DOCSLIB.ORG

A Cytoskeleton Regulator AVIL Drives Tumorigenesis in Glioblastoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Cytoskeleton Regulator AVIL Drives Tumorigenesis in Glioblastoma ARTICLE https://doi.org/10.1038/s41467-020-17279-1 OPEN A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma Zhongqiu Xie 1, Pawel Ł. Janczyk2,8, Ying Zhang3,8, Aiqun Liu4, Xinrui Shi1, Sandeep Singh 1, Loryn Facemire1, ✉ Kristopher Kubow5,ZiLi6, Yuemeng Jia1, Dorothy Schafer7, James W. Mandell1, Roger Abounader3 & Hui Li1,2 Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is 1234567890():,; overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain. Glioma patients with increased AVIL expression have a worse prognosis. Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells. Conversely, overexpressing AVIL promoted cell proliferation and migration, enabled fibroblasts to escape contact inhibition, and transformed immortalized astrocytes, supporting AVIL being a bona fide oncogene. We provide evidence that the tumorigenic effect of AVIL is partly mediated by FOXM1, which regulates LIN28B, whose expression also correlates with clinical prognosis. AVIL regulates the cytoskeleton through modulating F-actin, while mutants disrupting F-actin binding are defective in its tumorigenic capabilities. 1 Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 2 Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 3 Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. 4 Tumor Hospital, Guangxi Medical University, Nanning 530021, China. 5 Department of Biology, James Madison University, Harrisonburg, VA 22807, USA. 6 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha 410011, China. 7 Department of Biology, University of Virginia, Charlottesville, VA 22908, USA. 8These authors contributed equally: Pawel Ł. ✉ Janczyk, Ying Zhang. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:3457 | https://doi.org/10.1038/s41467-020-17279-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17279-1 lioblastoma (GBM) is the most common primary brain reorganization21. The expression of AVIL is more restricted, Gtumor and among the deadliest of human cancers. being low or undetectable in most tissues (Supplementary Despite advances in surgery, radiation and chemotherapy, Fig. 1c). As with many gene fusions, including IGH-MYC, and survival of patients affected by GBM remains dismal (~15 months TMPRSS2-ERG, the expression of a proto-oncogene may be after diagnosis)1–3. Clearly, better treatment options, and identi- misregulated by subjecting itself to the control elements of its fication of selective therapeutic targets are urgently needed. fusion partner. We suspected that fusion to MARS in rhabdo- Oncogene addiction describes a phenomenon according to myosarcoma is one mechanism to misregulate AVIL gene which tumor cells become reliant on the activity of a particular expression, and that AVIL may be misregulated by other oncogene and die once this activity is inhibited4,5. Many of the mechanisms in other cancers. We found that the AVIL locus is targeted cancer therapies exploit this concept6. It is perhaps best amplified in 15–18% of glioblastoma cases in The Cancer Gen- exemplified by the successful use of imatinib in the therapy of ome Atlas (TCGA) studies22,23 via cBioPortal analysis (Fig. 1a). chronic myelogenous leukemia (CML)7. In CML, the major dri- We confirmed such a copy number gain by FISH analyses, using a ver of tumorigenesis is the BCR-ABL fusion oncogene; imatinib probe covering the AVIL locus (Fig. 1b). The AVIL locus is inhibits the constitutively active BCR-ABL protein kinase, to amplified in two glioblastoma cell lines, SF767 and A172, but not which leukemic cells become addicted. Other successful examples in three other glioblastoma lines, U87, U251, T98G, or in an include trastuzumab targeting ERBB2 addiction8, and vemur- immortalized astrocyte culture. afenib targeting BRAF addiction9. The challenge is to find such 12q13-15 is frequently amplified in multiple tumor types key oncogenes. Even though large sets of genome and tran- including glioma24. AVIL is located on 12q14, 45 kb away from scriptome data are available to facilitate the identification of CDK4 