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http://www.ncbi.nlm.nih.gov/pubmed/1175600 | 1. Eur J Biochem. 1975 Jun 16;55(1):147-55. doi:
10.1111/j.1432-1033.1975.tb02147.x.
Initiation of transcription within an RNA-polymerase binding site.
Heyden B, Nüsslein C, Schaller H.
1. The 5'-terminal sequence of the RNA transcribed from bacteriophage fd
replicative form DNA under the control of promotor region I has been determined
to be ppp(Gp)nUpApApApGpApCpCpUpGpApUpUp. . . 2. This sequence is complementary
to the 5'-terminal sequence of the minus strand of the corresponding RNA
polymerase binding site I, the starting point for RNA synthesis lying
approximately in the middle of the binding site. 3. This initial sequence is
also transcribed faithfully from isolated complexes of RNA polymerase and
binding site I, obtained by DNase digestion of complexes between RNA polymerase
and fd replicative form DNA. These highly stable complexes can not be
reconstituted from binding site and enzyme. 4. It is concluded that RNA
polymerase binding site and initiation site are identical parts of a promoter
region, and that no "drift" between these sites is required as a step in RNA
chain initiation. An additional non-transcribed outside region is implicated as
essential for full promoter function.
DOI: 10.1111/j.1432-1033.1975.tb02147.x
PMID: 1175600 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17997859 | 1. BMC Mol Biol. 2007 Nov 12;8:102. doi: 10.1186/1471-2199-8-102.
Localization of TFIIB binding regions using serial analysis of chromatin
occupancy.
Yochum GS(1), Rajaraman V, Cleland R, McWeeney S.
Author information:
(1)Vollum Institute, Oregon Health and Science University, Portland, OR 97239,
USA.
BACKGROUND: RNA Polymerase II (RNAP II) is recruited to core promoters by the
pre-initiation complex (PIC) of general transcription factors. Within the PIC,
transcription factor for RNA polymerase IIB (TFIIB) determines the start site of
transcription. TFIIB binding has not been localized, genome-wide, in metazoans.
Serial analysis of chromatin occupancy (SACO) is an unbiased methodology used to
empirically identify transcription factor binding regions. In this report, we
use TFIIB and SACO to localize TFIIB binding regions across the rat genome.
RESULTS: A sample of the TFIIB SACO library was sequenced and 12,968 TFIIB
genomic signature tags (GSTs) were assigned to the rat genome. GSTs are 20-22
base pair fragments that are derived from TFIIB bound chromatin. TFIIB localized
to both non-protein coding and protein-coding loci. For 21% of the 1783
protein-coding genes in this sample of the SACO library, TFIIB binding mapped
near the characterized 5' promoter that is upstream of the transcription start
site (TSS). However, internal TFIIB binding positions were identified in 57% of
the 1783 protein-coding genes. Internal positions are defined as those within an
inclusive region greater than 2.5 kb downstream from the 5' TSS and 2.5 kb
upstream from the transcription stop. We demonstrate that both TFIIB and TFIID
(an additional component of PICs) bound to internal regions using chromatin
immunoprecipitation (ChIP). The 5' cap of transcripts associated with internal
TFIIB binding positions were identified using a cap-trapping assay. The 5' TSSs
for internal transcripts were confirmed by primer extension. Additionally, an
analysis of the functional annotation of mouse 3 (FANTOM3) databases indicates
that internally initiated transcripts identified by TFIIB SACO in rat are
conserved in mouse.
CONCLUSION: Our findings that TFIIB binding is not restricted to the 5' upstream
region indicates that the propensity for PIC to contribute to transcript
diversity is far greater than previously appreciated.
DOI: 10.1186/1471-2199-8-102
PMCID: PMC2211499
PMID: 17997859 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11439189 | 1. Cell. 2001 Jun 29;105(7):935-44. doi: 10.1016/s0092-8674(01)00398-1.
A coiled-coil from the RNA polymerase beta' subunit allosterically induces
selective nontemplate strand binding by sigma(70).
Young BA(1), Anthony LC, Gruber TM, Arthur TM, Heyduk E, Lu CZ, Sharp MM, Heyduk
T, Burgess RR, Gross CA.
Author information:
(1)Department of Biochemistry and Biophysics, University of California, San
Francisco, San Francisco, CA 94143, USA.
For transcription to initiate, RNA polymerase must recognize and melt promoters.
Selective binding to the nontemplate strand of the -10 region of the promoter is
central to this process. We show that a 48 amino acid (aa) coiled-coil from the
beta' subunit (aa 262--309) induces sigma(70) to perform this function almost as
efficiently as core RNA polymerase itself. We provide evidence that interaction
between the beta' coiled-coil and region 2.2 of sigma(70) promotes an allosteric
transition that allows sigma(70) to selectively recognize the nontemplate
strand. As the beta' 262--309 peptide can function with the previously
crystallized portion of sigma(70), nontemplate recognition can be reconstituted
with only 47 kDa, or 1/10 of holoenzyme.
DOI: 10.1016/s0092-8674(01)00398-1
PMID: 11439189 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23086998 | 1. Science. 2012 Nov 23;338(6110):1076-80. doi: 10.1126/science.1227786. Epub
2012 Oct 18.
Structural basis of transcription initiation.
Zhang Y(1), Feng Y, Chatterjee S, Tuske S, Ho MX, Arnold E, Ebright RH.
Author information:
(1)Howard Hughes Medical Institute, Waksman Institute, and Department of
Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
During transcription initiation, RNA polymerase (RNAP) binds and unwinds
promoter DNA to form an RNAP-promoter open complex. We have determined crystal
structures at 2.9 and 3.0 Å resolution of functional transcription initiation
complexes comprising Thermus thermophilus RNA polymerase, σ(A), and a promoter
DNA fragment corresponding to the transcription bubble and downstream
double-stranded DNA of the RNAP-promoter open complex. The structures show that
σ recognizes the -10 element and discriminator element through interactions that
include the unstacking and insertion into pockets of three DNA bases and that
RNAP recognizes the -4/+2 region through interactions that include the
unstacking and insertion into a pocket of the +2 base. The structures further
show that interactions between σ and template-strand single-stranded DNA (ssDNA)
preorganize template-strand ssDNA to engage the RNAP active center.
DOI: 10.1126/science.1227786
PMCID: PMC3593053
PMID: 23086998 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2649403 | 1. FASEB J. 1989 Apr;3(6):1723-33. doi: 10.1096/fasebj.3.6.2649403.
Promoter specificity and modulation of RNA polymerase II transcription.
Saltzman AG(1), Weinmann R.
Author information:
(1)Wistar Institute, Philadelphia, Pennsylvania 19104.
RNA polymerase II is a multisubunit enzyme involved in the transcription of
protein encoding genes. Recently acquired knowledge of the transcription process
and of the RNA polymerase molecule as well as the isolation of subunit clones
have led to a better understanding of the enzyme's functional regulation.
Specific transcription initiation occurs at promoter regions located upstream of
the gene and requires a minimum of five basic factors in addition to the enzyme.
Furthermore, proteins that bind to specific DNA elements within the promoter
also regulate transcriptional activity. Additional factors are required for the
elongation and, possibly, termination of transcription. Two elongation factors,
SII and TFIIF, interact directly with the RNA polymerase II molecule. Functional
domains of RNA polymerase II have been determined by analysis of genomic clones
for the two largest subunits of the enzyme. For example, the 240-kDa largest
subunit contains a highly phosphorylated carboxyl-terminal heptapeptide domain
repeated 26-52 times that is absolutely required for transcription in vivo.
Analysis of the polymerase molecule and its interaction with basic gene-specific
transcription factors will aid in our studies of the control of gene expression.
DOI: 10.1096/fasebj.3.6.2649403
PMID: 2649403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9311784 | 1. Nature. 1997 Sep 25;389(6649):399-402. doi: 10.1038/38763.
Transcription factor TFIID recruits factor CPSF for formation of 3' end of mRNA.
Dantonel JC(1), Murthy KG, Manley JL, Tora L.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire
CNRS/INSERM/ULP, Collège de France, Strasbourg.
Initiation of transcription by RNA polymerase II from a promoter region on DNA
requires the assembly of several initiation factors to form a preinitiation
complex. Assembly of this complex is initiated by the binding of the
transcription factor TFIID, composed of the TATA-box binding protein (TBP) and
TBP-associated factors (TAF[II]s), to the promoter. We have now characterized an
immunopurified TFIID complex which we unexpectedly find contains the
cleavage-polyadenylation specificity factor (CPSF), one of the factors required
for formation of the 3' end of messenger RNA. CPSF is brought to the
preinitiation complex by TFIID, but after transcription starts, CPSF dissociates
from TFIID and becomes associated with the elongating polymerase. We also show
that overexpression of recombinant TBP in HeLa cells decreases polyadenylation
without affecting the correct initiation of transcription of the reporter gene.
This indicates that, owing to incomplete assembly of TFIID on recombinant TBP,
CPSF is not brought to the promoter and therefore polyadenylation becomes less
efficient. Our observations have thus revealed a link between transcription
initiation and elongation by RNA polymerase II and processing of the 3' end of
mRNA.
DOI: 10.1038/38763
PMID: 9311784 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29168694 | 1. Elife. 2017 Nov 23;6:e32038. doi: 10.7554/eLife.32038.
The mechanism of variability in transcription start site selection.
Yu L(#)(1)(2), Winkelman JT(#)(1)(2)(3), Pukhrambam C(2)(3), Strick TR(4)(5)(6),
Nickels BE(2)(3), Ebright RH(1)(2).
Author information:
(1)Department of Chemistry, Rutgers University, Piscataway, United States.
(2)Waksman Institute, Rutgers University, Piscataway, United States.
(3)Department of Genetics, Rutgers University, Piscataway, United States.
(4)Ecole Normale Supérieure, Institut de Biologie de l'Ecole Normale Supérieure
(IBENS), CNRS, INSERM, PSL Research University, Paris, France.
(5)Programme Equipe Labellisées, Ligue Contre le Cancer, Paris, France.
(6)Institut Jacques Monod, CNRS, UMR7592, University Paris Diderot, Paris,
France.
(#)Contributed equally
During transcription initiation, RNA polymerase (RNAP) binds to promoter DNA,
unwinds promoter DNA to form an RNAP-promoter open complex (RPo) containing a
single-stranded 'transcription bubble,' and selects a transcription start site
(TSS). TSS selection occurs at different positions within the promoter region,
depending on promoter sequence and initiating-substrate concentration.
Variability in TSS selection has been proposed to involve DNA 'scrunching' and
'anti-scrunching,' the hallmarks of which are: (i) forward and reverse movement
of the RNAP leading edge, but not trailing edge, relative to DNA, and (ii)
expansion and contraction of the transcription bubble. Here, using in vitro and
in vivo protein-DNA photocrosslinking and single-molecule nanomanipulation, we
show bacterial TSS selection exhibits both hallmarks of scrunching and
anti-scrunching, and we define energetics of scrunching and anti-scrunching. The
results establish the mechanism of TSS selection by bacterial RNAP and suggest a
general mechanism for TSS selection by bacterial, archaeal, and eukaryotic RNAP.
DOI: 10.7554/eLife.32038
PMCID: PMC5730371
PMID: 29168694 [Indexed for MEDLINE]
Conflict of interest statement: No competing interests declared. |
http://www.ncbi.nlm.nih.gov/pubmed/34924398 | 1. J Neuromuscul Dis. 2022;9(2):321-334. doi: 10.3233/JND-210704.
A Longitudinal Study of Quantitative Muscle Strength and Functional Motor
Ability in Ambulatory Boys with Duchenne Muscular Dystrophy.
Buckon CE(1), Sienko SE(1), Fowler EG(2), Bagley AM(3), Staudt LA(2),
Sison-Williamson M(2), Heberer KR(2), McDonald CM(4), Sussman MD(1).
Author information:
(1)Shriners Hospitals for Children, Portland, OR, USA.
(2)Department of Orthopaedics, University of California, Los Angeles, CA, USA.
(3)Shriners Hospitals for Children, Sacramento, CA, USA.
(4)Department of Physical Medicine, University of California Davis Medical
Center, Sacramento, CA, USA.
BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic
disorder, that is characterized by progressive muscle degeneration and loss of
ambulation between 7-13 years of age. Novel pharmacological agents targeting the
genetic defects and disease mechanisms are becoming available; however,
corticosteroid (CS) therapy remains the standard of care.
OBJECTIVE: The purpose of this longitudinal study was to elucidate the effect of
CS therapy on the rate of muscle strength and gross motor skill decline in boys
with DMD and assess the sensitivity of selected outcome measures.
METHODS: Eighty-four ambulatory boys with DMD (49-180 months), 70 on CS, 14
corticosteroid naïve (NCS), participated in this 8-year multi-site study.
Outcomes included; isokinetic dynamometry, the Standing (STD) and
Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure
(GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures
determined the rate of change with age and the influence of steroids.
RESULTS: Despite CS therapy the rate of decline in strength with age was
significant in all muscle groups assessed. CS therapy significantly slowed
decline in knee extensor strength, as the NCS group declined at 3x the rate of
the CS group. Concurrently, WRJ skills declined in the NCS group at twice the
rate of the CS group. 4-stair climb and 10 meter walk/run performance was
superior in the boys on CS therapy.
CONCLUSION: CS therapy slowed the rate of muscle strength decline and afforded
longer retention of select gross motor skills in boys on CS compared to boys who
were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may
prove informative in assessing the efficacy of new therapeutics in ambulatory
boys with DMD.
DOI: 10.3233/JND-210704
PMID: 34924398 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34348142 | 1. Cell Rep. 2021 Aug 3;36(5):109464. doi: 10.1016/j.celrep.2021.109464.
Spliceosomal component PRP-40 is a central regulator of microexon splicing.
Choudhary B(1), Marx O(1), Norris AD(2).
Author information:
(1)Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA.
(2)Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA.
Electronic address: adnorris@smu.edu.
Microexons (≤27 nt) play critical roles in nervous system development and
function but create unique challenges for the splicing machinery. The mechanisms
of microexon regulation are therefore of great interest. We performed a genetic
screen for alternative splicing regulators in the C. elegans nervous system and
identify PRP-40, a core component of the U1 snRNP. RNA-seq reveals that PRP-40
is required for inclusion of alternatively spliced, but not constitutively
spliced, exons. PRP-40 is particularly required for inclusion of neuronal
microexons, and our data indicate that PRP-40 is a central regulator of
microexon splicing. Microexons can be relieved from PRP-40 dependence by
artificially increasing exon size or reducing flanking intron size, indicating
that PRP-40 is specifically required for microexons surrounded by conventionally
sized introns. Knockdown of the orthologous PRPF40A in mouse neuroblastoma cells
causes widespread dysregulation of microexons but not conventionally sized
exons. PRP-40 regulation of neuronal microexons is therefore a widely conserved
phenomenon.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2021.109464
PMCID: PMC8378409
PMID: 34348142 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33215271 | 1. Nervenarzt. 2021 Apr;92(4):359-366. doi: 10.1007/s00115-020-01019-3. Epub 2020
Nov 19.
[Expert recommendation: treatment of nonambulatory patients with Duchenne
muscular dystrophy].
[Article in German; Abstract available in German from the publisher]
Bernert G(1), Hahn A(2), Köhler C(3), Meyer S(4), Schara U(5), Schlachter K(6),
Trollmann R(7), Walter MC(8).
Author information:
(1)Sozialmedizinisches Zentrum Süd, Kaiser-Franz-Josef-Spital mit Gottfried von
Preyer'schem Kinderspital, Wien, Österreich.
(2)Abteilung Kinderneurologie, Sozialpädiatrie und Epileptologie, Zentrum
Kinderheilkunde, Justus-Liebig-Universität, Gießen, Deutschland.
(3)Abteilung Neuropädiatrie, Sozialpädiatrie, Klinik für Kinder- und
Jugendmedizin, Ruhr-Universität Bochum, Bochum, Deutschland.
(4)Sektion Neuropädiatrie, Klinik für Allgemeine Pädiatrie und Neonatologie,
Universitätsklinikum des Saarlandes, Homburg, Deutschland.
(5)Abteilung für Neuropädiatrie, Zentrum für neuromuskuläre Erkrankungen des
Kindes- und Jugendalters, Universitätsklinikum Essen, Universität
Duisburg-Essen, Essen, Deutschland.
(6)Abteilung Kinder- und Jugendheilkunde, Landeskrankenhaus (LKH) Bregenz,
Bregenz, Österreich.
(7)Abteilung Neuropädiatrie und Sozialpädiatrisches Zentrum, Kinder- und
Jugendklinik am Universitätsklinikum, Friedrich-Alexander-Universität
Erlangen-Nürnberg, Erlangen, Deutschland.
(8)Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik, Klinikum der
Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336, München,
Deutschland. maggie.walter@lrz.uni-muenchen.de.
BACKGROUND: Duchenne muscular dystrophy (DMD) is the most frequent genetic
neuromuscular disease in childhood with loss of ambulation usually occurring
around the age of 9-11 years.
OBJECTIVE, MATERIAL AND METHODS: Based on current guidelines and clinical
trials, neuropediatric and neurological experts developed recommendations for
the treatment of nonambulatory DMD patients focusing on drug treatment of
adults. This advisory board was sponsored by PTC Therapeutics, the distributers
of the substance ataluren.
RESULTS AND CONCLUSION: Loss of ambulation is heterogeneously defined across
clinical trials. Among others, the need of a wheelchair, ambulation without
mobility aids or maximum walking distance can be suitable parameters for
assessment. Treatment of DMD patients at any stage of the disease is based on
supportive and symptomatic measures, which should be continued after loss of
ambulation. In addition, disease-modifying drugs are available for the treatment
of DMD and glucocorticoids are the usual standard of care treatment even beyond
the loss of ambulation. Ataluren, a potentially dystrophin restorative,
disease-modifying treatment, has been approved for patients with DMD due to
a nonsense mutation (nmDMD), which applies to approximately 13% of DMD patients
and is usually combined with steroids. Clinical data from the STRIDE registry
demonstrated a delayed disease progression even after loss of ambulation.
Currently, no reliable data are available for exon skipping approaches in adult
DMD patients. The antioxidant idebenone could be an option in nonambulant
adolescent patients not treated with glucocorticoids and without other
therapeutic options. A combination treatment of idebenone and glucocorticoids is
currently being investigated in a clinical trial. Add-on treatment with
idebenone in addition to ataluren may be considered for nonambulant nmDMD
patients. Some of the discussed treatment options are still in clinical trials
or there are not enough data for older DMD patients; therefore, these expert
recommendations correspond to evidence class IV.
Publisher: ZUSAMMENFASSUNG: HINTERGRUND: Die Muskeldystrophie Duchenne (DMD) ist
die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es
meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.
ZIEL DER ARBEIT UND MATERIAL UND METHODEN: Auf der Grundlage aktueller
Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten
im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main,
Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards
Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt
medikamentöse Therapien von Erwachsenen.
ERGEBNISSE UND DISKUSSION: Der Verlust der Gehfähigkeit wird in Studien sehr
unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das
selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der
Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und
symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der
Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den
Patienten medikamentöse Therapien mit dem Ziel der Modifikation des
Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der
medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann
meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer
Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als
potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur
Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte
Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping
liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das
Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne
therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden
können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit
Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird
derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon
zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen.
Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen
noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur
begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um
Expertenempfehlungen entsprechend der Evidenzklasse IV.
DOI: 10.1007/s00115-020-01019-3
PMCID: PMC8026471
PMID: 33215271 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18521075 | 1. Nat Rev Microbiol. 2008 Jul;6(7):507-19. doi: 10.1038/nrmicro1912. Epub 2008
Jun 3.
Advances in bacterial promoter recognition and its control by factors that do
not bind DNA.
Haugen SP(1), Ross W, Gourse RL.
Author information:
(1)Department of Bacteriology, University of Wisconsin- Madison, 1550 Linden
Drive, Madison, Wisconsin 53706, USA.
Early work identified two promoter regions, the -10 and -35 elements, that
interact sequence specifically with bacterial RNA polymerase (RNAP). However, we
now know that several additional promoter elements contact RNAP and influence
transcription initiation. Furthermore, our picture of promoter control has
evolved beyond one in which regulation results solely from activators and
repressors that bind to DNA sequences near the RNAP binding site: many important
transcription factors bind directly to RNAP without binding to DNA. These
factors can target promoters by affecting specific kinetic steps on the pathway
to open complex formation, thereby regulating RNA output from specific
promoters.
DOI: 10.1038/nrmicro1912
PMCID: PMC3700611
PMID: 18521075 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10382913 | 1. Neuromuscul Disord. 1999 May;9(3):176-81. doi: 10.1016/s0960-8966(98)00113-8.
Lower limb surgery in Duchenne muscular dystrophy.
Forst J(1), Forst R.
Author information:
(1)Orthopaedic Department, University Hospital RWTH Aachen, Germany.
j.forst@t-online.de
Two hundred and thirteen of 428 patients with Duchenne muscular dystrophy (DMD)
of a prospective and open study were operated on bilaterally with hip and knee
release, aponeurectomy of the iliotibial band and Achilles tendon lengthening.
In 87 patients the operation was carried out during early restrictions of the
lower limb joint mobility at an average age of 6.56 years (4.02-8.26, SD 1.42).
The follow-up was on average 5.4 years (0.25-9.01, SD 2.7). This group was
compared to a control group (natural history) consisting of 100 non-operated DMD
patients. A significant (P < 0.001) release of the contractures could be
obtained. Loss of walking ability occurred in the control group at an average of
9.29 years (5.85-13.63, SD 1.98) and in the operated group at an average of
10.55 years (8.17-14.39, SD 1.76). This shows that early lower limb surgery
leads to a prolongation of independent ambulation of 1.25 years on average. In
contrast to the patients of the control group all treated patients between ages
6 and 8 years could walk independently. The positive influence of early lower
limb surgery could also be shown by the development of Hammersmith motor ability
score, CIDD (Council of Investigation of Duchenne Dystrophy) grading and Vignos
scale. Nevertheless, in consideration of the well-known course of DMD not only
the prolongation of ambulation but also the achieved prolongation of assisted
standing ability with no or mild contractures are aims of lower limb surgery.
Since no improvement of muscle strength could be observed after lower limb
surgery, further studies have to investigate if additionally administered
steroids can prolong ambulation after early lower limb surgery.
DOI: 10.1016/s0960-8966(98)00113-8
PMID: 10382913 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26022172 | 1. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008.
Epub 2015 Apr 20.
Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.
Wein N(1), Alfano L(2), Flanigan KM(3).
