Updates in Tumor Profiling in Gastrointestinal Cancers
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
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. -
Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1. -
WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). -
X-Linked Diseases: Susceptible Females
REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome. -
High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype
Supplementary Information High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype Håkon Reikvam 1,2,*, Elise Aasebø 1, Annette K. Brenner 2, Sushma Bartaula-Brevik 1, Ida Sofie Grønningsæter 2, Rakel Brendsdal Forthun 2, Randi Hovland 3,4 and Øystein Bruserud 1,2 1 Department of Clinical Science, University of Bergen, 5020, Bergen, Norway 2 Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway 3 Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway 4 Institute of Biomedicine, University of Bergen, 5020, Bergen, Norway * Correspondence: [email protected]; Tel.: +55-97-50-00 J. Clin. Med. 2019, 8, x 2 of 36 Figure S1. Mutational studies in a cohort of 71 AML patients. The figure shows the number of patients with the various mutations (upper), the number of mutations in for each patient (middle) and the number of main classes with mutation(s) in each patient (lower). 2 J. Clin. Med. 2019, 8, x; doi: www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, x 3 of 36 Figure S2. The immunophenotype of primary human AML cells derived from 62 unselected patients. The expression of the eight differentiation markers CD13, CD14, CD15, CD33, CD34, CD45, CD117 and HLA-DR was investigated for 62 of the 71 patients included in our present study. We performed an unsupervised hierarchical cluster analysis and identified four patient main clusters/patient subsets. The mutational profile for each f the 62 patients is also given (middle), no individual mutation of main class of mutations showed any significant association with any of the for differentiation marker clusters (middle). -
Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo
TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genetik Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in vitro and in vivo - Towards Response Prediction in Cancer Therapy with Kinase Inhibitors Michaela Bairlein Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. -Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. A. Gierl 2. Hon.-Prof. Dr. h.c. A. Ullrich (Eberhard-Karls-Universität Tübingen) 3. Univ.-Prof. A. Schnieke, Ph.D. Die Dissertation wurde am 07.01.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 19.04.2010 angenommen. FOR MY PARENTS 1 Contents 2 Summary ................................................................................................................................................................... 5 3 Zusammenfassung .................................................................................................................................................... 6 4 Introduction .............................................................................................................................................................. 8 4.1 Cancer .............................................................................................................................................................. -
Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................ -
The Mtor Substrate S6 Kinase 1 (S6K1)
The Journal of Neuroscience, July 26, 2017 • 37(30):7079–7095 • 7079 Cellular/Molecular The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury X Hassan Al-Ali,1,2,3* Ying Ding,5,6* Tatiana Slepak,1* XWei Wu,5 Yan Sun,5,7 Yania Martinez,1 Xiao-Ming Xu,5 Vance P. Lemmon,1,3 and XJohn L. Bixby1,3,4 1Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33136, 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, 4Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China, and 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China Themammaliantargetofrapamycin(mTOR)positivelyregulatesaxongrowthinthemammaliancentralnervoussystem(CNS).Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demon- strate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. -
The Mtor Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury
This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System injury Hassan Al-Ali1,2,3, Ying Ding5,6, Tatiana Slepak1, Wei Wu5, Yan Sun5,7, Yania Martinez1, Xiao-Ming Xu5, V.P. Lemmon1,3 and J.l. Bixby1,3,4 1The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 4Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. DOI: 10.1523/JNEUROSCI.0931-17.2017 Received: 4 April 2017 Revised: 18 May 2017 Accepted: 27 May 2017 Published: 16 June 2017 Author contributions: H.A.-A., Y.D., T.S., W.W., Y.S., X.-M.X., V.P.L., and J.B. designed research; H.A.-A., Y.D., T.S., W.W., Y.S., and Y.M. -
CENTOGENE's Severe and Early Onset Disorder Gene List