toward centromere, and around 10 MB from MDM2 driver mutations in cancer, true signals are often buried in a large toward telomere. Given the importance of CDK4 and MDM2 in number of passenger events. In contrast to adult cancers, pedia- tumorigenesis, it is possible that AVIL amplification is only a tric tumors tend to have fewer point mutations and structural byproduct of a larger fragment amplification. However, AVIL changes. While studying a pediatric cancer, rhabdomyosarcoma, expression seems to be upregulated through additional mechan- we discovered a gene fusion, which results in the juxtaposition of isms: at the protein level AVIL was not detected in the normal a house-keeping gene next to the AVIL gene. Suspecting that astrocytes; in contrast, all of the tumor cell lines tested had higher other tumors may also dysregulate AVIL expression, we exam- AVIL protein expression, including the ones that do not have ined AVIL in adult cancers and found its critical role in the AVIL locus amplification (Fig. 1c). This difference was not tumorigenesis of GBM. We believe that the same approach can be obvious at the RNA level (Supplementary Fig. 2), suggesting that applied to the discovery of other oncogenes. some post-transcriptional mechanism may be at play. The cytoskeleton of the cells plays important roles in addition The overexpression of AVIL protein in GBMs was further to maintain the cell size and shape. Many critical processes confirmed by immunohistochemistry assays. Staining in normal including cell proliferation, migration, and even transcriptional human cerebral cortical gray matter was low, and largely regulations have been connected to the cytoskeleton10. Various restricted to a subpopulation of pyramidal neurons. Normal genes that modulate cytoskeleton have been associated with white matter demonstrated minimal immunoreactivity. In enhanced infiltrative and proliferative capacity11. For instance, in contrast, all the glioblastomas we tested had much stronger GBM, CTTN, an actin nucleating factor is overexpressed, and this signals (Fig. 1d, and Supplementary Fig. 3). overexpression is associated with an enhanced infiltrative capacity, We then examined the REMBRANDT database, which has and poor prognosis12,13. Here, we report an oncogene, AVIL, microarray data for 28 non-tumor brain tissues, 148 astrocytomas which encodes a protein that regulates F-actin dynamics and (WHO grade II or III), and 228 GBM (WHO grade IV) cases25. cytoskeleton. We found that AVIL is overexpressed in GBM cells Two different microarray probes showed that AVIL expression including GBM stem cells, and that AVIL overexpression is crucial correlates with tumor grade, with the highest levels in GBMs for GBM proliferation and migration. Mechanistically, AVIL (Fig. 1e). In our own collection of eight non-tumor brain tissues, functions upstream of FOXM1. FOXM1 is a member of FOX and 36 glioblastoma cases, we also confirmed the significant family. While it is silenced in differentiated cells, it is over- difference in AVIL RNA expression levels between the two groups expressed in a number of solid tumors including GBMs14. It has (Fig. 1f). To examine the expression levels of AVIL across the been also reported to mediated critical processes of tumorigenesis, major subclasses of glioma recently established and implemented such as tumor invasion, angiogenesis, and metastasis14–18.On in diagnostic neuropathology, we interrogate the RNA- the other hand, let-7 family of microRNAs functions as tumor sequencing dataset from the TCGA diffuse glioma study26. Here suppressors and inhibits glioma malignancy19. We showed mul- we subdivided the TCGA samples into GBMs with IDH-wild tiple lines of evidence supporting that AVIL regulates type, GBMs with IDH-mutant, Lower-grade glioma (LGG) with FOXM1 stability, which in turn regulates LIN28B/let-7. These IDH-wild type, LGG with mutant IDH and 1p/19q codeletion, findings support the critical role of cytoskeleton dynamics in and LGG with IDH mutant without 1p/19q codeletion. GBMs, and connect cytoskeleton regulation to the stability of Consistent with REMBRANT data, GBMs with or without IDH FOXM1 and let-7 expression. mutation have high level of AVIL