Author information:
(1)The Center for Gene Therapy, The Research Institute, Nationwide Children's
Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
(2)The Center for Gene Therapy, The Research Institute, Nationwide Children's
Hospital, 700 Children's Drive, Columbus, OH 43205, USA; Department of Physical
Therapy, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH
43205, USA.
(3)The Center for Gene Therapy, The Research Institute, Nationwide Children's
Hospital, 700 Children's Drive, Columbus, OH 43205, USA; Department of
Pediatrics, Ohio State University, 700 Children's Drive, Columbus, OH 43205,
USA; Department of Neurology, Ohio State University, 700 Children's Drive,
Columbus, OH 43205, USA. Electronic address:
kevin.flanigan@nationwidechildrens.org.
Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to
absent or altered expression of the dystrophin protein. The more severe Duchenne
muscular dystrophy typically presents around ages 2 to 5 with gait disturbance,
and historically has led to the loss of ambulation by age 12. It is important
for the practicing pediatrician, however, to be aware of other presenting signs,
such as delayed motor or cognitive milestones, or elevated serum transaminases.
Becker muscular dystrophy is milder, often presenting after age 5, with
ambulation frequently preserved past 20 years and sometimes into late decades.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pcl.2015.03.008
PMID: 26022172 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21784636 | 1. Neuromuscul Disord. 2011 Nov;21(11):800-2. doi: 10.1016/j.nmd.2011.06.006.
Epub 2011 Jul 23.
Combination of steroids and ischial weight-bearing knee ankle foot orthoses in
Duchenne's muscular dystrophy prolongs ambulation past 20 years of age--a case
report.
Pardo AC(1), Do T, Ryder T, Meyer A, Miles L, Wong BL.
Author information:
(1)Department of Pediatric Neurology, Cincinnati Children's Hospital Medical
Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. andrea.pardo@cchmc.org
Patients with Duchenne muscular dystrophy (DMD) lose ambulation by age 12.
Long-term steroids have lengthened ambulation by 2-5 years. Ischial
weight-bearing knee ankle foot orthoses prolong ambulation for 2-3 years. We
report the outcome of the ambulatory status of a patient with DMD treated with
daily steroid therapy and orthoses. This male patient was diagnosed with DMD at
age of 2. He has been treated with daily steroids since age 7 years. He lost the
ability to arise from the floor and walk up steps at age 14 and lost ambulation
by age 16. He was fitted with orthoses at age 16 following surgical correction
of his lower extremity contractures and regained independent ambulation. At age
20, he was able to stand independently in his orthoses and take steps with
moderate support. We conclude that a combination of daily steroids and orthoses
prolongs ambulation beyond that of the natural history DMD.
Copyright © 2011 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2011.06.006
PMID: 21784636 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23440719 | 1. Ann Neurol. 2013 Apr;73(4):481-8. doi: 10.1002/ana.23819. Epub 2013 Feb 20.
LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy.
Flanigan KM(1), Ceco E, Lamar KM, Kaminoh Y, Dunn DM, Mendell JR, King WM,
Pestronk A, Florence JM, Mathews KD, Finkel RS, Swoboda KJ, Gappmaier E, Howard
MT, Day JW, McDonald C, McNally EM, Weiss RB; United Dystrophinopathy Project.
Collaborators: Soltanzadeh P, Sampson JB, Bromberg MB, Butterfield R, Kerr L,
Hart K, Moural C, Hak K, Heidarian L, Lowes L, Viollet L, Rankin C, Wall C,
Gailey S, Taylor LE, Connolly AM, Lopate G, Golumbek P, Schierbecker J, Malkus
B, Renna R, Siener C, Stephan C, Laubenthal K, Baldwin K, Bonnemann CG, Medne L,
Glanzman AM, Flickinger J, Wong B, Morehart P, Meyer A, Naughton CE, Margolis M,
Abresch R, Cregan M, Han JJ, Henricson E, Johnson L.
Author information:
(1)Center for Gene Therapy, Nationwide Children' Hospital, Columbus, OH;
Department of Pediatrics, Ohio State University, Columbus, OH; Department of
Neurology, Ohio State University, Columbus, OH.
OBJECTIVE: Duchenne muscular dystrophy (DMD) displays a clinical range that is
not fully explained by the primary DMD mutations. Ltbp4, encoding latent
transforming growth factor-β binding protein 4, was previously discovered in a
genome-wide scan as a modifier of murine muscular dystrophy. We sought to
determine whether LTBP4 genotype influenced DMD severity in a large patient
cohort.
METHODS: We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from
human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs,
V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes.
RESULTS: Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory
significantly longer than those heterozygous or homozygous for the VTTT
haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost
ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT
heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth
factor (TGF) β displayed reduced phospho-SMAD signaling compared to VTTT
fibroblasts, consistent with LTBP4' role as a regulator of TGFβ.
INTERPRETATION: LTBP4 haplotype influences age at loss of ambulation, and should
be considered in the management of DMD patients.
Copyright © 2013 American Neurological Association.
DOI: 10.1002/ana.23819
PMCID: PMC4106425
PMID: 23440719 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27382620 | 1. Int Sch Res Notices. 2014 Oct 29;2014:965235. doi: 10.1155/2014/965235.
eCollection 2014.
Corticosteroid Treatment Impact on Spinal Deformity in Duchenne Muscular
Dystrophy.
Sanzarello I(1), Merlini L(2), Traina F(3), Rosa MA(1), Faldini C(3).
Author information:
(1)Section of Orthopedics and Traumatology, University of Messina, 98125
Messina, Italy.
(2)Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute,
IRCCS, 40136 Bologna, Italy.
(3)General Orthopedic Surgery, Rizzoli-Sicilia Department, Rizzoli Orthopedic
Institute, Bagheria, 90011 Palermo, Italy.
Duchenne muscular dystrophy is a progressive disease with loss of ambulation at
around 9-10 years of age, followed, if untreated, by development of scoliosis,
respiratory insufficiency, and death in the second decade of life. This review
highlights the natural history of the disease, in particular, with regard to the
development of the spinal deformity and how this complication has been modified
by surgical interventions and overall by corticosteroid treatment. The
beneficial effect of corticosteroids may have also an impact on the clinical
trial design of the new emerging causative therapies.
DOI: 10.1155/2014/965235
PMCID: PMC4897302
PMID: 27382620 |
http://www.ncbi.nlm.nih.gov/pubmed/12026233 | 1. J Child Neurol. 2002 Mar;17(3):183-90. doi: 10.1177/088307380201700306.
Corticosteroids in Duchenne muscular dystrophy: a reappraisal.
Wong BL(1), Christopher C.
Author information:
(1)Division of Child Neurology, Children's Hospital Medical Center, Cincinnati,
OH 45229-3039, USA. wono41@chmcc.org
Duchenne muscular dystrophy is the most common and most severe form of childhood
muscular dystrophies, resulting in early loss of ambulation between the ages of
7 and 13 years and death in the teens and twenties. Despite the phenomenal
advances made in the understanding of the molecular genetics of the disease, no
definitive cure has been found. Of all of the therapeutic drugs studied in
Duchenne muscular dystrophy, only prednisone seems to have the potential for
providing interim functional improvement for boys with Duchenne muscular
dystrophy while they wait for a cure with gene or cell therapy. There is still
no consensus regarding recommending corticosteroids as standard therapy for
boys. This is an evidence-based review of all of the studies of corticosteroids
(prednisone, deflazacort, and oxandrolone) in Duchenne muscular dystrophy. From
this review, it is clear that until a definitive treatment for Duchenne muscular
dystrophy is available, the use of deflazacort and prednisone with judicious
dietary control and close clinical monitoring for side effects seems the best
intervention for interim preservation of function in such a common devastating
disorder of young growing boys.
DOI: 10.1177/088307380201700306
PMID: 12026233 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17388226 | 1. Spec Care Dentist. 2007 Jan-Feb;27(1):23-5. doi:
10.1111/j.1754-4505.2007.tb00323.x.
Duchenne muscular dystrophy--a dental healthcare program.
Mielnik-Błaszczak M(1), Małgorzata B.
Author information:
(1)Paedodontics Department, Medical University of Lublin, Poland.
maria.mielnik@am.lublin.pl
Duchenne muscular dystrophy (DMD) is a genetically determined disease. The chief
characteristic of this clinical syndrome is a progressive degeneration of
particular groups of muscles. Initially there is physical impairment,
contractures, and muscular atrophy. Subsequently, the disease immobilizes the
patient (ages 9 to 14 years) and severe respiratory failure occurs due to chest
and vertebral column deformity. We present principles for the dental care of
patients with DMD. It is important to introduce dental and prophylactic
treatment at a very early age for children with DMD.
DOI: 10.1111/j.1754-4505.2007.tb00323.x
PMID: 17388226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16322188 | 1. Pediatrics. 2005 Dec;116(6):1569-73. doi: 10.1542/peds.2005-2448.
Cardiovascular health supervision for individuals affected by Duchenne or Becker
muscular dystrophy.
American Academy of Pediatrics Section on Cardiology and Cardiac Surgery.
Comment in
Pediatrics. 2006 May;117(5):1864; author reply 1865. doi:
10.1542/peds.2005-3189.
Duchenne muscular dystrophy is the most common and severe form of the childhood
muscular dystrophies. The disease is typically diagnosed between 3 and 7 years
of age and follows a predictable clinical course marked by progressive skeletal
muscle weakness with loss of ambulation by 12 years of age. Death occurs in
early adulthood secondary to respiratory or cardiac failure. Becker muscular
dystrophy is less common and has a milder clinical course but also results in
respiratory and cardiac failure. The natural history of the cardiomyopathy in
these diseases has not been well established. As a result, patients
traditionally present for cardiac evaluation only after clinical symptoms become
evident. The purpose of this policy statement is to provide recommendations for
optimal cardiovascular evaluation to health care specialists caring for
individuals in whom the diagnosis of Duchenne or Becker muscular dystrophy has
been confirmed.
DOI: 10.1542/peds.2005-2448
PMID: 16322188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12466073 | 1. An Esp Pediatr. 2002 Dec;57(6):518-23.
[Effects of corticosteroids in the management of Duchenne muscular dystrophy:
our experience].
[Article in Spanish]
Rafia S(1), Pascual-Pascual SI, Martínez-Granero MA, Pascual-Castroviejo I.
Author information:
(1)Servicio de Neurología Pediátrica. Hospital Universitario La Paz. Madrid.
España.
Objective To evaluate the clinical course in patients with Duchenne muscular
dystrophy admitted to our department who received corticosteroid treatment and
to compare their course with that in patients who did not receive corticosteroid
treatment.Patients and methodsWe performed a retrospective study of 20 pediatric
patients with a diagnosis of Duchenne muscular dystrophy who were offered
corticosteroid treatment: 10 patients received deflazacort and 10 refused the
treatment. The MRC muscular strength scale and Vignos' functional scale were
used to evaluate clinical course, which was compared in both
groups.ResultsUntreated patients showed progressive worsening.
Corticosteroid-treated patients showed disease stabilization both in muscular
strength and functional performance. In addition, muscular balance improved in
70 % of these patients, but only 2 % showed functional improvement. The positive
effect of steroid treatment had a mean duration of 12 months. Loss of
independent gait occurred at similar ages in both groups (10.3 vs. 10.5 years).
The results of Achilles' tendon surgery were poor.ConclusionsCorticosteroids
produced clinical stabilization and improved muscular strength. Functional
improvement was not significant, including loss of gait, probably because this
loss also depends on an increase in joint contracture. Good coordination among
multiprofessional teams is essential to achieve optimal results.
PMID: 12466073 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8496368 | 1. J Pediatr Orthop. 1993 May-Jun;13(3):336-40. doi:
10.1097/01241398-199305000-00012.
Prolongation of ambulation in children with Duchenne muscular dystrophy by
subcutaneous lower limb tenotomy.
Smith SE(1), Green NE, Cole RJ, Robison JD, Fenichel GM.
Author information:
(1)Department of Orthopaedic Surgery, Vanderbilt University Medical Center,
Nashville, Tennessee.
To assess the effect of subcutaneous (s.c.) lower limb tenotomies on the
ambulatory ability of patients with Duchenne muscular dystrophy (DMD), 54
patients were followed. Twenty-nine patients underwent hip, knee, and ankle
tenotomies at a mean age of 10 2/12 years and were followed postoperatively for
an average of 3 9/12 years. These children continued ambulation in long-leg
braces to a mean age of 12 8/12 years and stood to an average of 13 5/12 years.
Contracture correction was 49% at the hip, 58% at the knee, and 100% at the
ankle. A separate group of 25 children to whom operation was offered but
declined, was followed: these children ceased ambulating at a mean age of 10
years and ceased standing at a mean age of 10 2/12 years. Thus, we propose that
s.c. tenotomy is effective in allowing braced ambulation well beyond what the
natural history would allow.
DOI: 10.1097/01241398-199305000-00012
PMID: 8496368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35590041 | 1. CNS Drugs. 2022 Jun;36(6):569-589. doi: 10.1007/s40263-022-00920-6. Epub 2022
May 19.
Antidrug Antibodies Against Biological Treatments for Multiple Sclerosis.
Sorensen PS(1).
Author information:
(1)Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen
University Hospital Rigshospitalet, Copenhagen, Denmark. pss@rh.dk.
Erratum in
CNS Drugs. 2022 Aug;36(8):917. doi: 10.1007/s40263-022-00942-0.
The development of antidrug antibodies (ADAs) is a major problem in several
recombinant protein therapies used in the treatment of multiple sclerosis (MS).
The etiology of ADAs is multifaceted. The predisposition for a breakdown of
immune tolerance is probably genetically determined, and many factors may
contribute to the immunogenicity, including structural properties, formation of
aggregates, and presence of contaminants and impurities from the industrial
manufacturing process. ADAs may have a neutralizing capacity and can reduce or
abrogate the bioactivity and therapeutic efficacy of the drug and cause safety
issues. Interferon (IFN)-β was the first drug approved for the treatment of MS,
and-although it is generally recognized that neutralizing antibodies (NAbs)
appear and potentially have a negative effect on therapeutic efficacy-the use of
routine measurements of NAbs and the interpretation of the presence of NAbs has
been debated at length. NAbs appear after 9-18 months of therapy in up to 40% of
patients treated with IFNβ, and the frequency and titers of NAbs depend on the
IFNβ preparation. Although all pivotal clinical trials of approved IFNβ products
in MS exhibited a detrimental effect of NAbs after prolonged therapy, some
subsequent studies did not observe clinical effects from NAbs, which led to the
claim that NAbs did not matter. However, it is now largely agreed that
persistently high titers of NAbs indicate an abrogation of the biological
response and, hence, an absence of therapeutic efficacy, and this observation
should lead to a change of therapy. Low and medium titers are ambiguous, and
treatment decisions should be guided by determination of in vivo messenger RNA
myxovirus resistance protein A induction after IFNβ administration and clinical
disease activity. During treatment with glatiramer acetate, ADAs occur
frequently but do not appear to adversely affect treatment efficacy or result in
adverse events. ADAs occur in approximately 5% of patients treated with
natalizumab within 6 months of therapy, and persistent NAbs are associated with
a lack of efficacy and acute infusion-related reactions and should instigate a
change of therapy. When using the anti-CD20 monoclonal antibodies ocrelizumab
and ofatumumab in the treatment of MS, it is not necessary to test for NAbs as
these occur very infrequently. Alemtuzumab is immunogenic, but routine
measurements of ADAs are not recommended as the antibodies in the pivotal 2-year
trials at the population level did not influence lymphocyte depletion or
repopulation, efficacy, or safety. However, in some individuals, NAbs led to
poor lymphocyte depletion.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40263-022-00920-6
PMID: 35590041 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35583174 | 1. Cochrane Database Syst Rev. 2022 May 18;5(5):CD013247. doi:
10.1002/14651858.CD013247.pub2.
Ocrelizumab for multiple sclerosis.
Lin M(1), Zhang J(1), Zhang Y(1), Luo J(1), Shi S(1).
Author information:
(1)Department of Neurology, Second Affiliated Hospital of Guangxi Medical
University, Nanning, China.
Update of
doi: 10.1002/14651858.CD013247.
BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed
for the treatment of multiple sclerosis (MS). It was approved by the Food and
Drug Administration (FDA) in March 2017 for using in adults with
relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple
sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT)
approved for PPMS. In November 2017, the European Medicines Agency (EMA) also
approved ocrelizumab as the first drug for people with early PPMS. Therefore, it
is important to evaluate the benefits, harms, and tolerability of ocrelizumab in
people with MS.
OBJECTIVES: To assess the benefits, harms, and tolerability of ocrelizumab in
people with RRMS and PPMS.
SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, and two trials registers
on 8 October 2021. We screened reference lists, contacted experts, and contacted
the main authors of studies.
SELECTION CRITERIA: All randomised controlled trials (RCTs) involving adults
diagnosed with RRMS or PPMS according to the McDonald criteria, comparing
ocrelizumab alone or associated with other medications, at the approved dose of
600 mg every 24 weeks for any duration, versus placebo or any other active drug
therapy.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures
expected by Cochrane.
MAIN RESULTS: Four RCTs met our selection criteria. The overall population
included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181
controls. Among the controls, 298 participants received placebo and 883 received
interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks
in two studies, and at least 120 weeks in one study. One study was at high risk
of allocation concealment and blinding of participants and personnel; all four
studies were at high risk of bias for incomplete outcome data. For RRMS,
compared with interferon beta-1a, ocrelizumab was associated with: 1. lower
relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2
studies, 1656 participants; moderate-certainty evidence); 2. a lower number of
participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to
0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no
difference in the number of participants with any adverse event (RR 1.00, 95% CI
0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4.
little to no difference in the number of participants with any serious adverse
event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty
evidence); 5. a lower number of participants experiencing treatment
discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2
studies, 1651 participants; low-certainty evidence); 6. a lower number of
participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging
(MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty
evidence); 7. a lower number of participants with new or enlarging
T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656
participants; low-certainty evidence) at 96 weeks. For PPMS, compared with
placebo, ocrelizumab was associated with: 1. a lower number of participants with
disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants;
low-certainty evidence); 2. a higher number of participants with any adverse
events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants;
moderate-certainty evidence); 3. little to no difference in the number of
participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1
study, 725 participants; low-certainty evidence); 4. little to no difference in
the number of participants experiencing treatment discontinuation caused by
adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants;
low-certainty evidence) for at least 120 weeks. There were no data for number of
participants with gadolinium-enhancing T1 lesions on MRI and number of
participants with new or enlarging T2-hyperintense lesions on MRI.
AUTHORS' CONCLUSIONS: For people with RRMS, ocrelizumab probably results in a
large reduction in relapse rate and little to no difference in adverse events
when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence).
Ocrelizumab may result in a large reduction in disability progression, treatment
discontinuation caused by adverse events, number of participants with
gadolinium-enhancing T1 lesions on MRI, and number of participants with new or
enlarging T2-hyperintense lesions on MRI, and may result in little to no
difference in serious adverse events (low-certainty evidence). For people with
PPMS, ocrelizumab probably results in a higher rate of adverse events when
compared with placebo for at least 120 weeks (moderate-certainty evidence).
Ocrelizumab may result in a reduction in disability progression and little to no
difference in serious adverse events and treatment discontinuation caused by
adverse events (low-certainty evidence). Ocrelizumab was well tolerated
clinically; the most common adverse events were infusion-related reactions and
nasopharyngitis, and urinary tract and upper respiratory tract infections.
Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons,
Ltd.
DOI: 10.1002/14651858.CD013247.pub2
PMCID: PMC9115862
PMID: 35583174 [Indexed for MEDLINE]
Conflict of interest statement: ML: none. JZ: none. YZ: none. CY: none. JL:
none. SS: none. |
http://www.ncbi.nlm.nih.gov/pubmed/35192158 | 1. Drugs. 2022 Feb;82(3):323-334. doi: 10.1007/s40265-022-01672-9. Epub 2022 Feb
22.
Ocrelizumab: A Review in Multiple Sclerosis.
Lamb YN(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. demail@springer.com.
Ocrelizumab (Ocrevus®) is an intravenously administered, humanized anti-CD20
monoclonal antibody approved for the treatment of adults with relapsing forms of
multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The
efficacy of ocrelizumab in reducing relapse rates and disease activity in
patients with RMS was demonstrated in pivotal trials (versus interferon β-1a)
and supporting single-arm studies in specific subpopulations. In patients with
PPMS, ocrelizumab reduced measures of clinical and MRI progression relative to
placebo. Clinical benefits were maintained over ≥ 7.5 study years of treatment.
Ocrelizumab was generally well tolerated and no new safety signals have emerged
with long-term use. Extensive (albeit short-term) real-world data pertaining to
ocrelizumab is consistent with that from clinical trials. Ocrelizumab provides
the convenience of short, half-yearly infusions. Ocrelizumab continues to
represent a generally well-tolerated, high-efficacy disease-modifying therapy
(DMT) for RMS and is a valuable treatment for delaying disease progression in
patients with PPMS (for whom there are currently no other approved DMTs).
Plain Language Summary: Multiple sclerosis (MS) is a chronic, immune-mediated,
neurodegenerative disease of the CNS. In most patients, it starts as
relapsing-remitting MS (RRMS), which involves exacerbations of neurological
symptoms (i.e. relapses) followed by periods of remission. In the less common
primary progressive MS (PPMS), disability accrues steadily from disease onset.
It is now understood that B cells play key roles in MS pathophysiology.
Ocrelizumab (Ocrevus®), a monoclonal antibody that selectively depletes CD20+ B
cells, is approved for treating adults with RMS and PPMS in various countries
worldwide. Ocrelizumab reduces relapse rates and indicators of disease activity
in patients with RMS, and delays the worsening of disability in patients with
RMS and PPMS. Of convenience to patients, ocrelizumab is intravenously
administered every six months and can be infused rapidly (over ≈ 2 hours)
without its safety being substantially altered. Ocrelizumab is a generally
well-tolerated and highly effective treatment option for RMS and constitutes the
first approved pharmacotherapy for PPMS.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01672-9
PMCID: PMC8862399
PMID: 35192158 [Indexed for MEDLINE]
Conflict of interest statement: Yvette Lamb is a salaried employee of Adis
International Ltd/Springer Nature, and declares no relevant conflicts of
interest. All authors contributed to the review and are responsible for the
article content. |
http://www.ncbi.nlm.nih.gov/pubmed/36130805 | 1. Can J Surg. 2022 Sep 21;65(5):E630-E634. doi: 10.1503/cjs.019821. Print 2022
Sep-Oct.
Lymph node mapping in gastric cancer: a pilot study in Western patients.
Watanabe A(1), Hamilton TD(2).
Author information:
(1)From the Department of Surgery, University of British Columbia, Vancouver,
B.C. (Watanabe, Hamilton) a.watanabe@alumni.ubc.ca.
