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http://www.ncbi.nlm.nih.gov/pubmed/30849537
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1. Gene. 2019 Jun 15;701:161-168. doi: 10.1016/j.gene.2019.02.073. Epub 2019 Mar
5.
Co-polysomy of 1p/19q in glial tumors: Retrospective analysis of 221 cases from
single center.
Kuskucu A(1), Tuysuz EC(2), Gurkan S(1), Demir Z(1), Yaltirik CK(3), Ozkan F(4),
Ekici ID(4), Bayrak OF(5), Ture U(6).
Author information:
(1)Department of Medical Genetics, Yeditepe University Medical School, 34755
Istanbul, Turkey.
(2)Department of Medical Genetics, Yeditepe University Medical School, 34755
Istanbul, Turkey; Department of Biotechnology, Institute of Science, Yeditepe
University, 34755 Istanbul, Turkey.
(3)Department of Neurosurgery, Yeditepe University Medical School, Yeditepe
University, 34755 Istanbul, Turkey.
(4)Department of Medical Pathology, Yeditepe University Medical School, Yeditepe
University, 34755 Istanbul, Turkey.
(5)Department of Medical Genetics, Yeditepe University Medical School, 34755
Istanbul, Turkey. Electronic address: [email protected].
(6)Department of Neurosurgery, Yeditepe University Medical School, Yeditepe
University, 34755 Istanbul, Turkey. Electronic address: [email protected].
Glial tumors are malignant brain tumors that arise from glial cells of brain or
spine and have genetic aberrations in their genome. 1p/19q co-deletion is
associated with increased Overall Survival (OS) time with enhanced response to
chemo- and radio-therapy in oligodendrogliomas. However, prognostic significance
of 1p/19q co-polysomy is still unclear. We evaluated 1p/19q status of 221
patients with glial tumor by Fluorescent in situ Hybridization (FISH). Records
of the patients were collected retrospectively. Our results demonstrated that
1p/19q co-polysomy was associated with decreased OS time, high P53 expression
and frequently located in temporal lobe, whereas 1p/19q co-deletion was
associated with increased overall survival time, low P53 expression and frontal
lobe location. Furthermore, classification of patients based on both 1p/19q
status and P53 expression revealed that patients with 1p/19q co-polysomy and
high P53 expression had the worst prognosis. Lastly, our bioinformatic survival
analysis revealed that high expression of SRM, ICMT, and FTL located in
1p36.13-p36.31 and 19q13.2-q13.33 region were related with decreased OS time in
patients with Low Grade Glioma (LGG). The study demonstrated that 1p/19q
co-polysomy is a poor prognostic marker for glial tumor.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2019.02.073
PMID: 30849537 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20446099
|
1. Acta Neurochir (Wien). 2010 Aug;152(8):1425-9. doi: 10.1007/s00701-010-0674-x.
Epub 2010 May 6.
Leptomeningeal dissemination of a pediatric neoplasm with 1p19q deletion showing
mixed immunohistochemical features of an oligodendroglioma and neurocytoma.
Rhiew RB(1), Manjila S, Lozen A, Guthikonda M, Sood S, Kupsky WJ.
Author information:
(1)Department of Neurosurgery, Wayne State University School of Medicine,
Detroit, MI 48201, USA.
Leptomeningeal dissemination of an oligodendroglioma is rarely reported in the
neurosurgical literature, especially in cases with a classical 1p19q deletion.
The authors describe a case wherein a 1p19q deletion in a disseminated tumor
with mixed immunohistochemical features of oligodendroglioma and neurocytoma was
encountered and treated. Stereotactic right frontal craniotomy was undertaken
for obtaining definitive histological diagnosis. The results revealed a
neuroectodermal neoplasm with histologic and immunohistochemical features of
oligodendroglioma and neurocytoma. FISH analysis confirmed classical 1p19q
deletion. The patient was treated postoperatively with chemotherapy and
radiation therapy. He showed good clinical response and remains alive 16 months
after diagnosis.
DOI: 10.1007/s00701-010-0674-x
PMID: 20446099 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19624298
|
1. J Med Imaging Radiat Oncol. 2009 Jun;53(3):305-9. doi:
10.1111/j.1754-9485.2009.02074.x.
Retrospective review of prognostic factors, including 1p19q deletion, in
low-grade oligodendrogliomas and a review of recent published works.
Capelle L(1), Oei P, Teoh H, Hamilton D, Palmer D, Low I, Campbell G.
Author information:
(1)Department of Radiation Oncology, Auckland City Hospital, Auckland, New
Zealand.
The purpose of the present study was to investigate potential prognostic factors
in low-grade oligodendrogliomas (LGOs), particularly 1p19q deletion, due to its
proven prognostic significance in anaplastic oligodendrogliomas. We carried out
a retrospective review of patients with a histological diagnosis of LGO between
1990 and 2000 in Auckland and Wellington, New Zealand. All cases underwent
central histopathological review and FISH testing for 1p19q status. Univariate
analysis of potential prognostic factors including 1p19q status, age, tumour
size, tumour crossing midline, tumour enhancement, extent of surgery and
seizures at diagnosis was carried out. Thirty-one patients were eligible and
FISH testing was successful in 28 specimens (90%). Twenty-three specimens (82%)
had 1p19q deletion; four (14%) had no 1p19q deletion; and one (4%) had 1p
deletion alone. At a median follow-up of 87 months (0-147 months), median
survival had not been reached and no significant difference in overall survival
(OS) based on 1p19q status was detected (1p19q deletion OS 56%; 1p19q intact OS
0%; 1p deletion alone 100% (P = 0.38)). None of the other prognostic factors
investigated reached statistical significance. We confirmed the high incidence
(82%) of combined 1p19q deletion in LGOs and the feasibility of successful FISH
testing in paraffin embedded specimens up to 10-years-old. Analysis of potential
prognostic factors was limited by the lack of events during the follow-up
period.
DOI: 10.1111/j.1754-9485.2009.02074.x
PMID: 19624298 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32906679
|
1. Cancers (Basel). 2020 Sep 7;12(9):2543. doi: 10.3390/cancers12092543.
CeRNA Network Analysis Representing Characteristics of Different Tumor
Environments Based on 1p/19q Codeletion in Oligodendrogliomas.
Ahn JW(1), Park Y(1), Kang SJ(1), Hwang SJ(2), Cho KG(2), Lim J(2), Kwack K(1).
Author information:
(1)Department of Biomedical Science, College of Life Science, CHA University,
Seongnam 13488, Korea.
(2)Department of Neurosurgery, Bundang CHA Medical Center, CHA University School
of Medicine, Seongnam 13496, Korea.
Erratum in
Cancers (Basel). 2021 Jan 27;13(3):478. doi: 10.3390/cancers13030478.
Oligodendroglioma (OD) is a subtype of glioma occurring in the central nervous
system. The 1p/19q codeletion is a prognostic marker of OD with an isocitrate
dehydrogenase (IDH) mutation and is associated with a clinically favorable
overall survival (OS); however, the exact underlying mechanism remains unclear.
Long non-coding RNAs (lncRNAs) have recently been suggested to regulate
carcinogenesis and prognosis in cancer patients. Here, we performed in silico
analyses using low-grade gliomas from datasets obtained from The Cancer Genome
Atlas to investigate the effects of ceRNA with 1p/19q codeletion on ODs. Thus,
we selected modules of differentially expressed genes that were closely related
to 1p/19q codeletion traits using weighted gene co-expression network analysis
and constructed 16 coding RNA-miRNA-lncRNA networks. The ceRNA network
participated in ion channel activity, insulin secretion, and collagen network
and extracellular matrix (ECM) changes. In conclusion, ceRNAs with a 1p/19q
codeletion can create different tumor microenvironments via potassium ion
channels and ECM composition changes; furthermore, differences in OS may occur.
Moreover, if extrapolated to gliomas, our results can provide insights into the
consequences of identical gene expression, indicating the possibility of
tracking different biological processes in different subtypes of glioma.
DOI: 10.3390/cancers12092543
PMCID: PMC7564449
PMID: 32906679
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/23681562
|
1. J Neurooncol. 2013 Aug;114(1):85-91. doi: 10.1007/s11060-013-1152-0. Epub 2013
May 17.
Combining two biomarkers, IDH1/2 mutations and 1p/19q codeletion, to stratify
anaplastic oligodendroglioma in three groups: a single-center experience.
Frenel JS(1), Leux C, Loussouarn D, Le Loupp AG, Leclair F, Aumont M, Mervoyer
A, Martin S, Denis MG, Campone M.
Author information:
(1)Medical Oncology Department, Institut de Cancérologie de l'Ouest, Centre René
Gauducheau, 11 Boulevard Jacques Monod, 44800, Saint-Herblain, Nantes, France.
[email protected]
IDH1/2 mutations and 1p/19q codeletion occur frequently in anaplastic gliomas
and are prognostic factors. We combined these two biomarkers to stratify
patients treated for anaplastic oligodendroglioma (AO). 43 consecutive WHO AO
were selected. We combined immunohistochemistry (IHC) with the monoclonal
antibody mIDH1R132H and DNA sequencing of IDH1 and IDH2 genes. Fluorescence in
situ hybridization was carried out to evaluate 1p/19q codeletion. These
biomarkers were correlated with progression-free survival (PFS) and overall
survival (OS). IDH1/IDH2 mutations occurred in 23/43 (54 %) patients: 20/43
IDH1-R132H mutation in IHC, 2/43 IDH1-R132G mutation and 1/43 IDH2-R172K
mutation identified by DNA sequencing. 1p/19q codeletion was detected for 23/43
patients. With median follow-up of 19 months (range 1.4-128), median PFS and OS
were 22 and 35 months respectively. IDH1/IDH2 mutations were strongly associated
with improved PFS and OS: 5-year PFS was 86 versus 6 % and 5-year OS was 91
versus 9 % for patients with IDH1/IDH2 mutations versus wild-type IDH
respectively. In multivariate analyses, IDH1/IDH2 mutations and 1p/19q loss were
independent prognostic factors. Three groups with distinct prognostic features
were identified: patients with IDH1/2 mutations and 1p/19q loss (median PFS,
median OS not reached), patients with IDH1/2 mutations or 1p/19q loss (median
PFS: 22 months, median OS: 30 months), and patients without IDH1/2 mutations nor
1p/19q loss with a bad prognosis (median PFS: 8.6 months, median OS: 9.9
months). Combining two biomarkers, IDH1/2 and 1p/19q codeletion, makes it
possible to stratify AO in three groups with very distinct prognostic features.
DOI: 10.1007/s11060-013-1152-0
PMID: 23681562 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12429693
|
1. Annu Rev Genet. 2002;36:233-78. doi: 10.1146/annurev.genet.36.042902.092433.
Epub 2002 Jun 11.
Xist RNA and the mechanism of X chromosome inactivation.
Plath K(1), Mlynarczyk-Evans S, Nusinow DA, Panning B.
Author information:
(1)Department of Biochemistry & Biophysics, University of California San
Francisco, San Francisco, California 94143, USA. [email protected]
Dosage compensation in mammals is achieved by the transcriptional inactivation
of one X chromosome in female cells. From the time X chromosome inactivation was
initially described, it was clear that several mechanisms must be precisely
integrated to achieve correct regulation of this complex process. X-inactivation
appears to be triggered upon differentiation, suggesting its regulation by
developmental cues. Whereas any number of X chromosomes greater than one is
silenced, only one X chromosome remains active. Silencing on the inactive X
chromosome coincides with the acquisition of a multitude of chromatin
modifications, resulting in the formation of extraordinarily stable facultative
heterochromatin that is faithfully propagated through subsequent cell divisions.
The integration of all these processes requires a region of the X chromosome
known as the X-inactivation center, which contains the Xist gene and its
cis-regulatory elements. Xist encodes an RNA molecule that plays critical roles
in the choice of which X chromosome remains active, and in the initial spread
and establishment of silencing on the inactive X chromosome. We are now on the
threshold of discovering the factors that regulate and interact with Xist to
control X-inactivation, and closer to an understanding of the molecular
mechanisms that underlie this complex process.
DOI: 10.1146/annurev.genet.36.042902.092433
PMID: 12429693 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12900550
|
1. Cytogenet Genome Res. 2002;99(1-4):92-8. doi: 10.1159/000071579.
Ectopic XIST transcripts in human somatic cells show variable expression and
localization.
Chow JC(1), Hall LL, Lawrence JB, Brown CJ.
Author information:
(1)Department of Medical Genetics, University of British Columbia, Vancouver,
BC, Canada.
XIST encodes a functional RNA that is expressed exclusively from the inactive X
in female mammals and is required for the silencing of most of the genes on the
chromosome. XIST transcripts remain in the nucleus, and their specific
localization to the inactive X is important for silencing; however, it is not
known how these transcripts localize to the inactive X chromosome. Expression of
mouse and human XIST from ectopic sites has suggested that localization to the
chromosome from which the gene is expressed may be dependent upon either the
copy number of the integrated constructs or the level of ectopic XIST
expression. To further examine the behavior of XIST transgenes when expressed
from ectopic sites, we introduced an XIST-containing PAC into the human male
somatic cell line HT-1080. In five different transformant clones, the degree of
localization and associated DNA condensation of the surrounding chromatin varied
within nuclei of the same clone, as well as among different clones. Comparing
the number of integrated transgenes and the levels of XIST expression revealed
that neither factor was sufficient for a tight localization of the XIST signal.
Therefore, the extent of expression and localization of XIST transcripts from
ectopic transgenes is likely dependent upon many interacting factors, including
the number of integrated transgenes, the level of XIST expression, and the site
of integration.
Copyright 2002 S. Karger AG, Basel
DOI: 10.1159/000071579
PMID: 12900550 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23689617
|
1. Acta Neuropathol. 2013 Aug;126(2):277-89. doi: 10.1007/s00401-013-1130-9. Epub
2013 May 21.
Codeletion of 1p and 19q determines distinct gene methylation and expression
profiles in IDH-mutated oligodendroglial tumors.
Mur P(1), Mollejo M, Ruano Y, de Lope ÁR, Fiaño C, García JF, Castresana JS,
Hernández-Laín A, Rey JA, Meléndez B.
Author information:
(1)Molecular Pathology Research Unit, Department of Pathology, Virgen de la
Salud Hospital, Avda. Barber 30, 45004, Toledo, Spain.
Oligodendroglial tumors (OTs) are primary brain tumors that show variable
clinical and biological behavior. The 1p/19q codeletion is frequent in these
tumors, indicating a better prognosis and/or treatment response. Recently, the
prognostically favorable CpG island methylator phenotype (CIMP) in gliomas
(G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and
isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP- tumors,
highlighting the relevance of epigenetic mechanisms. We performed a whole-genome
methylation study in 46 OTs, and a gene expression study of 25 tumors,
correlating the methylation and transcriptomic profiles with molecular and
clinical variables. Here, we identified two different epigenetic patterns within
the previously described main G-CIMP+ profile. Both IDH mutation-associated
methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most
of which were pure oligodendrogliomas, and a second group with intact 1p/19q and
frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology.
A third group of OTs lacking the CIMP profile (CIMP-), and with a wild-type IDH
and an intact 1p/19q, similar to the G-CIMP- subgroup, was also observed. The
three CIMP groups presented a significantly better (CD-CIMP+), intermediate
(CIMP+) or worse (CIMP-) prognosis. Furthermore, transcriptomic analyses
revealed CIMP-specific gene expression signatures, indicating the impact of
genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene
expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles
contributed to the identification of subgroups of OTs characterized by different
prognoses, histopathologies, molecular features and gene expression signatures,
which may help in the classification of OTs.