expression. Within LGG, the group with IDH WT is the highest and not statically different from the GBMs. LGG IDH MT without 1p/19q codeletion is Results slightly higher than the group with codeletion (Fig. 1g). AVIL is frequently upregulated in glioblastomas. Previously, we We then examined the AVIL protein in 12 non-tumor brain identified a gene fusion in alveolar rhabdomyosarcoma, a tissues, and 14 GBMs. The AVIL protein was absent, or barely pediatric cancer20. We noticed that even though PAX3-FOXO1 is detected in the non-tumor cases, but higher levels of AVIL the most well-known fusion in this type of rhabdomyosarcoma, protein expression were seen in almost all of the GBM cases
Load more

Recommended publications
  • Exome Sequencing Reveals Cubilin Mutation As a Single-Gene Cause of Proteinuria
    BRIEF COMMUNICATION www.jasn.org Exome Sequencing Reveals Cubilin Mutation as a Single-Gene Cause of Proteinuria Bugsu Ovunc,*† Edgar A. Otto,* Virginia Vega-Warner,* Pawaree Saisawat,* Shazia Ashraf,* Gokul Ramaswami,* Hanan M. Fathy,‡ Dominik Schoeb,* Gil Chernin,* Robert H. Lyons,§ ʈ Engin Yilmaz,† and Friedhelm Hildebrandt* ¶ ʈ Departments of *Pediatrics and Human Genetics, §Department of Biological Chemistry and DNA Sequencing Core, and ¶Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan; †Department of Medical Biology, Hacettepe University, Ankara, Turkey; and ‡The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt ABSTRACT In two siblings of consanguineous parents with intermittent nephrotic-range pro- tion is still unknown.7 This forbids the use of teinuria, we identified a homozygous deleterious frameshift mutation in the gene cohort studies for gene identification and ne- CUBN, which encodes cubulin, using exome capture and massively parallel re- cessitates the ability to identify disease-caus- sequencing. The mutation segregated with affected members of this family and ing genes in single families. We therefore was absent from 92 healthy individuals, thereby identifying a recessive mutation in combined whole genome homozygosity CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations mapping with consecutive whole human ex- cause a hereditary form of megaloblastic anemia secondary to vitamin B12 defi- ome capture (WHEC) and massively par- ciency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both allel re-sequencing to overcome this lim- 6 the intestinal vitamin B12-intrinsic factor complex and the tubular reabsorption of itation. In this way we here identify a protein in the proximal tubule.
    [Show full text]
  • 140503 IPF Signatures Supplement Withfigs Thorax
    Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network.
    [Show full text]
  • Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis Through MDM2-Mediated Ubiquitination and Destabilization of P53
    Author Manuscript Published OnlineFirst on February 17, 2020; DOI: 10.1158/0008-5472.CAN-19-1912 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hypomethylation-linked activation of PLCE1 impedes autophagy and promotes tumorigenesis through MDM2-mediated ubiquitination and destabilization of p53 Yunzhao Chen1,3*, Huahua Xin1*, Hao Peng1*, Qi Shi1, Menglu Li1, Jie Yu3, Yanxia Tian1, Xueping Han1, Xi Chen1, Yi Zheng4, Jun Li5, Zhihao Yang1, Lan Yang1, Jianming Hu1, Xuan Huang2, Zheng Liu2, Xiaoxi Huang2, Hong Zhou6, Xiaobin Cui1**, Feng Li1,2** 1 Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 2 Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; 3 The people's hospital of Suzhou National Hi-Tech District, Suzhou 215010, China; 4 Department of Gastroenterology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 5 Department of Ultrasound, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China; 6 Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, Australia. Running title: PLCE1 impedes autophagy via MDM2-p53 axis in ESCC *These authors contributed equally to this work. Corresponding authors: **Xiaobin Cui, Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832002, China. Phone: 86.0377.2850955; E-mail: [email protected]; **Feng Li, Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
    [Show full text]
  • Hypomethylation-Linked Activation of PLCE1 Impedes
