DOCSLIB.ORG

Mp200859.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mp200859.Pdf Molecular Psychiatry (2008) 13, 800–812 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp ORIGINAL ARTICLE Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response M-L Wong, C Dong, J Maestre-Mesa and J Licinio Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL, USA There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic–pituitary– adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome b4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose–effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic–pituitary–adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups. Molecular Psychiatry (2008) 13, 800–812; doi:10.1038/mp.2008.59; published online 27 May 2008 Keywords: TBX21; PSMB4; major depression; genetic; SNP; cytokine Introduction in which a sustained focus on the threatening stimulus, fear-related behaviors and stereotyped Major depressive disorder (MDD) is a common and states of cognition and affect are matched with complex disorder of unknown etiology that affects indices of physiological hyperarousal, such as activa- about 15% of the population.1 Despite recent scien- tion of the hypothalamic–pituitary–adrenal (HPA) tific advances and its enormous social costs,2 MDD axis and sympathetic activation, and inhibition of is still currently thought to be a gene-environment counterproductive neurovegetative functions during disorder of polygenic nature with a descriptive life-threatening situations.5,6 Depression-like symp- diagnosis and no known biomarkers.1 Although the toms have been associated with activation of the HPA contributions of immune mediators to the pathophysio- axis, sympathetic nervous system and inflammatory logy and treatment of psychiatric disorders may be response characterized by hypercortisolaemia,7 increased traced back to over 80 years with the work of Nobel central corticotropin-releasing hormone (CRH)8–10 and laureate Julius Wagner-Jauregg,3 evidence from clin- norepineprhine11,12 functions, increased numbers of ical and basic research have recently supported a role peripheral leukocytes, positive acute phase proteins for dysregulation of the immune system in MDD.4 and proinflammatory cytokines.13 Both acute stress and MDD are states of hyperarousal, We and others have proposed a role for proin- flammatory cytokines in the pathophysiology of Correspondence: Dr M-L Wong, Department of Psychiatry and MDD, with activation of the immune system and of Behavioral Sciences, Center on Pharmacogenomics, School of the cellular immune response.14,15 Even though still Medicine at the University of Miami, 1580 NW 10th Avenue, underexplored in MDD, the T-cell arm of the immune Room 633-A, Miami, FL 33136, USA. system has been emerging as the centerpiece of the E-mail: [email protected] Received 5 February 2008; revised 10 April 2008; accepted 14 continued debate over the role of the immuno- April 2008; published online 27 May 2008 mediators in depression.15,16 Data supporting either Inflammation-related genes in major depression M-L Wong et al 801 a predominance of cytokine-producing helper T-cells, (Table 1). We also conducted multiplex assays of 21 type 1 (Th1) or type 2 (Th2) have accumulated. The circulating cytokines in a subset of our patients. overactivity of the hallmarks of Th1 immunity, such as interferon-g (IFNg), tumor necrosis factor-a or Methods interleukin-1 (IL-1),17 or predominant Th2 patterns Genetic study of production supported by increased levels of IL-6, IL-10 or IL-1316 have continued to fuel this discus- Study population. This study was approved by the sion. At least two fundamental processes may institutional review boards of the University of contribute to the role of the T-cell arm of adaptive California Los Angeles and the University of Miami, immunity in MDD: T-cell programmed differentiation and it has been registered in the public database and antigen processing. ClinicalTrials.gov (NCT00265292). The study Naive CD4 þ T lymphocytes proliferate and differ- population consisted of 284 depressed Mexican entiate into two main lineages defined by distinct Americans enrolled in a pharmacogenetic study cytokine profiles18 after encountering antigen-carry- of antidepressant treatment response as previously ing dendritic cells in secondary lymphoid organs. described.26,27 We also studied 331 control The balance of two main subtypes of cytokine- individuals recruited from the same Mexican- producing Th1/Th2 determines the immune response American community in Los Angeles and studied to pathogens. Clinically, Th1 patterns of cytokine by the same bilingual clinical research team. Controls production are associated with inflammation and for our genomic studies were in general good health autoimmune disease, whereas Th2 patterns are but were not screened for medical or psychiatric related to allergic responses and asthma.19 Th1 cell- illness. All patients were Mexican-American men and lineage commitment is controlled by the key trans- women aged 21–68 years, with