DOI: 10.1007/s00401-013-1130-9
PMID: 23689617 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29237010
|
1. Nucleic Acids Res. 2018 Mar 16;46(5):e26. doi: 10.1093/nar/gkx1227.
CRISPR/Cas9-mediated modulation of splicing efficiency reveals short splicing
isoform of Xist RNA is sufficient to induce X-chromosome inactivation.
Yue M(1)(2), Ogawa Y(1)(2).
Author information:
(1)Division of Reproductive Sciences, Division of Developmental Biology,
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati,
OH 45229, USA.
(2)Department of Pediatrics, University of Cincinnati College of Medicine,
Cincinnati, OH 45267, USA.
Alternative splicing of mRNA precursors results in multiple protein variants
from a single gene and is critical for diverse cellular processes and
development. Xist encodes a long noncoding RNA which is a central player to
induce X-chromosome inactivation in female mammals and has two major splicing
variants: long and short isoforms of Xist RNA. Although a
differentiation-specific and a female-specific expression of Xist isoforms have
been reported, the functional role of each Xist RNA isoform is largely
unexplored. Using CRISPR/Cas9-mediated targeted modification of the 5' splice
site in Xist intron 7, we create mutant female ES cell lines which dominantly
express the long- or short-splicing isoform of Xist RNA from the inactive
X-chromosome (Xi) upon differentiation. Successful execution of CRISPR/Cas-based
splicing modulation indicates that our CRISPR/Cas-based targeted modification of
splicing sites is a useful approach to study specific isoforms of a transcript
generated by alternative splicing. Upon differentiation of splicing-mutant Xist
female ES cells, we find that both long and short Xist isoforms can induce
X-chromosome inactivation normally during ES cell differentiation, suggesting
that the short splicing isoform of Xist RNA is sufficient to induce X-chromosome
inactivation.
DOI: 10.1093/nar/gkx1227
PMCID: PMC5861412
PMID: 29237010 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25636755
|
1. Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):268-76. doi:
10.1016/j.ijrobp.2014.10.027.
Impact of 1p/19q codeletion and histology on outcomes of anaplastic gliomas
treated with radiation therapy and temozolomide.
Speirs CK(1), Simpson JR(1), Robinson CG(1), DeWees TA(1), Tran DD(2), Linette
G(2), Chicoine MR(3), Dacey RG(3), Rich KM(3), Dowling JL(3), Leuthardt EC(3),
Zipfel GJ(3), Kim AH(3), Huang J(4).
Author information:
(1)Department of Radiation Oncology, Washington University School of Medicine,
St. Louis, Missouri.
(2)Department of Medicine, Division of Medical Oncology, Washington University
School of Medicine, St. Louis, Missouri.
(3)Department of Neurosurgery, Washington University School of Medicine, St.
Louis, Missouri.
(4)Department of Radiation Oncology, Washington University School of Medicine,
St. Louis, Missouri. Electronic address: [email protected].
PURPOSE: Anaplastic gliomas represent a heterogeneous group of primary
high-grade brain tumors, and the optimal postoperative treatment remains
controversial. In this report, we present our institutional data on the clinical
outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic
gliomas, stratified by histology and 1p/19q codeletion.
METHODS AND MATERIALS: A single-institution retrospective review was conducted
of patients with supratentorial anaplastic oligodendroglioma (AO), mixed
anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After
surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in
daily fractions. All patients received standard concurrent TMZ, with or without
adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA,
non-codeleted AO/AOA, and AA.
RESULTS: From 2000 to 2012, 111 cases met study criteria and were evaluable.
Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91%
vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS)
was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA
had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively,
P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate
analysis, age, performance status, and histological or molecular subtype were
independent predictors for both PFS and OS. Compared to historical controls, RT
+ TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine
(RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted
AO/AOA, and similar OS to RT alone for AA.
CONCLUSIONS: RT + TMZ may be a promising treatment for both codeleted and
non-codeleted AO/AOA, but its role for AA remains unclear.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ijrobp.2014.10.027
PMID: 25636755 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12492109
|
1. Mol Cancer Ther. 2002 Aug;1(10):769-76.
Relationship of XIST expression and responses of ovarian cancer to chemotherapy.
Huang KC(1), Rao PH, Lau CC, Heard E, Ng SK, Brown C, Mok SC, Berkowitz RS, Ng
SW.
Author information:
(1)Laboratory of Gynecologic Oncology, Department of Obstetrics and Gynecology,
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
02115, USA.
Expression profiling to characterize cancer pharmacology has become a new
approach to discover novel molecular targets for prognostic markers and cancer
therapy. In a study to compare the global RNA expression profiles between
primary and recurrent ovarian tumors from the same patient, we have identified
XIST (inactive X chromosome-specific transcripts) as the most differentially
expressed gene that was down-regulated in the recurrent tumor. XIST encodes a
spliced noncoding polyadenylated transcript that is unique in being expressed
exclusively from the inactive X chromosome and is involved in the X-inactivation
process. Subsequent characterization of XIST expression in a panel of female
cancer cell lines showed that the expression level of XIST correlates
significantly with Taxol sensitivity. The clinical relevance of this observation
is demonstrated by the strong association between XIST RNA levels and
disease-free periods of ovarian cancer patients in a group of 21 ovarian cancer
cases with Taxol in the therapeutic regiments. Cytogenetic studies on ovarian
cancer cell lines indicated that loss of inactive X chromosome is one mechanism
for the loss of XIST transcripts in the cell lines. Our data suggest that XIST
expression may be a potential marker for chemotherapeutic responses in ovarian
cancer.
PMID: 12492109 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25200388
|
1. BMC Genet. 2014 Sep 9;15:89. doi: 10.1186/s12863-014-0089-4.
Differentially methylated CpG island within human XIST mediates alternative P2
transcription and YY1 binding.
Chapman AG(1), Cotton AM(2), Kelsey AD(3), Brown CJ(4).
Author information:
(1)Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences
Center, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
[email protected].
(2)Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences
Center, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
[email protected].
(3)Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences
Center, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
[email protected].
(4)Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences
Center, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
[email protected].
BACKGROUND: X-chromosome inactivation silences one X chromosome in females to
achieve dosage compensation with the single X chromosome in males. While most
genes are silenced on the inactive X chromosome, the gene for the long
non-coding RNA XIST is silenced on the active X chromosome and expressed from
the inactive X chromosome with which the XIST RNA associates, triggering
silencing of the chromosome. In mouse, an alternative Xist promoter, P2 is also
the site of YY1 binding, which has been shown to serve as a tether between the
Xist RNA and the DNA of the chromosome. In humans there are many differences
from the initial events of mouse Xist activation, including absence of a
functional antisense regulator Tsix, and absence of strictly paternal
inactivation in extraembryonic tissues, prompting us to examine regulatory
regions for the human XIST gene.
RESULTS: We demonstrate that the female-specific DNase hypersensitivity site
within XIST is specific to the inactive X chromosome and correlates with
transcription from an internal P2 promoter. P2 is located within a CpG island
that is differentially methylated between males and females and overlaps
conserved YY1 binding sites that are only bound on the inactive X chromosome
where the sites are unmethylated. However, YY1 binding is insufficient to drive
P2 expression or establish the DHS, which may require a development-specific
factor. Furthermore, reduction of YY1 reduces XIST transcription in addition to
causing delocalization of XIST.
CONCLUSIONS: The differentially methylated DNase hypersensitive site within XIST
marks the location of an alternative promoter, P2, that generates a transcript
of unknown function as it lacks the A repeats that are critical for silencing.
In addition, this region binds YY1 on the unmethylated inactive X chromosome,
and depletion of YY1 untethers the XIST RNA as well as decreasing transcription
of XIST.
DOI: 10.1186/s12863-014-0089-4
PMCID: PMC4363909
PMID: 25200388 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26282267
|
1. Genome Biol. 2015 Aug 15;16(1):166. doi: 10.1186/s13059-015-0733-y.
Xist localization and function: new insights from multiple levels.
Cerase A(1), Pintacuda G(2), Tattermusch A(2), Avner P(3)(4).
Author information:
(1)EMBL Mouse Biology Unit, Monterotondo, 00015 (RM), Italy.
[email protected].
(2)Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
(3)EMBL Mouse Biology Unit, Monterotondo, 00015 (RM), Italy. [email protected].
(4)Institut Pasteur, Unite de Genetique Moleculaire Murine, CNRS, URA2578,
Paris, France. [email protected].
In female mammals, one of the two X chromosomes in each cell is
transcriptionally silenced in order to achieve dosage compensation between the
genders in a process called X chromosome inactivation. The master regulator of
this process is the long non-coding RNA Xist. During X-inactivation, Xist
accumulates in cis on the future inactive X chromosome, triggering a cascade of
events that provoke the stable silencing of the entire chromosome, with
relatively few genes remaining active. How Xist spreads, what are its binding
sites, how it recruits silencing factors and how it induces a specific
topological and nuclear organization of the chromatin all remain largely
unanswered questions. Recent studies have improved our understanding of Xist
localization and the proteins with which it interacts, allowing a reappraisal of
ideas about Xist function. We discuss recent advances in our knowledge of
Xist-mediated silencing, focusing on Xist spreading, the nuclear organization of
the inactive X chromosome, recruitment of the polycomb complex and the role of
the nuclear matrix in the process of X chromosome inactivation.
DOI: 10.1186/s13059-015-0733-y
PMCID: PMC4539689
PMID: 26282267 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26477563
|
1. Nat Commun. 2015 Oct 19;6:8564. doi: 10.1038/ncomms9564.
An Xist-activating antisense RNA required for X-chromosome inactivation.
Sarkar MK(1), Gayen S(1), Kumar S(1), Maclary E(1), Buttigieg E(1), Hinten M(1),
Kumari A(1), Harris C(1), Sado T(2), Kalantry S(1).
Author information:
(1)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, Michigan 48109, USA.
(2)Department of Advanced Bioscience, Graduate School of Agriculture, Kinki
University, 3327-204 Nakamachi, Nara 631-8505, Japan.
The transcriptional imbalance due to the difference in the number of X
chromosomes between male and female mammals is remedied through X-chromosome
inactivation, the epigenetic transcriptional silencing of one of the two X
chromosomes in females. The X-linked Xist long non-coding RNA functions as an X
inactivation master regulator; Xist is selectively upregulated from the
prospective inactive X chromosome and is required in cis for X inactivation.
Here we discover an Xist antisense long non-coding RNA, XistAR (Xist Activating
RNA), which is encoded within exon 1 of the mouse Xist gene and is transcribed
only from the inactive X chromosome. Selective truncation of XistAR, while
sparing the overlapping Xist RNA, leads to a deficiency in Xist RNA expression
in cis during the initiation of X inactivation. Thus, the Xist gene carries
within its coding sequence an antisense RNA that drives Xist expression.
DOI: 10.1038/ncomms9564
PMCID: PMC4616153
PMID: 26477563 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20950563
|
1. Biol Aujourdhui. 2010;204(3):199-204. doi: 10.1051/jbio/2010013. Epub 2010 Oct
13.
[Establishing transcriptional silencing of the X chromosome during early
embryogenesis].
[Article in French]
Nora EP(1), Heard E.
Author information:
(1)Epigenese et developpement des mammiferes, Institut Curie, Paris, France.
Early development of female mammals is accompanied by transcriptional
inactivation of one of their two X chromosomes. This process, known as
X-chromosome inactivation, relies on monoallelic activation of the Xist gene.
Xist produces a non-coding RNA that can coat the chromosome from which it is
transcribed in cis and trigger its silencing. How Xist expression is controlled
and how it initiates transcriptional repression are central questions for our
understanding of how this chromosome-wide monoallelic program is expressed.
Several trans-acting factors have been identified as regulators of Xist
expression. Interestingly, some Xist activators are encoded by the X chromosome
itself, thereby efficiently promoting Xist expression in females (XX) but not in
males (XY). Female cells also display transient physical pairing between their
two X chromosomes at the level of their Xics (X inactivation centers) during the
time window when X inactivation is initiated. It has been proposed that these
pairing events may play a role in Xist activation and its monoallelic
regulation. Xist RNA accumulates over the X chromosome from which it is
expressed and rapidly triggers the exclusion of the transcription machinery.
Genic sequences are initially located outside of this Xist RNA coated domain but
as they become progressively silenced they are relocated into this silent
nuclear compartment created by Xist. However genes are not all silenced with the
same kinetics. Furthermore, some genes can escape X inactivation and remain
located outside the Xist-coated compartment. Recent findings have revealed that
young, active LINE-1 retrotransposons are expressed from the inactive X
chromosome and may facilitate X inactivation, particularly in regions of the X
that would otherwise be prone to escape.
© Société de Biologie, 2010.
DOI: 10.1051/jbio/2010013
PMID: 20950563 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26739568
|
1. Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E309-18. doi:
10.1073/pnas.1515971113. Epub 2016 Jan 6.
Sex-specific silencing of X-linked genes by Xist RNA.
Gayen S(1), Maclary E(1), Hinten M(1), Kalantry S(2).
Author information:
(1)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI 48109.
(2)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI 48109 [email protected].
X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to
catalyze silencing of X-linked genes in cis during X-chromosome inactivation,
which equalizes X-linked gene dosage between male and female mammals. To test
the impact of Xist RNA on X-linked gene silencing, we ectopically induced
endogenous Xist by ablating the antisense repressor Tsix in mice. We find that
ectopic Xist RNA induction and subsequent X-linked gene silencing is sex
specific in embryos and in differentiating embryonic stem cells (ESCs) and
epiblast stem cells (EpiSCs). A higher frequency of X(ΔTsix)Y male cells
displayed ectopic Xist RNA coating compared with X(ΔTsix)X female cells. This
increase reflected the inability of X(ΔTsix)Y cells to efficiently silence
X-linked genes compared with X(ΔTsix)X cells, despite equivalent Xist RNA
induction and coating. Silencing of genes on both Xs resulted in significantly
reduced proliferation and increased cell death in X(ΔTsix)X female cells
relative to X(ΔTsix)Y male cells. Thus, whereas Xist RNA can inactivate the X
chromosome in females it may not do so in males. We further found comparable
silencing in differentiating X(ΔTsix)Y and 39,X(ΔTsix) (X(ΔTsix)O) ESCs,
excluding the Y chromosome and instead implicating the X-chromosome dose as the
source of the sex-specific differences. Because X(ΔTsix)X female embryonic
epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic
inactivation of the active X(ΔTsix) X chromosome, we propose that the increased
expression of one or more X-inactivation escapees activates Xist and,
separately, helps trigger X-linked gene silencing.
DOI: 10.1073/pnas.1515971113
PMCID: PMC4725534
PMID: 26739568 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/32535328
|
1. Curr Opin Cell Biol. 2020 Jun;64:139-147. doi: 10.1016/j.ceb.2020.04.009. Epub
2020 Jun 11.
Xist drives spatial compartmentalization of DNA and protein to orchestrate
initiation and maintenance of X inactivation.
Strehle M(1), Guttman M(2).
Author information:
(1)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, CA 91125, USA.
(2)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, CA 91125, USA. Electronic address: [email protected].
X chromosome inactivation (XCI) is the process whereby one of the X chromosomes
in female mammalian cells is silenced to equalize X-linked gene expression with
males. XCI depends on the long noncoding RNA Xist, which coats the inactive X
chromosome in cis and triggers a cascade of events that ultimately lead to
chromosome-wide transcriptional silencing that is stable for the lifetime of an
organism. In recent years, the discovery of proteins that interact with Xist
have led to new insights into how the initiation of XCI occurs. Nevertheless,
there are still various unknowns about the mechanisms by which Xist orchestrates
and maintains stable X-linked silencing. Here, we review recent work elucidating
the role of Xist and its protein partners in mediating chromosome-wide
transcriptional repression, as well as discuss a model by which Xist may
compartmentalize proteins across the inactive X chromosome to enable both the
initiation and maintenance of XCI.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ceb.2020.04.009
PMID: 32535328 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement Nothing declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/29910081
|
1. Trends Cell Biol. 2018 Dec;28(12):999-1013. doi: 10.1016/j.tcb.2018.05.005.
Epub 2018 Jun 14.
