAPII) (log2) Fold change (RNAPII) (log2) B chr5: chrX: 56 _ 104 _ DMSO DMSO 1 _ 1 _ 56 _ 104 _ TA TA 1 _ 1 _ 56 _ 104 _ TNF TNF Cluster 1 1 _ Cluster 2 1 _ 56 _ 104 _ TA+TNF TA+TNF 1 _ 1 _ CCNB1 TSC22D3 chr20: chr17: 25 _ 33 _ DMSO DMSO 1 _ 1 _ 25 _ 33 _ TA TA 1 _ 1 _ 25 _ 33 _ TNF TNF Cluster 3 1 _ Cluster 4 1 _ 25 _ 33 _ TA+TNF TA+TNF 1 _ 1 _ GPCPD1 CCL2 chr6: chr22: 77 _ 35 _ DMSO DMSO 1 _ 77 _ 1 _ 35 _ TA TA 1 _ 1 _ 77 _ 35 _ TNF Cluster 5 Cluster 6 TNF 1 _ 1 _ 77 _ 35 _ TA+TNF TA+TNF 1 _ 1 _ TNFAIP3 DGCR6 2 Supplementary Figure 1.
  • Duplication 9P and Their Implication to Phenotype

    Duplication 9P and Their Implication to Phenotype

    Guilherme et al. BMC Medical Genetics (2014) 15:142 DOI 10.1186/s12881-014-0142-1 RESEARCH ARTICLE Open Access Duplication 9p and their implication to phenotype Roberta Santos Guilherme1, Vera Ayres Meloni1, Ana Beatriz Alvarez Perez1, Ana Luiza Pilla1, Marco Antonio Paula de Ramos1, Anelisa Gollo Dantas1, Sylvia Satomi Takeno1, Leslie Domenici Kulikowski2 and Maria Isabel Melaragno1* Abstract Background: Trisomy 9p is one of the most common partial trisomies found in newborns. We report the clinical features and cytogenomic findings in five patients with different chromosome rearrangements resulting in complete 9p duplication, three of them involving 9p centromere alterations. Methods: The rearrangements in the patients were characterized by G-banding, SNP-array and fluorescent in situ hybridization (FISH) with different probes. Results: Two patients presented de novo dicentric chromosomes: der(9;15)t(9;15)(p11.2;p13) and der(9;21)t(9;21) (p13.1;p13.1). One patient presented two concomitant rearranged chromosomes: a der(12)t(9;12)(q21.13;p13.33) and an psu i(9)(p10) which showed FISH centromeric signal smaller than in the normal chromosome 9. Besides the duplication 9p24.3p13.1, array revealed a 7.3 Mb deletion in 9q13q21.13 in this patient. The break in the psu i(9) (p10) probably occurred in the centromere resulting in a smaller centromere and with part of the 9q translocated to the distal 12p with the deletion 9q occurring during this rearrangement. Two patients, brother and sister, present 9p duplication concomitant to 18p deletion due to an inherited der(18)t(9;18)(p11.2;p11.31)mat.