a current episode of criptional factor TBX21 (Tbet),20 which is rapidly major depression as diagnosed by DSM-IV (Diagnostic produced early in Th1 differentiation and gradually and Statistical Manual of Mental Disorders, decreases at later stages.21 TBX21 has the ability to 4th edn).28 In our study, all Mexican-American simultaneously drive Th1 genetic programs and subjects had at least three grandparents born in repress the development of the opposing Th2 Mexico.26 All patients had comprehensive subset; it may also redirect fully polarized Th2 cells psychiatric and medical assessments. We used into Th1 cells. diagnostic and ratings instruments that have been Proteasomes (prosome, macropain) are the major fully validated in English and Spanish, and intracellular extralysosomal organelle for protein conducted all assessments in the subject’s primary degradation and a central source of antigenic peptides language. in the endogenous pathway; they are utilized in major Inclusion criteria included DSM-IV diagnosis of histocompatibility complex molecules class I current, unipolar major depressive episode, with a 21- (MHC1) antigen processing and protein degradation. item Hamilton Depression Rating Scale (HAM-D21)29 Proteasomes are highly abundant in the cytosol and score of 18 or greater with item number 1 (depressed nucleus and are organized as multiunit protease mood) rated 2 or greater. There was no anxiety complexes. Protein degradation is central to threshold for inclusion. Subjects with any primary many important biological functions, including axis I other than MDD (for example, dementia, cell-cycle progression, apoptosis, synaptic reorgani- psychotic illness, bipolar disorder, adjustment dis- zation, DNA repair, normal immune surveillance order), electroconvulsive therapy in the past 6 months mechanisms and immune response networks. or previous lack of response to desipramine or Disruption of the proteasomal degradation pathway fluoxetine were excluded. As anxiety can be a has been implicated in a wide range of human manifestation of depression, patients who met criteria disorders; immune abnormalities include the devel- for depression and also anxiety disorder were not opment of CD8 þ T lymphocytes and MHC1 excluded. Exclusion criteria included active medical molecules, and MHC1-restricted antigen presentation illnesses that could be etiologically related to the have been described in mice lacking proteasome ongoing depressive episode (for example, untreated subunits.22 Independent lines of research have hypothyroidism, cardiovascular accident within the supported the role of protein synthesis/degradation past 6 months, uncontrolled hypertension or dia- in MDD-like neuropsychiatric symptoms in autoim- betes), current, active suicidal ideation with a plan mune disorders23 and in the central actions of and strong intent, pregnancy, lactation, current use of antidepressant drugs.24 medications with significant central nervous system We used a combination strategy consisting of activity, which interfere with electroencephalography genetic analyses and functional
Load more

Recommended publications
  • View of HER2: Human Epidermal Growth Factor Receptor 2; TNBC: Triple-Negative Breast Resistance to Systemic Therapy in Patients with Breast Cancer
    Wen et al. Cancer Cell Int (2018) 18:128 https://doi.org/10.1186/s12935-018-0625-9 Cancer Cell International PRIMARY RESEARCH Open Access Sulbactam‑enhanced cytotoxicity of doxorubicin in breast cancer cells Shao‑hsuan Wen1†, Shey‑chiang Su2†, Bo‑huang Liou3, Cheng‑hao Lin1 and Kuan‑rong Lee1* Abstract Background: Multidrug resistance (MDR) is a major obstacle in breast cancer treatment. The predominant mecha‑ nism underlying MDR is an increase in the activity of adenosine triphosphate (ATP)-dependent drug efux trans‑ porters. Sulbactam, a β-lactamase inhibitor, is generally combined with β-lactam antibiotics for treating bacterial infections. However, sulbactam alone can be used to treat Acinetobacter baumannii infections because it inhibits the expression of ATP-binding cassette (ABC) transporter proteins. This is the frst study to report the efects of sulbactam on mammalian cells. Methods: We used the breast cancer cell lines as a model system to determine whether sulbactam afects cancer cells. The cell viabilities in the present of doxorubicin with or without sulbactam were measured by MTT assay. Protein identities and the changes in protein expression levels in the cells after sulbactam and doxorubicin treatment were determined using LC–MS/MS. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to analyze the change in mRNA expression levels of ABC transporters after treatment of doxorubicin with or without sulbactam. The efux of doxorubicin was measures by the doxorubicin efux assay. Results: MTT assay revealed that sulbactam enhanced the cytotoxicity of doxorubicin in breast cancer cells. The results of proteomics showed that ABC transporter proteins and proteins associated with the process of transcription and initiation of translation were reduced.