The Role of Xist in X-Chromosome Dosage Compensation.
Sahakyan A(1), Yang Y(1), Plath K(2).
Author information:
(1)David Geffen School of Medicine, Department of Biological Chemistry, Eli and
Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson
Comprehensive Cancer Center, Molecular Biology Institute, University of
California Los Angeles, Los Angeles, CA 90095, USA.
(2)David Geffen School of Medicine, Department of Biological Chemistry, Eli and
Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson
Comprehensive Cancer Center, Molecular Biology Institute, University of
California Los Angeles, Los Angeles, CA 90095, USA. Electronic address:
[email protected].
In each somatic cell of a female mammal one X chromosome is transcriptionally
silenced via X-chromosome inactivation (XCI), initiating early in development.
Although XCI events are conserved in mouse and human postimplantation
development, regulation of X-chromosome dosage in preimplantation development
occurs differently. In preimplantation development, mouse embryos undergo
imprinted form of XCI, yet humans lack imprinted XCI and instead regulate gene
expression of both X chromosomes by dampening transcription. The long non-coding
RNA Xist/XIST is expressed in mouse and human preimplantation and
postimplantation development to orchestrate XCI, but its role in dampening is
unclear. In this review, we discuss recent advances in our understanding of the
role of Xist in X chromosome dosage compensation in mouse and human.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2018.05.005
PMCID: PMC6249047
PMID: 29910081 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28236732
|
1. Curr Opin Cell Biol. 2017 Jun;46:54-61. doi: 10.1016/j.ceb.2017.01.007. Epub
2017 Feb 23.
X chromosome inactivation: silencing, topology and reactivation.
Robert Finestra T(1), Gribnau J(2).
Author information:
(1)Department of Developmental Biology, Erasmus MC, Wytemaweg 80, Rotterdam CN
3015, The Netherlands.
(2)Department of Developmental Biology, Erasmus MC, Wytemaweg 80, Rotterdam CN
3015, The Netherlands. Electronic address: [email protected].
To ensure X-linked gene dosage compensation between females (XX) and males (XY),
one X chromosome undergoes X chromosome inactivation (XCI) in female cells. This
process is tightly regulated throughout development by many different factors,
with Xist as a key regulator, encoding a long non-coding RNA, involved in
establishment of several layers of repressive epigenetic modifications. Several
recent studies on XCI focusing on identification and characterization of Xist
RNA-protein interactors, revealed new factors involved in gene silencing, genome
topology and nuclear membrane attachment, amongst others. Also, new insights in
higher order chromatin organization have been presented, revealing differences
between the topological organization of active and inactive X chromosomes (Xa
and Xi), with associated differences in gene expression. Finally, further
evidence indicates that the inactive state of the Xi can be (partially)
reversed, and that this X chromosome reactivation (XCR) might be associated with
disease.
Copyright © 2017. Published by Elsevier Ltd.
DOI: 10.1016/j.ceb.2017.01.007
PMID: 28236732 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31537017
|
1. PLoS Genet. 2019 Sep 19;15(9):e1008333. doi: 10.1371/journal.pgen.1008333.
eCollection 2019 Sep.
Xist RNA in action: Past, present, and future.
Loda A(1), Heard E(1)(2).
Author information:
(1)Directors' research, European Molecular Biology Laboratory (EMBL),
Heidelberg, Germany.
(2)Collège de France, Paris, France.
In mammals, dosage compensation of sex chromosomal genes between females (XX)
and males (XY) is achieved through X-chromosome inactivation (XCI). The X-linked
X-inactive-specific transcript (Xist) long noncoding RNA is indispensable for
XCI and initiates the process early during development by spreading in cis
across the X chromosome from which it is transcribed. During XCI, Xist RNA
triggers gene silencing, recruits a plethora of chromatin modifying factors, and
drives a major structural reorganization of the X chromosome. Here, we review
our knowledge of the multitude of epigenetic events orchestrated by Xist RNA to
allow female mammals to survive through embryonic development by establishing
and maintaining proper dosage compensation. In particular, we focus on recent
studies characterizing the interaction partners of Xist RNA, and we discuss how
they have affected the field by addressing long-standing controversies or by
giving rise to new research perspectives that are currently being explored. This
review is dedicated to the memory of Denise Barlow, pioneer of genomic
imprinting and functional long noncoding RNAs (lncRNAs), whose work has
revolutionized the epigenetics field and continues to inspire generations of
scientists.
DOI: 10.1371/journal.pgen.1008333
PMCID: PMC6752956
PMID: 31537017 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/29701779
|
1. Hum Mol Genet. 2018 Aug 1;27(R2):R242-R249. doi: 10.1093/hmg/ddy148.
The eXceptional nature of the X chromosome.
Balaton BP(1), Dixon-McDougall T(1), Peeters SB(1), Brown CJ(1).
Author information:
(1)Molecular Epigenetics Group, Department of Medical Genetics, Life Sciences
Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
The X chromosome is unique in the genome. In this review we discuss recent
advances in our understanding of the genetics and epigenetics of the X
chromosome. The X chromosome shares limited conservation with its ancestral
homologue the Y chromosome and the resulting difference in X-chromosome dosage
between males and females is largely compensated for by X-chromosome
inactivation. The process of inactivation is initiated by the long non-coding
RNA X-inactive specific transcript (XIST) and achieved through interaction with
multiple synergistic silencing pathways. Identification of Xist-interacting
proteins has given insight into these processes yet the cascade of events from
initiation to maintenance have still to be resolved. In particular, the
initiation of inactivation in humans has been challenging to study as: it occurs
very early in development; most human embryonic stem cell lines already have an
inactive X; and the process seems to differ from mouse. Another difference
between human and mouse X inactivation is the larger number of human genes that
escape silencing. In humans over 20% of X-linked genes continue to be expressed
from the otherwise inactive X chromosome. We are only beginning to understand
how such escape occurs but there is growing recognition that escapees contribute
to sexually dimorphic traits. The unique biology and epigenetics of the X
chromosome have often led to its exclusion from disease studies, yet the X
constitutes 5% of the genome and is an important contributor to disease, often
in a sex-specific manner.
DOI: 10.1093/hmg/ddy148
PMCID: PMC6061837
PMID: 29701779 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32482714
|
1. Genes Dev. 2020 Jun 1;34(11-12):733-744. doi: 10.1101/gad.337196.120.
Progress toward understanding chromosome silencing by Xist RNA.
Brockdorff N(1), Bowness JS(1), Wei G(1).
Author information:
(1)Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United
Kingdom.
The X inactive-specific transcript (Xist) gene is the master regulator of X
chromosome inactivation in mammals. Xist produces a long noncoding (lnc)RNA that
accumulates over the entire length of the chromosome from which it is
transcribed, recruiting factors to modify underlying chromatin and silence
X-linked genes in cis Recent years have seen significant progress in identifying
important functional elements in Xist RNA, their associated RNA-binding proteins
(RBPs), and the downstream pathways for chromatin modification and gene
silencing. In this review, we summarize progress in understanding both how these
pathways function in Xist-mediated silencing and the complex interplay between
them.
© 2020 Brockdorff et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gad.337196.120
PMCID: PMC7263139
PMID: 32482714 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28947655
|
1. Philos Trans R Soc Lond B Biol Sci. 2017 Nov 5;372(1733):20160356. doi:
10.1098/rstb.2016.0356.
Mechanistic insights in X-chromosome inactivation.
Lu Z(1), Carter AC(1), Chang HY(2).
Author information:
(1)Center for Dynamic Personal Regulomes, Stanford University, Stanford, CA
94305, USA.
(2)Center for Dynamic Personal Regulomes, Stanford University, Stanford, CA
94305, USA [email protected].
X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing
gene dosage between XY males and XX females in eutherian mammals. A long
non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this
multi-step process, resulting in the inheritable silencing of one of the two
X-chromosomes in females. The XIST RNA is large and complex, exemplifying the
unique challenges associated with the structural and functional analysis of
lncRNAs. Recent technological advances in the analysis of macromolecular
structure and interactions have enabled us to systematically dissect the XIST
ribonucleoprotein complex, which is larger than the ribosome, and its place of
action, the inactive X-chromosome. These studies shed light on key mechanisms of
XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and
histone modification enzymes, and compaction and compartmentalization of the
inactive X. Here, we summarize recent studies on XCI, highlight the critical
contributions of new technologies and propose a unifying model for XIST function
in XCI where modular domains serve as the structural and functional units in
both lncRNA-protein complexes and DNA-protein complexes in chromatin.This
article is part of the themed issue 'X-chromosome inactivation: a tribute to
Mary Lyon'.
© 2017 The Author(s).
DOI: 10.1098/rstb.2016.0356
PMCID: PMC5627158
PMID: 28947655 [Indexed for MEDLINE]
Conflict of interest statement: We have no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/23166390
|
1. Philos Trans R Soc Lond B Biol Sci. 2013 Jan 5;368(1609):20110325. doi:
10.1098/rstb.2011.0325.
Advances in understanding chromosome silencing by the long non-coding RNA Xist.
Sado T(1), Brockdorff N.
Author information:
(1)Division of Epigenomics, Medical Institute of Bioregulation, Kyushu
University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
[email protected]
In female mammals, one of the two X chromosomes becomes genetically silenced to
compensate for dosage imbalance of X-linked genes between XX females and XY
males. X chromosome inactivation (X-inactivation) is a classical model for
epigenetic gene regulation in mammals and has been studied for half a century.
In the last two decades, efforts have been focused on the X inactive-specific
transcript (Xist) locus, discovered to be the master regulator of
X-inactivation. The Xist gene produces a non-coding RNA that functions as the
primary switch for X-inactivation, coating the X chromosome from which it is
transcribed in cis. Significant progress has been made towards understanding how
Xist is regulated at the onset of X-inactivation, but our understanding of the
molecular basis of silencing mediated by Xist RNA has progressed more slowly. A
picture has, however, begun to emerge, and new tools and resources hold out the
promise of further advances to come. Here, we provide an overview of the current
state of our knowledge, what is known about Xist RNA and how it may trigger
chromosome silencing.
DOI: 10.1098/rstb.2011.0325
PMCID: PMC3539355
PMID: 23166390 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17333537
|
1. Chromosome Res. 2007;15(2):127-36. doi: 10.1007/s10577-006-1115-9. Epub 2007
Mar 5.
Genes flanking Xist in mouse and human are separated on the X chromosome in
American marsupials.
Shevchenko AI(1), Zakharova IS, Elisaphenko EA, Kolesnikov NN, Whitehead S, Bird
C, Ross M, Weidman JR, Jirtle RL, Karamysheva TV, Rubtsov NB, VandeBerg JL,
Mazurok NA, Nesterova TB, Brockdorff N, Zakian SM.
Author information:
(1)Institute of Cytology and Genetics, Russian Academy of Sciences, Siberian
Department, Novosibirsk, Russia.
X inactivation, the transcriptional silencing of one of the two X chromosomes in
female mammals, achieves dosage compensation of X-linked genes relative to XY
males. In eutherian mammals X inactivation is regulated by the X-inactive
specific transcript (Xist), a cis-acting non-coding RNA that triggers silencing
of the chromosome from which it is transcribed. Marsupial mammals also undergo X
inactivation but the mechanism is relatively poorly understood. We set out to
analyse the X chromosome in Monodelphis domestica and Didelphis virginiana,
focusing on characterizing the interval defined by the Chic1 and Slc16a2 genes
that in eutherians flank the Xist locus. The synteny of this region is retained
on chicken chromosome 4 where other loci belonging to the evolutionarily ancient
stratum of the human X chromosome, the so-called X conserved region (XCR), are
also located. We show that in both M. domestica and D. virginiana an
evolutionary breakpoint has separated the Chic1 and Slc16a2 loci. Detailed
analysis of opossum genomic sequences revealed linkage of Chic1 with the Lnx3
gene, recently proposed to be the evolutionary precursor of Xist, and Fip1, the
evolutionary precursor of Tsx, a gene located immediately downstream of Xist in
eutherians. We discuss these findings in relation to the evolution of Xist and X
inactivation in mammals.
DOI: 10.1007/s10577-006-1115-9
PMCID: PMC2797855
PMID: 17333537 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30496473
|
1. Nucleic Acids Res. 2019 Feb 20;47(3):1532-1543. doi: 10.1093/nar/gky1198.
Developmental Xist induction is mediated by enhanced splicing.
Stork C(1), Li Z(2), Lin L(3), Zheng S(1)(2)(3).
Author information:
(1)Graduate Program in Cell, Molecular and Developmental Biology, University of
California, Riverside, Riverside, CA 92521, USA.
(2)Graduate Program in Genetics, Genomics and Bioinformatics, University of
California, Riverside, Riverside, CA 92521, USA.
(3)Division of Biomedical Sciences, University of California, Riverside,
Riverside, CA 92521, USA.
X-inactive-specific transcript (Xist) is a long noncoding RNA (lncRNA) essential
for inactivating one of the two X chromosomes in mammalian females. Random X
chromosome inactivation is mediated by Xist RNA expressed from the inactive X
chromosome. We found that Xist RNA is unspliced in naïve embryonic stem (ES)
cells. Upon differentiation, Xist splicing becomes efficient across all exons
independent of transcription, suggesting interdependent or coordinated removal
of Xist introns. In female cells with mutated polypyrimidine tract binding
protein 1 (Ptbp1), differentiation fails to substantially upregulate mature Xist
RNA because of a defect in Xist splicing. We further found both Xist129 and
XistCAS RNA are unspliced in Mus musculus 129SvJ/Mus castaneous (CAS) hybrid
female ES cells. Upon differentiation, Xist129 exhibits a higher splicing
efficiency than XistCAS, likely contributing to preferential inhibition of the
X129 chromosome. Single cell analysis shows that the allelic choice of Xist
splicing is linked to the inactive X chromosome. We conclude
post-transcriptional control of Xist RNA splicing is an essential regulatory
step of Xist induction. Our studies shed light on the developmental roles of
splicing for nuclear-retained Xist lncRNA and suggest inefficient Xist splicing
is an additional fail-safe mechanism to prevent Xist activity in ES cells.
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gky1198
PMCID: PMC6379716
PMID: 30496473 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26489649
|
1. Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14415-22. doi:
10.1073/pnas.1519528112. Epub 2015 Oct 21.
Xist imprinting is promoted by the hemizygous (unpaired) state in the male germ
line.
Sun S(1), Payer B(2), Namekawa S(3), An JY(2), Press W(2), Catalan-Dibene J(4),
Sunwoo H(2), Lee JT(5).
Author information:
(1)Department of Molecular Biology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114; Department of Genetics, Harvard Medical
School, Boston, MA 02114; Department of Developmental and Cell Biology, School
of Biological Sciences, University of California, Irvine, CA 92697;
(2)Department of Molecular Biology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114; Department of Genetics, Harvard Medical
School, Boston, MA 02114;
(3)Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's
Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics,
University of Cincinnati College of Medicine, Cincinnati, OH 45229;
(4)Department of Developmental and Cell Biology, School of Biological Sciences,
University of California, Irvine, CA 92697;
(5)Department of Molecular Biology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114; Department of Genetics, Harvard Medical
School, Boston, MA 02114; Howard Hughes Medical Institute, Harvard Medical
School, Boston, MA 02114 [email protected].
Comment in
Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14408-9. doi:
10.1073/pnas.1520097112.
The long noncoding X-inactivation-specific transcript (Xist gene) is responsible
for mammalian X-chromosome dosage compensation between the sexes, the process by
which one of the two X chromosomes is inactivated in the female soma. Xist is
essential for both the random and imprinted forms of X-chromosome inactivation.