(2)From the Department of Surgery, University of British Columbia, Vancouver,
B.C. (Watanabe, Hamilton).
In East Asia, the role of lymph node (LN) mapping in assisting surgical
lymphadenectomy, which is integral to the management of gastric cancer, has been
explored. We sought to evaluate its safety and utility in Western patients.
Thirteen patients with nonmetastatic gastric adenocarcinoma received endoscopic,
peritumoural, submucosal indocyanine green fluorescence (ICG) injections before
surgery, and ICG was assessed intraoperatively using a laparoscopic detection
system. All patients underwent a laparoscopic subtotal gastrectomy, and 10 of
them received D2 lymphadenectomies. ICG-mapped LNs fell outside the D1
distribution in all cases, outside the D1+ distribution in 54%, and within the
D2 distribution in all cases. There were no ICG-related allergies, procedural
complications, or perioperative deaths. We conclude that ICG LN mapping is safe
and feasible in assisting LN dissections and localizing the primary tumour in
Western patients. D2 dissections should be performed in patients with advanced
gastric cancer, as LNs drained outside the D1/D1+ distributions in most cases.
© 2022 CMA Impact Inc. or its licensors.
DOI: 10.1503/cjs.019821
PMCID: PMC9503569
PMID: 36130805 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35046184 | 1. J Minim Access Surg. 2022 Jul-Sep;18(3):478-483. doi:
10.4103/jmas.jmas_233_21.
Robotic fluorescence-guided anatomical segment IVb and V liver resection with
radical lymphadenectomy for gall bladder cancer.
Kalayarasan R(1), Narayanan S(1), James M(1).
Author information:
(1)Department of Surgical Gastroenterology, Jawaharlal Institute of Post
graduate Medical Education and Research, Puducherry, India.
Radical surgery remains the primary treatment option for gall bladder cancer
(GBC). Margin-negative liver resection is a critical component of radical
cholecystectomy. Anatomical segment IVb and V resection is preferred in primary
GBC with liver infiltration and incidental GBC patients with puckering of gall
bladder (GB) bed. Despite the initial scepticism, minimally invasive radical
cholecystectomy is recommended as a treatment option in selected GBC patients.
However, anatomical Segment IVb and V resection using the minimally invasive
approach is scarcely reported. The standardised technique of robotic
(daVinci®XiTM) anatomical Segment IVb and V liver resection guided by
indocyanine green fluorescence is described here. The systematic
fluorescence-guided anatomical resection described in this report could
facilitate minimally invasive Segment IVb and V resection with radical
lymphadenectomy in selected patients with GBC.
DOI: 10.4103/jmas.jmas_233_21
PMCID: PMC9306125
PMID: 35046184
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/35046172 | 1. J Minim Access Surg. 2022 Apr-Jun;18(2):320-323. doi:
10.4103/jmas.jmas_183_21.
Fluorescent ureterography with indocyanine green in laparoscopic colorectal
surgery: A safe method to prevent intraoperative ureteric injury.
V R Satish VN(1), Acharya A(2), Ramachandran S(1), Narasimhan M(1), Ardhanari
R(1).
Author information:
(1)Department of Surgical Gastroenterology, Meenakshi Mission Hospital and
Research Centre, Madurai, Tamil Nadu, India.
(2)Department of General Surgery, Kasturba Medical College, Mangalore, Manipal
Academy of Higher Education, Manipal, India.
Intraoperative injuries to the ureter can occur in complicated colorectal and
gynaecologic procedures in minimal access surgery. The majority of these go
unrecognised at the time of the operation, which can be disastrous to the
patient. The routine use of ureteric stents is controversial, with some studies
showing that stents only enable detection of ureteric injury but do not prevent
it. Fluorescent image-guided surgery with indocyanine green (ICG) to visualise
the ureter is a relatively new technique. We report our method of visualisation
of the ureter in two patients undergoing laparoscopic anterior resection and
Hartmann procedure, respectively. After induction of anaesthesia, retrograde
catheterisation of both ureters was performed by the urologist. 2.5 mg ICG was
injected into each catheter at the start of the procedure. Both ureters were
visualised very well throughout the procedure with no post-operative
complications. This technique using ICG adds visual cues to make up for the loss
of tactile feedback, making it a safe strategy to prevent intraoperative
ureteric injury.
DOI: 10.4103/jmas.jmas_183_21
PMCID: PMC8973486
PMID: 35046172
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/36466057 | 1. Case Rep Ophthalmol. 2022 Nov 17;13(3):892-896. doi: 10.1159/000526583.
eCollection 2022 Sep-Dec.
An Elderly Man with Atypical Multiple Evanescent White Dot Syndrome.
Wang L(1), Lankry P(2), Rabinovitch D(2), Gallo R(1), Laiginhas R(1), Iyer P(1),
Shulman S(2), Trivizki O(1)(2).
Author information:
(1)Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami
Miller School of Medicine, Miami, Florida, USA.
(2)Department of Ophthalmology, Tel Aviv Medical Center, University of Tel Aviv,
Tel Aviv, Israel.
A rare occurrence of an atypical case of multiple evanescent white dot syndrome
(MEWDS) in a 75-year-old man without viral prodrome or white dots on fundus that
presented with acute, severe left eye visual loss, which returned to baseline
without treatment in several weeks. Multimodal imaging, including fluorescein
angiography (FA), fundus autofluorescence (FAF), indocyanine green angiography
(ICG), and optical coherence tomography (OCT) demonstrated classical
presentation of MEWDS with wreath-like lesions and inflammatory foci in the
retinal pigment epithelium that correlated among modalities. Possible underlying
systemic disorders were ruled out through extended work up. To the best of our
knowledge, this is the first report to show atypical MEWDS in an elderly man
with classic changes on FA, FAF, ICG, and OCT.
Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.
DOI: 10.1159/000526583
PMCID: PMC9710463
PMID: 36466057
Conflict of interest statement: The authors have no disclosures. |
http://www.ncbi.nlm.nih.gov/pubmed/34855637 | 1. J Craniofac Surg. 2022 Jul-Aug 01;33(5):1322-1326. doi:
10.1097/SCS.0000000000008397. Epub 2021 Dec 1.
Use of Indocyanine Green Angiography to Identify the Superficial Temporal Artery
and Vein in Forehead Flaps for Facial Reconstruction.
Zang M(1), Zhu S, Chen B, Li S, Han T, Liu Y.
Author information:
(1)Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital,
Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing,
China.
The superficial temporal artery (STA) frontal branch flap is susceptible to
venous congestion because of its unpredictable and variable outflow. The authors
applied indocyanine green angiogra-phy in identifying the superficial temporal
vessels to help surgeons with proper flap designs to avoid severe complications.
A retrospective review from 2015 to 2020 was conducted. All the patients who
underwent indocyanine green angiography before forehead flap transfer for facial
defect reconstruction were reviewed. The STA and vein were observed using
indocyanine green angiography preoperatively. The relationship between the
artery and vein was investigated. The venous anatomy was analyzed to guide the
pedicle design. The survival of the flap and complications were assessed. A
total of 12 patients were identified and included in this study. Indocyanine
green angiography allows clear visualization of the detailed anatomy of the STA
and vein. The frontal branch of the vein had great variations and generally
diverged from the arterial branch. The tiny venae comitantes provided sufficient
drainage for 2 small forehead flaps. The frontal branch of the vein entered the
forehead and was used as the outflow channel in 4 patients. The parietal branch
of the vein, which consistently gave off secondary tributaries to the superior
forehead, was included in the pedicle in 6 patients. All flaps survived without
complications. indocyanine green angiography provided accurate localization of
the superficial temporal vessels. This technique may be helpful in the precise
planning forehead flap surgeries and in avoiding the risk of venous congestion.
Copyright © 2021 by Mutaz B. Habal, MD.
DOI: 10.1097/SCS.0000000000008397
PMID: 34855637 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest and Source of Funding: Dr.
Mengqing Zang is currently receiving a grant (No. 3332019061) from Fundamental
Research Funds for the Central Universities. For the remaining authors, none
were declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35046169 | 1. J Minim Access Surg. 2022 Apr-Jun;18(2):314-316. doi:
10.4103/jmas.jmas_142_21.
Indocyanine green imaging to identify intralobar pulmonary sequestration for
uniportal thoracoscopic resection.
Lian KH(1), Lin MW(1).
Author information:
(1)Department of Surgery, National Taiwan University Hospital and National
Taiwan University College of Medicine, Taipei, Taiwan.
Surgical excision of pulmonary sequestration is a definite treatment, but
dissection of the arterial supply from systemic circulation and determination of
the boundary are always challenging. We reported a case utilising pre-operative
three-dimensional reconstruction and indocyanine green injection to make the
procedure minimally invasive, precise and safe.
DOI: 10.4103/jmas.jmas_142_21
PMCID: PMC8973490
PMID: 35046169
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/15069433 | 1. Eye (Lond). 2004 Apr;18(4):376-8. doi: 10.1038/sj.eye.6700666.
Macular hole surgery with and without indocyanine green assistance.
Slaughter K(1), Lee IL.
Author information:
(1)Ophthalmology Department, Royal Brisbane Hospital, Herston, Queensland,
Australia. kcutbush@bigpond.net.au
Comment in
Eye (Lond). 2005 Sep;19(9):1020-1. doi: 10.1038/sj.eye.6701714.
PURPOSE: To compare the results of macular hole surgery with the use of
indocyanine green (ICG) to assist internal limiting membrane (ILM) peeling and
macular hole surgery without indocyanine green use.
METHODS: A retrospective, comparative, consecutive study of 68 patients with
macular holes. In total, 34 patients underwent vitrectomy and ILM peeling, and
34 patients underwent vitrectomy and ILM peeling with the assistance of
indocyanine green. The main outcome measures were postoperative visual acuity
and macular hole status.
RESULTS: Indocyanine green increased the ability to visualise and peel the ILM.
The average preoperative visual acuity in the group where ICG was used was 6/36
and the group where ICG was not used was 6/60. The average follow-up was 25
weeks for the ICG group and 53 weeks for the group with no ICG. Both groups were
also compared at 25 weeks follow-up. Hole closure rate for the group with ICG
was 97% compared to 91% without ICG. The mean postoperative visual acuity was
6/24 for the group with ICG and 6/12 for the group without ICG, a difference of
two lines on the Snellen chart when compared with the preoperative acuity
(P-value 0.299, Student's t-test). Both groups had a mean improvement of Snellen
acuity of two lines (ICG group: P-value 0.0002, Student's t-test; no ICG group:
P-value 0.00004, Student's t-test). In all, 83% of patients in the ICG group
maintained or improved their visual acuity compared to 91% in the group without
ICG.
DISCUSSION: There is no doubt that indocyanine green stains and assists in
visualisation and therefore increases the ease of peeling the ILM in macular
hole surgery. Initially, there was concern regarding a poorer outcome for
patients with the use of ICG, which has also been previously discussed in the
literature. When the two groups were compared at a similar follow-up time of
approximately 25 weeks, it was shown that there was no statistically significant
difference between the outcomes in the two groups. This study had an improved
hole closure rate for the group where ICG was used, although it was not
statistically significant.
DOI: 10.1038/sj.eye.6700666
PMID: 15069433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31882459 | 1. In Vivo. 2020 Jan-Feb;34(1):23-32. doi: 10.21873/invivo.11741.
Intraoperative Indocyanine Green (ICG) Angiography for the Identification of the
Parathyroid Glands: Current Evidence and Future Perspectives.
Spartalis E(#)(1)(2), Ntokos G(#)(2)(3), Georgiou K(4), Zografos G(3),
Tsourouflis G(2)(5), Dimitroulis D(2)(5), Nikiteas NI(4)(2).
Author information:
(1)Laboratory of Experimental Surgery and Surgical Research "N.S. Christeas",
National and Kapodistrian University of Athens Medical School, Athens, Greece
eleftherios.spartalis@gmail.com.
(2)Hellenic Minimally Invasive and Robotic Surgery (MIRS) Study Group, Athens,
Greece.
(3)3rd Surgical Department, "George Gennimatas" General Hospital, Athens,
Greece.
(4)Laboratory of Experimental Surgery and Surgical Research "N.S. Christeas",
National and Kapodistrian University of Athens Medical School, Athens, Greece.
(5)2nd Department of Propaedeutic Surgery, National and Kapodistrian University
of Athens Medical School, Athens, Greece.
(#)Contributed equally
BACKGROUND/AIM: Recently, indocyanine green (ICG) fluorescence imaging has been
used for the identification of the parathyroid glands (PG) during thyroid and
parathyroid surgery. However, an overall consensus on the optimal technique, the
dosage, the timing of the ICG administration and finally its interpretation and
clinical usefulness is still lacking evidence. The aim of this review is to
investigate the use of ICG angiography during thyroidectomy and/or
parathyroidectomy for identification as well as for the perfusion integrity of
the parathyroid glands.
MATERIALS AND METHODS: The PubMed database was systematically searched for
publications regarding intraoperative ICG imaging in patients that undergo
thyroidectomy or parathyroidectomy.
RESULTS: Eighteen publications reporting on 612 patients, namely 71
parathyroidectomy and 541 thyroidectomy patients met the inclusion criteria.
Eleven publications reported the use of ICG angiography for the identification
of the parathyroid glands during thyroidectomy and seven during
parathyroidectomy for primary and secondary hyperparathyroidism.
CONCLUSION: ICG fluorescence imaging is a simple, fast and reproducible method
capable of intraoperatively visualizing and assessing the function of
parathyroid glands, and can, therefore, assist surgeons in their
decision-making. Despite all this, ICG fluorescence imaging technique for PG
detection still lacks standardization and further studies are needed to
establish its clinical utility.
Copyright© 2020, International Institute of Anticancer Research (Dr. George J.
Delinasios), All rights reserved.
DOI: 10.21873/invivo.11741
PMCID: PMC6984100
PMID: 31882459 [Indexed for MEDLINE]
Conflict of interest statement: No conflicts of interest or financial
relationships to be disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/31129192 | 1. Urology. 2019 Oct;132:10-17. doi: 10.1016/j.urology.2019.05.008. Epub 2019 May
23.
Indocyanine Green (ICG) in Urologic Surgery.
Kaplan-Marans E(1), Fulla J(2), Tomer N(2), Bilal K(2), Palese M(2).
Author information:
(1)Department of Urology, Mount Sinai Health System, New York, NY. Electronic
address: Ebk2126@columbia.edu.
(2)Department of Urology, Mount Sinai Health System, New York, NY.
Indocyanine green (ICG) is a dye used for fluorescent-guided surgery. This
review article addresses the recent surge in reported uses of ICG in various
surgical fields and provides a comprehensive and up to date review of the uses
of ICG in urologic surgery.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.urology.2019.05.008
PMID: 31129192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34589458 | 1. Front Pediatr. 2021 Sep 13;9:736242. doi: 10.3389/fped.2021.736242.
eCollection 2021.
The Use of Indocyanine Green Fluorescence Angiography in Pediatric Surgery: A
Systematic Review and Narrative Analysis.
Le-Nguyen A(1), O'Neill Trudeau M(2), Dodin P(3), Keezer MR(4)(5)(6), Faure
C(7), Piché N(2).
Author information:
(1)Department of General Surgery, Université de Montréal, Montréal, QC, Canada.
(2)Department of Pediatric Surgery, Centre Hospitalier Universitaire
Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
(3)Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal,
Montréal, QC, Canada.
(4)Department of Neurosciences, Université de Montréal, Montréal, QC, Canada.
(5)Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada.
(6)School of Public Health, Université de Montréal, Montréal, QC, Canada.
(7)Department of Gastroenterology, Hepatology, and Nutrition, Centre Hospitalier
Universitaire Sainte-Justine, Université de Montréal, Montréal, QC, Canada.
Purpose: Indocyanine green fluorescence angiography (ICG-FA) is a validated
non-invasive imaging technique used to assess tissue vascularization and guide
intraoperative decisions in many surgical fields including plastic surgery,
neurosurgery, and general surgery. While this technology is well-established in
adult surgery, it remains sparsely used in pediatric surgery. Our aim was to
systematically review and provide an overview of all available evidence on the
perioperative use of indocyanine green fluorescence angiography in pediatric
surgical patients. Methods: We conducted a systematic review with narrative
synthesis in conformity with the PRISMA guidelines using PubMed, Medline, All
EBM Reviews, EMBASE, PsycINFO, and CINAHL COMPLETE databases to identify
articles describing the perioperative use of ICG-FA in pediatric patients. Two
independent authors screened all included articles for eligibility and inclusion
criteria. We extracted data on study design, demographics, surgical indications,
indocyanine green dose, and perioperative outcomes. We developed a risk of bias
assessment tool to evaluate the methodological quality of included studies.
Results: Of 1,031 articles retrieved, a total of 64 articles published between
2003 and 2020 were included reporting on 664 pediatric patients. Most articles
were case reports and case series (n = 36; 56%). No adverse events related to
ICG-FA were reported in the included articles. Risk of bias was high. We did not
conduct a meta-analysis given the heterogeneous nature of the populations,
interventions, and outcome measures. A narrative synthesis is presented.
Conclusion: Indocyanine green fluorescence angiography is a safe imaging
technology and its use is increasing rapidly in pediatric surgical specialties.
However, the quality of evidence supporting this trend currently appears low.
Case-control and randomized trials are needed to determine the adequate
pediatric dose and to confirm the potential benefits of ICG-FA in pediatric
surgical patients. Systematic Review Registration: This study was registered on
Prospero a priori, identifier: CRD42020151981.
Copyright © 2021 Le-Nguyen, O'Neill Trudeau, Dodin, Keezer, Faure and Piché.
DOI: 10.3389/fped.2021.736242
PMCID: PMC8473799
PMID: 34589458
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/10946079 | 1. Surv Ophthalmol. 2000 Jul-Aug;45(1):15-27. doi: 10.1016/s0039-6257(00)00123-5.
Fluorescence properties and metabolic features of indocyanine green (ICG) as
related to angiography.
Desmettre T(1), Devoisselle JM, Mordon S.
Author information:
(1)INSERM (French Institute of Health and Medical Research), Lille, France.
desmettre@lille.inserm.fr
Indocyanine green (ICG) is a fluorescent dye that has been used for the imaging
of retinal and choroidal vasculatures for more than 30 years. Its high molecular
weight, specific metabolic features, and its infrared spectra make the
specificity of the images obtained with this dye in ophthalmology. The focus of
this paper is to review the basic properties of ICG and to show how some
clinical features related to basic properties also depend on the instrumentation
used to perform ICG angiography. Indocyanine green has a complex molecular
structure that leads to amphiphilic properties, that is, both hydrophilic and
lipophilic properties. These properties explain that a specific interaction with
phospholipids influences the emission spectrum and the fluorescence yield of
ICG. The composition of cell membranes mainly composed of phospholipid bilayers
is consistent with a binding and/or a diffusion of ICG molecules observed on
angiograms. Likewise, ICG can bind to the lipid component of miliary drusen,
explaining their hyperfluorescence. A knowledge of ICG basic properties and
interactions may allow a better understanding of angiograms performed with this
dye.
DOI: 10.1016/s0039-6257(00)00123-5
PMID: 10946079 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34760625 | 1. Tzu Chi Med J. 2021 Apr 1;33(4):317-322. doi: 10.4103/tcmj.tcmj_216_20.
eCollection 2021 Oct-Dec.
Indocyanine green: An old drug with novel applications.
Lu CH(1), Hsiao JK(1)(2).
Author information:
(1)Department of Medical Imaging, Taipei Tzu Chi Hospital, Buddhist Tzu Chi
Medical Foundation, New Taipei, Taiwan.
(2)School of Medicine, Tzu Chi University, Hualien, Taiwan.
Indocyanine green (ICG), a US Food and Drug Administration-approved fluorescent
compound, has been on the medical stage for more than 60 years. Current uses
include hepatic function evaluation before surgical procedure and fundus
evaluation. The large safety margin and near-infrared fluorescent optical
advantage of the drug have proved useful in several clinical trials of
intraoperative systems for tumor removal. Several nanoparticle-sized
formulations for thermal ablation and photodynamic therapy have also been
evaluated in animal experiments. Studies have attempted to manipulate ICG as a
reporter fluorophore with initial success. In this article, we reviewed ICG's
histological applications, chemical and physical properties, current clinical
applications, ongoing clinical trials, and biomedical studies and prospects. We
believe that ICG could be used with novel biotechnological techniques, such as
fluorescent endoscopy and photoacoustic equipment, in a range of biomedical
fields.
Copyright: © 2021 Tzu Chi Medical Journal.
DOI: 10.4103/tcmj.tcmj_216_20
PMCID: PMC8532591
PMID: 34760625
Conflict of interest statement: Dr. Jong-Kai Hsiao, an editorial board member at
Tzu Chi Medical Journal, had no role in the peer review process of or decision
to publish this article. The other author declared no conflict of interest in
writing this paper. |
http://www.ncbi.nlm.nih.gov/pubmed/18670454 | 1. Eye (Lond). 2009 Mar;23(3):504-18. doi: 10.1038/eye.2008.249. Epub 2008 Aug 1.
Vital staining with indocyanine green: a review of the clinical and experimental
studies relating to safety.
Stanescu-Segall D(1), Jackson TL.
Author information:
(1)Department of Ophthalmology, King's College Hospital, London, UK.
Indocyanine green (ICG) is extremely effective when used as a vital stain during
macular hole surgery. By staining the internal limiting membrane, ICG
facilitates removal of this delicate and sometimes hard to visualize structure.
There is, however, considerable debate regarding its safety. This review
considers the clinical and experimental studies of ICG and a related agent,
infracyanine green. Some clinical papers show visual field defects, reduced
visual acuity, and persistence of ICG at the macula and optic nerve. Other
clinical studies fail to demonstrate toxicity. The experimental studies are also
conflicting, but there are emerging trends. These suggest that surgeons who
continue to use ICG should use concentrations not greater than 0.05 mg/ml, in
fluid-filled eyes, with short exposure times, iso-osmolar solutions, and avoid
proximal or prolonged endoillumination of stained tissue. A smaller number of
studies suggest that infracyanine green produces similar staining to ICG, and
may possibly be safer, but there are too few well-designed studies to reach a
conclusion. Although the use of ICG continues, on the balance of evidence, this
review suggests that it is has the potential to produce subtle visual damage.
DOI: 10.1038/eye.2008.249
PMID: 18670454 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24710988 | 1. Lasers Med Sci. 1998 Dec;13(4):279-82. doi: 10.1007/s101030050008.
A preliminary study of the in vivo behaviour of an emulsion formulation of
indocyanine green.
Devoisselle JM(1), Soulié-Bégu S, Mordon S, Desmettre T, Maillols H.