    [Show full text]
  • Analysis of the Stability of 70 Housekeeping Genes During Ips Reprogramming Yulia Panina1,2*, Arno Germond1 & Tomonobu M
    www.nature.com/scientificreports OPEN Analysis of the stability of 70 housekeeping genes during iPS reprogramming Yulia Panina1,2*, Arno Germond1 & Tomonobu M. Watanabe1 Studies on induced pluripotent stem (iPS) cells highly rely on the investigation of their gene expression which requires normalization by housekeeping genes. Whether the housekeeping genes are stable during the iPS reprogramming, a transition of cell state known to be associated with profound changes, has been overlooked. In this study we analyzed the expression patterns of the most comprehensive list to date of housekeeping genes during iPS reprogramming of a mouse neural stem cell line N31. Our results show that housekeeping genes’ expression fuctuates signifcantly during the iPS reprogramming. Clustering analysis shows that ribosomal genes’ expression is rising, while the expression of cell-specifc genes, such as vimentin (Vim) or elastin (Eln), is decreasing. To ensure the robustness of the obtained data, we performed a correlative analysis of the genes. Overall, all 70 genes analyzed changed the expression more than two-fold during the reprogramming. The scale of this analysis, that takes into account 70 previously known and newly suggested genes, allowed us to choose the most stable of all genes. We highlight the fact of fuctuation of housekeeping genes during iPS reprogramming, and propose that, to ensure robustness of qPCR experiments in iPS cells, housekeeping genes should be used together in combination, and with a prior testing in a specifc line used in each study. We suggest that the longest splice variants of Rpl13a, Rplp1 and Rps18 can be used as a starting point for such initial testing as the most stable candidates.
    [Show full text]
  • Isolation and Characterization of Lymphocyte-Like Cells from a Lamprey
    Isolation and characterization of lymphocyte-like cells from a lamprey Werner E. Mayer*, Tatiana Uinuk-ool*, Herbert Tichy*, Lanier A. Gartland†, Jan Klein*, and Max D. Cooper†‡ *Max-Planck-Institut fu¨r Biologie, Abteilung Immungenetik, Corrensstrasse 42, D-72076 Tu¨bingen, Germany; and †Howard Hughes Medical Institute, University of Alabama, 378 Wallace Tumor Institute, Birmingham, AL 35294 Contributed by Max D. Cooper, August 30, 2002 Lymphocyte-like cells in the intestine of the sea lamprey, Petro- existence of the adaptive immune system in jawless fishes, myzon marinus, were isolated by flow cytometry under light- the identity of these cells has remained in doubt. The aim of the scatter conditions used for the purification of mouse intestinal present study was to exploit contemporary methods of cell lymphocytes. The purified lamprey cells were morphologically separation to isolate the agnathan lymphocyte-like cells to indistinguishable from mammalian lymphocytes. A cDNA library characterize them morphologically and by the genes they was prepared from the lamprey lymphocyte-like cells, and more express. than 8,000 randomly selected clones were sequenced. Homology searches comparing these ESTs with sequences deposited in the Materials and Methods databases led to the identification of numerous genes homologous Source and Preparation of Cell Suspension. Ammocoete larvae to those predominantly or characteristically expressed in mamma- (8–13 cm long) of the sea lamprey, Petromyzon marinus (from lian lymphocytes, which included genes controlling lymphopoiesis, Lake Huron, MI) were dissected along the ventral side to extract intracellular signaling, proliferation, migration, and involvement the intestine and the associated typhlosole (spiral valve). Cells of lymphocytes in innate immune responses.