In the imprinted form, Xist is paternally marked to be expressed in female
embryos. To investigate the mechanism of Xist imprinting, we introduce Xist
transgenes (Tg) into the male germ line. Although ectopic high-level Xist
expression on autosomes can be compatible with viability, transgenic animals
demonstrate reduced fitness, subfertility, defective meiotic pairing, and other
germ-cell abnormalities. In the progeny, paternal-specific expression is
recapitulated by the 200-kb Xist Tg. However, Xist imprinting occurs efficiently
only when it is in an unpaired or unpartnered state during male meiosis. When
transmitted from a hemizygous father (+/Tg), the Xist Tg demonstrates
paternal-specific expression in the early embryo. When transmitted by a
homozygous father (Tg/Tg), the Tg fails to show imprinted expression. Thus, Xist
imprinting is directed by sequences within a 200-kb X-linked region, and the
hemizygous (unpaired) state of the Xist region promotes its imprinting in the
male germ line.
DOI: 10.1073/pnas.1519528112
PMCID: PMC4664331
PMID: 26489649 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/14973270
|
1. Development. 2004 Mar;131(5):975-82. doi: 10.1242/dev.00995.
De novo DNA methylation is dispensable for the initiation and propagation of X
chromosome inactivation.
Sado T(1), Okano M, Li E, Sasaki H.
Author information:
(1)Division of Human Genetics, National Institute of Genetics, 1111 Yata,
Mishima 411-8540, Japan. [email protected]
Xist (X-inactive specific transcript) plays a crucial role in X-inactivation.
This non-coding RNA becomes upregulated on the X chromosome that is to be
inactivated upon differentiation. Previous studies have revealed that although
maintenance-type DNA methylation is not essential for X-inactivation to occur,
it is required for the stable repression of Xist in differentiated cells.
However, it is unknown whether differential de novo methylation at the Xist
promoter, which is mediated by Dnmt3a and/or Dnmt3b, is a cause or a consequence
of monoallelic expression of Xist. We show that Xist expression is appropriately
regulated in the absence of Dnmt3a and Dnmt3b and that a single X chromosome
undergoes proper inactivation in mutant females. Our results indicate that a
mechanism(s) other than DNA methylation plays a principal role in initiating
X-inactivation. We also demonstrate that delayed upregulation of Xist does not
induce X-inactivation, consistent with a crucial developmental window for the
chromosomal silencing.
DOI: 10.1242/dev.00995
PMID: 14973270 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21212949
|
1. World J Surg. 2011 Aug;35(8):1751-6. doi: 10.1007/s00268-010-0951-0.
Expression and function of a large non-coding RNA gene XIST in human cancer.
Weakley SM(1), Wang H, Yao Q, Chen C.
Author information:
(1)Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery,
Baylor College of Medicine, One Baylor Plaza, Mail stop: BCM391, Houston, TX
77030, USA.
BACKGROUND: X inactive-specific transcript (XIST) RNA is involved in X
chromosome silencing in female cells and allows X chromosome equilibration with
males. X inactive-specific transcript expression has been found to be
dysregulated in a variety of human cancers when compared to normal cells;
meanwhile, the inactivated X chromosome has been noted to be conspicuously
absent in human cancer specimens, whereas X chromosome duplications are widely
noted. The specific pathways whereby changes in X chromosome status and XIST
expression occur in cancer remain incompletely described. Nevertheless, a role
for XIST in BRCA1-mediated epigenetic activity has been proposed.
METHODS: Here we review the data regarding XIST expression and X chromosome
status in a variety of female, male, and non-sex-related human cancers.
CONCLUSIONS: It is not yet known whether X chromosome duplication, XIST
dysregulation, and over-expression of X-linked genes represent important factors
in tumorgenesis or are simply a consequence of overall epigenetic instability in
these cancers.
DOI: 10.1007/s00268-010-0951-0
PMCID: PMC3275083
PMID: 21212949 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33348832
|
1. Cells. 2020 Dec 17;9(12):2706. doi: 10.3390/cells9122706.
New Insights into X-Chromosome Reactivation during Reprogramming to
Pluripotency.
Panda A(1), Zylicz JJ(2), Pasque V(1).
Author information:
(1)Laboratory of Cellular Reprogramming and Epigenetic Regulation, Department of
Development and Regeneration, Leuven Stem Cell Institute, KU Leuven-University
of Leuven, 3000 Leuven, Belgium.
(2)The Novo Nordisk Foundation Center for Stem Cell Biology, University of
Copenhagen, 2200 Copenhagen, Denmark.
Dosage compensation between the sexes results in one X chromosome being
inactivated during female mammalian development. Chromosome-wide transcriptional
silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a
process termed X-chromosome reactivation (XCR), which has emerged as a paradigm
for studying the reversal of chromatin silencing. XCR is linked with germline
development and induction of naive pluripotency in the epiblast, and also takes
place upon reprogramming somatic cells to induced pluripotency. XCR depends on
silencing of the long non-coding RNA (lncRNA) X inactive specific transcript
(Xist) and is linked with the erasure of chromatin silencing. Over the past
years, the advent of transcriptomics and epigenomics has provided new insights
into the transcriptional and chromatin dynamics with which XCR takes place.
However, multiple questions remain unanswered about how chromatin and
transcription related processes enable XCR. Here, we review recent work on
establishing the transcriptional and chromatin kinetics of XCR, as well as
discuss a model by which transcription factors mediate XCR not only via Xist
repression, but also by direct targeting of X-linked genes.
DOI: 10.3390/cells9122706
PMCID: PMC7766869
PMID: 33348832 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no known conflict of
interest. The funders had no role the writing of the manuscript.
|
http://www.ncbi.nlm.nih.gov/pubmed/11780141
|
1. Nat Genet. 2002 Feb;30(2):167-74. doi: 10.1038/ng820. Epub 2002 Jan 7.
Chromosomal silencing and localization are mediated by different domains of Xist
RNA.
Wutz A(1), Rasmussen TP, Jaenisch R.
Author information:
(1)Whitehead Institute for Biomedical Research, Nine Cambridge Center,
Cambridge, Massachusetts 02142, USA.
The gene Xist initiates the chromosomal silencing process of X inactivation in
mammals. Its product, a noncoding RNA, is expressed from and specifically
associates with the inactive X chromosome in female cells. Here we use an
inducible Xist expression system in mouse embryonic stem cells that
recapitulates long-range chromosomal silencing to elucidate which Xist RNA
sequences are necessary for chromosomal association and silencing. We show that
chromosomal association and spreading of Xist RNA can be functionally separated
from silencing by specific mutations. Silencing requires a conserved repeat
sequence located at the 5' end of Xist. Deletion of this element results in Xist
RNA that still associates with chromatin and spreads over the chromosome but
does not effect transcriptional repression. Association of Xist RNA with
chromatin is mediated by functionally redundant sequences that act cooperatively
and are dispersed throughout the remainder of Xist but show little or no
homology.
DOI: 10.1038/ng820
PMID: 11780141 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25489864
|
1. J Vis Exp. 2014 Nov 26;(93):e52053. doi: 10.3791/52053.
Quick fluorescent in situ hybridization protocol for Xist RNA combined with
immunofluorescence of histone modification in X-chromosome inactivation.
Yue M(1), Charles Richard JL(1), Yamada N(1), Ogawa A(2), Ogawa Y(3).
Author information:
(1)Division of Reproductive Sciences, Cincinnati Children's Hospital Medical
Center; Department of Pediatrics, University of Cincinnati College of Medicine.
(2)Division of Reproductive Sciences, Cincinnati Children's Hospital Medical
Center.
(3)Division of Reproductive Sciences, Cincinnati Children's Hospital Medical
Center; Department of Pediatrics, University of Cincinnati College of Medicine;
[email protected].
Combining RNA fluorescent in situ hybridization (FISH) with immunofluorescence
(immuno-FISH) creates a technique that can be employed at the single cell level
to detect the spatial dynamics of RNA localization with simultaneous insight
into the localization of proteins, epigenetic modifications and other details
which can be highlighted by immunofluorescence. X-chromosome inactivation is a
paradigm for long non-coding RNA (lncRNA)-mediated gene silencing. X-inactive
specific transcript (Xist) lncRNA accumulation (called an Xist cloud) on one of
the two X-chromosomes in mammalian females is a critical step to initiate
X-chromosome inactivation. Xist RNA directly or indirectly interacts with
various chromatin-modifying enzymes and introduces distinct epigenetic
landscapes to the inactive X-chromosome (Xi). One known epigenetic hallmark of
the Xi is the Histone H3 trimethyl-lysine 27 (H3K27me3) modification. Here, we
describe a simple and quick immuno-FISH protocol for detecting Xist RNA using
RNA FISH with multiple oligonucleotide probes coupled with immunofluorescence of
H3K27me3 to examine the localization of Xist RNA and associated epigenetic
modifications. Using oligonucleotide probes results in a shorter incubation time
and more sensitive detection of Xist RNA compared to in vitro transcribed RNA
probes (riboprobes). This protocol provides a powerful tool for understanding
the dynamics of lncRNAs and its associated epigenetic modification, chromatin
structure, nuclear organization and transcriptional regulation.
DOI: 10.3791/52053
PMCID: PMC4354415
PMID: 25489864 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16679409
|
1. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7706-11. doi:
10.1073/pnas.0602021103. Epub 2006 May 5.
Attenuated spread of X-inactivation in an X;autosome translocation.
Popova BC(1), Tada T, Takagi N, Brockdorff N, Nesterova TB.
Author information:
(1)Developmental Epigenetics, Medical Research Council Clinical Sciences Center,
Imperial College Faculty of Medicine, Hammersmith Hospital, DuCane Road, London
W12 ONN, United Kingdom.
X inactivation in female mammals involves transcriptional silencing of an entire
chromosome in response to a cis-acting noncoding RNA, the X inactive-specific
transcript (Xist). Xist can also inactivate autosomal sequences, for example, in
X;autosome translocations; but here, silencing appears to be relatively
inefficient. This variation has been attributed to either attenuated spreading
of Xist RNA at the onset of X inactivation or inefficient maintenance of
autosomal silencing. Evidence to date has favored the latter. Here, we
demonstrate attenuated spreading of Xist RNA at the onset of X inactivation in
the T(X;4)37H X;autosome translocation. Our findings provide direct evidence
that underlying chromosome/chromatin features can disrupt spreading of the
primary inactivating signal.
DOI: 10.1073/pnas.0602021103
PMCID: PMC1472509
PMID: 16679409 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: No conflicts
declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/30539545
|
1. Methods Mol Biol. 2019;1870:41-50. doi: 10.1007/978-1-4939-8808-2_3.
Visualization of Xist Long Noncoding RNA with a Fluorescent CRISPR/Cas9 System.
Waśko U(1), Zheng Z(1), Bhatnagar S(2).
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Virginia
School of Medicine, Charlottesville, VA, USA.
(2)Department of Biochemistry and Molecular Genetics, University of Virginia
School of Medicine, Charlottesville, VA, USA. [email protected].
X-inactive specific transcript (Xist) is a long noncoding RNA that is essential
for initiating and maintaining epigenetic silencing of one copy of the X
chromosome in mammalian females. But the mechanism by which Xist localizes and
spreads on the X chromosome and facilitates transcriptional silencing remains
largely unknown. This limited understanding, at least in part, is due to the
technical difficulties in the visualization and functional characterization of
Xist. Development of a successful method for Xist tracking is a key to better
understanding of the X chromosome silencing, as well as to gain insight into the
regulatory role of other long noncoding RNAs. Here, we describe an alternative
method for visualization of Xist lncRNA in cells using a CRISPR/Cas9-based
approach. This strategy is relatively simple approach to track Xist at different
stages of cell differentiation, providing mechanistic insights into the
initiation, maintenance, and establishment of X inactivation.
DOI: 10.1007/978-1-4939-8808-2_3
PMID: 30539545 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22722828
|
1. Nature. 2012 Jul 12;487(7406):254-8. doi: 10.1038/nature11171.
Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation.
Grant J(1), Mahadevaiah SK, Khil P, Sangrithi MN, Royo H, Duckworth J, McCarrey
JR, VandeBerg JL, Renfree MB, Taylor W, Elgar G, Camerini-Otero RD, Gilchrist
MJ, Turner JM.
Author information:
(1)MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London
NW71AA, UK.
In female (XX) mammals, one of the two X chromosomes is inactivated to ensure an
equal dose of X-linked genes with males (XY). X-chromosome inactivation in
eutherian mammals is mediated by the non-coding RNA Xist. Xist is not found in
metatherians (marsupials), and how X-chromosome inactivation is initiated in
these mammals has been the subject of speculation for decades. Using the
marsupial Monodelphis domestica, here we identify Rsx (RNA-on-the-silent X), an
RNA that has properties consistent with a role in X-chromosome inactivation. Rsx
is a large, repeat-rich RNA that is expressed only in females and is transcribed
from, and coats, the inactive X chromosome. In female germ cells, in which both
X chromosomes are active, Rsx is silenced, linking Rsx expression to
X-chromosome inactivation and reactivation. Integration of an Rsx transgene on
an autosome in mouse embryonic stem cells leads to gene silencing in cis. Our
findings permit comparative studies of X-chromosome inactivation in mammals and
pose questions about the mechanisms by which X-chromosome inactivation is
achieved in eutherians.
DOI: 10.1038/nature11171
PMCID: PMC3484893
PMID: 22722828 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30091314
|
1. Yonsei Med J. 2018 Sep;59(7):816-826. doi: 10.3349/ymj.2018.59.7.816.
XIST Induced by JPX Suppresses Hepatocellular Carcinoma by Sponging miR-155-5p.
Lin XQ(1), Huang ZM(1), Chen X(1), Wu F(1), Wu W(2).
Author information:
(1)Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China.
(2)Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China. [email protected].
PURPOSE: The influence of X-inactive specific transcript (XIST) and X-chromosome
inactivation associated long non-coding RNAs (lncRNAs) just proximal to XIST
(JPX) on hepatocellular carcinoma (HCC) remains controversial in light of
previous reports, which the present study aimed to verify.
MATERIALS AND METHODS: The DIANA lncRNA-microRNA (miRNA) interaction database
was used to explore miRNA interactions with JPX or XIST. JPX, XIST, and
miR-155-5p expression levels in paired HCC specimens and adjacent normal tissue
were analyzed by RT-qPCR. Interaction between XIST and miR-155-5p was verified
by dual luciferase reporter assay. Expression levels of miR-155-5p and its known
target genes, SOX6 and PTEN, were verified by RT-qPCR and Western blot in HepG2
cells with or without XIST knock-in. The potential suppressive role of XIST and
JPX on HCC was verified by cell functional assays and tumor formation assay
using a xenograft model.
RESULTS: JPX and XIST expression was significantly decreased in HCC pathologic
specimens, compared to adjacent tissue, which correlated with HCC progression
and increased miR-155-5p expression. Dual luciferase reporter assay revealed
XIST as a direct target of miR-155-5p. XIST knock-in significantly reduced
miR-155-5p expression level and increased that of SOX6 and PTEN, while
significantly inhibiting HepG2 cell growth in vitro, which was partially
reversed by miR-155-5p mimic transfection. JPX knock-in significantly increased
XIST expression and inhibited HepG2 cell growth in vitro or tumor formation in
vivo in a XIST dependent manner.
CONCLUSION: JPX and XIST play a suppressive role in HCC. JPX increases
expression levels of XIST in HCC cells, which suppresses HCC development by
sponging the cancer promoting miR-155-5p.
© Copyright: Yonsei University College of Medicine 2018.
DOI: 10.3349/ymj.2018.59.7.816
PMCID: PMC6082978
PMID: 30091314 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no financial conflicts of
interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/25000994
|
1. Annu Rev Cell Dev Biol. 2014;30:561-80. doi:
10.1146/annurev-cellbio-101512-122415. Epub 2014 Jun 27.