Author information:
(1)Laboratoire de Technique Pharmaceutique Industrielle, UFR des Sciences
Pharmaceutiques, Montpellier, FR.
Indocyanine green (ICG) is a fluorescent dye largely used as functional
indicator, fluorescent imaging contrast agent and recently as enhancer during
diode laser photocoagulation. In this study, indocyanine green was incorporated
in an emulsion to increase its residence time in blood. In vitro results to show
that indocyanine green absorption peak is shifted towards longer wavelength
(from 778 nm to 794 nm) close to the peak emission wavelength of the near
infrared diode laser (805 nm) used during laser-induced photocoagulation.
Plasmatic clearance is slower (in the 15-60 min time interval) compared to the
plasmatic clearance of ICG administered as an aqueous solution. The absorbing
capacity of ICG at 805 nm shows a two- to threefold increase when indocyanine
green is incorporated in this emulsion.
DOI: 10.1007/s101030050008
PMID: 24710988 |
http://www.ncbi.nlm.nih.gov/pubmed/9190133 | 1. J Am Optom Assoc. 1997 Jun;68(6):343-52.
Role of indocyanine green fluorescence videoangiography in evaluation of
subretinal disease.
Lampariello DA(1), Primo SA.
Author information:
(1)New England College of Optomatry, Boston, Massachusetts 02116, USA.
BACKGROUND: Indocyanine green (ICG) is a sterile, water-soluble, tricarbocyanine
dye that can be used in fundus angiography as an adjunct to sodium fluorescein.
It has a peak spectral absorption of 805 nm in blood plasma or blood, as
compared with fluorescein, which has a peak spectral absorption of 465 nm.
Because the absorption and emission of ICG lies around 835 nm, transmission of
energy by the retinal pigment epithelium (RPE) and serosanguinated material is
more efficient in this region than in the region of visible light energy. ICG
has the property of being approximately 98% bound to blood protein, disallowing
extravasation of excessive dye in the highly fenestrated choroidal vasculature.
METHODS: The characteristics of ICG are discussed, including administration and
dosage, adverse reactions and use of infrared filters for fundus photography. In
addition, two cases are presented to illustrate the clinical application of ICG
for diagnosis and treatment of choroidal neovascular membranes.
RESULTS: ICG videoangiography can be used to reveal subfoveal choroidal
neovascular membranes not previously identified with fluorescein; angiograms can
also be used to dramatically highlight retinal and choroidal changes.
CONCLUSIONS: The use of ICG for fundus videoangiography provides a more accurate
and complete evaluation in certain cases of subretinal and choroidal disease.
PMID: 9190133 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3679580 | 1. Int J Biomed Comput. 1987 Nov;21(3-4):197-204. doi:
10.1016/0020-7101(87)90087-0.
Indocyanine green pharmacokinetics calculations using Lotus 123 spreadsheet.
Holmes RA(1).
Author information:
(1)Department of Veterinary Clinical Sciences, School of Veterinary Medicine,
Louisiana State University, Baton Rouge 70803.
Indocyanine green (ICG; Cardio Green, Hynson, Westcott & Dunning, Baltimore, MD)
is a cholephilic dye that is commonly used as a liver function test. In order to
obtain the pharmacokinetic values of ICG needed for liver function
determinations, a linear and a log-linear regression must be done in addition to
other calculations. Results can be obtained graphically, but are not as accurate
as mathematical calculations. To obtain accurate results and expedite
calculation time, a program was developed using the Lotus 123 spreadsheet
program (Lotus 123, Lotus Development Corporation, Cambridge, MA) and an IBM
compatible computer to do these calculations.
DOI: 10.1016/0020-7101(87)90087-0
PMID: 3679580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33965600 | 1. Photodiagnosis Photodyn Ther. 2021 Jun;34:102336. doi:
10.1016/j.pdpdt.2021.102336. Epub 2021 May 14.
Preliminary application of indocyanine green fluorescence imaging in
postoperative gastrointestinal fistula.
Peng Y(1), Fang C(1), Zhu G(1), Peng F(1), Tian J(2), Su S(1), Li B(3), Yang
X(4).
Author information:
(1)Department of General Surgery (Hepatobiliary Surgery), The Affiliated
Hospital of Southwest Medical University, Luzhou, 646000, China; Academician
(Expert) Workstation of Sichuan Province, Luzhou, 646000, China.
(2)Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy
of Sciences, Beijing, China.
(3)Department of General Surgery (Hepatobiliary Surgery), The Affiliated
Hospital of Southwest Medical University, Luzhou, 646000, China; Academician
(Expert) Workstation of Sichuan Province, Luzhou, 646000, China. Electronic
address: liboer2002@126.com.
(4)Department of General Surgery (Hepatobiliary Surgery), The Affiliated
Hospital of Southwest Medical University, Luzhou, 646000, China; Academician
(Expert) Workstation of Sichuan Province, Luzhou, 646000, China. Electronic
address: 344920646@qq.com.
We describe a case using indocyanine green (ICG) fluorescence imaging for
diagnosis of postoperative gastrointestinal fistula. When the fistula is very
large, both indocyanine green and methylene blue can be found in the
postoperative drainage. After treatment, when the leak became small, only ICG
fluorescence imaging continued to be demonstrated. ICG fluorescence imaging is
likely to prove to be a safe and effective method of examination, and one that
is very practical and easy to execute for the diagnosis of postoperative
gastrointestinal fistula.
Copyright © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.pdpdt.2021.102336
PMID: 33965600 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35668312 | 1. Surg Endosc. 2022 Dec;36(12):8943-8949. doi: 10.1007/s00464-022-09343-2. Epub
2022 Jun 6.
When should indocyanine green be assessed in colorectal surgery, and at what
distance from the tissue? Quantitative measurement using the SERGREEN program.
Serra-Aracil X(1)(2), Lucas-Guerrero V(3), Garcia-Nalda A(3), Mora-López L(3),
Pallisera-Lloveras A(3), Serracant A(3), Navarro-Soto S(3).
Author information:
(1)Unidad de Coloproctología. Servicio de Cirugía General y del Aparato
Digestivo, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona,
Parc Tauli s/n, 08208, Sabadell, Barcelona, Spain. xserraa@gmail.com.
(2)Unidad de Cirugía Colorrectal, Departamento de Cirugía General y Ap
Digestivo, Hospital Universitari Parc Taulí, Universitat Autonoma de Barcelona
(UAB), Parc Taulí s/n, 08208, Sabadell, Barcelona, Spain. xserraa@gmail.com.
(3)Unidad de Coloproctología. Servicio de Cirugía General y del Aparato
Digestivo, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona,
Parc Tauli s/n, 08208, Sabadell, Barcelona, Spain.
BACKGROUND: Suture dehiscence is one of the most feared postoperative
complications. Correct intestinal vascularization is essential for its
prevention. Indocyanine green (ICG) is one of the methods used to assess
vascularization, but this assessment is usually subjective. Our group designed
the SERGREEN program to obtain an objective measurement of the degree of
vascularization. We do not know how long after ICG administration the
fluorescence of the tissues should be evaluated, or how far away the measurement
should be performed. The aim of this study is to establish the optimal moment
and distance for analyzing the fluorescence saturation of ICG.
METHODS: Prospective observational study in patients undergoing elective
laparoscopic colorectal surgery. The optimal time for ICG analysis was tested in
a sample of 20 patients (10 right colon and 10 left colon), and the optimal
distance in a sample of ten patients. ICG was administered intravenously, and
colon vascularization was quantified using SERGREEN; RGB (Red, Green, Blue)
encoding was used. The intensity curve of the ICG was analyzed for ten minutes
after its administration. Distances of 1, 3, and 5 cm were tested.
RESULTS: The intensity of fluorescence increased until 1.5 min after ICG
administration (reaching figures of 112.49 in the right colon and 93.95 in the
left). It then remained fairly stable until 3.5 min (98.49 in the right and
83.35 in the left), at which point it began to decrease gradually. ICG
saturation was inversely proportional to the distance between the camera and the
tissue. The best distance was 5 cm, where the confidence interval was narrower
[CI 86.66-87.53].
CONCLUSION: The optimal time for determining ICG in the colon is between 1.5 and
3.5 min, in both right and left colon. The optimal distance is 5 cm. This
information will help to establish parameters of comparison in normal and
pathological situations.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s00464-022-09343-2
PMID: 35668312 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11084282 | 1. J Cataract Refract Surg. 2000 Nov;26(11):1691-3. doi:
10.1016/s0886-3350(00)00432-6.
Indocyanine green staining in traumatic cataract.
Newsom TH, Oetting TA.
Comment in
J Cataract Refract Surg. 2001 May;27(5):647-8. doi:
10.1016/s0886-3350(01)00883-5.
J Cataract Refract Surg. 2001 Sep;27(9):1342. doi:
10.1016/s0886-3350(01)01110-5.
We report the first case of indocyanine green (ICG) being used in an eye with an
anterior capsule that was not completely intact. We found that ICG seems to have
a selective affinity for the anterior capsule over cortical lens material. The
patient had a corneal perforation with a wire and developed endophthalmitis
requiring pars plana vitrectomy with intravitreal antibiotics. He subsequently
developed a white traumatic cataract with an anterior capsule tear. Five months
after the injury, he had cataract extraction. Indocyanine green was used to
better visualize the anterior capsule before capsulotomy. The anterior capsule
stained green, but the cortical material exposed to ICG did not stain.
DOI: 10.1016/s0886-3350(00)00432-6
PMID: 11084282 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15871512 | 1. J Neurosurg. 2005 Apr;102(4):692-8. doi: 10.3171/jns.2005.102.4.0692.
Intraoperative control of extracranial-intracranial bypass patency by
near-infrared indocyanine green videoangiography.
Woitzik J(1), Horn P, Vajkoczy P, Schmiedek P.
Author information:
(1)Department of Neurosurgery, University Hospital of Mannheim, Faculty for
Clinical Medicine of the University of Heidelberg, Mannheim, Germany.
OBJECT: Recently, intraoperative fluorescence angiography in which indocyanine
green (ICG) is used as a tracer has been introduced as a novel technique to
confirm successful aneurysm clipping. The aim of the present study was to assess
whether ICG videoangiography is also suitable for intraoperative confirmation of
extracranial-intracranial bypass patency.
METHODS: Forty patients undergoing cerebral revascularization for hemodynamic
cerebral ischemia (11 patients), moya-moya disease (18 patients), or complex
intracranial aneurysms (11 patients) were included. Superficial temporal artery
(STA)-middle cerebral artery (MCA) bypass surgery was performed 35 times in 30
patients (five patients with moyamoya underwent bilateral procedures),
STA-posterior cerebral artery bypass surgery in two patients, and saphenous vein
(SV) high-flow bypass surgery in eight patients. In each patient, following the
completion of the anastomosis, ICG (0.3 mg/kg body weight) was given
systemically via an intravenous bolus injection. A near-infrared light emitted
by laser diodes was used to illuminate the operating field and the intravascular
fluorescence was recorded using an optical filter-equipped video camera. The
findings of ICG videoangiography were compared with those of postoperative
digital subtraction (DS) or computerized tomography (CT) angiography. In all
cases excellent visualization of cerebral arteries, the bypass graft, and brain
perfusion was noted. Indocyanine green videoangiography was used to identify
four nonfunctioning STA-MCA bypasses, which could be revised successfully in all
cases. In two cases of SV high-flow bypasses, ICG videoangiography revealed
stenosis at the proximal anastomotic site, which was also revised successfully.
In all cases the final findings of ICG videoangiography could be positively
validated during the postoperative course by performing DS or CT angiography.
CONCLUSIONS: Indocyanine green videoangiography provides a reliable and rapid
intraoperative assessment of bypass patency. Thus, ICG videoangiography may help
reduce the incidence of early bypass graft failure.
DOI: 10.3171/jns.2005.102.4.0692
PMID: 15871512 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12880353 | 1. J Biomed Opt. 2003 Jul;8(3):472-8. doi: 10.1117/1.1578643.
Metal-enhanced emission from indocyanine green: a new approach to in vivo
imaging.
Malicka J(1), Gryczynski I, Geddes CD, Lakowicz JR.
Author information:
(1)University of Maryland School of Medicine, Department of Biochemistry &
Molecular Biology, Center for Fluorescence Spectroscopy, 725 W. Lombard Street,
Baltimore, Maryland 21201-1503, USA.
Indocyanine green (ICG) is widely used in medical imaging and testing. Its
complex spectral behavior and low quantum yield limits some applications. We
show that proximity of ICG to a metallic silver particle increases its intensity
approximately 20-fold and decreases the decay time. Since the rate of
photobleaching is not increased, our results suggest that ICG-silver particle
complexes can yield at least 20-fold more photons per ICG molecule for improved
medical imaging.
(c) 2003 Society of Photo-Optical Instrumentation Engineers.
DOI: 10.1117/1.1578643
PMCID: PMC6942523
PMID: 12880353 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19065196 | 1. Opt Express. 2008 Dec 8;16(25):20577-87. doi: 10.1364/oe.16.020577.
In-vivo fluorescence imaging of mammalian organs using charge-assembled
mesocapsule constructs containing indocyanine green.
Yaseen MA(1), Yu J, Wong MS, Anvari B.
Author information:
(1)Department of Bioengineering, Rice University, MS-142 6100 Main St, Houston,
TX 77005, USA.
Indocyanine green (ICG) is a fluorescent probe used in clinical imaging.
However, its utility remains limited by optical instability, rapid circulation
kinetics, and exclusive uptake by the liver. Using mesocapsule (MC) constructs
to encapsulate ICG, we have developed a technology to stabilize ICG's optical
properties and alter its biodistribution. We present in vivo fluorescence images
of mammalian organs to demonstrate the potential application of our ICG
encapsulation technology for optical imaging of specific tissues.
(c) 2008 Optical Society of America
DOI: 10.1364/oe.16.020577
PMID: 19065196 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9018428 | 1. Curr Eye Res. 1996 Dec;15(12):1149-55. doi: 10.3109/02713689608995149.
Angiographic abnormalities of experimental autoimmune uveoretinitis.
Howe LJ(1), Stanford MR, Whiston R, Dewhirst R, Marshall J.
Author information:
(1)Department of Ophthalmology, United Medical School, St. Thomas' Hospital,
London, UK.
PURPOSE: Experimental autoimmune uveoretinitis (EAU) is an invaluable animal
model for studying inflammatory eye disease in humans. Indocyanine green (ICG)
is a fluorescent dye that can be used to image both retinal and choroidal
vessels. This study was performed to examined the retinal and choroidal vascular
abnormalities of a rat model of EAU using ICG and fluorescein as the contrast
media to assess the suitability of this model for studying ICG angiographic
abnormalities in inflammatory eye disease in humans.
METHODS: Twenty-six black-hooded Lister rats were inoculated with bovine retinal
S-antigen plus adjuvant with or without Bordetella pertussis antigen.
Fluorescein and ICG angiograms were performed at different stages of clinical
disease with a scanning laser ophthalmoscope.
RESULTS: EAU was more severe and primarily choroidal disease in rats given
Bordetella pertussis, but no animals showed evidence of dye leakage from large
choroidal vessels. There was frank leakage of indocyanine green from retinal
vessels. Leakage of both fluorescein and ICG retinal vessels largely correlated
with disease activity. Retinal pigment epithelial lesions either corresponded to
areas of hypofluorescence on the ICG angiogram alone or were represented by
areas of ICG hyperfluorescence that had overlying areas of fluorescein leakage
from retinal capillaries.
CONCLUSIONS: This study has demonstrated the vascular abnormalities of this
model of EAU using ICG and fluorescein as the contrast media. The suitability of
this method for studying ICG angiographic abnormalities in inflammatory eye
disease in humans is encouraging.
DOI: 10.3109/02713689608995149
PMID: 9018428 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12140046 | 1. Am J Ophthalmol. 2002 Aug;134(2):285-6. doi: 10.1016/s0002-9394(02)01543-x.
Altered uptake of infrared diode laser by retina after intravitreal indocyanine
green dye and internal limiting membrane peeling.
Blem RI(1), Huynh PD, Thall EH.
Author information:
(1)Department of Ophthalmology and Visual Sciences, Vitreoretinal Service,
University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1141,
USA. Robert_Blem@hotmail.com
PURPOSE: To report an altered uptake and possible complication associated with
the use of indocyanine green (ICG) dye, internal limiting membrane (ILM)
peeling, and infrared diode laser.
DESIGN: Interventional case report.
METHODS: In two eyes (two patients) three-port pars plana vitrectomy was
performed. Indocyanine green was injected into the vitreous cavity according to
previously published protocol. The ILM was removed with a bent-tipped
microvitreoretinal blade and ILM forceps. Photocoagulation was performed with an
810-nm infrared diode endolaser.
RESULTS: Photocoagulation of the retina stained with ICG in areas with intact
ILM produced more intense and superficial appearing retinal burns than
photocoagulation where the ILM had been peeled. The retinal burns in areas of
intact ILM stained with ICG also appeared more superficial than those typical of
this laser when ICG is not used.
CONCLUSIONS: Indocyanine green absorbs infrared laser light and produces a
photothermal effect. Unwanted damage to the inner retinal layers may occur.
Laser energy may also be prevented from reaching the deeper retinal layers,
reducing the efficacy of treatment.
DOI: 10.1016/s0002-9394(02)01543-x
PMID: 12140046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35662771 | 1. Clin Case Rep. 2022 Jun 3;10(6):e05942. doi: 10.1002/ccr3.5942. eCollection
2022 Jun.
Hepatectomy guided by indocyanine green fluorescent imaging for visualizing bile
leakage (with video).
Hanaki T(1), Tokuyasu N(1), Sakamoto T(1), Fujiwara Y(1).
Author information:
(1)Department of Gastrointestinal and Pediatric Surgery School of Medicine
Tottori University Faculty of Medicine Yonago Japan.
Using indocyanine green (ICG), a standard reagent used in liver function tests,
bile leaks from exfoliated liver sections can be detected with higher
sensitivity than naked-eye observation. This presentation will introduce the
technique of using ICG to detect bile leaks that cannot be detected by the naked
eye.
© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
DOI: 10.1002/ccr3.5942
PMCID: PMC9165200
PMID: 35662771
Conflict of interest statement: The authors have no conflicts of interest or
financial ties to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/28316935 | 1. Urol Case Rep. 2017 Mar 10;12:37-38. doi: 10.1016/j.eucr.2017.02.006.
eCollection 2017 May.
Anaphylactic Shock After Intravenous Administration of Indocyanine Green During
Robotic Partial Nephrectomy.
Chu W(1), Chennamsetty A(1), Toroussian R(2), Lau C(1).
Author information:
(1)City of Hope National Medical Center, Department of Urology and Urologic
Oncology, Duarte, CA, USA.
(2)City of Hope National Medical Center, Department of Anesthesia, Duarte, CA,
USA.
Indocyanine Green (ICG) is frequently used during urologic robotic procedures
and is generally considered to be safe. However, there are reported cases of
severe complications from ICG when used for non-urologic purposes. We present
the first case to our knowledge of anaphylactic shock in response to intravenous
ICG during a robotic partial nephrectomy.
DOI: 10.1016/j.eucr.2017.02.006
PMCID: PMC5349462
PMID: 28316935 |
http://www.ncbi.nlm.nih.gov/pubmed/11351215 | 1. J Fr Ophtalmol. 2001 Apr;24(4):401-10.
[Indocyanine green angiography and occult neovascularization in age-related
macular degeneration].
[Article in Spanish]
Mauget-Faÿsse M(1).
Author information:
(1)Centre Ophtalmologique d'Imagerie Laser et de Rééducation de la Basse
Vision,14, rue Rabelais, 69003 Lyon, France. mm411-1@dial.oleane.com
INTRODUCTION: Since early 90th, infra-red angiography using indocyanine green,
is an additional examination done after fluorescein angiography (FA) very often
used in ARMD allowing deep retinal layers and choroid analysis. ICG angiography
increases occult new vessels delimitation poorly defined by FA, thus extending
the scope of therapy. Clinical applications:
CONCLUSION: ICG angiography, with better choroidal visualization, is nowadays of
great importance in ARMD exploration.
PMID: 11351215 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34720528 | 1. World J Gastroenterol. 2021 Oct 14;27(38):6374-6386. doi:
10.3748/wjg.v27.i38.6374.
Intraoperative use of indocyanine green fluorescence imaging in rectal cancer
surgery: The state of the art.
Peltrini R(1), Podda M(2), Castiglioni S(3), Di Nuzzo MM(4), D'Ambra M(4),
Lionetti R(4), Sodo M(4), Luglio G(4), Mucilli F(3), Di Saverio S(5), Bracale
U(4), Corcione F(4).
Author information:
(1)Department of Public Health, University of Naples Federico II, Napoli 80131,
Italy. roberto.peltrini@gmail.com.
(2)Department of Emergency Surgery, Cagliari University Hospital "Duilio
Casula", Azienda Ospedaliero-Universitaria di Cagliari, Cagliari 09100, Italy.
(3)Department of Medical, Oral and Biotechnological Sciences, University G.
D'Annunzio Chieti-Pescara, Pescara 65100, Italy.
(4)Department of Public Health, University of Naples Federico II, Napoli 80131,
Italy.
(5)Department of General Surgery, University of Insubria, ASST Sette Laghi,
Varese 21100, Italy.
Indocyanine green (ICG) fluorescence imaging is widely used in abdominal
surgery. The implementation of minimally invasive rectal surgery using new
methods like robotics or a transanal approach required improvement of optical
systems. In that setting, ICG fluorescence optimizes intraoperative vision of
anatomical structures by improving blood and lymphatic flow. The purpose of this
review was to summarize all potential applications of this upcoming technology
in rectal cancer surgery. Each type of use has been separately addressed and the
evidence was investigated. During rectal resection, ICG fluorescence angiography
is mainly used to evaluate the perfusion of the colonic stump in order to reduce
the risk of anastomotic leaks. In addition, ICG fluorescence imaging allows easy
visualization of organs such as the ureter or urethra to protect them from
injury. This intraoperative technology is a valuable tool for conducting lymph
node dissection along the iliac lymphatic chain or to better identifying the
rectal dissection planes when a transanal approach is performed. This is an
overview of the applications of ICG fluorescence imaging in current surgical
practice and a synthesis of the results obtained from the literature. Although
further studies are need to investigate the real clinical benefits, these
findings may enhance use of ICG fluorescence in current clinical practice and
stimulate future research on new applications.
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights
reserved.