    [Show full text]
  • Reference Gene Validation Via RT–Qpcr for Human Ipsc-Derived Neural Stem Cells and Neural Progenitors
    Molecular Neurobiology https://doi.org/10.1007/s12035-019-1538-x Reference Gene Validation via RT–qPCR for Human iPSC-Derived Neural Stem Cells and Neural Progenitors Justyna Augustyniak1 & Jacek Lenart2 & Gabriela Lipka1 & Piotr P. Stepien3 & Leonora Buzanska1 Received: 26 November 2018 /Accepted: 22 February 2019 # The Author(s) 2019 Abstract Correct selection of the reference gene(s) is the most important step in gene expression analysis. The aims of this study were to identify and evaluate the panel of possible reference genes in neural stem cells (NSC), early neural progenitors (eNP) and neural progenitors (NP) obtained from human-induced pluripotent stem cells (hiPSC). The stability of expression of genes commonly used as the reference in cells during neural differentiation is variable and does not meet the criteria for reference genes. In the present work, we evaluated the stability of expression of 16 candidate reference genes using the four most popular algorithms: the ΔCt method, BestKeeper, geNorm and NormFinder. All data were analysed using the online tool RefFinder to obtain a comprehensive ranking. Our results indicate that NormFinder is the best tool for reference gene selection in early stages of hiPSC neural differentiation. None of the 16 tested genes is suitable as reference gene for all three stages of development. We recommend using different genes (panel of genes) to normalise RT–qPCR data for each of the neural differentiation stages. Keywords human induced Pluripotent Stem Cell (hiPSC) . Neural Stem Cells . Neural
    [Show full text]
  • Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database
    Supplementary Table S1. Correlation between the mutant p53-interacting partners and PTTG3P, PTTG1 and PTTG2, based on data from StarBase v3.0 database. PTTG3P PTTG1 PTTG2 Gene ID Coefficient-R p-value Coefficient-R p-value Coefficient-R p-value NF-YA ENSG00000001167 −0.077 8.59e-2 −0.210 2.09e-6 −0.122 6.23e-3 NF-YB ENSG00000120837 0.176 7.12e-5 0.227 2.82e-7 0.094 3.59e-2 NF-YC ENSG00000066136 0.124 5.45e-3 0.124 5.40e-3 0.051 2.51e-1 Sp1 ENSG00000185591 −0.014 7.50e-1 −0.201 5.82e-6 −0.072 1.07e-1 Ets-1 ENSG00000134954 −0.096 3.14e-2 −0.257 4.83e-9 0.034 4.46e-1 VDR ENSG00000111424 −0.091 4.10e-2 −0.216 1.03e-6 0.014 7.48e-1 SREBP-2 ENSG00000198911 −0.064 1.53e-1 −0.147 9.27e-4 −0.073 1.01e-1 TopBP1 ENSG00000163781 0.067 1.36e-1 0.051 2.57e-1 −0.020 6.57e-1 Pin1 ENSG00000127445 0.250 1.40e-8 0.571 9.56e-45 0.187 2.52e-5 MRE11 ENSG00000020922 0.063 1.56e-1 −0.007 8.81e-1 −0.024 5.93e-1 PML ENSG00000140464 0.072 1.05e-1 0.217 9.36e-7 0.166 1.85e-4 p63 ENSG00000073282 −0.120 7.04e-3 −0.283 1.08e-10 −0.198 7.71e-6 p73 ENSG00000078900 0.104 2.03e-2 0.258 4.67e-9 0.097 3.02e-2 Supplementary Table S2.