Noncoding RNAs and epigenetic mechanisms during X-chromosome inactivation.
Gendrel AV(1), Heard E.
Author information:
(1)Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology
Unit, Institut Curie, 75248 Paris, France; email: [email protected].
In mammals, the process of X-chromosome inactivation ensures equivalent levels
of X-linked gene expression between males and females through the silencing of
one of the two X chromosomes in female cells. The process is established early
in development and is initiated by a unique locus, which produces a long
noncoding RNA, Xist. The Xist transcript triggers gene silencing in cis by
coating the future inactive X chromosome. It also induces a cascade of chromatin
changes, including posttranslational histone modifications and DNA methylation,
and leads to the stable repression of all X-linked genes throughout development
and adult life. We review here recent progress in our understanding of the
molecular mechanisms involved in the initiation of Xist expression, the
propagation of the Xist RNA along the chromosome, and the cis-elements and
trans-acting factors involved in the maintenance of the repressed state. We also
describe the diverse strategies used by nonplacental mammals for X-chromosome
dosage compensation and highlight the common features and differences between
eutherians and metatherians, in particular regarding the involvement of long
noncoding RNAs.
DOI: 10.1146/annurev-cellbio-101512-122415
PMID: 25000994 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20657585
|
1. Nat Struct Mol Biol. 2010 Aug;17(8):948-54. doi: 10.1038/nsmb.1877. Epub 2010
Jul 25.
The A-repeat links ASF/SF2-dependent Xist RNA processing with random choice
during X inactivation.
Royce-Tolland ME(1), Andersen AA, Koyfman HR, Talbot DJ, Wutz A, Tonks ID, Kay
GF, Panning B.
Author information:
(1)Department of Biochemistry and Biophysics, University of California, San
Francisco, California, USA.
One X chromosome, selected at random, is silenced in each female mammalian cell.
Xist encodes a noncoding RNA that influences the probability that the cis-linked
X chromosome will be silenced. We found that the A-repeat, a highly conserved
element within Xist, is required for the accumulation of spliced Xist RNA. In
addition, the A-repeat is necessary for X-inactivation to occur randomly. In
combination, our data suggest that normal Xist RNA processing is important in
the regulation of random X-inactivation. We propose that modulation of Xist RNA
processing may be part of the stochastic process that determines which X
chromosome will be inactivated.
DOI: 10.1038/nsmb.1877
PMCID: PMC4336797
PMID: 20657585 [Indexed for MEDLINE]
Conflict of interest statement: COMPETING FINANCIAL INTERESTS The authors
declare no competing financial interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/21626138
|
1. Hum Genet. 2011 Aug;130(2):223-36. doi: 10.1007/s00439-011-1008-7. Epub 2011
May 28.
Xist regulation and function explored.
Pontier DB(1), Gribnau J.
Author information:
(1)Department of Reproduction and Development, Erasmus MC, Dr. Molewaterplein
50, 3015 GE Rotterdam, The Netherlands.
X chromosome inactivation (XCI) is a process in mammals that ensures equal
transcript levels between males and females by genetic inactivation of one of
the two X chromosomes in females. Central to XCI is the long non-coding RNA
Xist, which is highly and specifically expressed from the inactive X chromosome.
Xist covers the X chromosome in cis and triggers genetic silencing, but its
working mechanism remains elusive. Here, we review current knowledge about Xist
regulation, structure, function and conservation and speculate on possible
mechanisms by which its action is restricted in cis. We also discuss dosage
compensation mechanisms other than XCI and how knowledge from invertebrate
species may help to provide a better understanding of the mechanisms of
mammalian XCI.
DOI: 10.1007/s00439-011-1008-7
PMCID: PMC3132428
PMID: 21626138 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28408975
|
1. F1000Res. 2017 Mar 27;6:F1000 Faculty Rev-344. doi:
10.12688/f1000research.10707.1. eCollection 2017.
X chromosome inactivation: new players in the initiation of gene silencing.
Pinheiro I(1), Heard E(1).
Author information:
(1)Mammalian Developmental Epigenetics Group (équipe labellisée La Ligue),
Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, 26 Rue
d'Ulm, 11 75248 Paris Cedex 05, France.
X chromosome inactivation (XCI) is a dosage compensation process that was
adopted by female mammals to balance gene dosage between XX females and XY
males. XCI starts with the upregulation of the non-coding RNA Xist, after which
most X-linked genes are silenced and acquire a repressive chromatin state. Even
though the chromatin marks of the inactive X have been fairly well described,
the mechanisms responsible for the initiation of XCI remain largely unknown. In
this review, we discuss recent developments that revealed unexpected factors
playing a role in XCI and that might be of crucial importance to understand the
mechanisms responsible for the very first steps of this chromosome-wide
gene-silencing event.
DOI: 10.12688/f1000research.10707.1
PMCID: PMC5373419
PMID: 28408975
Conflict of interest statement: Competing interests: The authors declare that
they have no competing interests.No competing interests were disclosed.No
competing interests were disclosed.
|
http://www.ncbi.nlm.nih.gov/pubmed/26004255
|
1. Curr Opin Genet Dev. 2015 Apr;31:57-66. doi: 10.1016/j.gde.2015.04.002. Epub
2015 May 22.
X-chromosome inactivation: new insights into cis and trans regulation.
Galupa R(1), Heard E(2).
Author information:
(1)Mammalian Developmental Epigenetics Group, Institut Curie, PSL University,
CNRS UMR3215, INSERM U934, 26, rue d'Ulm, 75005 Paris, France.
(2)Mammalian Developmental Epigenetics Group, Institut Curie, PSL University,
CNRS UMR3215, INSERM U934, 26, rue d'Ulm, 75005 Paris, France. Electronic
address: [email protected].
X-chromosome inactivation (XCI) is a developmentally associated process that
evolved in mammals to enable gene dosage compensation between XX and XY
individuals. In placental mammals, it is triggered by the long noncoding RNA
Xist, which is produced from a complex regulatory locus, the X-inactivation
centre (Xic). Recent insights into the regulatory landscape of the Xic,
including its partitioning into topological associating domains (TADs) and its
genetic dissection, have important implications for the monoallelic regulation
of Xist. Here, we present some of the latest studies on X inactivation with a
special focus on the regulation of Xist, its various functions and the putative
role of chromosome conformation in regulating the dynamics of this locus during
development and differentiation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.gde.2015.04.002
PMID: 26004255 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34178980
|
1. Front Cell Dev Biol. 2021 Jun 10;9:645647. doi: 10.3389/fcell.2021.645647.
eCollection 2021.
Biological Function of Long Non-coding RNA (LncRNA) Xist.
Wang W(1), Min L(1), Qiu X(1), Wu X(1), Liu C(1), Ma J(1), Zhang D(1), Zhu L(1).
Author information:
(1)Department of Biology and Chemistry, College of Liberal Arts and Sciences,
National University of Defense Technology, Changsha, China.
Long non-coding RNAs (lncRNAs) regulate gene expression in a variety of ways at
epigenetic, chromatin remodeling, transcriptional, and translational levels.
Accumulating evidence suggests that lncRNA X-inactive specific transcript
(lncRNA Xist) serves as an important regulator of cell growth and development.
Despites its original roles in X-chromosome dosage compensation, lncRNA Xist
also participates in the development of tumor and other human diseases by
functioning as a competing endogenous RNA (ceRNA). In this review, we
comprehensively summarized recent progress in understanding the cellular
functions of lncRNA Xist in mammalian cells and discussed current knowledge
regarding the ceRNA network of lncRNA Xist in various diseases. Long non-coding
RNAs (lncRNAs) are transcripts that are more than 200 nt in length and without
an apparent protein-coding capacity (Furlan and Rougeulle, 2016; Maduro et al.,
2016). These RNAs are believed to be transcribed by the approximately 98-99%
non-coding regions of the human genome (Derrien et al., 2012; Fu, 2014;
Montalbano et al., 2017; Slack and Chinnaiyan, 2019), as well as a large variety
of genomic regions, such as exonic, tronic, and intergenic regions. Hence,
lncRNAs are also divided into eight categories: Intergenic lncRNAs, Intronic
lncRNAs, Enhancer lncRNAs, Promoter lncRNAs, Natural antisense/sense lncRNAs,
Small nucleolar RNA-ended lncRNAs (sno-lncRNAs), Bidirectional lncRNAs, and
non-poly(A) lncRNAs (Ma et al., 2013; Devaux et al., 2015; St Laurent et al.,
2015; Chen, 2016; Quinn and Chang, 2016; Richard and Eichhorn, 2018; Connerty et
al., 2020). A range of evidence has suggested that lncRNAs function as key
regulators in crucial cellular functions, including proliferation,
differentiation, apoptosis, migration, and invasion, by regulating the
expression level of target genes via epigenomic, transcriptional, or
post-transcriptional approaches (Cao et al., 2018). Moreover, lncRNAs detected
in body fluids were also believed to serve as potential biomarkers for the
diagnosis, prognosis, and monitoring of disease progression, and act as novel
and potential drug targets for therapeutic exploitation in human disease (Jiang
W. et al., 2018; Zhou et al., 2019a). Long non-coding RNA X-inactive specific
transcript (lncRNA Xist) are a set of 15,000-20,000 nt sequences localized in
the X chromosome inactivation center (XIC) of chromosome Xq13.2 (Brown et al.,
1992; Debrand et al., 1998; Kay, 1998; Lee et al., 2013; da Rocha and Heard,
2017; Yang Z. et al., 2018; Brockdorff, 2019). Previous studies have indicated
that lncRNA Xist regulate X chromosome inactivation (XCI), resulting in the
inheritable silencing of one of the X-chromosomes during female cell
development. Also, it serves a vital regulatory function in the whole spectrum
of human disease (notably cancer) and can be used as a novel diagnostic and
prognostic biomarker and as a potential therapeutic target for human disease in
the clinic (Liu et al., 2018b; Deng et al., 2019; Dinescu et al., 2019; Mutzel
and Schulz, 2020; Patrat et al., 2020; Wang et al., 2020a). In particular,
lncRNA Xist have been demonstrated to be involved in the development of multiple
types of tumors including brain tumor, Leukemia, lung cancer, breast cancer, and
liver cancer, with the prominent examples outlined in Table 1. It was also
believed that lncRNA Xist (Chaligne and Heard, 2014; Yang Z. et al., 2018)
contributed to other diseases, such as pulmonary fibrosis, inflammation,
neuropathic pain, cardiomyocyte hypertrophy, and osteoarthritis chondrocytes,
and more specific details can be found in Table 2. This review summarizes the
current knowledge on the regulatory mechanisms of lncRNA Xist on both chromosome
dosage compensation and pathogenesis (especially cancer) processes, with a focus
on the regulatory network of lncRNA Xist in human disease.
Copyright © 2021 Wang, Min, Qiu, Wu, Liu, Ma, Zhang and Zhu.
DOI: 10.3389/fcell.2021.645647
PMCID: PMC8222981
PMID: 34178980
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/30171939
|
1. Gene. 2018 Dec 30;679:28-35. doi: 10.1016/j.gene.2018.08.071. Epub 2018 Aug
29.
X-inactive-specific transcript: A long noncoding RNA with complex roles in human
cancers.
Yang Z(1), Jiang X(2), Jiang X(3), Zhao H(4).
Author information:
(1)Department of General Surgery, The Fourth Affiliated Hospital of China
Medical University, Shenyang, China.
(2)Department of Infectious Diseases, Shengjing Hospital of China Medical
University, Shenyang, China.
(3)Department of General Surgery, The Fourth Affiliated Hospital of China
Medical University, Shenyang, China. Electronic address: [email protected].
(4)Department of General Surgery, The Fourth Affiliated Hospital of China
Medical University, Shenyang, China. Electronic address: [email protected].
The X-inactive-specific transcript (XIST/Xist) is one of the first long
non-coding RNAs discovered in mammals and plays an essential role in X
chromosome inactivation. XIST is dysregulated and acts as an oncogene or a tumor
suppressor in different human malignancies. XIST is implicated in many aspects
of carcinogenesis including tumor initiation, invasion, metastasis, apoptosis,
cell cycle, stemness, autophagy, and drug resistance. This review focuses on
research progress on the roles of XIST in tumor development. The multiple
pathological functions of XIST in various cancers are systematically reviewed to
elucidate the molecular basis of its biological roles and to provide new
directions for future research.
Copyright © 2018 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2018.08.071
PMID: 30171939 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29302591
|
1. Front Mol Biosci. 2017 Dec 19;4:90. doi: 10.3389/fmolb.2017.00090. eCollection
2017.
Function by Structure: Spotlights on Xist Long Non-coding RNA.
Pintacuda G(1), Young AN(2), Cerase A(2).
Author information:
(1)Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
(2)European Molecular Biology Laboratory, Monterotondo, Italy.
Recent experimental evidence indicates that lncRNAs can act as regulatory
molecules in the context of development and disease. Xist, the master regulator
of X chromosome inactivation, is a classic example of how lncRNAs can exert
multi-layered and fine-tuned regulatory functions, by acting as a molecular
scaffold for recruitment of distinct protein factors. In this review, we discuss
the methodologies employed to define Xist RNA structures and the tight interplay
between structural clues and functionality of lncRNAs. This model of modular
function dictated by structure, can be also generalized to other lncRNAs, beyond
the field of X chromosome inactivation, to explain common features of similarly
folded RNAs.
DOI: 10.3389/fmolb.2017.00090
PMCID: PMC5742192
PMID: 29302591
|
http://www.ncbi.nlm.nih.gov/pubmed/23816838
|
1. J Mol Biol. 2013 Oct 9;425(19):3698-706. doi: 10.1016/j.jmb.2013.06.031. Epub
2013 Jun 28.
Guided by RNAs: X-inactivation as a model for lncRNA function.
Froberg JE(1), Yang L, Lee JT.
Author information:
(1)Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of
Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA;
Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
The recent revolution in sequencing technology has helped to reveal a large
transcriptome of long non-coding RNAs (lncRNAs). A major challenge in the years
to come is to determine what biological functions, if any, they serve. Although
the purpose of these transcripts is largely unknown at present, existing
examples suggest that lncRNAs play roles in a wide variety of biological
processes. Exemplary cases are lncRNAs within the X-inactivation center. Indeed,
lncRNAs dominate control of random X-chromosome inactivation (XCI). The
RNA-based regulatory mechanisms of XCI include recruitment of chromatin
modifiers, formation of RNA-based subnuclear compartments, and regulation of
transcription by antisense transcription. XCI and lncRNAs now also appear to be
very relevant in the development and progression of cancer. This perspective
focuses on new insights into lncRNA-dependent regulation of XCI, which we
believe serve as paradigms for understanding lncRNA function more generally.
© 2013.
DOI: 10.1016/j.jmb.2013.06.031
PMCID: PMC3771680
PMID: 23816838 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35895262
|
1. Methods Mol Biol. 2022;2537:129-147. doi: 10.1007/978-1-0716-2521-7_8.
Identification and Quantification of Microexons Using Bulk and Single-Cell
RNA-Seq Data.
Parada GE(1)(2), Hemberg M(3)(4).
Author information:
(1)Wellcome Sanger Institute, Cambridge, UK.
(2)Donnelly Centre for Cellular and Biomolecular Research and Department of
Molecular Genetics, University of Toronto, Toronto, ON, Canada.
(3)Wellcome Sanger Institute, Cambridge, UK. [email protected].
(4)Evergrande Center for Immunologic Diseases, Harvard Medical School and
Brigham and Women's Hospital, Boston, MA, USA. [email protected].