DOI: 10.3748/wjg.v27.i38.6374
PMCID: PMC8517789
PMID: 34720528 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest statement: Authors declare
no conflict of interests for this article. |
http://www.ncbi.nlm.nih.gov/pubmed/36203048 | 1. Updates Surg. 2023 Feb;75(2):357-365. doi: 10.1007/s13304-022-01361-y. Epub
2022 Oct 6.
Application of indocyanine green (ICG)-guided surgery in clinical practice:
lesson to learn from other organs-an overview on clinical applications and
future perspectives.
Cassinotti E(1), Boni L(2), Baldari L(2).
Author information:
(1)Department of Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore
Policlinico, Milan, Lombardia, Italy. elisa.cassinotti@policlinico.mi.it.
(2)Department of Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore
Policlinico, Milan, Lombardia, Italy.
Indocyanine green (ICG) fluorescence-guided surgery is a modality of
intra-operative navigation that might support the surgeon with enhanced
visualization of anatomical structures in real time. Over the last years, it has
emerged as one of the most promising and rapidly developing technical
innovations in surgery. The most popular current clinical applications include
fluorescence cholangiography, bowel anastomotic perfusion assessment,
fluorescence-guided lymphography for sentinel lymph-node identification and
guided lymphadenectomy and the possible use in oncological surgery for the
identification and localization of tumors and the diagnosis and treatment of
peritoneal carcinosis. This paper provides an overview of the multiple fields of
applications of ICG fluorescence-guided surgery in visceral and oncological
surgery, discussing indications summarizing most recent and significative
available literature and giving technical notes of use.
© 2022. Italian Society of Surgery (SIC).
DOI: 10.1007/s13304-022-01361-y
PMID: 36203048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31034577 | 1. Surg Technol Int. 2019 May 15;34:282-292.
Application of Indocyanine Green in Gynecology: Review of the Literature.
Ferreira H(1), Smith AV(2), Wattiez A(3).
Author information:
(1)Minimally Invasive Gynecological Surgery Unit of Centro Hospitalar
Universitário do Porto, Instituto de Ciências Biomédicas Abel Salazar
Universidade do Porto, Porto, Portugal.
(2)Minimally Invasive Gynecological Surgery Unit of Centro Hospitalar
Universitário do Porto, Porto, Portugal.
(3)Department of Gynecology, University of Strasbourg, Strasbourg, France ,
Latifa Hospital, Dubai, United Arab Emirates.
The present review aims to analyze the current data available on the different
applications of indocyanine green (ICG) in gynecology. A semantic review of
English-language publications was performed by searching for MeSH terms and
keywords in the PubMed and Google Scholar databases. The studies were finally
selected by one author according to the aim of this review. ICG is a highly
water-soluble tricarbocyanine dye that fluoresces in the NIR spectrum. Approved
by the FDA in 1959, it can be administered either IV (usual dose of 5 mg) or
locally/submucosally (usual dose of 5-6.25 mg) according to the pathology or
indication. It is used most often in the setting of oncology, endometriosis and
other gynecological conditions. In oncological applications, ICG is used to
identify sentinel lymph nodes (SLN) using near-infrared light in endometrial,
cervical and vulvar cancers. The main advantages that it offers include a
reduction of surgical time, improved SLN detection rates, and the ability to
avoid radioactivity. In cases of endometrial (submucosal or hysteroscopic
applications) or cervical (intracervical administration) cancer, ICG can detect
SLN at an accuracy of 95% to 98%. For vulvar cancer, the SLN detection rate can
reach 100%. In endometriosis, the lack of good evidence hinders the final
evaluation of this method in both diagnostic and therapeutic scenarios. An
analytical, well-designed, prospective study is currently underway.
PMID: 31034577 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29074233 | 1. Trends Plant Sci. 2018 Feb;23(2):140-150. doi: 10.1016/j.tplants.2017.09.019.
Epub 2017 Oct 23.
Alternative Splicing Control of Abiotic Stress Responses.
Laloum T(1), Martín G(1), Duque P(2).
Author information:
(1)Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
(2)Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic
address: duquep@igc.gulbenkian.pt.
Alternative splicing, which generates multiple transcripts from the same gene,
is an important modulator of gene expression that can increase proteome
diversity and regulate mRNA levels. In plants, this post-transcriptional
mechanism is markedly induced in response to environmental stress, and recent
studies have identified alternative splicing events that allow rapid adjustment
of the abundance and function of key stress-response components. In agreement,
plant mutants defective in splicing factors are severely impaired in their
response to abiotic stress. Notably, mounting evidence indicates that
alternative splicing regulates stress responses largely by targeting the
abscisic acid (ABA) pathway. We review here current understanding of
post-transcriptional control of plant stress tolerance via alternative splicing
and discuss research challenges for the near future.
Copyright © 2017 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tplants.2017.09.019
PMID: 29074233 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22961303 | 1. Protoplasma. 2013 Jun;250(3):639-50. doi: 10.1007/s00709-012-0448-9. Epub 2012
Sep 8.
On the physiological significance of alternative splicing events in higher
plants.
Carvalho RF(1), Feijão CV, Duque P.
Author information:
(1)Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156, Oeiras,
Portugal.
Alternative splicing, which generates multiple transcripts from the same gene
and potentially different protein isoforms, is a key posttranscriptional
regulatory mechanism for expanding proteomic diversity and functional complexity
in higher eukaryotes. The most recent estimates, based on whole transcriptome
sequencing, indicate that about 95 % of human and 60 % of Arabidopsis multi-exon
genes undergo alternative splicing, suggesting important roles for this
mechanism in biological processes. However, while the misregulation of
alternative splicing has been associated with many human diseases, its
biological relevance in plant systems is just beginning to unfold. We review
here the few plant genes for which the production of multiple splice isoforms
has been reported to have a clear in vivo functional impact. These case studies
implicate alternative splicing in the control of a wide range of physiological
and developmental processes, including photosynthetic and starch metabolism,
hormone signaling, seed germination, root growth and flowering, as well as in
biotic and abiotic stress responses. Future functional characterization of
alternative splicing events and identification of the transcripts targeted by
major regulators of this versatile means of modulating gene expression should
uncover the breadth of its physiological significance in higher plants.
DOI: 10.1007/s00709-012-0448-9
PMID: 22961303 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24369421 | 1. Nucleic Acids Res. 2014 Mar;42(5):2856-69. doi: 10.1093/nar/gkt1338. Epub 2013
Dec 24.
Computational analysis reveals a correlation of exon-skipping events with
splicing, transcription and epigenetic factors.
Ye Z(1), Chen Z, Lan X, Hara S, Sunkel B, Huang TH, Elnitski L, Wang Q, Jin VX.
Author information:
(1)Departments of Molecular Medicine, University of Texas Health Science Center
at San Antonio, San Antonio, TX 78229, Department of Molecular and Cellular
Biochemistry and the Comprehensive Cancer Center, The Ohio State University,
Columbus, OH 43210, USA, Department of Biomedical Informatics, The Ohio State
University, Columbus, OH 43210, USA Genome Technology Branch, National Human
Genome Research Institute, National Institutes of Health, Rockville, MD 20852,
USA and Deparment of Epidemiology and Biostatistics, University of Texas Health
Science Center at San Antonio, San Antonio, TX 78229, USA.
Alternative splicing (AS), in higher eukaryotes, is one of the mechanisms of
post-transcriptional regulation that generate multiple transcripts from the same
gene. One particular mode of AS is the skipping event where an exon may be
alternatively excluded or constitutively included in the resulting mature mRNA.
Both transcript isoforms from this skipping event site, i.e. in which the exon
is either included (inclusion isoform) or excluded (skipping isoform), are
typically present in one cell, and maintain a subtle balance that is vital to
cellular function and dynamics. However, how the prevailing conditions dictate
which isoform is expressed and what biological factors might influence the
regulation of this process remain areas requiring further exploration. In this
study, we have developed a novel computational method, graph-based exon-skipping
scanner (GESS), for de novo detection of skipping event sites from raw RNA-seq
reads without prior knowledge of gene annotations, as well as for determining
the dominant isoform generated from such sites. We have applied our method to
publicly available RNA-seq data in GM12878 and K562 cells from the ENCODE
consortium and experimentally validated several skipping site predictions by
RT-PCR. Furthermore, we integrated other sequencing-based genomic data to
investigate the impact of splicing activities, transcription factors (TFs) and
epigenetic histone modifications on splicing outcomes. Our computational
analysis found that splice sites within the skipping-isoform-dominated group
(SIDG) tended to exhibit weaker MaxEntScan-calculated splice site strength
around middle, 'skipping', exons compared to those in the
inclusion-isoform-dominated group (IIDG). We further showed the positional
preference pattern of splicing factors, characterized by enrichment in the
intronic splice sites immediately bordering middle exons. Finally, our analysis
suggested that different epigenetic factors may introduce a variable obstacle in
the process of exon-intron boundary establishment leading to skipping events.
DOI: 10.1093/nar/gkt1338
PMCID: PMC3950716
PMID: 24369421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25577391 | 1. Methods Mol Biol. 2015;1269:365-78. doi: 10.1007/978-1-4939-2291-8_23.
ASPicDB: a database web tool for alternative splicing analysis.
D'Antonio M(1), Castrgnanò T, Pallocca M, D'Erchia AM, Picardi E, Pesole G.
Author information:
(1)Consorzio Interuniversitario CINECA, 00185, Rome, Italy.
Alternative splicing (AS) is a basic molecular phenomenon that increases the
functional complexity of higher eukaryotic transcriptomes. Indeed, through AS
individual gene loci can generate multiple RNAs from the same pre-mRNA. AS has
been investigated in a variety of clinical and pathological studies, such as the
transcriptome regulation in cancer. In human, recent works based on massive RNA
sequencing indicate that >95 % of pre-mRNAs are processed to yield multiple
transcripts. Given the biological relevance of AS, several computational efforts
have been done leading to the implementation of novel algorithms and specific
specialized databases. Here we describe the web application ASPicDB that allows
the recovery of detailed biological information about the splicing mechanism.
ASPicDB provides powerful querying systems to interrogate AS events at gene,
transcript, and protein levels. Finally, ASPicDB includes web visualization
instruments to browse and export results for further off-line analyses.
DOI: 10.1007/978-1-4939-2291-8_23
PMID: 25577391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28273663 | 1. Sex Dev. 2017;11(2):94-108. doi: 10.1159/000456022. Epub 2017 Mar 9.
Sex-Specific Transcript Diversity in the Fly Head Is Established during Pupal
Stages and Adulthood and Is Largely Independent of the Mating Process and the
Germline.
Mohr C(1), Kleiner S, Blanchette M, Pyrowolakis G, Hartmann B.
Author information:
(1)Institute for Human Genetics, Medical Center, University of Freiburg,
Freiburg, Germany.
Alternative splicing (AS), the process which generates multiple RNA and protein
isoforms from a single pre-mRNA, greatly contributes to transcript diversity and
compensates for the fact that the gene number does not scale with organismal
complexity. A number of genomic approaches have established that the extent of
AS is much higher than previously expected, raising questions on its
spatio-temporal regulation and function. In the present study, we address AS in
the context of sex-specific neuronal development in the model Drosophila
melanogaster. We report that at least 47 genes display sex-specific AS in the
adult fly head. Unlike targets of the classical Sex lethal-dependent sex
determination cascade, sex-specific isoforms of the vast majority of these genes
are not present during larval development but start accumulating during
metamorphosis or later, indicating the existence of novel mechanisms in the
induction of sex-specific AS. We also established that sex-specific AS in the
adult fly head is largely independent of the germline or the mating process.
Finally, we investigated the role of sex-specific AS of the sulfotransferase
Tango13 pre-mRNA and provide first evidence that differential expression of
certain isoforms of this protein significantly affects courtship and mating
behavior in male flies.
© 2017 S. Karger AG, Basel.
DOI: 10.1159/000456022
PMID: 28273663 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30014301 | 1. Mar Biotechnol (NY). 2018 Dec;20(6):729-738. doi: 10.1007/s10126-018-9844-2.
Epub 2018 Jul 16.
Increased Alternative Splicing as a Host Response to Edwardsiella ictaluri
Infection in Catfish.
Tan S(1), Wang W(1), Zhong X(1), Tian C(1), Niu D(1)(2), Bao L(1), Zhou T(1),
Jin Y(1), Yang Y(1), Yuan Z(1), Gao D(1), Dunham R(1), Liu Z(3).
Author information:
(1)The Fish Molecular Genetics and Biotechnology Laboratory, School of
Fisheries, Aquaculture and Aquatic Sciences, Auburn University, Auburn, AL,
36849, USA.
(2)College of Life Sciences, Shanghai Ocean University, Shanghai, China.
(3)Department of Biology, College of Art and Sciences, Syracuse University,
Syracuse, NY, 13244, USA. johnliu@syr.edu.
Alternative splicing is the process of generating multiple transcripts from a
single pre-mRNA used by eukaryotes to regulate gene expression and increase
proteomic complexity. Although alternative splicing profiles have been well
studied in mammalian species, they have not been well studied in aquatic
species, especially after biotic stresses. In the present study, genomic
information and RNA-Seq datasets were utilized to characterize alternative
splicing profiles and their induced changes after bacterial infection with
Edwardsiella ictaluri in channel catfish (Ictalurus punctatus). A total of
27,476 alternative splicing events, derived from 9694 genes, were identified in
channel catfish. Exon skipping was the most abundant while mutually exclusive
exon was the least abundant type of alternative splicing. Alternative splicing
was greatly induced by E. ictaluri infection with 21.9% increase in alternative
splicing events. Interestingly, genes involved in RNA binding and RNA splicing
themselves were significantly enriched in differentially alternatively spliced
genes after infection. Sequence analyses of splice variants of a representative
alternatively spliced gene, splicing factor srsf2, revealed that certain spliced
transcripts may undergo nonsense-mediated decay (NMD), suggesting functional
significance of the induced alternative splicing. Although statistical analysis
was not possible with such large datasets, results from quantitative real-time
PCR from representative differential alternative splicing events provided
general validation of the bacterial infection-induced alternative splicing. This
is the first comprehensive study of alternative splicing and its changes in
response to bacterial infection in fish species, providing insights into the
molecular mechanisms of host responses to biotic stresses.
DOI: 10.1007/s10126-018-9844-2
PMID: 30014301 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30852095 | 1. Trends Plant Sci. 2019 Jun;24(6):496-506. doi: 10.1016/j.tplants.2019.02.006.
Epub 2019 Mar 6.
Perspective on Alternative Splicing and Proteome Complexity in Plants.
Chaudhary S(1), Jabre I(1), Reddy ASN(2), Staiger D(3), Syed NH(4).
Author information:
(1)School of Human and Life Sciences, Canterbury Christ Church University,
Canterbury, CT1 1QU, UK; These authors contributed equally to this work.
(2)Department of Biology and Program in Cell and Molecular Biology, Colorado
State University, Fort Collins, CO 80523-1878, USA.
(3)RNA Biology and Molecular Physiology, Faculty of Biology, Bielefeld
University, Bielefeld, Germany.
(4)School of Human and Life Sciences, Canterbury Christ Church University,
Canterbury, CT1 1QU, UK. Electronic address: naeem.syed@canterbury.ac.uk.
Alternative splicing (AS) generates multiple transcripts from the same gene,
however, AS contribution to proteome complexity remains elusive in plants. AS is
prevalent under stress conditions in plants, but it is counterintuitive why
plants would invest in protein synthesis under declining energy supply. We
propose that plants employ AS not only to potentially increasing proteomic
complexity, but also to buffer against the stress-responsive transcriptome to
reduce the metabolic cost of translating all AS transcripts. To maximise
efficiency under stress, plants may make fewer proteins with disordered domains
via AS to diversify substrate specificity and maintain sufficient regulatory
capacity. Furthermore, we suggest that chromatin state-dependent AS engenders
short/long-term stress memory to mediate reproducible transcriptional response
in the future.
Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tplants.2019.02.006
PMID: 30852095 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32811430 | 1. BMC Plant Biol. 2020 Aug 18;20(1):379. doi: 10.1186/s12870-020-02570-6.
Systematic characterization of the branch point binding protein, splicing factor
1, gene family in plant development and stress responses.
Zhang KL(1), Feng Z(2), Yang JF(3), Yang F(4), Yuan T(4), Zhang D(4), Hao GF(3),
Fang YM(1), Zhang J(4)(5), Wu C(2), Chen MX(6), Zhu FY(7).
Author information:
(1)Co-Innovation Center for Sustainable Forestry in Southern China, College of
Biology and the Environment, Nanjing Forestry University, Nanjing, 210037,
Jiangsu Province, China.
(2)College of Light Industry and Food Engineering, Nanjing Forestry University,
Nanjing, 210037, Jiangsu Province, China.
(3)Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan, 430079, China.
(4)Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen,
China.
(5)Department of Biology, Hong Kong Baptist University, and State Key Laboratory
of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong.
(6)Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced
Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China.
(7)Co-Innovation Center for Sustainable Forestry in Southern China, College of
Biology and the Environment, Nanjing Forestry University, Nanjing, 210037,
Jiangsu Province, China. fyzhu@njfu.edu.cn.
BACKGROUND: Among eukaryotic organisms, alternative splicing is an important
process that can generate multiple transcripts from one same precursor messenger
RNA, which greatly increase transcriptome and proteome diversity. This process
is carried out by a super-protein complex defined as the spliceosome.
Specifically, splicing factor 1/branchpoint binding protein (SF1/BBP) is a
single protein that can bind to the intronic branchpoint sequence (BPS),
connecting the 5' and 3' splice site binding complexes during early spliceosome
assembly. The molecular function of this protein has been extensively
investigated in yeast, metazoa and mammals. However, its counterpart in plants
has been seldomly reported.
RESULTS: To this end, we conducted a systematic characterization of the SF1 gene
family across plant lineages. In this work, a total of 92 sequences from 59
plant species were identified. Phylogenetic relationships of these sequences
were constructed, and subsequent bioinformatic analysis suggested that this
family likely originated from an ancient gene transposition duplication event.
Most plant species were shown to maintain a single copy of this gene.
Furthermore, an additional RNA binding motif (RRM) existed in most members of
this gene family in comparison to their animal and yeast counterparts,
indicating that their potential role was preserved in the plant lineage.
CONCLUSION: Our analysis presents general features of the gene and protein
structure of this splicing factor family and will provide fundamental
information for further functional studies in plants.
DOI: 10.1186/s12870-020-02570-6
PMCID: PMC7433366
PMID: 32811430 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interest to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/26327458 | 1. PLoS One. 2015 Sep 1;10(9):e0136653. doi: 10.1371/journal.pone.0136653.
eCollection 2015.
RNA-Seq Analysis of Differential Splice Junction Usage and Intron Retentions by
DEXSeq.
Li Y(1), Rao X(2), Mattox WW(2), Amos CI(1), Liu B(2).
Author information:
(1)Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth
College, Hanover, New Hampshire, 03755, United States of America.
(2)Center for Genetics and Genomics, Department of Genetics, The University of
Texas MD Anderson Cancer Center, Houston, Texas, 77030, United States of
America.
Alternative splicing is an important biological process in the generation of
multiple functional transcripts from the same genomic sequences. Differential
analysis of splice junctions (SJs) and intron retentions (IRs) is helpful in the
detection of alternative splicing events. In this study, we conducted
differential analysis of SJs and IRs by use of DEXSeq, a Bioconductor package
originally designed for differential exon usage analysis in RNA-seq data
analysis. We set up an analysis pipeline including mapping of RNA-seq reads, the
preparation of count tables of SJs and IRs as the input files, and the
differential analysis in DEXSeq. We analyzed the public RNA-seq datasets
generated from RNAi experiments on Drosophila melanogaster S2-DRSC cells to
deplete RNA-binding proteins (GSE18508). The analysis confirmed previous
findings on the alternative splicing of the trol and Ant2 (sesB) genes in the
CG8144 (ps)-depletion experiment and identified some new alternative splicing
events in other RNAi experiments. We also identified IRs that were confirmed in
our SJ analysis. The proposed method used in our study can output the genomic
coordinates of differentially used SJs and thus enable sequence motif search.
Sequence motif search and gene function annotation analysis helped us infer the
underlying mechanism in alternative splicing events. To further evaluate this
method, we also applied the method to public RNA-seq data from human breast
cancer (GSE45419) and the plant Arabidopsis (SRP008262). In conclusion, our
study showed that DEXSeq can be adapted to differential analysis of SJs and IRs,
which will facilitate the identification of alternative splicing events and
provide insights into the molecular mechanisms of transcription processes and
disease development.
DOI: 10.1371/journal.pone.0136653
PMCID: PMC4556662
PMID: 26327458 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/33406240 | 1. Nucleic Acids Res. 2021 Jan 25;49(2):1133-1151. doi: 10.1093/nar/gkaa1260.
Targeting alternative splicing by RNAi: from the differential impact on splice
variants to triggering artificial pre-mRNA splicing.
Fuchs A(1), Riegler S(1)(2), Ayatollahi Z(1), Cavallari N(1), Giono LE(3),
Nimeth BA(2), Mutanwad KV(2), Schweighofer A(4), Lucyshyn D(2), Barta A(1),
Petrillo E(1)(3), Kalyna M(2).
Author information:
(1)Max Perutz Labs, Medical University of Vienna, Vienna 1030, Austria.
(2)Department of Applied Genetics and Cell Biology, University of Natural
Resources and Life Sciences Vienna, Vienna 1190, Austria.
(3)Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE),
CONICET-Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina.
(4)Max Perutz Labs, University of Vienna, Vienna 1030, Austria.
Alternative splicing generates multiple transcript and protein isoforms from a
single gene and controls transcript intracellular localization and stability by
coupling to mRNA export and nonsense-mediated mRNA decay (NMD). RNA interference
(RNAi) is a potent mechanism to modulate gene expression. However, its
interactions with alternative splicing are poorly understood. We used artificial
microRNAs (amiRNAs, also termed shRNAmiR) to knockdown all splice variants of
selected target genes in Arabidopsis thaliana. We found that splice variants,
which vary by their protein-coding capacity, subcellular localization and
sensitivity to NMD, are affected differentially by an amiRNA, although all of
them contain the target site. Particular transcript isoforms escape
amiRNA-mediated degradation due to their nuclear localization. The nuclear and
NMD-sensitive isoforms mask RNAi action in alternatively spliced genes.
Interestingly, Arabidopsis SPL genes, which undergo alternative splicing and are
targets of miR156, are regulated in the same manner. Moreover, similar results
were obtained in mammalian cells using siRNAs, indicating cross-kingdom
conservation of these interactions among RNAi and splicing isoforms.
Furthermore, we report that amiRNA can trigger artificial alternative splicing,
thus expanding the RNAi functional repertoire. Our findings unveil novel
interactions between different post-transcriptional processes in defining
transcript fates and regulating gene expression.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkaa1260
PMCID: PMC7826280
PMID: 33406240 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35269461 | 1. Cells. 2022 Mar 1;11(5):840. doi: 10.3390/cells11050840.