    Published OnlineFirst February 17, 2020; DOI: 10.1158/0008-5472.CAN-19-1912 CANCER RESEARCH | MOLECULAR CELL BIOLOGY Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53 Yunzhao Chen1,2, Huahua Xin1, Hao Peng1, Qi Shi1, Menglu Li1,JieYu2, Yanxia Tian1, Xueping Han1, Xi Chen1, Yi Zheng3,JunLi4, Zhihao Yang1, Lan Yang1, Jianming Hu1, Xuan Huang5, Zheng Liu5, Xiaoxi Huang5, Hong Zhou6, Xiaobin Cui1, and Feng Li1,5 ABSTRACT ◥ Esophageal squamous cell carcinoma (ESCC) is one of the dead- Significance: These findings identify hypomethylation- liest malignant diseases. Multiple studies with large clinic-based mediated activation of PLCE1 as a potential oncogene that cohorts have revealed that variations of phospholipase C epsilon 1 blocks cellular autophagy of esophageal carcinoma by facilitat- (PLCE1) correlate with esophageal cancer susceptibility. However, ing the MDM2-dependent ubiquitination of p53 and subsequent the causative role of PLCE1 in ESCC has remained elusive. Here, we degradation. observed that hypomethylation-mediated upregulation of PLCE1 Graphical Abstract: http://cancerres.aacrjournals.org/content/ expression was implicated in esophageal carcinogenesis and poor canres/80/11/2175/F1.large.jpg. prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and Normal cells Cancer cells promoted p53 ubiquitination, whereas it increased the half-life of PLCE1 Cytoplasm Cytoplasm mouse double minute 2 homolog (MDM2) and inhibited its ubiqui- wtp53 wtp53 tination, leading to MDM2 stabilization. Mechanistically, the func- MDM2 MDM2 wtp53 MDM2 MDM2 Nucleus tion of PLCE1 correlated with its direct binding to both p53 and Nucleus wtp53 Ub Ub MDM2, which promoted MDM2-dependent ubiquitination of p53 PLCE1 MDM2 wtp53 Ub wtp53 wtp53 and subsequent degradation in vitro.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome
    BASIC RESEARCH www.jasn.org Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome Ge´raldine Mollet,*† Julien Ratelade,*† Olivia Boyer,*†‡ Andrea Onetti Muda,*§ ʈ Ludivine Morisset,*† Tiphaine Aguirre Lavin,*† David Kitzis,*† Margaret J. Dallman, ʈ Laurence Bugeon, Norbert Hubner,¶ Marie-Claire Gubler,*† Corinne Antignac,*†** and Ernie L. Esquivel*† *INSERM, U574, Hoˆpital Necker-Enfants Malades, Paris, France; †Faculte´deMe´ decine Rene´ Descartes, Universite´ Paris Descartes, Paris, France; ‡Pediatric Nephrology Department and **Department of Genetics, Hoˆpital Necker- Enfants Malades, Assistance Publique-Hoˆpitaux de Paris, Paris, France; §Department of Pathology, Campus ʈ Biomedico University, Rome, Italy; Department of Biological Sciences, Imperial College London, London, England; and ¶Max-Delbruck Center for Molecular Medicine, Berlin, Germany ABSTRACT Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitu- lated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptJAMA Psychiatry Author Manuscript. Author Author Manuscript manuscript; available in PMC 2015 August 03. Published in final edited form as: JAMA Psychiatry. 2014 June ; 71(6): 657–664. doi:10.1001/jamapsychiatry.2014.176. Identification of Pathways for Bipolar Disorder A Meta-analysis John I. Nurnberger Jr, MD, PhD, Daniel L. Koller, PhD, Jeesun Jung, PhD, Howard J. Edenberg, PhD, Tatiana Foroud, PhD, Ilaria Guella, PhD, Marquis P. Vawter, PhD, and John R. Kelsoe, MD for the Psychiatric Genomics Consortium Bipolar Group Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (Nurnberger, Koller, Edenberg, Foroud); Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis (Nurnberger, Foroud); Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism Intramural Research Program, Bethesda, Maryland (Jung); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (Edenberg); Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine (Guella, Vawter); Department of Psychiatry, School of Medicine, Corresponding Author: John I. Nurnberger Jr, MD, PhD, Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Dr, Indianapolis, IN 46202 ([email protected]). Author Contributions: Drs Koller and Vawter had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Nurnberger, Koller, Edenberg, Vawter. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Nurnberger, Koller, Jung, Vawter.