The analysis of RNA-seq has greatly improved the characterization and
understanding of the transcriptome. In particular, RNA-seq experiments have
extended catalogs of alternative splicing events. However, the analysis of
RNAs-seq data for detection and quantification of microexons, extremely short
exons of length up to 30 nt, require specialized computational workflows. Here,
we describe MicroExonator, a reproducible computational workflow for microexon
splicing analysis using bulk or single-cell RNA-seq data.
© 2022. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2521-7_8
PMID: 35895262 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35364798
|
1. Drugs. 2022 Apr;82(6):703-710. doi: 10.1007/s40265-022-01704-4.
Tebentafusp: First Approval.
Dhillon S(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. [email protected].
Tebentafusp (tebentafusp-tebn; Kimmtrak®) is a first-in-class, bispecific gp100
peptide-HLA-A*02:01 directed T cell receptor (TCR) CD3 T cell engager being
developed by Immunocore for the treatment of uveal melanoma and malignant
melanoma. The TCR arm of tebentafusp binds to HLA-A*02:01-positive uveal
melanoma cells and activates polyclonal T cells, through CD3, to release
inflammatory cytokines and cytolytic proteins, resulting in the direct lysis of
tumour cells. In January 2022, tebentafusp received its first approval in the
USA for the treatment of HLA-A*02:01-positive adults with unresectable or
metastatic uveal melanoma, and in February 2022 received a Positive Opinion from
the EU Committee for Medicinal Products for Human Use for the treatment of uveal
melanoma. Tebentafusp is under regulatory review for the treatment of metastatic
uveal melanoma in the UK, Australia and Canada. Clinical studies of tebentafusp
are underway for uveal melanoma and cutaneous melanoma in several countries
worldwide. This article summarizes the milestones in the development of
tebentafusp leading to this first approval for unresectable or metastatic uveal
melanoma.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01704-4
PMID: 35364798 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35364557
|
1. Transl Oncol. 2022 Jun;20:101408. doi: 10.1016/j.tranon.2022.101408. Epub 2022
Mar 29.
Tebentafusp in first-line melanoma trials: An outperforming outlier.
Olivier T(1), Prasad V(2).
Author information:
(1)Department of Oncology, Geneva University Hospital, 4 Gabrielle-Perret-Gentil
Street, Geneva 1205, Switzerland; Department of Epidemiology and Biostatistics,
University of California San Francisco, 550 16th St, 2nd Fl, San Francisco, CA
94158, USA. Electronic address: [email protected].
(2)Department of Epidemiology and Biostatistics, University of California San
Francisco, 550 16th St, 2nd Fl, San Francisco, CA 94158, USA.
Uveal melanoma is distinct from other melanomas. In the advanced and metastatic
stages, little to no improvement have been seen over time. Tebentafusp is a
novel mechanism of action bispecific gp100 peptide-HLA-directed CD3 T-cell
engager fusion protein ("-fusp"). Tebentafusp was granted full approval on
January 25th 2022 in the setting of HLA-A*02:01-positive adult patients with
unresectable or metastatic uveal melanoma. The approval was based on the overall
survival advantage of tebentafusp over physician's choice therapy, in previously
untreated uveal melanoma patients, based on the IMCgp100-202 trial. While we
welcome positive results for this unmet need, three issues are raised by the
trial. First, the control arm was restricted, precluding important options.
Second, post-progression treatment was provided to a smaller fraction of
patients than in real-life, which raises the question of whether overall
survival was negatively impacted by limited care after the trial ended. Finally,
the discrepancy between overall survival and progression-free survival benefit
is an outlier in the context of previous melanoma trials. While it is clear that
tebentafusp has an important role to play in this tumor type, the exact line is
not yet well known. Confirmatory trials are needed for this compound.
Copyright © 2022. Published by Elsevier Inc.
DOI: 10.1016/j.tranon.2022.101408
PMCID: PMC8968051
PMID: 35364557
Conflict of interest statement: Vinay Prasad's Disclosures: Research funding:
Arnold Ventures; Royalties: Johns Hopkins Press, Medscape; Honoraria: Grand
Rounds/lectures from universities, medical centers, non-profits, and
professional societies; Consulting: UnitedHealthcare; Speaking fees: Evicore;
Other: Plenary Session podcast has Patreon backers. Timothée Olivier have no
financial nor non-financial conflicts of interest to report.
|
http://www.ncbi.nlm.nih.gov/pubmed/34999237
|
1. Prog Retin Eye Res. 2022 Sep;90:101041. doi: 10.1016/j.preteyeres.2022.101041.
Epub 2022 Jan 6.
Metastatic uveal melanoma: The final frontier.
Rantala ES(1), Hernberg MM(2), Piperno-Neumann S(3), Grossniklaus HE(4), Kivelä
TT(5).
Author information:
(1)Ocular Oncology Service, Department of Ophthalmology, University of Helsinki
and Helsinki University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029, HUS,
Helsinki, Finland. Electronic address: [email protected].
(2)Comprehensive Cancer Center, Department of Oncology, Helsinki University
Hospital and University of Helsinki, Paciuksenkatu 3, PL 180, FI-00029, HUS,
Helsinki, Finland. Electronic address: [email protected].
(3)Department of Medical Oncology, Institut Curie, 26, rue d'Ulm, 75005, Paris,
France. Electronic address: [email protected].
(4)Section of Ocular Oncology, Emory Eye Center, 1365 Clifton Road B, Atlanta,
GA, 30322, USA. Electronic address: [email protected].
(5)Ocular Oncology Service, Department of Ophthalmology, University of Helsinki
and Helsinki University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029, HUS,
Helsinki, Finland. Electronic address: [email protected].
Treatment of primary intraocular uveal melanoma has developed considerably, its
driver genes are largely unraveled, and the ways to assess its risk for
metastases are very precise, being based on an international staging system and
genetic data. Unfortunately, the risk of distant metastases, which emerge in
approximately one half of all patients, is unaltered. Metastases are the leading
single cause of death after uveal melanoma is diagnosed, yet no consensus exists
regarding surveillance, staging, and treatment of disseminated disease, and
survival has not improved until recently. The final frontier in conquering uveal
melanoma lies in solving these issues to cure metastatic disease. Most studies
on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not
report staging. Meta-analyses confirm a median overall survival of 10-13 months,
and a cure rate that approaches nil, although survival exceeding 5 years is
possible, estimated 2% either with first-line treatment or with best supportive
care. Hepatic ultrasonography and magnetic resonance imaging as surveillance
methods have a sensitivity of 95-100% and 83-100%, respectively, to detect
metastases without radiation hazard according to prevailing evidence, but
computed tomography is necessary for staging. No blood-based tests additional to
liver function tests are generally accepted. Three validated staging systems
predict, each in defined situations, overall survival after metastasis. Their
essential components include measures of tumor burden, liver function, and
performance status or metastasis free interval. Age and gender may additionally
influence survival. Exceptional mutational events in metastases may make them
susceptible to checkpoint inhibitors. In a large meta-analysis, surgical
treatment was associated with 6 months longer median overall survival as
compared to conventional chemotherapy and, recently, tebentafusp as first-line
treatment at the first interim analysis of a randomized phase III trial likewise
provided a 6 months longer median overall survival compared to investigator's
choice, mostly pembrolizumab; these treatments currently apply to selected
patients. Promoting dormancy of micrometastases, harmonizing surveillance
protocols, promoting staging, identifying predictive factors, initiating
controlled clinical trials, and standardizing reporting will be critical
steppingstones in reaching the final frontier of curing metastatic uveal
melanoma.
Copyright © 2022. Published by Elsevier Ltd.
DOI: 10.1016/j.preteyeres.2022.101041
PMID: 34999237 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35257475
|
1. Aging Cell. 2022 Apr;21(4):e13579. doi: 10.1111/acel.13579. Epub 2022 Mar 8.
Deuterated docosahexaenoic acid protects against oxidative stress and geographic
atrophy-like retinal degeneration in a mouse model with iron overload.
Liu Y(1), Bell BA(1), Song Y(1), Zhang K(1), Anderson B(1), Axelsen PH(2),
Bohannan W(3), Agbaga MP(3), Park HG(4), James G(4), Brenna JT(4), Schmidt K(5),
Dunaief JL(1), Shchepinov MS(5).
Author information:
(1)F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman
School of Medicine at the University of Pennsylvania, Philadelphia,
Pennsylvania, USA.
(2)Department of Pharmacology, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, Pennsylvania, USA.
(3)Departments of Cell Biology and Ophthalmology, University of Oklahoma Health
Sciences Center and the Dean McGee Eye Institute, Oklahoma City, Oklahoma, USA.
(4)Dell Pediatric Research Institute, University of Texas at Austin, Austin,
Texas, USA.
(5)Retrotope, Inc., Los Altos, California, USA.
Oxidative stress plays a central role in age-related macular degeneration (AMD).
Iron, a potent generator of hydroxyl radicals through the Fenton reaction, has
been implicated in AMD. One easily oxidized molecule is docosahexaenoic acid
(DHA), the most abundant polyunsaturated fatty acid in photoreceptor membranes.
Oxidation of DHA produces toxic oxidation products including carboxyethylpyrrole
(CEP) adducts, which are increased in the retinas of AMD patients. In this
study, we hypothesized that deuterium substitution on the bis-allylic sites of
DHA in photoreceptor membranes could prevent iron-induced retinal degeneration
by inhibiting oxidative stress and lipid peroxidation. Mice were fed with either
DHA deuterated at the oxidation-prone positions (D-DHA) or control natural DHA
and then given an intravitreal injection of iron or control saline. Orally
administered D-DHA caused a dose-dependent increase in D-DHA levels in the
neural retina and retinal pigment epithelium (RPE) as measured by mass
spectrometry. At 1 week after iron injection, D-DHA provided nearly complete
protection against iron-induced retinal autofluorescence and retinal
degeneration, as determined by in vivo imaging, electroretinography, and
histology. Iron injection resulted in carboxyethylpyrrole conjugate
immunoreactivity in photoreceptors and RPE in mice fed with natural DHA but not
D-DHA. Quantitative PCR results were consistent with iron-induced oxidative
stress, inflammation, and retinal cell death in mice fed with natural DHA but
not D-DHA. Taken together, our findings suggest that DHA oxidation is central to
the pathogenesis of iron-induced retinal degeneration. They also provide
preclinical evidence that dosing with D-DHA could be a viable therapeutic
strategy for retinal diseases involving oxidative stress.
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley &
Sons Ltd.
DOI: 10.1111/acel.13579
PMCID: PMC9009113
PMID: 35257475 [Indexed for MEDLINE]
Conflict of interest statement: MSS and KS are employed by Retrotope, Inc. JTB
is a shareholder in and receives research support from Retrotope, Inc. MPA
receives research support from Retrotope, Inc. The other authors declare that
they have no commercial or financial relationships that could be construed as a
potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/21280898
|
1. J Biomed Opt. 2011 Jan-Feb;16(1):011011. doi: 10.1117/1.3524304.
Mechanism of ceroid formation in atherosclerotic plaque: in situ studies using a
combination of Raman and fluorescence spectroscopy.
Haka AS(1), Kramer JR, Dasari RR, Fitzmaurice M.
Author information:
(1)Massachusetts Institute of Technology, G. R. Harrison Spectroscopy
Laboratory, Cambridge, Massachusetts 02139, USA. [email protected]
Accumulation of the lipid-protein complex ceroid is a characteristic of
atherosclerotic plaque. The mechanism of ceroid formation has been extensively
studied, because the complex is postulated to contribute to plaque
irreversibility. Despite intensive research, ceroid deposits are defined through
their fluorescence and histochemical staining properties, while their
composition remains unknown. Using Raman and fluorescence spectral microscopy,
we examine the composition of ceroid in situ in aorta and coronary artery
plaque. The synergy of these two types of spectroscopy allows for identification
of ceroid via its fluorescence signature and elucidation of its chemical
composition through the acquisition of a Raman spectrum. In accordance with in
vitro predictions, low density lipoprotein (LDL) appears within the deposits
primarily in its peroxidized form. The main forms of modified LDL detected in
both coronary artery and aortic plaques are peroxidation products from the
Fenton reaction and myeloperoxidase-hypochlorite pathway. These two peroxidation
products occur in similar concentrations within the deposits and represent ∼40
and 30% of the total LDL (native and peroxidized) in the aorta and coronary
artery deposits, respectively. To our knowledge, this study is the first to
successfully employ Raman spectroscopy to unravel a metabolic pathway involved
in disease pathogenesis: the formation of ceroid in atherosclerotic plaque.
DOI: 10.1117/1.3524304
PMCID: PMC3041153
PMID: 21280898 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29227084
|
1. Ukr Biochem J. 2016 Jan-Feb;88(1):79-87. doi: 10.15407/ubj88.01.079.
Amine oxidases as important agents of pathological processes of rhabdomyolysis
in rats.
Gudkova OO, Latyshko NV, Shandrenko SG.
In this study we have tested an idea on the important role of amine oxidases
(semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase) as
an additional source of oxidative/carbonyl stress under glycerol-induced
rhabdomyolysis, since the enhanced formation of reactive oxygen species and
reactive carbonyl species in a variety of tissues is linked to various diseases.
In our experiments we used the sensitive fluorescent method devised for
estimation of amine oxidases activity in the rat kidney and thymus as targeted
organs under rhabdomyolysis. We have found in vivo the multiple rises in
activity of semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine
oxidase (2-4.5 times) in the corresponding cell fractions, whole cells or their
lysates at the 3-6th day after glycerol injection. Aberrant antioxidant
activities depended on rhabdomyolysis stage and had organ specificity.
Additional treatment of animals with metal chelator ‘Unithiol’ adjusted only the
activity of antioxidant enzymes but not amine oxidases in both organs.
Furthermore the in vitro experiment showed that Fenton reaction (hydrogen
peroxide in the presence of iron) products alone had no effect on
semicarbazide-sensitive amine oxidase activity in rat liver cell fraction
whereas supplementation with methylglyoxal resulted in its significant 2.5-fold
enhancement. Combined action of the both agents had additive effect on
semicarbazide-sensitive amine oxidase activity. We can assume that biogenic
amine and polyamine catabolism by amine oxidases is upregulated by oxidative and
carbonyl stress factors directly under rhabdomyolysis progression, and the
increase in catabolic products concentration contributes to tissue damage in
glycerol-induced acute renal failure and apoptosis stimulation in thymus.
DOI: 10.15407/ubj88.01.079
PMID: 29227084 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35775547
|
1. Int J Mycobacteriol. 2022 Apr-Jun;11(2):150-158. doi: 10.4103/ijmy.ijmy_58_22.
Mycobacterium smegmatis strains genetically resistant to moxifloxacin emerge de
novo from the moxifloxacin-surviving population containing high levels of
superoxide, H(2)O(2), hydroxyl radical, and Fe (II).
Paul A(1), Nair RR(1), Jakkala K(1), Ajitkumar P(1).
Author information:
(1)Department of Microbiology and Cell Biology, Indian Institute of Science,
Bengaluru, Karnataka, India.
BACKGROUND: The antibiotic-exposed bacteria often contain the reactive oxygen
species (ROS), hydroxyl radical, which inflicts genome-wide mutations, causing
the de novo formation of antibiotic-resistant strains. Hydroxyl radical is
generated by Fenton reaction of Fe (II) with the ROS, H2O2, which, in turn, is
formed by the dismutation of the ROS, superoxide. Therefore, for the emergence
of bacterial strains genetically resistant to antibiotics, increased levels of
superoxide, H2O2, hydroxyl radical, and Fe (II) should be present in the
antibiotic-exposed bacteria. Here, we verified this premise by finding out
whether the in vitro cultures of M. smegmatis, exposed to MBC of moxifloxacin
for a prolonged duration, contain significantly high levels of superoxide, H2O2,
hydroxyl radical, and Fe (II).