What's in a Gene? The Outstanding Diversity of MAPT.
Ruiz-Gabarre D(1)(2)(3), Carnero-Espejo A(1)(3), Ávila J(2)(4), García-Escudero
V(1)(2)(3).
Author information:
(1)Anatomy, Histology and Neuroscience Department, School of Medicine,
Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
(2)Centro de Biología Molecular Severo Ochoa (UAM-CSIC), 28049 Madrid, Spain.
(3)Graduate Program in Neuroscience, Universidad Autónoma de Madrid (UAM), 28029
Madrid, Spain.
(4)Networking Research Center on Neurodegenerative Diseases (CIBERNED),
Instituto de Salud Carlos III, 28031 Madrid, Spain.
Tau protein is a microtubule-associated protein encoded by the MAPT gene that
carries out a myriad of physiological functions and has been linked to certain
pathologies collectively termed tauopathies, including Alzheimer's disease,
frontotemporal dementia, Huntington's disease, progressive supranuclear palsy,
etc. Alternative splicing is a physiological process by which cells generate
several transcripts from one single gene and may in turn give rise to different
proteins from the same gene. MAPT transcripts have been proven to be subjected
to alternative splicing, generating six main isoforms in the central nervous
system. Research throughout the years has demonstrated that the splicing
landscape of the MAPT gene is far more complex than that, including at least
exon skipping events, the use of 3' and 5' alternative splice sites and, as has
been recently discovered, also intron retention. In addition, MAPT alternative
splicing has been showed to be regulated spatially and developmentally, further
evidencing the complexity of the gene's splicing regulation. It is unclear what
would drive the need for the existence of so many isoforms encoded by the same
gene, but a wide range of functions have been ascribed to these Tau isoforms,
both in physiology and pathology. In this review we offer a comprehensive
up-to-date exploration of the mechanisms leading to the outstanding diversity of
isoforms expressed from the MAPT gene and the functions in which such isoforms
are involved, including their potential role in the onset and development of
tauopathies such as Alzheimer's disease.
DOI: 10.3390/cells11050840
PMCID: PMC8909800
PMID: 35269461 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18088312 | 1. Plant J. 2008 Mar;53(6):1035-48. doi: 10.1111/j.1365-313X.2007.03392.x. Epub
2007 Dec 15.
Monitoring changes in alternative precursor messenger RNA splicing in multiple
gene transcripts.
Simpson CG(1), Fuller J, Maronova M, Kalyna M, Davidson D, McNicol J, Barta A,
Brown JW.
Author information:
(1)Genetics Programme, SCRI, Invergowrie, Dundee DD2 5DA, UK.
craig.simpson@scri.ac.uk
Alternative splicing (AS) increases the proteomic and functional capacity of
genomes through the generation of alternative mRNA transcripts from the same
gene. AS is now estimated to occur in a third of Arabidopsis and rice genes, and
includes genes involved in the control of growth and development, responses to
stress and signalling. Regulation of AS reflects the interactions between
positive and negative cis sequences in the precursor messenger RNA and a range
of trans-acting factors. The levels and activities of these factors differ in
different cells and growth conditions. To identify changes in AS in multiple
genes simultaneously, we have established a reproducible RT-PCR panel that can
analyse 96 alternative splicing events and accurately measure the ratio of
alternatively spliced products. This procedure detected statistically
significant changes in AS in different plant organs, in plants grown under
different light and day-length conditions, and in plants overexpressing splicing
factors. The system provides a convenient, medium-throughput means of monitoring
changes in AS in multiple genes. It can readily be applied to much larger or
targeted sets of gene transcripts to generate information on the significance
and regulation of AS in plant growth and development, specific processes and
responses to external stimuli.
DOI: 10.1111/j.1365-313X.2007.03392.x
PMID: 18088312 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16054339 | 1. J Dermatol Sci. 2005 Nov;40(2):73-84. doi: 10.1016/j.jdermsci.2005.05.006.
Epub 2005 Jul 27.
Normal and abnormal mechanisms of gene splicing and relevance to inherited skin
diseases.
Wessagowit V(1), Nalla VK, Rogan PK, McGrath JA.
Author information:
(1)Genetic Skin Disease Group, St. John's Institute of Dermatology, The Guy's,
King's College and St. Thomas' Hospitals' Medical School, St. Thomas Hospital,
Lambeth Palace Road, London SE1 7EH, England, UK.
The process of excising introns from pre-mRNA complexes is directed by specific
genomic DNA sequences at intron-exon borders known as splice sites. These
regions contain well-conserved motifs which allow the splicing process to
proceed in a regulated and structured manner. However, as well as conventional
splicing, several genes have the inherent capacity to undergo alternative
splicing, thus allowing synthesis of multiple gene transcripts, perhaps with
different functional properties. Within the human genome, therefore, through
alternative splicing, it is possible to generate over 100,000 physiological gene
products from the 35,000 or so known genes. Abnormalities in normal or
alternative splicing, however, account for about 15% of all inherited single
gene disorders, including many with a skin phenotype. These splicing
abnormalities may arise through inherited mutations in constitutive splice sites
or other critical intronic or exonic regions. This review article examines the
process of normal intron-exon splicing, as well as what is known about
alternative splicing of human genes. The review then addresses pathological
disruption of normal intron-exon splicing that leads to inherited skin diseases,
either resulting from mutations in sequences that have a direct influence on
splicing or that generate cryptic splice sites. Examples of aberrant splicing,
especially for the COL7A1 gene in patients with dystrophic epidermolysis
bullosa, are discussed and illustrated. The review also examines a number of
recently introduced computational tools that can be used to predict whether
genomic DNA sequences changes may affect splice site selection and how robust
the influence of such mutations might be on splicing.
DOI: 10.1016/j.jdermsci.2005.05.006
PMCID: PMC1351063
PMID: 16054339 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21896509 | 1. Bioinformatics. 2011 Nov 1;27(21):3010-6. doi: 10.1093/bioinformatics/btr508.
Epub 2011 Sep 6.
SpliceTrap: a method to quantify alternative splicing under single cellular
conditions.
Wu J(1), Akerman M, Sun S, McCombie WR, Krainer AR, Zhang MQ.
Author information:
(1)Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
MOTIVATION: Alternative splicing (AS) is a pre-mRNA maturation process leading
to the expression of multiple mRNA variants from the same primary transcript.
More than 90% of human genes are expressed via AS. Therefore, quantifying the
inclusion level of every exon is crucial for generating accurate transcriptomic
maps and studying the regulation of AS.
RESULTS: Here we introduce SpliceTrap, a method to quantify exon inclusion
levels using paired-end RNA-seq data. Unlike other tools, which focus on
full-length transcript isoforms, SpliceTrap approaches the expression-level
estimation of each exon as an independent Bayesian inference problem. In
addition, SpliceTrap can identify major classes of alternative splicing events
under a single cellular condition, without requiring a background set of reads
to estimate relative splicing changes. We tested SpliceTrap both by simulation
and real data analysis, and compared it to state-of-the-art tools for transcript
quantification. SpliceTrap demonstrated improved accuracy, robustness and
reliability in quantifying exon-inclusion ratios.
CONCLUSIONS: SpliceTrap is a useful tool to study alternative splicing
regulation, especially for accurate quantification of local exon-inclusion
ratios from RNA-seq data.
AVAILABILITY AND IMPLEMENTATION: SpliceTrap can be implemented online through
the CSH Galaxy server http://cancan.cshl.edu/splicetrap and is also available
for download and installation at http://rulai.cshl.edu/splicetrap/.
CONTACT: michael.zhang@utdallas.edu.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
DOI: 10.1093/bioinformatics/btr508
PMCID: PMC3198574
PMID: 21896509 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35821097 | 1. Nat Rev Genet. 2022 Nov;23(11):697-710. doi: 10.1038/s41576-022-00514-4. Epub
2022 Jul 12.
Alternative splicing as a source of phenotypic diversity.
Wright CJ(1)(2), Smith CWJ(3), Jiggins CD(4).
Author information:
(1)Tree of Life, Wellcome Sanger Institute, Cambridge, UK. cw22@sanger.ac.uk.
(2)Department of Zoology, University of Cambridge, Cambridge, UK.
cw22@sanger.ac.uk.
(3)Department of Biochemistry, University of Cambridge, Cambridge, UK.
cwjs1@cam.ac.uk.
(4)Department of Zoology, University of Cambridge, Cambridge, UK.
c.jiggins@zoo.cam.ac.uk.
A major goal of evolutionary genetics is to understand the genetic processes
that give rise to phenotypic diversity in multicellular organisms. Alternative
splicing generates multiple transcripts from a single gene, enriching the
diversity of proteins and phenotypic traits. It is well established that
alternative splicing contributes to key innovations over long evolutionary
timescales, such as brain development in bilaterians. However, recent
developments in long-read sequencing and the generation of high-quality genome
assemblies for diverse organisms has facilitated comparisons of splicing
profiles between closely related species, providing insights into how
alternative splicing evolves over shorter timescales. Although most splicing
variants are probably non-functional, alternative splicing is nonetheless
emerging as a dynamic, evolutionarily labile process that can facilitate
adaptation and contribute to species divergence.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41576-022-00514-4
PMID: 35821097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26273603 | 1. Biomed Res Int. 2015;2015:287048. doi: 10.1155/2015/287048. Epub 2015 Jul 26.
Posttranscriptional Regulation of Splicing Factor SRSF1 and Its Role in Cancer
Cell Biology.
Gonçalves V(1), Jordan P(1).
Author information:
(1)Department of Human Genetics, National Health Institute Dr. Ricardo Jorge,
Avenida Padre Cruz, 1649-016 Lisboa, Portugal ; Biosystems and Integrative
Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, 1749-016
Lisboa, Portugal.
Over the past decade, alternative splicing has been progressively recognized as
a major mechanism regulating gene expression patterns in different tissues and
disease states through the generation of multiple mRNAs from the same gene
transcript. This process requires the joining of selected exons or usage of
different pairs of splice sites and is regulated by gene-specific combinations
of RNA-binding proteins. One archetypical splicing regulator is SRSF1, for which
we review the molecular mechanisms and posttranscriptional modifications
involved in its life cycle. These include alternative splicing of SRSF1 itself,
regulatory protein phosphorylation events, and the role of nuclear versus
cytoplasmic SRSF1 localization. In addition, we resume current knowledge on
deregulated SRSF1 expression in tumors and describe SRSF1-regulated alternative
transcripts with functional consequences for cancer cell biology at different
stages of tumor development.
DOI: 10.1155/2015/287048
PMCID: PMC4529898
PMID: 26273603 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18817741 | 1. Anal Biochem. 2008 Dec 15;383(2):307-10. doi: 10.1016/j.ab.2008.09.002. Epub
2008 Sep 10.
Identification of low-abundance alternatively spliced mRNA variants by exon
exclusive reverse transcriptase polymerase chain reaction.
Wang F(1), Zhao Y, Hao Y, Tan Z.
Author information:
(1)State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of
Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of
China.
Alternative splicing of messenger RNA (mRNA) precursors generates multiple
transcripts from a single primary transcript. Identification and verification of
splice variants and cloning of the corresponding isoforms is crucial for
analyzing gene expression and understanding the related functions. For a
specific gene, the abundance of the transcripts produced can vary significantly
and is subject to various regulations. It can be difficult to detect low-level
splicing variants when others are present in high abundance. Here we describe a
method for the amplification of low-abundance mRNA splicing variants for such
situations. This method introduces a hydrolysis step prior to the conventional
reverse transcriptase polymerase chain reaction (RT-PCR). After the transcripts
are reverse-transcripted into complementary DNA (cDNA), the cDNA of
high-abundance transcript is suppressed from amplification by cleavage at the
chosen exon to enhance the amplification of the low-abundance transcripts that
do not have the targeted exon and are normally undetectable. We provide two
examples to illustrate the detection of low-abundance splicing variants from two
genes.
DOI: 10.1016/j.ab.2008.09.002
PMID: 18817741 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22811948 | 1. Int J Evol Biol. 2012;2012:596274. doi: 10.1155/2012/596274. Epub 2012 Jul 2.
Alternative splicing: a potential source of functional innovation in the
eukaryotic genome.
Chen L(1), Tovar-Corona JM, Urrutia AO.
Author information:
(1)Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Alternative splicing (AS) is a common posttranscriptional process in eukaryotic
organisms, by which multiple distinct functional transcripts are produced from a
single gene. The release of the human genome draft revealed a much smaller
number of genes than anticipated. Because of its potential role in expanding
protein diversity, interest in alternative splicing has been increasing over the
last decade. Although recent studies have shown that 94% human multiexon genes
undergo AS, evolution of AS and thus its potential role in functional innovation
in eukaryotic genomes remain largely unexplored. Here we review available
evidence regarding the evolution of AS prevalence and functional role. In
addition we stress the need to correct for the strong effect of transcript
coverage in AS detection and set out a strategy to ultimately elucidate the
extent of the role of AS in functional innovation on a genomic scale.
DOI: 10.1155/2012/596274
PMCID: PMC3395134
PMID: 22811948 |
http://www.ncbi.nlm.nih.gov/pubmed/28064309 | 1. Mol Biol (Mosk). 2016 Nov-Dec;50(6):935-943. doi: 10.7868/S0026898416060173.
[Role of pre-mRNA secondary structures in the regulation of alternative
splicing].
[Article in Russian]
Rubtsov PM(1)(2).
Author information:
(1)Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,
Moscow, 119991 Russia.
(2)rubtsov@eimb.ru.
Alternative splicing of pre-mRNA is one of the main mechanisms regulating gene
expression that generates multiple transcripts from one gene. The review
considers the specific role that intramolecular secondary structures arising
through the interaction of distant complementary regions of introns play in
regulating alternative splicing. Examples where aberrant splicing associated
with hereditary disorders is corrected by altering the pre-mRNA secondary
structures are described. The advances and prospects in whole transcriptome
analysis of structured RNA regions and studies of their role in regulating
alternative splicing are discussed.
DOI: 10.7868/S0026898416060173
PMID: 28064309 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2788825 | 1. Nature. 1989 Sep 7;341(6237):76-80. doi: 10.1038/341076a0.
Alternative production of calcitonin and CGRP mRNA is regulated at the
calcitonin-specific splice acceptor.
Emeson RB(1), Hedjran F, Yeakley JM, Guise JW, Rosenfeld MG.
Author information:
(1)Eukaryotic Regulatory Biology Program, University of California, San Diego,
La Jolla 92093.
Alternative splicing of eukaryotic messenger RNA precursors represents a common
mechanism for generating multiple transcripts from a single gene. Although there
has been increasing information concerning the sequence requirements and the
biochemical mechanisms involved in the constitutive splicing of primary RNA
transcripts, very little is known about the sequences or mechanisms which
determine alternative RNA-processing events in complex transcription units. The
calcitonin/calcitonin gene-related peptide (CGRP) primary RNA transcript
undergoes tissue-specific alternative processing, resulting in the differential
production of calcitonin mRNA in thyroid C cells and CGRP mRNA in neurons of the
central and peripheral nervous systems. To elucidate the molecular mechanisms
underlying these alternative RNA processing events, we have examined the
nucleotide sequences involved in the production of calcitonin and CGRP mRNAs.
Analyses of HeLa and F9 cell lines transfected with a variety of mutant
calcitonin/CGRP transcription units have demonstrated that alternative
splice-site selection is primarily regulated by cis-active element(s) near the
calcitonin-specific 3'-splice junction. We suggest that the tissue-specific
pattern of alternative RNA processing is conferred by sequence information at
the calcitonin-specific acceptor which serves to inhibit the production of
calcitonin transcripts in CGRP-producing cells.
DOI: 10.1038/341076a0
PMID: 2788825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28402429 | 1. Nucleic Acids Res. 2017 May 19;45(9):5061-5073. doi: 10.1093/nar/gkx267.
A high quality Arabidopsis transcriptome for accurate transcript-level analysis
of alternative splicing.
Zhang R(1), Calixto CPG(2), Marquez Y(3), Venhuizen P(3), Tzioutziou NA(2), Guo
W(1)(2), Spensley M(4), Entizne JC(2), Lewandowska D(5), Ten Have S(6), Frei Dit
Frey N(7), Hirt H(7), James AB(8), Nimmo HG(8), Barta A(3), Kalyna M(9), Brown
JWS(2)(5).
Author information:
(1)Informatics and Computational Sciences, The James Hutton Institute,
Invergowrie, Dundee DD2 5DA, UK.
(2)Plant Sciences Division, College of Life Sciences, University of Dundee,
Invergowrie, Dundee DD2 5DA, UK.
(3)Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohrgasse 9/3,
1030 Vienna, Austria.
(4)The Donnelly Centre, University of Toronto, 160 College Street, Toronto,
Ontario, Canada.
(5)Cell and Molecular Sciences, The James Hutton Institute, Invergowrie, Dundee
DD2 5DA, UK.
(6)Centre for Gene Regulation and Expression, School of Life Sciences,
University of Dundee, Dundee, UK.
(7)Institute of Plant Sciences Paris Saclay, INRA-CNRS-UEVE, Orsay 91405,
France.
(8)Institute of Molecular, Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
(9)Department of Applied Genetics and Cell Biology, University of Natural
Resources and Life Sciences - BOKU, Muthgasse 18, 1190 Vienna, Austria.
Alternative splicing generates multiple transcript and protein isoforms from the
same gene and thus is important in gene expression regulation. To date,
RNA-sequencing (RNA-seq) is the standard method for quantifying changes in
alternative splicing on a genome-wide scale. Understanding the current
limitations of RNA-seq is crucial for reliable analysis and the lack of high
quality, comprehensive transcriptomes for most species, including model
organisms such as Arabidopsis, is a major constraint in accurate quantification
of transcript isoforms. To address this, we designed a novel pipeline with
stringent filters and assembled a comprehensive Reference Transcript Dataset for
Arabidopsis (AtRTD2) containing 82,190 non-redundant transcripts from 34 212
genes. Extensive experimental validation showed that AtRTD2 and its modified
version, AtRTD2-QUASI, for use in Quantification of Alternatively Spliced
Isoforms, outperform other available transcriptomes in RNA-seq analysis. This
strategy can be implemented in other species to build a pipeline for
transcript-level expression and alternative splicing analyses.
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkx267
PMCID: PMC5435985
PMID: 28402429 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25577379 | 1. Methods Mol Biol. 2015;1269:173-88. doi: 10.1007/978-1-4939-2291-8_11.
Transcriptome assembly and alternative splicing analysis.
Bonizzoni P(1), Della Vedova G, Pesole G, Picardi E, Pirola Y, Rizzi R.
Author information:
(1)Department of Informatics, Systems and Communication (DISCo), University of
Milano-Bicocca, Viale Sarca 336, Milano, 20126, Italy,
bonizzoni@disco.unimib.it.
Alternative Splicing (AS) is the molecular phenomenon whereby multiple
transcripts are produced from the same gene locus. As a consequence, it is
responsible for the expansion of eukaryotic transcriptomes. Aberrant AS is
involved in the onset and progression of several human diseases. Therefore, the
characterization of exon-intron structure of a gene and the detection of
corresponding transcript isoforms is an extremely relevant biological task.
Nonetheless, the computational prediction of AS events and the repertoire of
alternative transcripts is yet a challenging issue. Hereafter we introduce
PIntron, a software package to predict the exon-intron structure and the
full-length isoforms of a gene given a genomic region and a set of transcripts
(ESTs and/or mRNAs). The software is open source and available at
http://pintron.algolab.eu. PIntron has been designed for (and extensively tested
on) a standard workstation without requiring dedicated expensive hardware. It
easily manages large genomic regions and more than 20,000 ESTs, achieving good
accuracy as shown in an experimental evaluation performed on 112 well-annotated
genes selected from the ENCODE human regions used as training set in the EGASP
competition.
DOI: 10.1007/978-1-4939-2291-8_11
PMID: 25577379 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20815140 | 1. Int J Data Min Bioinform. 2010;4(4):411-30. doi: 10.1504/ijdmb.2010.034197.
Prediction of alternatively spliced exons using support vector machines.
Xia J(1), Caragea D, Brown SJ.
Author information:
(1)Department of Computing and Information Sciences, Kansas State University,
234 Nichols Hall, Manhattan, KS 66506, USA. xiajing@ksu.edu
Alternative splicing is a mechanism for generating different gene transcripts
(called isoforms) from the same genomic sequence. In this paper, we explore the
predictive power of a large set of diverse gene features that have been
experimentally shown to have effect on alternative splicing. We use such
features to build support vector machine classifiers for predicting
alternatively spliced exons. Experimental results show that classifiers built
from the diverse set of features give better results than those that consider
only basic sequence features. Furthermore, we use feature selection methods to
identify the most informative features for the prediction problem at hand.
DOI: 10.1504/ijdmb.2010.034197
PMCID: PMC5448713
PMID: 20815140 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34440445 | 1. Genes (Basel). 2021 Aug 20;12(8):1272. doi: 10.3390/genes12081272.
Alternative Splicing and Hypoxia Puzzle in Alzheimer's and Parkinson's Diseases.
Jakubauskienė E(1), Kanopka A(1).
Author information:
(1)Institute of Biotechnology, Life Sciences Center, Vilnius University,
Sauletekio al. 7, LT-10257 Vilnius, Lithuania.
Alternative pre-mRNA splicing plays a very important role in expanding protein
diversity as it generates numerous transcripts from a single protein-coding
gene. Therefore, alterations lead this process to neurological human disorders,
including Alzheimer's and Parkinson's diseases. Moreover, accumulating evidence
indicates that the splicing machinery highly contributes to the cells' ability
to adapt to different altered cellular microenvironments, such as hypoxia.
Hypoxia is known to have an effect on the expression of proteins involved in a
multiple of biological processes, such as erythropoiesis, angiogenesis, and
neurogenesis, and is one of the important risk factors in neuropathogenesis. In
this review, we discuss the current knowledge of alternatively spliced genes,
which, as it is reported, are associated with Alzheimer's and Parkinson's
diseases. Additionally, we highlight the possible influence of cellular hypoxic
microenvironment for the formation of mRNA isoforms contributing to the
development of these neurodegenerative diseases.
DOI: 10.3390/genes12081272
PMCID: PMC8394294
PMID: 34440445 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34383135 | 1. Rice (N Y). 2021 Aug 12;14(1):75. doi: 10.1186/s12284-021-00516-6.
Global Survey of Alternative Splicing in Rice by Direct RNA Sequencing During
Reproductive Development: Landscape and Genetic Regulation.
Li H(#)(1)(2), Li A(#)(3), Shen W(2), Ye N(4), Wang G(5)(6), Zhang J(7)(8).