    [Show full text]
  • PLCE1 Rs2274223 A>G Polymorphism and Its Functional Role In
    Universidade de Lisboa Faculdade de Medicina de Lisboa PLCE1 rs2274223 A>G Polymorphism and its Functional Role in Colorectal Cancer António Manuel Marujo Palma Orientadores: Doutora Marta Sofia Alves Martins Prof. Doutor Luís António Marquês da Costa Dissertação especialmente elaborada para obtenção do grau de Mestre em Oncobiologia 2019 Universidade de Lisboa Faculdade de Medicina de Lisboa PLCE1 rs2274223 A>G Polymorphism and its Functional Role in Colorectal Cancer António Manuel Marujo Palma Orientadores: Doutora Marta Sofia Alves Martins Prof. Doutor Luís António Marquês da Costa Dissertação especialmente elaborada para obtenção do grau de Mestre em Oncobiologia 2019 Todas as afirmações efetuadas no presente documento são da exclusiva responsabilidade do seu autor, não cabendo qualquer responsabilidade à Faculdade de Medicina de Lisboa pelos conteúdos nele apresentados. A impressão desta dissertação foi aprovada pelo Conselho Científico da Faculdade de Medicina de Lisboa em reunião de 16 de Abril de 2019. Agradecimentos Quero dedicar este trabalho ao meu tio António pela força e coragem que tem tido a lutar contra esta doença e por essa razão tornou-se num exemplo para eu nunca desistir de atingir os meus objetivos. Quero ainda dedicar este trabalho à minha avó Dolores por todos os ensinamentos, pelo carinho e pelo amor que me deu. Infelizmente não conseguiu presenciar o seu neto a finalizar mais uma importante etapa na sua vida. Seja onde for, eu sei que estás comigo e nunca me vou esquecer de ti. Não teria sido possível chegar até aqui e terminar este trabalho sem o apoio incondicional de pessoas a quem eu quero expressar o meu mais sincero agradecimento.
    [Show full text]
  • Potent Lipolytic Activity of Lactoferrin in Mature Adipocytes
    Biosci. Biotechnol. Biochem., 77 (3), 566–571, 2013 Potent Lipolytic Activity of Lactoferrin in Mature Adipocytes y Tomoji ONO,1;2; Chikako FUJISAKI,1 Yasuharu ISHIHARA,1 Keiko IKOMA,1;2 Satoru MORISHITA,1;3 Michiaki MURAKOSHI,1;4 Keikichi SUGIYAMA,1;5 Hisanori KATO,3 Kazuo MIYASHITA,6 Toshihide YOSHIDA,4;7 and Hoyoku NISHINO4;5 1Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa 256-0811, Japan 2Department of Supramolecular Biology, Graduate School of Nanobioscience, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan 3Food for Life, Organization for Interdisciplinary Research Projects, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan 4Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto 602-8566, Japan 5Research Organization of Science and Engineering, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan 6Department of Marine Bioresources Chemistry, Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minatocho, Hakodate, Hokkaido 041-8611, Japan 7Kyoto City Hospital, 1-2 Higashi-takada-cho, Mibu, Nakagyou-ku, Kyoto 604-8845, Japan Received October 22, 2012; Accepted November 26, 2012; Online Publication, March 7, 2013 [doi:10.1271/bbb.120817] Lactoferrin (LF) is a multifunctional glycoprotein resistance, high blood pressure, and dyslipidemia. To found in mammalian milk. We have shown in a previous prevent progression of metabolic syndrome, lifestyle clinical study that enteric-coated bovine LF tablets habits must be improved to achieve a balance between decreased visceral fat accumulation. To address the energy intake and consumption. In addition, the use of underlying mechanism, we conducted in vitro studies specific food factors as helpful supplements is attracting and revealed the anti-adipogenic action of LF in pre- increasing attention.