    [Show full text]
  • Original Article PSMB4 Promotes Glioma Proliferation Via NF-Κb Signaling
    Int J Clin Exp Med 2016;9(10):19164-19174 www.ijcem.com /ISSN:1940-5901/IJCEM0027183 Original Article PSMB4 promotes glioma proliferation via NF-κB signaling Xing Su1,2, Qi Yao2, Zhikai Gu2, Jianhong Shen2, Zhongyong Wang1, Jian Chen2, Qin Lan1 1Department of Neurosurgery, Second Affiliated Hospital of Suzhou University, 1055 Sanxiang Road, Suzhou 215004, People’s Republic of China; 2Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, People’s Republic of China Received March 3, 2016; Accepted September 10, 2016; Epub October 15, 2016; Published October 30, 2016 Abstract: Proteasomal subunit PSMB4 plays a dominant role in maintaining genomic stability and promoting tu- morigenesis. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we identified the expression and role of PSMB4 in glioma. We found a significant upregulation of PSMB4 both in glioma plasma and cell lines. Higher frequency of PSMB4 positive cells was detected in tumor tissues of gliomas compared to non-tumor tissues. Meanwhile the high frequency of PSMB4 expression was also remarkably associated with poor prognosis of glioma patients. Furthermore, ectopic overexpression of PSMB4 promoted the cell growth and colony forming ability of glioma cells, whereas inhibition of PSMB4 led to a decrease in such events. Our results demonstrated that the upregulation of PSMB4 enhanced cell proliferation of U251 cell line using a BrdU incorporation assay, whereas knockdown of PSMB4 markedly suppressed the cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of PCNA and CyclinD1, PSMB4 knockdown or NF-κB inhibition restrained colony forming ability in glioma cells.
    [Show full text]
  • Functional Gene Clusters in Global Pathogenesis of Clear Cell Carcinoma of the Ovary Discovered by Integrated Analysis of Transcriptomes
    International Journal of Environmental Research and Public Health Article Functional Gene Clusters in Global Pathogenesis of Clear Cell Carcinoma of the Ovary Discovered by Integrated Analysis of Transcriptomes Yueh-Han Hsu 1,2, Peng-Hui Wang 1,2,3,4,5 and Chia-Ming Chang 1,2,* 1 Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan; [email protected] (Y.-H.H.); [email protected] (P.-H.W.) 2 School of Medicine, National Yang-Ming University, Taipei 112, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan 4 Department of Medical Research, China Medical University Hospital, Taichung 440, Taiwan 5 Female Cancer Foundation, Taipei 104, Taiwan * Correspondence: [email protected]; Tel.: +886-2-2875-7826; Fax: +886-2-5570-2788 Received: 27 April 2020; Accepted: 31 May 2020; Published: 2 June 2020 Abstract: Clear cell carcinoma of the ovary (ovarian clear cell carcinoma (OCCC)) is one epithelial ovarian carcinoma that is known to have a poor prognosis and a tendency for being refractory to treatment due to unclear pathogenesis. Published investigations of OCCC have mainly focused only on individual genes and lack of systematic integrated research to analyze the pathogenesis of OCCC in a genome-wide perspective. Thus, we conducted an integrated analysis using transcriptome datasets from a public domain database to determine genes that may be implicated in the pathogenesis involved in OCCC carcinogenesis. We used the data obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) DataSets. We found six interactive functional gene clusters in the pathogenesis network of OCCC, including ribosomal protein, eukaryotic translation initiation factors, lactate, prostaglandin, proteasome, and insulin-like growth factor.