METHODS: Biological triplicate cultures of M. smegmatis, were exposed to MBC of
moxifloxacin for 84 h. The colony-forming units (CFUs) of the cultures were
determined on moxifloxacin-free and moxifloxacin-containing plates for the
entire 84 h at a regular interval of 6 h. The cultures were analyzed at specific
time points of killing phase (KP), antibiotic-surviving phase (ASP), and
regrowth phase (RGP) for the presence of superoxide, H2O2, hydroxyl radical, and
Fe (II) using the ROS- and Fe (II)-detecting fluorescence probes. The
experimental cultures were grown in the presence of ROS and Fe (II) quenchers
also and determined the levels of fluorescence corresponding to the ROS- and Fe
(II)-specific probes. This was performed to establish the specificity of
detection of ROS and Fe (II). Biological triplicate cultures, unexposed to
moxifloxacin but cultured for 84 h, were used as the control for the measurement
of ROS and Fe (II) levels. The CFUs of the cultures were determined on
moxifloxacin-free and moxifloxacin-containing plates for the entire 84 h at
regular intervals of 6 h. Flow cytometry analyses were performed for the
detection and quantitation of the levels of fluorescence of the ROS-and Fe
(II)-specific probes. The experimental cultures were grown in the presence of
thiourea and bipyridyl as the ROS and Fe (II) quenchers, respectively, for the
determination of the levels of fluorescence corresponding to the ROS- and Fe
(II)-specific probes. Paired t-test was used to calculate statistical
significance (n = 3).
RESULTS: The moxifloxacin-exposed cultures, but not the cultures unexposed to
moxifloxacin, showed a triphasic response with a KP, ASP, and RGP. The cells in
the late KP and ASP contained significantly elevated levels of superoxide, H2O2,
hydroxyl radical, and Fe (II). Thus, high levels of the ROS and Fe (II) were
found in the small population (in the ASP) of M. smegmatis cells that survived
the moxifloxacin-mediated killing. From this moxifloxacin-surviving population
(in the ASP), moxifloxacin-resistant genetic resisters emerged de novo at high
frequency, regrew, divided, and populated the cultures. The levels of these ROS,
Fe (II), and the high moxifloxacin resister generation frequency were quenched
in the cultures grown in the presence of the respective ROS and Fe (II)
quenchers. The cultures unexposed to moxifloxacin did not show any of these
responses, indicating that the whole response was specific to antibiotic
exposure.
CONCLUSIONS: Significantly high levels of superoxide, H2O2, hydroxyl radical,
and Fe (II) were generated in the M. smegmatis cultures exposed to moxifloxacin
for a prolonged duration. It promoted the de novo emergence of genetic resisters
to moxifloxacin at high frequency.
DOI: 10.4103/ijmy.ijmy_58_22
PMID: 35775547 [Indexed for MEDLINE]
Conflict of interest statement: None
|
http://www.ncbi.nlm.nih.gov/pubmed/16433646
|
1. J Prosthodont. 2006 Jan-Feb;15(1):9-19. doi: 10.1111/j.1532-849X.2006.00063.x.
Free radical damage in facsimile synovium: correlation with adhesion formation
in osteoarthritic TMJs.
Sheets DW Jr(1), Okamoto T, Dijkgraaf LC, Milam SB, Schmitz JP, Zardeneta G.
Author information:
(1)Department of Prosthodontics, Wilford Hall Medical Center, Lackland AFB, San
Antonio, TX, USA.
PURPOSE: The purpose of this study was to use the rat air pouch model of
facsimile synovium to evaluate oxidative stress as a primary mechanism in the
pathogenesis of degenerative temporomandibular joint (TMJ) disease.
MATERIALS AND METHODS: Forty-nine Sprague-Dawley adult female rats were used to
generate the standard rat air pouch model of facsimile synovium. This was
accomplished by daily air injections (20 cc) subdermally through the dorsal
skin. Hydrogen peroxide and ferrous iron (components of the Fenton reaction
which generate free radicals) were introduced into the pouches of the 4-, 7-,
and 14-day groups to generate oxidative stress. Control rats were injected with
phosphate-buffered solution (PBS), pH 7.4. Either N-acetylcysteine (NAC), a
powerful free radical scavenger, or ibuprofen were simultaneously injected with
the Fenton reagents into the pouches of the 14-day treatment groups to modulate
free radical-mediated protein damage to the synovium. Animals were euthanized at
appropriate experimental intervals and biopsies obtained from specimens to
analyze: (1) proteins' amino acid modification (carbonyl group formation), (2)
protein hydrophobicity, (3) detection of low molecular weight protein
degradation products, and (4) histological and gross anatomical observations.
RESULTS: Free radicals introduced into the rat air pouch interacted with
synovial tissues causing oxidation and breakdown of proteins. Clinical evidence
of adhesion formation consistent with features found in osteoarthritis of the
TMJ developed. The groups subjected to oxidative stress experienced
statistically significant (p < 0.05) increases in carbonyl formation,
carbonyls/protein, and low molecular weight protein fragments. These groups also
showed significant (p < 0.05) hydrophobicity changes consistent with free
radical attack. Control synovial tissues were statistically undamaged. The
14-day NAC and ibuprofen treatment groups experienced statistically significant
(p < 0.05) decreases in total carbonyl formation, carbonyls/protein, and
hydrophobicity. Histological and gross observations in free radical damaged
synovium exhibited features consistent with known arthoscopic and arthrocentesis
findings in diseased TMJs.
CONCLUSIONS: This study suggests that the rat air pouch model of facsimile
synovium develops clinical evidence of adhesions and biochemical signs of
protein modification when subjected to free radical attack. NAC and ibuprofen
prevented carbonyl formation as well as hydrophobicity changes indicative of
oxidative stress damage in facsimile synovium. These findings are consistent
with features of degenerative human TMJ disease. Future direction may be taken
from this study to postulate new analysis techniques and treatment modalities
for patients with degenerative TMJ disease.
Copyright (c) 2006 by The American College of Prosthodontists.
DOI: 10.1111/j.1532-849X.2006.00063.x
PMID: 16433646 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31143689
|
1. Avicenna J Phytomed. 2019 May-Jun;9(3):213-220.
Protective effect of Berberis vulgaris on Fenton reaction-induced DNA cleavage.
Sadat Asadi N(1), Heidari MM(1), Khatami M(1).
Author information:
(1)Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
OBJECTIVE: Berberis vulgaris contains antioxidants that can inhibit DNA
cleavage. The purpose of this study was to evaluate the antioxidant and
protective activity of B. vulgaris on DNA cleavage.
MATERIALS AND METHODS: In this study, the antioxidant capacity of B. vulgaris
was investigated using DPPH and its protective effect was evaluated on pBR322
plasmid and lymphocyte genomic DNA cleavage induced by Fenton reaction, by DNA
electrophoresis.
RESULTS: Aqueous extract of B. vulgaris presented dual behavior with a potent
antioxidant activity at 0.25and 0.75mg/ml for pBR322 plasmid and lymphocyte
genomic DNA, respectively, but a pro-oxidant activity was observed at higher
concentrations.
CONCLUSION: Our results indicated that B. vulgaris extract an inhibit Fenton
reaction-induced DNA cleavage and oxidative cleavage of double-stranded DNA
assay is a powerful technique that can be used to determine the antioxidant and
pro-oxidant properties of a compound on cellular components such as DNA.
PMCID: PMC6526040
PMID: 31143689
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/8597169
|
1. Toxicol Lett. 1995 Dec;82-83:969-74. doi: 10.1016/0378-4274(95)03532-x.
Toxicity of iron and hydrogen peroxide: the Fenton reaction.
Winterbourn CC(1).
Author information:
(1)Department of Pathology, Christchurch School of Medicine, New Zealand.
[email protected]
Iron and hydrogen peroxide are capable of oxidizing a wide range of substrates
and causing biological damage. The reaction, referred to as the Fenton reaction,
is complex and capable of generating both hydroxyl radicals and higher oxidation
states of the iron. The mechanism and how it is affected by different chelators,
and the interpretation of results obtained in biological systems, are discussed.
DOI: 10.1016/0378-4274(95)03532-x
PMID: 8597169 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/27340836
|
1. J Phys Chem A. 2016 Jul 21;120(28):5435-45. doi: 10.1021/acs.jpca.6b03805.
Epub 2016 Jul 12.
New Insights of the Fenton Reaction Using Glycerol as the Experimental Model.
Effect of O2, Inhibition by Mg(2+), and Oxidation State of Fe.
Vitale AA(1), Bernatene EA(2), Vitale MG(3), Pomilio AB(1)(2).
Author information:
(1)Area Hematología, Departamento de Bioquímica Clínica, Hospital de Clínicas
"José de San Martín", Universidad de Buenos Aires , Av. Córdoba 2351, C1120AAF
Buenos Aires, Argentina.
(2)Instituto de Bioquímica y Medicina Molecular (IBIMOL, CONICET-UBA) , Junín
956, C1113AAD Buenos Aires, Argentina.
(3)Hospital Infanto Juvenil "Dra. Carolina Tobar García", Universidad de Buenos
Aires , Doctor Ramón Carrillo 315, C1275AHG Buenos Aires, Argentina.
The use of iron ions as catalyst of oxidation with hydrogen peroxide, known as
the Fenton reaction, is important for industry and biological systems. It has
been widely studied since its discovery in the 19th century, but important
aspects of the reaction as which is the oxidant, the role of oxygen, and the
oxidation state of Fe still remain unclear. In this work new mechanistic
insights of the oxidation of carbohydrates by the Fenton reaction using glycerol
as experimental model are described. The reaction was studied by means of
oxidation reduction potential (ORP) measures. The stoichiometry was measured,
showing the important role of oxygen for lowering H2O2 consumption under aerobic
conditions. Evidence is provided to demonstrate that in this system Fe(2+)
generates a catalyst by reacting with a substrate to produce a complex, which
gives rise to singlet oxygen after reacting with H2O2. This is the first time
that the inhibitor effect of Mg(2+) is reported in this reaction, and its
participation in the mechanism is described. A rational mechanism for the
oxidation of glycerol using the Fenton reaction under these specific conditions
is proposed. The role of oxygen, the participation of Fe(2+), and the inhibition
by Mg(2+) are fully demonstrated experimentally.
DOI: 10.1021/acs.jpca.6b03805
PMID: 27340836
|
http://www.ncbi.nlm.nih.gov/pubmed/32668496
|
1. Water Environ Res. 2021 Apr;93(4):645-651. doi: 10.1002/wer.1397. Epub 2020
Nov 4.
A sandwich model of Cr(VI) adsorption and detoxification by Fenton modified
chitosan.
Jia N(1), Yun L(1), Huang J(1)(2), Chen H(3), Shen C(2), Wen Y(1).
Author information:
(1)MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College
of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China.
(2)College of Environmental Science and Engineering, Donghua University,
Shanghai, China.
(3)College of Science and Technology, Ningbo University, Ningbo, China.
The Fenton reaction has the advantages of short reaction time, low cost, no
toxicity, and straightforward application and control. The Fenton reaction
generates highly reactive HO•, which has been applied effectively. However, the
effect of the generated Fe3+ has not been investigated widely. In this study,
the Fenton reaction was used to improve the Cr(VI) adsorption and detoxification
capacities of chitosan. After the Fenton modification, chitosan efficiently
adsorbed Cr(VI) and transformed it into the less toxic Cr(III) in a wide pH
range as a result of layer formation, which was described by a sandwich model.
The adsorption of Cr(VI) onto the Fenton modified chitosan was in good agreement
with the Freundlich adsorption model, and the adsorption capacity exceeded
120 mg/g. During the Fenton reaction, H2 O2 and HO• with high oxidative activity
broke the hydrogen bonds in the chitosan structure, resulting in the release of
free amine groups for Fe3+ to form metal-binding biopolymers. The distance
between the chitosan polymers increased, and additional adsorption sites were
created. HCrO4 - entered the gap between the chitosan polymer and was adsorbed
on the newly created adsorption sites. The sandwich adsorption model indicated
that the Fenton modified chitosan provided a high concentration of active sites
for Cr(VI) capture and detoxification. PRACTITIONER POINTS: Fenton reaction was
used to improve the adsorption ability of chitosan. The formed Fe3+ in Fenton
reaction was utilized. HO· broke the hydrogen bonds and Fe3+ ions chelated with
chitosan in modification. Cr(VI) could be adsorbed and reduced efficiently by
Fenton modified chitosan. The Fenton modified chitosan provided a high
concentration of active sites for Cr(VI) capture and detoxification.
© 2020 Water Environment Federation.
DOI: 10.1002/wer.1397
PMID: 32668496 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36080218
|
1. Molecules. 2022 Aug 25;27(17):5451. doi: 10.3390/molecules27175451.
Current Use of Fenton Reaction in Drugs and Food.
Abe C(1), Miyazawa T(1), Miyazawa T(1).
Author information:
(1)New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai
980-8579, Japan.
Iron is the most abundant mineral in the human body and plays essential roles in
sustaining life, such as the transport of oxygen to systemic organs. The Fenton
reaction is the reaction between iron and hydrogen peroxide, generating hydroxyl
radical, which is highly reactive and highly toxic to living cells.
"Ferroptosis", a programmed cell death in which the Fenton reaction is closely
involved, has recently received much attention. Furthermore, various
applications of the Fenton reaction have been reported in the medical and
nutritional fields, such as cancer treatment or sterilization. Here, this review
summarizes the recent growing interest in the usefulness of iron and its
biological relevance through basic and practical information of the Fenton
reaction and recent reports.
DOI: 10.3390/molecules27175451
PMCID: PMC9457891
PMID: 36080218 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/30152511
|
1. Phys Chem Chem Phys. 2018 Sep 12;20(35):22890-22901. doi: 10.1039/c8cp04381g.
A computational study of the Fenton reaction in different pH ranges.
Lu HF (1), Chen HF , Kao CL , Chao I , Chen HY .
Author information:
(1)Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.
The reaction of iron(ii) and hydrogen peroxide, namely the Fenton reaction, is
well-known for its strong oxidizing capability. While the Fenton reactions are
ubiquitous and have wide applications in many areas, the detailed mechanism,
especially the nature of the reactive intermediates responsible for oxidation,
is not completely clear. In this work, the performances of various density
functional theory (DFT) methods on the relative energies of key Fenton
intermediates are evaluated. The DFT method selected from the benchmark study is
then exploited to investigate the aqueous Fenton reactions in different pH
conditions. The results show that at pH > 2.2, the major Fenton oxidants are
high-valent oxoiron(iv) aquo complexes. However, depending on the pH conditions,
these complexes can exist in three protonation states that display quite
different oxidation reactivities. The oxidizing power of FeIV[double bond,
length as m-dash]O is found to be principally determined by the total charge of
the ligands and is less influenced by the axial ligand effect. Moreover, the
calculations reveal that the presence of the hydronium ion can stabilize the
intermediate of the hydroxyl radical and further inhibit oxoiron(iv) formation
via proton transfer. The contribution of hydroxyl radicals could compete with
the oxoiron(iv) species at pH below 2.2. In addition, high-level ab initio
calculations question the existence of the iron(iv)-dihydroxo intermediate
suggested in the literature. The implications of the computational results for
the Fenton oxidation process, cytochrome P450, and catalyst design are
discussed.
DOI: 10.1039/c8cp04381g
PMID: 30152511
|
http://www.ncbi.nlm.nih.gov/pubmed/28531840
|
1. Chemosphere. 2017 Sep;182:738-744. doi: 10.1016/j.chemosphere.2017.05.039.
Epub 2017 May 7.
Hydroxyl radical yields in the Fenton process under various pH, ligand
concentrations and hydrogen peroxide/Fe(II) ratios.
Fischbacher A(1), von Sonntag C(2), Schmidt TC(3).