CENTOGENE’s severe and early onset disorder gene list USED IN PRENATAL WES ANALYSIS AND IDENTIFICATION OF “PATHOGENIC” AND “LIKELY PATHOGENIC” CENTOMD® VARIANTS IN NGS PRODUCTS The following gene list shows all genes assessed in prenatal WES tests or analysed for P/LP CentoMD® variants in NGS products after April 1st, 2020. For searching a single gene coverage, just use the search on www.centoportal.com AAAS, AARS1, AARS2, ABAT, ABCA12, ABCA3, ABCB11, ABCB4, ABCB7, ABCC6, ABCC8, ABCC9, ABCD1, ABCD4, ABHD12, ABHD5, ACACA, ACAD9, ACADM, ACADS, ACADVL, ACAN, ACAT1, ACE, ACO2, ACOX1, ACP5, ACSL4, ACTA1, ACTA2, ACTB, ACTG1, ACTL6B, ACTN2, ACVR2B, ACVRL1, ACY1, ADA, ADAM17, ADAMTS2, ADAMTSL2, ADAR, ADARB1, ADAT3, ADCY5, ADGRG1, ADGRG6, ADGRV1, ADK, ADNP, ADPRHL2, ADSL, AFF2, AFG3L2, AGA, AGK, AGL, AGPAT2, AGPS, AGRN, AGT, AGTPBP1, AGTR1, AGXT, AHCY, AHDC1, AHI1, AIFM1, AIMP1, AIPL1, AIRE, AK2, AKR1D1, AKT1, AKT2, AKT3, ALAD, ALDH18A1, ALDH1A3, ALDH3A2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDOA, ALDOB, ALG1, ALG11, ALG12, ALG13, ALG14, ALG2, ALG3, ALG6, ALG8, ALG9, ALMS1, ALOX12B, ALPL, ALS2, ALX3, ALX4, AMACR, AMER1, AMN, AMPD1, AMPD2, AMT, ANK2, ANK3, ANKH, ANKRD11, ANKS6, ANO10, ANO5, ANOS1, ANTXR1, ANTXR2, AP1B1, AP1S1, AP1S2, AP3B1, AP3B2, AP4B1, AP4E1, AP4M1, AP4S1, APC2, APTX, AR, ARCN1, ARFGEF2, ARG1, ARHGAP31, ARHGDIA, ARHGEF9, ARID1A, ARID1B, ARID2, ARL13B, ARL3, ARL6, ARL6IP1, ARMC4, ARMC9, ARSA, ARSB, ARSL, ARV1, ARX, ASAH1, ASCC1, ASH1L, ASL, ASNS, ASPA, ASPH, ASPM, ASS1, ASXL1, ASXL2, ASXL3, ATAD3A, ATCAY, ATIC, ATL1, ATM, ATOH7, -
Mapping the Mammalian Ribosome Quality Control Complex Interactome Using Proximity Labeling Approaches
M BoC | ARTICLE Mapping the mammalian ribosome quality control complex interactome using proximity labeling approaches Nathan Zuzow, Arit Ghosh, Marilyn Leonard, Jeffrey Liao, Bing Yang, and Eric J. Bennett* Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 ABSTRACT Previous genetic and biochemical studies from Saccharomyces cerevisiae have Monitoring Editor identified a critical ribosome-associated quality control complex (RQC) that facilitates resolu- Sandra Wolin tion of stalled ribosomal complexes. While components of the mammalian RQC have been National Cancer Institute, NIH examined in vitro, a systematic characterization of RQC protein interactions in mammalian Received: Dec 12, 2017 cells has yet to be described. Here we utilize both proximity-labeling proteomic approaches, Revised: Mar 6, 2018 BioID and APEX, and traditional affinity-based strategies to both identify interacting proteins Accepted: Mar 9, 2018 of mammalian RQC members and putative substrates for the RQC resident E3 ligase, Ltn1. Surprisingly, validation studies revealed that a subset of substrates are ubiquitylated by Ltn1 in a regulatory manner that does not result in subsequent substrate degradation. We demon- strate that Ltn1 catalyzes the regulatory ubiquitylation of ribosomal protein S6 kinase 1 and 2 (RPS6KA1, RPS6KA3). Further, loss of Ltn1 function results in hyperactivation of RSK1/2 signaling without impacting RSK1/2 protein turnover. These results suggest that Ltn1-medi- ated RSK1/2 ubiquitylation is inhibitory and establishes a new role for Ltn1 in regulating mi- togen-activated kinase signaling via regulatory RSK1/2 ubiquitylation. Taken together, our results suggest that mammalian RQC interactions are difficult to observe and may be more transient than the homologous complex in S. -
Global Phosphoproteomic Profiling Reveals Perturbed Signaling in a Mouse Model of Dilated Cardiomyopathy
Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy Uros Kuzmanova,b,1, Hongbo Guoa,1, Diana Buchsbaumc, Jake Cosmec, Cynthia Abbasic, Ruth Isserlina, Parveen Sharmac, Anthony O. Gramolinib,c,2, and Andrew Emilia,2 aDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1; bTed Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada M5G 1M1; and cDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5S 3E1 Edited by Christine E. Seidman, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, and approved August 30, 2016 (received for review April 27, 2016) + + Phospholamban (PLN) plays a central role in Ca2 homeostasis in kinase A (PKA) or Ca2 /calmodulin-dependent protein kinase II cardiac myocytes through regulation of the sarco(endo)plasmic re- (CaMKII) (3). ticulum Ca2+-ATPase 2A (SERCA2A) Ca2+ pump. An inherited mu- Proteomic analyses have revealed changes in the abundance tation converting arginine residue 9 in PLN to cysteine (R9C) results of other effector proteins in diverse biochemical pathways in in dilated cardiomyopathy (DCM) in humans and transgenic mice, DCM. Notably, shotgun proteomic analysis of membrane pro- but the downstream signaling defects leading to decompensation tein expression dynamics in heart microsomes isolated from mice and heart failure are poorly understood. Here we used precision overexpressing a superinhibitory (I40A) mutant of PLN revealed mass spectrometry to study the global phosphorylation dynamics changes in G protein-coupled receptor-mediated pathways leading of 1,887 cardiac phosphoproteins in early affected heart tissue in a to activation of protein kinase C (PKC) (4).