    [Show full text]
  • Additive Loss-Of-Function Proteasome Subunit Mutations in CANDLE/PRAAS Patients Promote Type I IFN Production
    Amendment history: Erratum (February 2016) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production Anja Brehm, … , Ivona Aksentijevich, Raphaela Goldbach-Mansky J Clin Invest. 2015;125(11):4196-4211. https://doi.org/10.1172/JCI81260. Research Article Immunology Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation inP SMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective
    [Show full text]
  • Stem Cells Ap7609a Protein Synthesis 17 % Protein Synthesis Protein Folding 4 % F
    Protein Survey STEM2PhD, J.Mountzouris 1PhD,CELL T.Gilliam 1 & C.Wu 1PhD www.abcepta.com (1) Abcepta Inc., 10320 Camino Santa Fe, Ste G, San Diego, CA 92121 (2) Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037 Distribution total transcription factors Apoptosis chromatin regulators 1 % Selected Abgent Products Surface antigens cell surface receptors 1 % Figure Target Tissue/Cell line Cat# signaling ligands DNA repair ECM and adhesion 2 % A. NANOG Human testis AP1486c A.A. BB.. cytoskeleton Protein folding SOX9 Human prostate carcinoma AP1409a RNA binding 2 % B. intracellular signaling Cell cycle C. ALDH1A1, RalDH1 Human hepatocarcinoma AP1465c DNA repair 2 % RNA binding proteins cell cycle 3 % D. PIWIL1, HIWI Human testis AP2731a Chromatin regulators apoptosis 3 % E. Eph4A, SEK, HEK8 Human stem cells AP7609a protein synthesis 17 % Protein synthesis protein folding 4 % F. Glypican-3 ,GPC3 Human liver carcinoma (HepG2) AP6337a protein processing Ligands CC.. DD.. 4 % G. KITLG, cKit ligand Human kidney (293) AP1484b metabolism Cyoskeletal proteins transport 4 % H. DRAGON, RGMB Human bone marrow (K562) AP1421b 0% 20% 40% 60% 80% 100% Protein processing TERT, Telomerase Human T cell leukemia (Jurkat) AP1410c I. HSC-LT HSC HSC-ST HSC/MPP 14 % J. SOX9 Human liver carcinoma (HepG2) AP1409c Distribution of gene products between HSC subtypes (Ref. 11,12) K. LMX1alpha HL60 AP1426c E.E. FF.. 7 % L. LIN28B Human bone marrow (K562) AP1485c Lin– Lin– Lin– M. SAE1, UBLE1A Mouse lung tissue lysate AP2011b SCA1 + SCA1 + SCA1 + KIT+ KIT+ KIT+ N. KIT, CD117, SCFR Mouse pancreas lysate AP7656b Thy1.1low Thy1.1low Thy1.1– FLT3– FLT3– FLT3+ Long-term HSC-LT HSC-ST MPP self-renewal potential Intracellular signaling + SP+ CD34 CD34 + low N-cad+ CD11b CD11b low Transcription factors TIE2+ CD48 + 13 % CD38 + MYC hi Metabolism CD150 + Rhohi 10 % Endoglin+ CD4 low Cell surface receptors MYC low Transporters 7 % Rholow ECM/cell adhesion 7 % G.