Author information:
(1)Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong.
(2)School of Life Sciences and State Key Laboratory of Agrobiotechnology, The
Chinese University of Hong Kong, Shatin, Hong Kong.
(3)CAS Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy
of Sciences, Beijing, China.
(4)Southern Regional Collaborative Innovation Center for Grain and Oil Crops in
China, College of Agriculture, Hunan Agricultural University, Changsha, 410128,
China.
(5)Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong.
guanqun0703@gmail.com.
(6)School of Life Sciences and State Key Laboratory of Agrobiotechnology, The
Chinese University of Hong Kong, Shatin, Hong Kong. guanqun0703@gmail.com.
(7)Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong.
jzhang@hkbu.edu.hk.
(8)School of Life Sciences and State Key Laboratory of Agrobiotechnology, The
Chinese University of Hong Kong, Shatin, Hong Kong. jzhang@hkbu.edu.hk.
(#)Contributed equally
Alternative splicing is a widespread phenomenon, which generates multiple
isoforms of the gene product. Reproductive development is the key process for
crop production. Although numerous forms of alternative splicing have been
identified in model plants, large-scale study of alternative splicing dynamics
during reproductive development in rice has not been conducted. Here, we
investigated alternative splicing of reproductive development of young panicles
(YP), unfertilized florets (UF) and fertilized florets (F) in rice using direct
RNA sequencing, small RNA sequencing, and degradome sequencing. We identified a
total of 35,317 alternative splicing (AS) events, among which 67.2% splicing
events were identified as novel alternative splicing events. Intron retention
(IR) was the most abundant alternative splicing subtype. Splicing factors that
differentially expressed and alternatively spliced could result in global
alternative splicing. Global analysis of miRNAs-targets prediction revealed that
alternative spliced transcripts affected miRNAs' targets during development.
Degradome sequencing detected only 6.8% of the differentially alternative
splicing transcripts, suggesting a productive transcripts generation during
development. In addition, alternative splicing isoforms of Co-like, a
transcription factor, interacted with Casein kinase 1-like protein HD1 (CKI)
examined in luciferase assay, which could modulate normal male-floral organs
development and flowering time. These results reveal that alternative splicing
is intensely associated with developmental stages, and a high complexity of gene
regulation.
© 2021. The Author(s).
DOI: 10.1186/s12284-021-00516-6
PMCID: PMC8360254
PMID: 34383135
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35327956 | 1. Genes (Basel). 2022 Feb 24;13(3):401. doi: 10.3390/genes13030401.
Alternative Splicing and Isoforms: From Mechanisms to Diseases.
Liu Q(1), Fang L(1), Wu C(1).
Author information:
(1)School of Biomedical Engineering, Dalian University of Technology, Dalian
116024, China.
Alternative splicing of pre-mRNA is a key mechanism for increasing the
complexity of proteins in humans, causing a diversity of expression of
transcriptomes and proteomes in a tissue-specific manner. Alternative splicing
is regulated by a variety of splicing factors. However, the changes and errors
of splicing regulation caused by splicing factors are strongly related to many
diseases, something which represents one of this study's main interests. Further
understanding of alternative splicing regulation mediated by cellular factors is
also a prospective choice to develop specific drugs for targeting the dynamic
RNA splicing process. In this review, we firstly concluded the basic principle
of alternative splicing. Afterwards, we showed how splicing isoforms affect
physiological activities through specific disease examples. Finally, the
available treatment methods relative to adjusting splicing activities have been
summarized.
DOI: 10.3390/genes13030401
PMCID: PMC8951537
PMID: 35327956 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33629774 | 1. Mol Carcinog. 2021 Apr;60(4):279-293. doi: 10.1002/mc.23291. Epub 2021 Feb 25.
Alternative splicing: An important regulatory mechanism in colorectal carcinoma.
Wang J(1), Wang C(1), Li L(1), Yang L(1), Wang S(1), Ning X(1), Gao S(1), Ren
L(1), Chaulagain A(2), Tang J(1)(3), Wang T(1).
Author information:
(1)Department of Pathology, Harbin Medical University, Harbin, China.
(2)Department of Microbiology, Harbin Medical University, Harbin, China.
(3)Department of Bioinformatics, School of Basic Medical Sciences, Southern
Medical University, Guangzhou, China.
Alternative splicing (AS) is a process that produces various mRNA splicing
isoforms via different splicing patterns of mRNA precursors (pre-mRNAs). AS is
the primary mechanism for increasing the types and quantities of proteins to
improve biodiversity and influence multiple biological processes, including
chromatin modification, signal transduction, and protein expression. It has been
reported that AS is involved in the tumorigenesis and development of colorectal
carcinoma (CRC). In this review, we delineate the concept, types, regulatory
processes, and technical advances of AS and focus on the role of AS in CRC
initiation, progression, treatment, and prognosis. This summary of the current
knowledge about AS will contribute to our understanding of CRC initiation and
development. This study will help in the discovery of novel biomarkers and
therapeutic targets for CRC prognosis and treatment.
© 2021 Wiley Periodicals LLC.
DOI: 10.1002/mc.23291
PMID: 33629774 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35339647 | 1. Ann Oncol. 2022 Jun;33(6):578-592. doi: 10.1016/j.annonc.2022.03.011. Epub
2022 Mar 23.
Alternative RNA splicing defects in pediatric cancers: new insights in
tumorigenesis and potential therapeutic vulnerabilities.
Venkataramany AS(1), Schieffer KM(2), Lee K(3), Cottrell CE(3), Wang PY(4),
Mardis ER(5), Cripe TP(6), Chandler DS(7).
Author information:
(1)Biomedical Sciences Graduate Program, The Ohio State University, Columbus,
USA; Medical Scientist Training Program, The Ohio State University, Columbus,
USA.
(2)The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide
Children's Hospital, Columbus, USA.
(3)The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide
Children's Hospital, Columbus, USA; Departments of Pediatrics, The Ohio State
University College of Medicine, Columbus, USA; Pathology, The Ohio State
University College of Medicine, Columbus, USA.
(4)Departments of Pediatrics, The Ohio State University College of Medicine,
Columbus, USA; Center for Childhood Cancer and Blood Diseases, Abigail Wexner
Research Institute at Nationwide Children's Hospital, Columbus, USA.
(5)The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide
Children's Hospital, Columbus, USA; Departments of Pediatrics, The Ohio State
University College of Medicine, Columbus, USA.
(6)Departments of Pediatrics, The Ohio State University College of Medicine,
Columbus, USA; Center for Childhood Cancer and Blood Diseases, Abigail Wexner
Research Institute at Nationwide Children's Hospital, Columbus, USA; Division of
Hematology, Oncology and Blood and Marrow Transplant, Department of Pediatrics,
The Ohio State University, Columbus, USA.
(7)Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research
Institute at Nationwide Children's Hospital, Columbus, USA; Molecular, Cellular
and Developmental Biology Graduate Program and The Center for RNA Biology, The
Ohio State University, Columbus, USA. Electronic address: chandler.135@osu.edu.
BACKGROUND: Compared with adult cancers, pediatric cancers are uniquely
characterized by a genomically stable landscape and lower tumor mutational
burden. Alternative splicing, however, a global cellular process that produces
different messenger RNA/protein isoforms from a single messenger RNA transcript,
has been increasingly implicated in the development of pediatric cancers.
DESIGN: We review the current literature on the role of alternative splicing in
adult cancer, cancer predisposition syndromes, and pediatric cancers. We also
describe multiple splice variants identified in adult cancers and confirmed
through comprehensive genomic profiling in our institutional cohort of rare,
refractory, and relapsed pediatric and adolescent young adult cancer patients.
Finally, we summarize the contributions of alternative splicing events to
neoantigens and chemoresistance and prospects for splicing-based therapies.
RESULTS: Published dysregulated splicing events can be categorized as exon
inclusion, exon exclusion, splicing factor up-regulation, or splice site
alterations. We observe these phenomena in cancer predisposition syndromes
(Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell
acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma,
osteosarcoma), retinoblastoma, Wilms' tumor, and neuroblastoma. Within our
institutional cohort, we demonstrate splice variants in key regulatory genes
(CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or
splice site alterations, which were predicted to impact functional protein
expression and promote tumorigenesis. Differentially spliced isoforms and
splicing proteins also impact neoantigen creation and treatment resistance, such
as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies
with the potential to change the therapeutic landscape of pediatric cancers
include antisense oligonucleotides, adeno-associated virus gene transfers, and
small molecule inhibitors.
CONCLUSIONS: Alternative splicing plays a critical role in the formation and
growth of pediatric cancers, and our institutional cohort confirms and
highlights the broad spectrum of affected genes in a variety of cancers. Further
studies that elucidate the mechanisms of disease-inducing splicing events will
contribute toward the development of novel therapeutics.
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.annonc.2022.03.011
PMID: 35339647 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure EM serves on the scientific advisory
boards of Scorpion Therapeutics, LLC and of PACT Pharma LLC, for which she
receives honoraria and restricted stock units. All other authors have declared
no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18369186 | 1. RNA. 2008 May;14(5):802-13. doi: 10.1261/rna.876308. Epub 2008 Mar 27.
Splicing regulation: from a parts list of regulatory elements to an integrated
splicing code.
Wang Z(1), Burge CB.
Author information:
(1)Department of Pharmacology, School of Medicine, University of North Carolina
at Chapel Hill, Chapel Hill, NC 27599, USA. zefeng@med.unc.edu
Alternative splicing of pre-mRNAs is a major contributor to both proteomic
diversity and control of gene expression levels. Splicing is tightly regulated
in different tissues and developmental stages, and its disruption can lead to a
wide range of human diseases. An important long-term goal in the splicing field
is to determine a set of rules or "code" for splicing that will enable
prediction of the splicing pattern of any primary transcript from its sequence.
Outside of the core splice site motifs, the bulk of the information required for
splicing is thought to be contained in exonic and intronic cis-regulatory
elements that function by recruitment of sequence-specific RNA-binding protein
factors that either activate or repress the use of adjacent splice sites. Here,
we summarize the current state of knowledge of splicing cis-regulatory elements
and their context-dependent effects on splicing, emphasizing recent
global/genome-wide studies and open questions.
DOI: 10.1261/rna.876308
PMCID: PMC2327353
PMID: 18369186 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33621242 | 1. PLoS Biol. 2021 Feb 23;19(2):e3001138. doi: 10.1371/journal.pbio.3001138.
eCollection 2021 Feb.
Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth
across cancers.
Head SA(1), Hernandez-Alias X(1), Yang JS(1)(2), Ciampi L(1), Beltran-Sastre
V(1), Torres-Méndez A(1), Irimia M(1)(3)(4), Schaefer MH(1)(5), Serrano
L(1)(3)(4).
Author information:
(1)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and
Technology, Barcelona, Spain.
(2)Centre de Recerca en Agrigenòmica, Consortium CSIC-IRTA-UAB-UB, Cerdanyola
del Vallès, Barcelona, Spain.
(3)Universitat Pompeu Fabra (UPF), Barcelona, Spain.
(4)ICREA, Barcelona, Spain.
(5)IEO European Institute of Oncology IRCCS, Department of Experimental
Oncology, Milan, Italy.
RNA splicing is widely dysregulated in cancer, frequently due to altered
expression or activity of splicing factors (SFs). Microexons are extremely small
exons (3-27 nucleotides long) that are highly evolutionarily conserved and play
critical roles in promoting neuronal differentiation and development. Inclusion
of microexons in mRNA transcripts is mediated by the SF Serine/Arginine
Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural
tissues. However, microexons have been largely overlooked in prior analyses of
splicing in cancer, as their small size necessitates specialized computational
approaches for their detection. Here, we demonstrate that despite having low
expression in normal nonneural tissues, SRRM4 is further silenced in tumors,
resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is
the most consistently silenced SF across all tumor types analyzed, implying a
general advantage of microexon down-regulation in cancer independent of its
tissue of origin. We show that this silencing is favorable for tumor growth, as
decreased SRRM4 expression in tumors is correlated with an increase in mitotic
gene expression, and up-regulation of SRRM4 in cancer cell lines
dose-dependently inhibits proliferation in vitro and in a mouse xenograft model.
Further, this proliferation inhibition is accompanied by induction of
neural-like expression and splicing patterns in cancer cells, suggesting that
SRRM4 expression shifts the cell state away from proliferation and toward
differentiation. We therefore conclude that SRRM4 acts as a proliferation brake,
and tumors gain a selective advantage by cutting off this brake.
DOI: 10.1371/journal.pbio.3001138
PMCID: PMC7935315
PMID: 33621242 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34645707 | 1. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.
Epub 2021 Oct 13.
Life Expectancy in Duchenne Muscular Dystrophy: Reproduced Individual Patient
Data Meta-analysis.
Broomfield J(1), Hill M(2), Guglieri M(2), Crowther M(2), Abrams K(2).
Author information:
(1)From the Department of Health Sciences (J.B., M.H.), University of Leicester;
Institute of Human Genetics (M.G.), Newcastle University, UK; Department of
Medical Epidemiology and Biostatistics (M.C.), Karolinska Institute, Stockholm,
Sweden; and Centre for Health Economics (K.A.), University of York, UK.
jb781@le.ac.uk.
(2)From the Department of Health Sciences (J.B., M.H.), University of Leicester;
Institute of Human Genetics (M.G.), Newcastle University, UK; Department of
Medical Epidemiology and Biostatistics (M.C.), Karolinska Institute, Stockholm,
Sweden; and Centre for Health Economics (K.A.), University of York, UK.
BACKGROUND AND OBJECTIVES: Duchenne muscular dystrophy (DMD) is a rare
progressive disease that is often diagnosed in early childhood and leads to
considerably reduced life expectancy; because of its rarity, research literature
and patient numbers are limited. To fully characterize the natural history, it
is crucial to obtain appropriate estimates of the life expectancy and mortality
rates of patients with DMD.
METHODS: A systematic review of the published literature on mortality in DMD up
to July 2020 was undertaken, specifically focusing on publications in which
Kaplan-Meier (KM) survival curves with age as a timescale were presented. These
were digitized, and individual patient data (IPD) were reconstructed. The pooled
IPD were analyzed with the KM estimator and parametric survival analysis models.
Estimates were also stratified by birth cohort.
RESULTS: Of 1,177 articles identified, 14 publications met the inclusion
criteria and provided data on 2,283 patients, of whom 1,049 had died. Median
life expectancy was 22.0 years (95% confidence interval [CI] 21.2, 22.4).
Analyses stratified by 3 time periods in which patients were born showed
markedly increased life expectancy in more recent patient populations; patients
born after 1990 have a median life expectancy of 28.1 years (95% CI 25.1, 30.3).
DISCUSSION: This article presents a full overview of mortality across the
lifetime of a patient with DMD and highlights recent improvements in survival.
In the absence of large-scale prospective cohort studies or trials reporting
mortality data for patients with DMD, extraction of IPD from the literature
provides a viable alternative to estimating life expectancy for this patient
population.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the American Academy of Neurology.
DOI: 10.1212/WNL.0000000000012910
PMCID: PMC8665435
PMID: 34645707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10193393 | 1. Thorax. 1998 Nov;53(11):949-52. doi: 10.1136/thx.53.11.949.
Impact of nasal ventilation on survival in hypercapnic Duchenne muscular
dystrophy.
Simonds AK(1), Muntoni F, Heather S, Fielding S.
Author information:
(1)Sleep and Ventilation Unit, Royal Brompton, London, UK.
Comment in
Thorax. 1999 Jun;54(6):564. doi: 10.1136/thx.54.6.562c.
BACKGROUND: Respiratory failure is the commonest cause of death in patients with
Duchenne muscular dystrophy (DMD). Life expectancy is less than one year once
diurnal hypercapnia develops. This study examines the effects of nasal
intermittent positive pressure ventilation (NIPPV) on survival in symptomatic
Duchenne patients with established ventilatory failure.
METHODS: Nocturnal NIPPV was applied in 23 consecutive patients with DMD of mean
(SD) age 20.3 (3.4) years who presented with diurnal and nocturnal hypercapnia.
RESULTS: One year and five year survival rates were 85% (95% CI 69 to 100) and
73% (95% CI 53 to 94), respectively. Early changes in arterial blood gas
tensions following NIPPV occurred with mean (SD) PO2 increasing from 7.6 (2.1)
kPa to 10.8 (1.3) kPa and mean (SD) PCO2 falling from 10.3 (4.5) kPa to 6.1
(1.0) kPa. Improvements in arterial blood gas tensions were maintained over five
years. Health perception and social aspects of SF-36 health related quality of
life index were reported as equivalent to other groups with nonprogressive
disorders using NIPPV.
CONCLUSIONS: Nasal ventilation is likely to increase survival in hypercapnic
patients with Duchenne muscular dystrophy and should be considered as a
treatment option when ventilatory failure develops.
DOI: 10.1136/thx.53.11.949
PMCID: PMC1745110
PMID: 10193393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26153505 | 1. Arch Dis Child. 2015 Dec;100(12):1173-7. doi:
10.1136/archdischild-2014-307962. Epub 2015 Jul 7.
Recent advances in the management of Duchenne muscular dystrophy.
Strehle EM(1), Straub V(1).
Author information:
(1)The John Walton Muscular Dystrophy Research Centre, Newcastle upon Tyne, UK.
Duchenne muscular dystrophy (DMD) is the commonest inherited neuromuscular
disorder of childhood and mainly affects males. Over the course of the last
century, the average life expectancy of these patients has doubled and now
stands at ∼25 years. This progress has been made possible through advances in
the diagnosis, treatment and long-term care of patients with DMD. Basic and
clinical research, national and international scientific networks, and parent
and patient support groups have all contributed to achieving this goal. The
advent of molecular genetic therapies and personalised medicine has opened up
new avenues and raised hopes that one day a cure for this debilitating orphan
disease will be found. The main purpose of this short review is to enable
paediatricians to have informed discussions with parents of boys with DMD about
recent scientific advances affecting their child's clinical care.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://www.bmj.com/company/products-services/rights-and-licensing/
DOI: 10.1136/archdischild-2014-307962
PMID: 26153505 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17939910 | 1. Arch Bronconeumol. 2007 Oct;43(10):557-61. doi: 10.1016/s1579-2129(07)60127-x.
[Pulmonary and nonpulmonary alterations in Duchenne muscular dystrophy].
[Article in Spanish]
Güell MR(1), Avendano M, Fraser J, Goldstein R.
Author information:
(1)Departament de Pneumologia, Hospital de la Santa Creu i de Sant Pau,
Barcelona, España. mguellr@santpau.es
OBJECTIVE: To describe our experience in managing patients with Duchenne
muscular dystrophy.
PATIENTS AND METHODS: We analyzed the following variables in a group of 27
patients with Duchenne muscular dystrophy: arterial blood gases, lung function
before and after mechanical ventilation, oxygen saturation (measured by pulse
oximetry), nocturnal PaCO2 (measured transcutaneously by capnography), heart
function, and dysphagia.
RESULTS: The mean (SD) age was 26 (6) years and the mean age at which mechanical
ventilation had initiated in the patients was 21 (5) years. Sixty-two percent
had undergone tracheostomy and invasive mechanical ventilation. Arterial blood
gas levels returned to normal once mechanical ventilation was administered and
remained so for the entire treatment period (mean duration of follow-up, 56 [49]
months). Thirteen patients had cardiac symptoms and they all presented abnormal
electrocardiograms and echocardiograms indicating dilated cardiomyopathy, left
ventricular dysfunction, and posterior hypokinesis. Only 9 patients were
receiving enteral nutrition (7 through a gastrostomy tube and 2 through a
nasogastric tube). The videofluoroscopic swallowing study confirmed that
dysphagia was related to neuromuscular disease rather than the presence or not
of a tracheostomy. Five patients (18%), 4 of whom were receiving invasive
mechanical ventilation, died during the follow-up period. Three patients had
serious heart disease.
CONCLUSIONS: Mechanical ventilation confers clinical benefits and prolongs life
expectancy in patients with Duchenne muscular dystrophy. Heart disease and
feeding difficulties are determining factors in the prognosis of these patients.
DOI: 10.1016/s1579-2129(07)60127-x
PMID: 17939910 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1450492 | 1. Intern Med. 1992 Jul;31(7):841-6. doi: 10.2169/internalmedicine.31.841.
Therapeutic trials on progressive muscular dystrophy.
Satoyoshi E(1).
Author information:
(1)National Center of Neurology and Psychiatry, Tokyo, Japan.
The special medical care in the National Sanatorium prolonged the life span of
the patients with progressive muscular dystrophy from 15.8 years to 20.4 years
over the last 20 years. Various new drug trials for muscular dystrophy have been
implemented in the last 12 years in Japan. Bestatin and Loxistatin, protease
inhibitors, showed definite improvement on dystrophic mice or hamsters, animal
models of muscular dystrophy. However clinical application of these drugs failed
to prove the effects on patients with Duchenne muscular dystrophy. The
difficulty of clinical evaluation and judgement of effects in progressive
neurological diseases is discussed.
DOI: 10.2169/internalmedicine.31.841
PMID: 1450492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34802091 | 1. Eur J Epidemiol. 2022 Feb;37(2):147-156. doi: 10.1007/s10654-021-00819-4. Epub
2021 Nov 21.
One in five patients with Duchenne muscular dystrophy dies from other causes
than cardiac or respiratory failure.
Wahlgren L(1)(2), Kroksmark AK(3)(4), Tulinius M(3)(5), Sofou K(3)(5).
Author information:
(1)The Queen Silvia Children's Hospital, Sahlgrenska University Hospital,
Gothenburg, Sweden. lisa.wahlgren@vgregion.se.
(2)Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska
Academy, University of Gothenburg, Gothenburg, Sweden.
lisa.wahlgren@vgregion.se.
(3)The Queen Silvia Children's Hospital, Sahlgrenska University Hospital,
Gothenburg, Sweden.
(4)Department for Health and Rehabilitation/Physiotherapy, University of
Gothenburg, Gothenburg, Sweden.
(5)Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska
Academy, University of Gothenburg, Gothenburg, Sweden.