    [Show full text]
  • Management of Steroid-Resistant Nephrotic Syndrome in Children and Adolescents
    Review Management of steroid-resistant nephrotic syndrome in children and adolescents Kjell Tullus, Hazel Webb, Arvind Bagga More than 85% of children and adolescents (majority between 1–12 years old) with idiopathic nephrotic syndrome Lancet Child Adolesc Health 2018 show complete remission of proteinuria following daily treatment with corticosteroids. Patients who do not show Published Online remission after 4 weeks’ treatment with daily prednisolone are considered to have steroid-resistant nephrotic October 17, 2018 syndrome (SRNS). Renal histology in most patients shows presence of focal segmental glomerulosclerosis, minimal http://dx.doi.org/10.1016/ S2352-4642(18)30283-9 change disease, and (rarely) mesangioproliferative glomerulonephritis. A third of patients with SRNS show mutations Nephrology Unit, Great in one of the key podocyte genes. The remaining cases of SRNS are probably caused by an undefined circulating Ormond Street Hospital for factor. Treatment with calcineurin inhibitors (ciclosporin and tacrolimus) is the standard of care for patients with Children, Great Ormond Street, non-genetic SRNS, and approximately 70% of patients achieve a complete or partial remission and show satisfactory London, UK (K Tullus MD, long-term outcome. Additional treatment with drugs that inhibit the renin–angiotensin axis is recommended for H Webb BSc) andDivision of Nephrology, Indian Council of hypertension and for reducing remaining proteinuria. Patients with SRNS who do not respond to treatment with Medical Research Advanced calcineurin inhibitors or other immunosuppressive drugs can show declining kidney function and are at risk for end- Center for Research in stage renal failure. Approximately a third of those who undergo renal transplantation show recurrent focal segmental Nephrology, All India Institute glomerulosclerosis in the allograft and often respond to combined treatment with plasma exchange, rituximab, and of Medical Sciences, New Delhi, India (Prof A Bagga MD) intensified immunosuppression.
    [Show full text]
  • Nuclear Receptor TLX Prevents Retinal Dystrophy and Recruits the Corepressor Atrophin1
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Chun-Li Zhang,1,2 Yuhua Zou,2 Ruth T. Yu,2 Fred H. Gage,3 and Ronald M. Evans1,2,4 1Howard Hughes Medical Institute, 2Gene Expression Laboratory, and 3Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx−/− mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx−/− mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration. [Keywords: Nuclear receptor; TLX; retinal dystrophy; PTEN; atrophin; neurodegeneration] Supplemental material is available at http://www.genesdev.org.
    [Show full text]
  • Genetic Testing Medical Policy – Genetics
    Genetic Testing Medical Policy – Genetics Please complete all appropriate questions fully. Suggested medical record documentation: • Current History & Physical • Progress Notes • Family Genetic History • Genetic Counseling Evaluation *Failure to include suggested medical record documentation may result in delay or possible denial of request. PATIENT INFORMATION Name: Member ID: Group ID: PROCEDURE INFORMATION Genetic Counseling performed: c Yes c No **Please check the requested analyte(s), identify number of units requested, and provide indication/rationale for testing. 81400 Molecular Pathology Level 1 Units _____ c ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (e.g., medium chain acyl dehydrogenase deficiency), K304E variant _____ c ACE (angiotensin converting enzyme) (e.g., hereditary blood pressure regulation), insertion/deletion variant _____ c AGTR1 (angiotensin II receptor, type 1) (e.g., essential hypertension), 1166A>C variant _____ c BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (e.g., maple syrup urine disease, type 1A), Y438N variant _____ c CCR5 (chemokine C-C motif receptor 5) (e.g., HIV resistance), 32-bp deletion mutation/794 825del32 deletion _____ c CLRN1 (clarin 1) (e.g., Usher syndrome, type 3), N48K variant _____ c DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), IVS14+1G>A variant _____ c F13B (coagulation factor XIII, B polypeptide) (e.g., hereditary hypercoagulability), V34L variant _____ c F2 (coagulation factor 2) (e.g.,
    [Show full text]