    [Show full text]
  • Gene Expression Profiles Reveal Alternative Targets of Therapeutic Intervention for the Treatment of Drug-Resistant Non-Small Cell Lung Cancers
    University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2017 GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG-RESISTANT NON-SMALL CELL LUNG CANCERS Madeline J. Krentz Gober University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-7761-6741 Digital Object Identifier: https://doi.org/10.13023/ETD.2017.309 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Krentz Gober, Madeline J., "GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG-RESISTANT NON-SMALL CELL LUNG CANCERS" (2017). Theses and Dissertations--Pharmacy. 78. https://uknowledge.uky.edu/pharmacy_etds/78 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • The Kinesin Spindle Protein Inhibitor Filanesib Enhances the Activity of Pomalidomide and Dexamethasone in Multiple Myeloma
    Plasma Cell Disorders SUPPLEMENTARY APPENDIX The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma Susana Hernández-García, 1 Laura San-Segundo, 1 Lorena González-Méndez, 1 Luis A. Corchete, 1 Irena Misiewicz- Krzeminska, 1,2 Montserrat Martín-Sánchez, 1 Ana-Alicia López-Iglesias, 1 Esperanza Macarena Algarín, 1 Pedro Mogollón, 1 Andrea Díaz-Tejedor, 1 Teresa Paíno, 1 Brian Tunquist, 3 María-Victoria Mateos, 1 Norma C Gutiérrez, 1 Elena Díaz- Rodriguez, 1 Mercedes Garayoa 1* and Enrique M Ocio 1* 1Centro Investigación del Cáncer-IBMCC (CSIC-USAL) and Hospital Universitario-IBSAL, Salamanca, Spain; 2National Medicines Insti - tute, Warsaw, Poland and 3Array BioPharma, Boulder, Colorado, USA *MG and EMO contributed equally to this work ©2017 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2017.168666 Received: March 13, 2017. Accepted: August 29, 2017. Pre-published: August 31, 2017. Correspondence: [email protected] MATERIAL AND METHODS Reagents and drugs. Filanesib (F) was provided by Array BioPharma Inc. (Boulder, CO, USA). Thalidomide (T), lenalidomide (L) and pomalidomide (P) were purchased from Selleckchem (Houston, TX, USA), dexamethasone (D) from Sigma-Aldrich (St Louis, MO, USA) and bortezomib from LC Laboratories (Woburn, MA, USA). Generic chemicals were acquired from Sigma Chemical Co., Roche Biochemicals (Mannheim, Germany), Merck & Co., Inc. (Darmstadt, Germany). MM cell lines, patient samples and cultures. Origin, authentication and in vitro growth conditions of human MM cell lines have already been characterized (17, 18). The study of drug activity in the presence of IL-6, IGF-1 or in co-culture with primary bone marrow mesenchymal stromal cells (BMSCs) or the human mesenchymal stromal cell line (hMSC–TERT) was performed as described previously (19, 20).
    [Show full text]
  • Colon Cancer and Its Molecular Subsystems: Network Approaches to Dissecting Driver Gene Biology
    COLON CANCER AND ITS MOLECULAR SUBSYSTEMS: NETWORK APPROACHES TO DISSECTING DRIVER GENE BIOLOGY by VISHAL N. PATEL Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Genetics CASE WESTERN RESERVE UNIVERSITY August 2011 Case Western Reserve University School of Graduate Studies We hereby approve the dissertation* of Vishal N. Patel, candidate for the degree of Doctor of Philosophy on July 6, 2011. Committee Chair: Georgia Wiesner Mark R. Chance Sudha Iyengar Mehmet Koyuturk * We also certify that written approval has been obtained for any proprietary material contained therein 2 Table of Contents I. List of Tables 6 II. List of Figures 7 III. List of Abbreviations 8 IV. Glossary 10 V. Abstract 14 VI. Colon Cancer and its Molecular Subsystems 15 Construction, Interpretation, and Validation a. Colon Cancer i. Etiology ii. Development iii. The Pathway Paradigm iv. Cancer Subtypes and Therapies b. Molecular Subsystems i. Introduction ii. Construction iii. Interpretation iv. Validation c. Summary VII. Prostaglandin dehydrogenase signaling 32 One driver and an unknown path a. Introduction i. Colon Cancer ii. Mass spectrometry 3 b. Methods c. Results d. Discussion e. Summary VIII. Apc signaling with Candidate Drivers 71 Two drivers, many paths a. Introduction b. Methods c. Results and Discussion d. Summary IX. Apc-Cdkn1a signaling 87 Two drivers, one path a. Introduction b. Methods c. Results i. Driver Gene Network Prediction ii. Single Node Perturbations 1. mRNA profiling 2. Proteomic profiling d. Discussion e. Summary X. Molecular Subsystems in Cancer 114 The Present to the Future XI. Appendix I 119 Prostaglandin dehydrogenase associated data XII.
    [Show full text]