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder with
increasing life expectancy from late teens to over 30 years of age. The aim of
this nationwide study was to explore the prevalence, life expectancy and leading
causes of death in patients with DMD in Sweden. Patients with DMD were
identified through the National Quality Registry for Neuromuscular Diseases in
Sweden, the Swedish Registry of Respiratory Failure, pathology laboratories,
neurology and respiratory clinics, and the national network for neuromuscular
diseases. Age and cause of death were retrieved from the Cause of Death Registry
and cross-checked with medical records. 373 DMD patients born 1970-2019 were
identified, of whom 129 patients deceased during the study period. Point
prevalence of adult patients with DMD on December 31st 2019 was 3.2 per 100,000
adult males. Birth prevalence was 19.2 per 100,000 male births. Median survival
was 29.9 years, the leading cause of death being cardiopulmonary in 79.9% of
patients. Non-cardiopulmonary causes of death (20.1% of patients) mainly
pertained to injury-related pulmonary embolism (1.3 per 1000 person-years),
gastrointestinal complications (1.0 per 1000 person-years), stroke (0.6 per 1000
person-years) and unnatural deaths (1.6 per 1000 person-years). Death from
non-cardiopulmonary causes occurred at younger ages (mean 21.0 years, SD 8.2;
p = 0.004). Age at loss of independent ambulation did not have significant
impact on overall survival (p = 0.26). We found that non-cardiopulmonary causes
contribute to higher mortality among younger patients with DMD. We present novel
epidemiological data on the increasing population of adult patients with DMD.
© 2021. The Author(s).
DOI: 10.1007/s10654-021-00819-4
PMCID: PMC8960570
PMID: 34802091 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/35298826 | 1. Drugs. 2022 Apr;82(5):601-607. doi: 10.1007/s40265-022-01699-y.
Daridorexant: First Approval.
Markham A(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
Erratum in
Drugs. 2022 May;82(7):841. doi: 10.1007/s40265-022-01719-x.
Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered
dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being
developed for the treatment of insomnia. It was selected from a pool of drug
candidates on the basis of an expected effect duration of ≈ 8 h at a dose of
25 mg, with a half-life intended to minimize residual effects that might impair
daytime functioning. Based on the results of two pivotal phase III trials,
daridorexant was recently approved in the USA for the treatment of adult
patients with insomnia characterized by difficulties with sleep onset and/or
sleep maintenance. This article summarizes the milestones in the development of
daridorexant leading to this first approval.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01699-y
PMCID: PMC9042981
PMID: 35298826 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. A. Markham is a salaried employee
of Adis International Ltd/Springer Nature, and declares no relevant conflicts of
interest. All authors contributed to the review and are responsible for the
article content. |
http://www.ncbi.nlm.nih.gov/pubmed/36473030 | 1. Int Clin Psychopharmacol. 2023 Jan 1;38(1):57-65. doi:
10.1097/YIC.0000000000000425. Epub 2022 Nov 30.
Safety and efficacy of daridorexant in the treatment of insomnia: a systematic
review and meta-analysis of randomized controlled trials.
Albadrani MS(1), Albadrani MS(1), Fadlalmola HA(2), Elhusein AM(3), Abobaker
RM(4), Merghani MM(5), Gomaa SM(5), Abdalla AM(6), Alhujaily M(7), Omair AA(8),
Ali Abdalla AM(9), Masada HK(10), Veerabhadra Swamy DS(11), Al-Sayaghi KM(12).
Author information:
(1)Department of Family and Community Medicine, College of Medicine, Taibah
University, Madinah.
(2)Department of Community Health Nursing, Nursing college, Taibah University.
(3)College of Aapplied Medical Science, Nursing Department, University of Bisha,
Bisha.
(4)Gulf Collages, Hospitals and Health Services Administration Department, Hafer
Al-Batin Governorate.
(5)Nursing Department, College of Applied Medical Sciences, Hafr Al-Batin
University.
(6)Department of Community and Mental Health, College of Nursing, Najran
University, Najran.
(7)Department of Clinical Laboratory Sciences, College of Applied Medical
Sciences, University of Bisha.
(8)Director of Nursing - Senior Specialist, Psychiatric and Long Term Care
Hospital (PLTCH), Bisha.
(9)Assistant Professor Applied Medical College, Nursing Department Shaqra
University.
(10)Maternal and Child Health Nursing Department, Northern College of Nursing,
Riyadh, Saudi Arabia.
(11)College of Applied Medical Science, Nursing Department, University of Bisha,
Bisha.
(12)Department of Medical Surgical Nursing, College of Nursing, Taibah
University, Al-Madinah Al-Munawarah, Saudi Arabia.
Daridorexant is a novel dual orexin receptor antagonist used in treating
insomnia disorder. Daridorexant improves sleep quality without impairing daytime
functioning. We assess the safety and efficacy of this novel drug in the
treatment of insomnia. We performed a systematic search for electronic databases
in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized
controlled trials were included in this review, with 2425 participants enrolled.
Daridorexant was superior to placebo in reducing wake time after sleep onset
(MD = -13.26; 95% CI, -15.48 to -11.03; P < 0.00001), latency to persistent
sleep (MD = -7.23; 95% CI, -9.60 to -4.85; P < 0.00001), with increasing the
total sleep time (MD = 14.80; 95% CI, 11.18-18.42; P < 0.00001) and subjective
total sleep time (MD = 14.80; 95% CI, 11.18-18.42], P < 0.00001). The 25 mg and
50 mg were the most officious doses. Treatment with daridorexant has resulted in
a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI,
1.05-1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13-3.23;
P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21-3.36; P = 0.007). Daridorexant
is superior to placebo in improving sleep quality. However, the drug resulted in
a slightly higher incidence of adverse events, including somnolence and fatigue.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/YIC.0000000000000425
PMID: 36473030 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34614145 | 1. Blood. 2022 Jan 20;139(3):439-451. doi: 10.1182/blood.2021014054.
Erythroid overproduction of erythroferrone causes iron overload and
developmental abnormalities in mice.
Coffey R(1), Jung G(1), Olivera JD(1), Karin G(1), Pereira RC(2), Nemeth E(1),
Ganz T(1)(3).
Author information:
(1)Department of Medicine.
(2)Department of Pathology, and.
(3)Department of Pediatrics, David Geffen School of Medicine at UCLA, Los
Angeles, CA.
Comment in
Blood. 2022 Jan 20;139(3):319-321. doi: 10.1182/blood.2021014326.
The hormone erythroferrone (ERFE) is produced by erythroid cells in response to
hemorrhage, hypoxia, or other erythropoietic stimuli, and it suppresses the
hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing
iron for erythropoiesis. Suppression of hepcidin by ERFE is believed to be
mediated by interference with paracrine bone morphogenetic protein (BMP)
signaling that regulates hepcidin transcription in hepatocytes. In anemias with
ineffective erythropoiesis, ERFE is pathologically overproduced, but its
contribution to the clinical manifestations of these anemias is not well
understood. We generated 3 lines of transgenic mice with graded erythroid
overexpression of ERFE and found that they developed dose-dependent iron
overload, impaired hepatic BMP signaling, and relative hepcidin deficiency.
These findings add to the evidence that ERFE is a mediator of iron overload in
conditions in which ERFE is overproduced, including anemias with ineffective
erythropoiesis. At the highest levels of ERFE overexpression, the mice
manifested decreased perinatal survival, impaired growth, small hypofunctional
kidneys, decreased gonadal fat depots, and neurobehavioral abnormalities, all
consistent with impaired organ-specific BMP signaling during development.
Neutralizing excessive ERFE in congenital anemias with ineffective
erythropoiesis may not only prevent iron overload but may have additional
benefits for growth and development.
© 2022 by The American Society of Hematology.
DOI: 10.1182/blood.2021014054
PMCID: PMC8777203
PMID: 34614145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31723763 | 1. Hemasphere. 2018 Mar 28;2(2):e35. doi: 10.1097/HS9.0000000000000035.
eCollection 2018 Mar-Apr.
Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism.
Coffey R(1), Ganz T(1).
Author information:
(1)Departments of Medicine and Pathology, University of California Los Angeles,
CA.
Iron homeostasis ensures adequate iron for biological processes while preventing
excessive iron accumulation, which can lead to tissue injury. In mammalian
systems, iron availability is controlled by the interaction of the
iron-regulatory hormone hepcidin with ferroportin, a molecule that functions
both as the hepcidin receptor as well as the sole known cellular exporter of
iron. By reducing iron export through ferroportin to blood plasma, hepcidin
inhibits the mobilization of iron from stores and the absorption of dietary
iron. Among the many processes requiring iron, erythropoiesis is the most
iron-intensive, consuming most iron circulating in blood plasma. Under
conditions of enhanced erythropoiesis, more iron is required to provide
developing erythroblasts with adequate iron for heme and hemoglobin synthesis.
Here the hormone erythroferrone, produced by erythroblasts, acts on hepatocytes
to suppress hepcidin production, and thereby increase dietary iron absorption
and mobilization from stores. This review focuses on the discovery of
erythroferrone and recent advances in understanding the role of this hormone in
the regulation of iron homeostasis during states of increased erythropoietic
demand. Gaps in our understanding of the role of erythroferrone are highlighted
for future study.
Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the European Hematology Association.
DOI: 10.1097/HS9.0000000000000035
PMCID: PMC6745900
PMID: 31723763 |
http://www.ncbi.nlm.nih.gov/pubmed/34772005 | 1. Materials (Basel). 2021 Oct 28;14(21):6480. doi: 10.3390/ma14216480.
Effect of Recombinant Human Erythroferrone Protein on Hepcidin Gene (Hamp1)
Expression in HepG2 and HuH7 Cells.
Than MM(1)(2), Koonyosying P(1), Ruangsuriya J(1), Junrungsee S(3), Uthaipibull
C(4), Srichairatanakool S(1).
Author information:
(1)Department of Biochemistry, Faculty of Medicine, Chiang Mai University,
Chiang Mai 50200, Thailand.
(2)Department of Biochemistry, University of Medicine, Mandalay 05021, Myanmar.
(3)Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai
50200, Thailand.
(4)Protein-Ligand Engineering and Molecular Biology Laboratory, National Center
for Genetic Engineering and Biotechnology, National Science and Technology
Development Agency, Thailand Science Park, Pathum Thani 12120, Thailand.
Iron is essential for all living organisms. It is strictly controlled by iron
transporters, transferrin receptors, ferroportin and hepcidin. Erythroferrone
(ERFE) is an iron-regulatory hormone which is highly expressed in erythroblasts
by erythropoietin (EPO) stimulation and osteoblasts independently of EPO by
sequestering bone morphogenetic proteins and inhibiting hepatic hepcidin
expression. Although the hepcidin suppressive function of ERFE is known, its
receptors still require investigation. Here, we aim to identify ERFE receptors
on the HepG2 and Huh7 cells responsible for ERFE. Recombinant ERFE (rERFE) was
first produced in HEK293 cells transfected with pcDNA3.1 + ERFE, then purified
and detected by Western blot. The liver cells were treated with an rERFE-rich
medium of transfected HEK293 cells and a purified rERFE-supplemented medium at
various time points, and hepcidin gene (Hamp1) expression was determined using
qRT-PCR. The results show that 37-kD rERFE was expressed in HEK293 cells. Hamp1
was suppressed at 3 h and 6 h in Huh7 cells after rERFE treatments (p < 0.05),
then restored to the original levels. Hamp1 was activated after treatment with
purified rERFE for 24 h and 48 h. Together, these results reveal that ERFE
suppressed Hamp1 expression in liver cells, possibly acting on membrane ERFE
receptor, which in Huh7 cells was more sensitive to the ERFE concentrate.
DOI: 10.3390/ma14216480
PMCID: PMC8585454
PMID: 34772005
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31899794 | 1. Blood. 2020 Feb 20;135(8):547-557. doi: 10.1182/blood.2019003140.
Antibodies against the erythroferrone N-terminal domain prevent hepcidin
suppression and ameliorate murine thalassemia.
Arezes J(1), Foy N(2), McHugh K(3), Quinkert D(3), Benard S(4), Sawant A(5),
Frost JN(1), Armitage AE(1), Pasricha SR(1)(6)(7), Lim PJ(1), Tam MS(5),
Lavallie E(5), Pittman DD(5), Cunningham O(2), Lambert M(2), Murphy JE(5),
Draper SJ(3), Jasuja R(5), Drakesmith H(1)(8).
Author information:
(1)MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine,
University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
(2)BioMedicine Design, Pfizer Biotherapeutics R&D, Dublin, Ireland.
(3)Jenner Institute, University of Oxford, Oxford, United Kingdom.
(4)BioMedicine Design, Pfizer Biotherapeutics R&D, Cambridge, MA.
(5)Rare Disease Research Unit, Pfizer Inc., Cambridge, MA.
(6)Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC,
Australia.
(7)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
Australia; and.
(8)Haematology Theme NIHR Oxford Biomedical Research Centre, Oxford, United
Kingdom.
Comment in
Blood. 2020 Feb 20;135(8):516-518. doi: 10.1182/blood.2019004678.
Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin
(EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin
suppression allows for the mobilization of iron to the bone marrow for the
production of red blood cells. Aberrantly high circulating ERFE in conditions of
stress erythropoiesis, such as in patients with β-thalassemia, promotes the
tissue iron accumulation that substantially contributes to morbidity in these
patients. Here we developed antibodies against ERFE to prevent hepcidin
suppression and to correct the iron loading phenotype in a mouse model of
β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further
characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with
nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We
found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived
from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7
hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the
N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and
in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum
and liver iron in anti-ERFE-treated Hbb(th3/+) mice, accompanied by an increase
in red blood cells and hemoglobin and a decrease in reticulocyte counts. In
summary, we show that ERFE binds BMP6 directly and with high affinity, and that
antibodies targeting the N-terminal domain of ERFE that prevent ERFE-BMP6
interactions constitute a potential therapeutic tool for iron loading anemias.
© 2020 by The American Society of Hematology.
DOI: 10.1182/blood.2019003140
PMCID: PMC7046598
PMID: 31899794 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: This work was
supported in part by funding from Pfizer to J.A., K.M., D.Q., S.J.D., and H.D.
N.F., A.S., S.B., E.L., M.S.T., D.D.P., O.C., M.L., J.E.M., and R.J. are
employed by Pfizer. N.F., O.C., R.J., J.A., K.M., S.J.D., and H.D. are named
inventors on a patent application currently under evaluation. The remaining
authors declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35464433 | 1. Front Immunol. 2022 Apr 8;13:867630. doi: 10.3389/fimmu.2022.867630.
eCollection 2022.
Characterization of Erythroferrone in a Teleost Fish (Dicentrarchus labrax) With
Two Functional Hepcidin Types: More Than an Erythroid Regulator.
Neves JV(1)(2)(3), Barroso C(1)(2)(4), Carvalho P(3), Nunes M(3), Gonçalves
JFM(3), Rodrigues PNS(1)(2)(3).
Author information:
(1)Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto,
Porto, Portugal.
(2)Iron and Innate Immunity, Instituto de Biologia Molecular e Celular (IBMC),
Universidade do Porto, Porto, Portugal.
(3)Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto,
Porto, Portugal.
(4)Programa Doutoral em Biologia Molecular e Celular (MCbiology), Instituto de
Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto,
Portugal.
Erythroferrone is a recently identified erythroid regulator produced by
erythroblasts in the mammalian bone marrow and extramedullary sites, known to be
induced in conditions of anemia or blood loss. Iron metabolism is affected by
erythroferrone through its capacity to inhibit hepcidin production, leading to
the increase of iron availability required for erythropoiesis. However, little
is known about erythroferrone function in other vertebrates, in particular
teleost fish, that unlike mammals, present two different functional types of
hepcidin, one type mostly involved in iron metabolism and the other in
antimicrobial response. The study of erythroferrone evolution and its biological
role in teleost fish can give us valuably new insights into its function. To
address these questions, we characterized erythroferrone in the European sea
bass (Dicentrarchus labrax), a species presenting two hepcidin types, and
evaluated variations in its expression levels in response to different
experimental conditions. During experimental anemia, erythroferrone responds by
increasing its expression and suppressing hepcidin production, following the
pattern observed in mammals, but it is not influenced by iron overload. However,
during bacterial infection, erythroferrone is downregulated and hepcidin levels
increase. Furthermore, administration of Hamp1 but not of Hamp2 peptides
suppresses erythroferrone expression. In conclusion, in dual hepcidin teleost
fish erythroferrone seems to only interact with type 1 hepcidin, known to be
involved in iron homeostasis, but not with type 2, which has an almost exclusive
antimicrobial role.
Copyright © 2022 Neves, Barroso, Carvalho, Nunes, Gonçalves and Rodrigues.
DOI: 10.3389/fimmu.2022.867630
PMCID: PMC9024048
PMID: 35464433 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30097509 | 1. Blood. 2018 Oct 4;132(14):1473-1477. doi: 10.1182/blood-2018-06-857995. Epub
2018 Aug 10.
Erythroferrone inhibits the induction of hepcidin by BMP6.
Arezes J(1), Foy N(2), McHugh K(3), Sawant A(4), Quinkert D(3), Terraube V(2),
Brinth A(2), Tam M(5)(6), LaVallie ER(5), Taylor S(7), Armitage AE(1), Pasricha
SR(1)(8)(9), Cunningham O(2), Lambert M(2), Draper SJ(3), Jasuja R(4),
Drakesmith H(1)(10).
Author information:
(1)Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall
Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital,
Oxford, United Kingdom.
(2)BioMedicine Design, Pfizer Biotherapeutics Research and Development (R&D),
Dublin, Ireland.
(3)The Jenner Institute, University of Oxford, Oxford, United Kingdom.
(4)Rare Disease Research Unit, Pfizer Inc., Cambridge, MA.
(5)BioMedicine Design, Pfizer Biotherapeutics R&D, Cambridge, MA.
(6)Pharmacokinetics, Dynamics and Metabolism, Pfizer Biotherapeutics R&D,
Andover, MA.
(7)Computational Biology Research Group, MRC Weatherall Institute of Molecular
Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
(8)Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC,
Australia.
(9)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
Australia; and.
(10)Haematology Theme Oxford Biomedical Research Centre, Oxford, United Kingdom.
Comment in
Blood. 2018 Oct 4;132(14):1463-1464. doi: 10.1182/blood-2018-08-869586.
Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess
iron is pathogenic in β-thalassemia. Erythropoietin (EPO) enhances
erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic
hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the
liver is critical for hepcidin control, and we show that EPO suppressed hepcidin
and other BMP target genes in vivo in a partially ERFE-dependent manner.
Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway
independently of changes in serum and liver iron. In vitro, ERFE decreased
SMAD1, SMAD5, and SMAD8 phosphorylation and inhibited expression of BMP target
genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and
BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or
activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting
hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved
fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for
binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic
BMP/SMAD signaling via preferentially impairing an evolutionarily closely
related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand
trap generated by stimulated erythropoiesis to regulate the availability of
iron.
© 2018 by The American Society of Hematology.
DOI: 10.1182/blood-2018-06-857995
PMCID: PMC6238155
PMID: 30097509 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: J.A., K.M.,
D.Q., S.J.D., and H.D. received funding from Pfizer. N.F., A.S., V.T., A.B.,
M.T., E.R.L., O.C., M.L., and R.J. are Pfizer employees. N.F., O.C., R.J., J.A.,
K.M., S.J.D., and H.D. are named inventors on a patent application currently
under evaluation. The remaining authors declare no competing financial
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/28739636 | 1. Blood. 2017 Sep 7;130(10):1243-1246. doi: 10.1182/blood-2017-04-777987. Epub
2017 Jul 24.
Immunoassay for human serum erythroferrone.
Ganz T(1)(2), Jung G(1), Naeim A(1), Ginzburg Y(3), Pakbaz Z(4)(5), Walter
PB(4)(6), Kautz L(7), Nemeth E(1).
Author information:
(1)Department of Medicine and.
(2)Department of Pathology, David Geffen School of Medicine at University of
California Los Angeles, Los Angeles, CA.
(3)Department of Medicine, Icahn School of Medicine at Mount Sinai, New York,
NY.
(4)UCSF Benioff Children's Hospital Oakland, Oakland, CA.
(5)UC Riverside School of Medicine, Riverside, CA.
(6)University of Victoria, Victoria, BC, Canada; and.
(7)Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM
U1220, Institut National de la Recherche Agronomique U1416, Ecole Nationale
Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France.
Erythroferrone (ERFE) is a glycoprotein hormone secreted by erythroblasts in
response to stimulation by erythropoietin (EPO). We previously demonstrated that
ERFE messenger RNA expression and serum protein concentration increase in mice
subjected to hemorrhage or EPO therapy, that ERFE acts on hepatocytes to
suppress hepcidin, and that the resulting decrease in hepcidin augments iron
delivery for intensified erythropoiesis. We also showed that ERFE contributes to
pathological hepcidin suppression and iron overload in mice with nontransfused
β-thalassemia. We now report the development and technical validation of a
rabbit monoclonal antibody-based sandwich immunoassay for human ERFE. We use
this assay to show that blood loss or EPO administration increases serum ERFE
concentrations in humans, and that patients with both nontransfused and
transfused β-thalassemia have very high serum ERFE levels, which decrease after
blood transfusion. The assay should be useful for human studies of normal and
disordered erythropoiesis and its effect on iron homeostasis.
© 2017 by The American Society of Hematology.
DOI: 10.1182/blood-2017-04-777987
PMCID: PMC5606005
PMID: 28739636 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: T.G., L.K., and
E.N. are inventors on a patent application on ERFE. T.G. and E.N. are scientific
founders of Intrinsic LifeSciences and Silarus Pharma, companies that have
interests related to ERFE. |
http://www.ncbi.nlm.nih.gov/pubmed/24880340 | 1. Nat Genet. 2014 Jul;46(7):678-84. doi: 10.1038/ng.2996. Epub 2014 Jun 1.
Identification of erythroferrone as an erythroid regulator of iron metabolism.
Kautz L(1), Jung G(1), Valore EV(1), Rivella S(2), Nemeth E(1), Ganz T(3).
Author information:
(1)Department of Medicine, David Geffen School of Medicine, University of
California, Los Angeles, Los Angeles, California, USA.
(2)1] Department of Pediatrics, Division of Hematology-Oncology, Weill Cornell
Medical College, New York, New York, USA. [2] Department of Cell and
Developmental Biology, Weill Cornell Medical College, New York, New York, USA.
(3)1] Department of Medicine, David Geffen School of Medicine, University of
California, Los Angeles, Los Angeles, California, USA. [2] Department of
Pathology, David Geffen School of Medicine, University of California, Los
Angeles, Los Angeles, California, USA.
Erratum in
Nat Genet. 2020 Apr;52(4):463. doi: 10.1038/s41588-019-0548-y.
Recovery from blood loss requires a greatly enhanced supply of iron to support
expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory
hormone hepcidin allows increased iron absorption and mobilization from stores.
We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin
suppression during stress erythropoiesis. ERFE is produced by erythroblasts in
response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin
rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE
expression is greatly increased in Hbb(th3/+) mice with thalassemia intermedia,
where it contributes to the suppression of hepcidin and the systemic iron
overload characteristic of this disease.
DOI: 10.1038/ng.2996
PMCID: PMC4104984
PMID: 24880340 [Indexed for MEDLINE] |