Author information:
(1)Instrumental Analytical Chemistry, University of Duisburg-Essen,
Universitätsstraße 5, 45141 Essen, Germany.
(2)Instrumental Analytical Chemistry, University of Duisburg-Essen,
Universitätsstraße 5, 45141 Essen, Germany; Max-Planck-Institut für
Bioanorganische Chemie, Stiftstr. 34-36, 45413 Mülheim an der Ruhr, Germany.
(3)Instrumental Analytical Chemistry, University of Duisburg-Essen,
Universitätsstraße 5, 45141 Essen, Germany; Centre for Water and Environmental
Research (ZWU), University of Duisburg-Essen, Universitätsstraße 2, 45141 Essen,
Germany. Electronic address: [email protected].
The Fenton process, one of several advanced oxidation processes, describes the
reaction of Fe(II) with hydrogen peroxide. Fe(II) is oxidized to Fe(III) that
reacts with hydrogen peroxide to Fe(II) and again initiates the Fenton reaction.
In the course of the reactions reactive species, e.g. hydroxyl radicals, are
formed. Conditions such as pH, ligand concentrations and the hydrogen
peroxide/Fe(II) ratio may influence the OH radical yield. It could be shown that
at pH < 2.7 and >3.5 the OH radical yield decreases significantly. Two ligands
were investigated, pyrophosphate and sulfate. It was found that pyrophosphate
forms a complex with Fe(III) that does not react with hydrogen peroxide and
thus, the Fenton reaction is terminated and the OH radical yields do not further
increase. The influence of sulfate is not as strong as that of pyrophosphate.
The OH radical yield is decreased when sulfate is added but even at higher
concentrations the Fenton reaction is not terminated.
Copyright © 2017 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chemosphere.2017.05.039
PMID: 28531840 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31259456
|
1. Macromol Rapid Commun. 2019 Sep;40(18):e1900220. doi: 10.1002/marc.201900220.
Epub 2019 Jul 1.
Fenton-Chemistry-Mediated Radical Polymerization.
Reyhani A(1), McKenzie TG(1), Fu Q(1), Qiao GG(1).
Author information:
(1)Polymer Science Group, Department of Chemical Engineering, The University of
Melbourne, Parkville, VIC, 3010, Australia.
In this review, the power of a classical chemical reaction, the Fenton reaction
for initiating radical polymerizations, is demonstrated. The reaction between
the Fenton reagents (i.e., Fe2+ and H2 O2 ) generates highly reactive hydroxyl
radicals, which can act as radical initiators for the polymerization of vinyl
monomers. Since the Fenton reaction is fast, easy to set up, cheap, and
biocompatible, this unique chemistry is widely employed in various polymer
synthesis studies via free radical polymerization or reversible
addition-fragmentation chain transfer polymerization, and is utilized in a wide
range of applications, such as the fabrication of biomaterials, hydrogels, and
core-shell particles. Biologically activated Fenton-mediated radical
polymerization, which can be performed in aerobic environments, are particularly
useful for applications in biomedical systems.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/marc.201900220
PMID: 31259456 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36113495
|
1. Lancet Neurol. 2022 Nov;21(11):994-1003. doi: 10.1016/S1474-4422(22)00294-0.
Epub 2022 Sep 13.
Safety and efficacy of erenumab in patients with trigeminal neuralgia in
Denmark: a double-blind, randomised, placebo-controlled, proof-of-concept study.
Schott Andersen AS(1), Maarbjerg S(1), Noory N(1), Heinskou TB(1), Forman JL(2),
Cruccu G(3), Ashina M(1), Bendtsen L(4).
Author information:
(1)Danish Headache Centre, Department of Neurology, Copenhagen University
Hospital, Glostrup, Denmark.
(2)Section of Biostatistics, Department of Public Health, University of
Copenhagen, Copenhagen, Denmark.
(3)Department of Neurology and Psychiatry, University of Rome-La Sapienza, Rome,
Italy.
(4)Danish Headache Centre, Department of Neurology, Copenhagen University
Hospital, Glostrup, Denmark. Electronic address: [email protected].
Comment in
Lancet Neurol. 2022 Nov;21(11):951-953. doi: 10.1016/S1474-4422(22)00389-1.
BACKGROUND: Trigeminal neuralgia is a severe facial pain disorder that is
difficult to treat. Erenumab, a monoclonal antibody against the calcitonin
gene-related peptide (CGRP) receptor, has proven efficacy in migraine. Erenumab
modulates sensory processing in peripheral trigeminal pain pathways in mice and
was reported to be effective for patients with trigeminal neuralgia in
open-label studies. We aimed to evaluate the efficacy of erenumab in patients
with trigeminal neuralgia.
METHODS: We did a randomised, double-blind, placebo-controlled trial in adults
(aged 18-85 years) with idiopathic or classic trigeminal neuralgia as defined by
the 3rd edition of the International Classification of Headache Disorders. The
trial was based at the Danish Headache Center, Copenhagen University Hospital.
Eligible participants had no clinically significant cerebrovascular or
cardiovascular disease, had self-reported pain intensity of at least 4 on the
11-point Numeric Rating Scale (0=no pain, 10=worst pain imaginable), and had at
least three daily pain paroxysms. After a 1-week pre-screening period, patients
entered a 4-week baseline period. Participants who met pain inclusion criteria
at the end of the baseline period were randomly assigned (1:1) to receive
subcutaneous injections of either erenumab 140 mg or placebo and entered the
4-week follow-up period. Randomisation was done in blocks of 10 using a
computer-generated schedule by a third-party company. Participants and assessors
were masked to treatment allocation, and erenumab and placebo were packed in
identical prefilled syringes. The primary outcome was the number of responders,
defined as patients who had a reduction of at least 30% in mean average daily
pain intensity during the follow-up period compared with during the baseline
period, analysed in the intention-to-treat population. This trial is registered
with the European Union Drug Regulating Authorities Clinical Trials Database,
EudraCT number 2019-000848-95.
FINDINGS: We assessed 860 patients for suitability and excluded 741 between Oct
28, 2019, and Sept 13, 2021. 119 participants entered a 1-week pre-screening
period and 26 were excluded, 93 participants entered a 4-week baseline period
with 13 excluded before randomisation, and 80 participants were randomly
assigned to erenumab 140 mg (n=40) or placebo (n=40). There was no difference
between groups in the number of responders at 4 weeks in the intention-to-treat
population (14 [35%] of 40 with erenumab vs 18 [45%] of 40 with placebo;
estimated effect size -10% [95% CI -31 to 11]; p=0·36). 20 (50%) of 40
participants reported adverse events in each group. The most common adverse
events were constipation (28%) and headache (10%) in the erenumab group, and
headache (13%), constipation (10%), and abdominal pain (10%) in the placebo
group.
INTERPRETATION: Erenumab did not reduce pain intensity compared with placebo in
patients with trigeminal neuralgia and CGRP probably does not have an important
role in paroxysmal pain. Well tolerated, effective treatments in trigeminal
neuralgia are still needed.
FUNDING: Novartis.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(22)00294-0
PMID: 36113495 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests LB has given lectures
and served on the scientific advisory board for Novartis, Allergan, Teva,
Lundbeck, and Eli Lilly. LB received a research grant from Novartis during this
study. GC has given lectures for Grunenthal and served as a consultant for Ely
Lilly and Angelini. MA received personal fees from AbbVie, Allergan, Amgen, Eli
Lilly, Lundbeck, Novartis, and Teva Pharmaceuticals during this study and has
served as associate editor of Cephalalgia. ASSA, SM, TH, NN, and JF declare no
competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/26771990
|
1. Ann N Y Acad Sci. 2015 Nov;1358:95-104. doi: 10.1111/nyas.12965.
The development of lurasidone for bipolar depression.
Loebel A(1), Xu J(1), Hsu J(1), Cucchiaro J(1), Pikalov A(1).
Author information:
(1)Sunovion Pharmaceuticals Inc., Fort Lee, New Jersey, and Marlborough,
Massachusetts.
Bipolar disorder is a chronic, recurrent illness that ranks among the top 10
causes of disability in the developed world. As the illness progresses, major
depressive episodes increasingly predominate. However, few treatment options are
available that have demonstrated efficacy in the treatment of bipolar
depression, either as monotherapy or adjunctive therapy in combination with mood
stabilizers. Lurasidone is an atypical antipsychotic drug that was initially
developed for the treatment of schizophrenia. Since no previous atypical
antipsychotic development program had proceeded directly from work on
schizophrenia to bipolar depression, the decision to focus on this indication
represented an innovation in central nervous system drug development and was
designed to address a clinically significant unmet need. The current review
summarizes key results of a clinical development program undertaken to
characterize the efficacy and safety of lurasidone in patients diagnosed with
bipolar depression. Lurasidone is currently the only treatment for bipolar
depression approved in the United States as both a monotherapy and an adjunctive
therapy with lithium or valproate. The approval of lurasidone expands available
treatment options for patients with bipolar depression and provides a therapy
with an overall favorable risk-benefit profile.
© 2015 The Authors. Annals of the New York Academy of Sciences published by
Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.
DOI: 10.1111/nyas.12965
PMID: 26771990 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33572131
|
1. Children (Basel). 2021 Feb 9;8(2):121. doi: 10.3390/children8020121.
The Effectiveness of Lurasidone Add-On for Residual Aggressive Behavior and
Obsessive Symptoms in Antipsychotic-Treated Children and Adolescents with
Tourette Syndrome: Preliminary Evidence from a Case Series.
Colizzi M(1)(2)(3), Bortoletto R(3), Zoccante L(3).
Author information:
(1)Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement
Sciences, University of Verona, 37134 Verona, Italy.
(2)Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London SE5 8AF, UK.
(3)Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care
Department, Integrated University Hospital of Verona, 37126 Verona, Italy.
Children and adolescents with Tourette syndrome may suffer from comorbid
psychological and behavioral difficulties, primarily Attention-Deficit
Hyperactivity Disorder-related manifestations including impulsive, aggressive,
and disruptive behavior, and Obsessive-Compulsive Disorder-related disturbances.
Often, such additional problems represent the major cause of disability,
requiring their prioritization above the tic symptomatology. Here, we present
six cases of children and adolescents with treatment-resistant Tourette syndrome
aged 11-17 years, whose symptoms, especially the non-tic symptoms such as
aggressive behavior and obsessive symptoms, failed to respond adequately to at
least two different antipsychotics and, where deemed appropriate, to a
combination with a medication with a different therapeutic indication or
chemical class (e.g., antidepressant or anticonvulsant). Such symptomatic
manifestations were significantly reduced by the time of the subsequent control
visit planned 30 days later, by using lurasidone as an add-on therapy to
risperidone or aripiprazole (all p ≤ 0.009). No significant neuromotor or
metabolic side effects were reported in all cases in a follow-up period ranging
from 4 months to 6 months, supporting the stability of the observed clinical
improvement. While still investigational, the preliminary evidence presented
here gives reason to hope that lurasidone could possibly be an effective option
in Tourette syndrome, warranting further investigation of its potential benefits
in neurodevelopmental conditions.
DOI: 10.3390/children8020121
PMCID: PMC7915970
PMID: 33572131
Conflict of interest statement: M.C. has been a consultant/advisor to GW Pharma
Limited, outside of this work. All the other authors declare no conflict of
interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/25698146
|
1. CNS Drugs. 2015 Mar;29(3):253-63. doi: 10.1007/s40263-015-0234-2.
Lurasidone: a review of its use in adult patients with bipolar I depression.
Sanford M(1), Dhillon S.
Author information:
(1)Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand,
[email protected].
Lurasidone (Latuda(®)), a benzisothiazole derivative antipsychotic, is approved
in the USA and Canada for the treatment of adults with major depressive episodes
(MDE) associated with bipolar I disorder; this article reviews studies of
lurasidone in this indication. In two 6-week, placebo-controlled trials in
adults with bipolar I depression, lurasidone 20-120 mg/day reduced depressive
symptoms, either as monotherapy or as an adjunct to lithium or valproate.
Lurasidone reduced the mean Montgomery-Åsberg Depression Rating Scale (MADRS)
total score from baseline (primary endpoint) by >50 %; the reductions in scores
were significantly greater than with placebo. The treatment effects were small
to medium and the numbers needed to treat to obtain an additional MDE response
(≥50 % reduction from baseline in the MADRS total score) were ≤7 across the
lurasidone groups. In a third, similarly designed trial of lurasidone 20-120
mg/day adjunctive to lithium or valproate, there was no significant
between-group difference in the change in the mean MADRS total score at week 6
(primary endpoint), although significant differences favouring lurasidone were
observed from week 2 to week 5. Across trials, the most frequently occurring
adverse events included akathisia, extrapyramidal symptoms and somnolence.
Lurasidone had a favourable profile with respect to weight gain and metabolic
disturbances, known to occur with some other antipsychotics. Thus, lurasidone
offers a valuable addition to the therapies available for adult patients with
bipolar depression, either as monotherapy or as an adjunct to lithium or
valproate.
DOI: 10.1007/s40263-015-0234-2
PMID: 25698146 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24955752
|
1. CNS Spectr. 2015 Apr;20(2):140-7. doi: 10.1017/S1092852914000285. Epub 2014
Jun 23.
Lurasidone for the treatment of depressive symptoms in schizophrenia: analysis
of 4 pooled, 6-week, placebo-controlled studies.
Nasrallah HA(1), Cucchiaro JB(2), Mao Y(2), Pikalov AA(2), Loebel AD(2).
Author information:
(1)1Department of Neurology and Psychiatry,St. Louis University,St.
Louis,Missouri,USA.
(2)2Sunovion Pharmaceuticals Inc.,Fort Lee,New Jersey,USA.
OBJECTIVE: Depressive symptoms are common in schizophrenia and can worsen
outcomes and increase suicide risk. Lurasidone is an atypical antipsychotic
agent indicated for the treatment of schizophrenia and for the treatment of
major depressive episodes associated with bipolar I disorder. This post hoc
analysis evaluated the effect of lurasidone on depressive symptoms in patients
with schizophrenia.
METHODS: Patient-level data were pooled from 4 similarly designed, double-blind,
placebo-controlled, 6-week registration studies of lurasidone (40-160 mg/d) in
adult patients with an acute exacerbation of schizophrenia. Changes in
depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale
(MADRS), were analyzed for the overall sample and for subgroups of patients
stratified by baseline MADRS scores.
RESULTS: MADRS assessments at baseline and endpoint (day 42 or last observation
carried forward [LOCF]) were available for 1330 patients. Patients receiving
lurasidone experienced significantly greater decreases in MADRS score (-2.8,
least-squares [LS] mean change, LOCF) compared with patients receiving placebo
(-1.4, P < .001, effect size 0.24). Analysis of change in MADRS score (LOCF) by
baseline symptom severity (MADRS score of ≥12, ≥14, ≥16, ≥18) showed
significantly greater improvement for lurasidone-treated patients across all
severity groups; effect sizes ranged from 0.25 to 0.34. Among patients with a
baseline MADRS score of ≥12, depressive symptom remission (defined as MADRS
score <10 at LOCF endpoint) was attained by 45.0% of lurasidone-treated patients
and 36.3% of patients receiving placebo (P < .05).
CONCLUSIONS: In a pooled analysis of short-term, placebo-controlled studies,
lurasidone significantly improved depressive symptoms in patients with
schizophrenia.
DOI: 10.1017/S1092852914000285
PMCID: PMC4411643
PMID: 24955752 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21446639
|
1. J Psychosoc Nurs Ment Health Serv. 2011 Apr;49(4):13-5. doi:
10.3928/02793695-20110311-99. Epub 2011 Mar 30.
Update on newer antipsychotic drugs.
Howland RH(1).
Author information:
(1)University of Pittsburgh School of Medicine, Western Psychiatric Institute
and Clinic, Pittsburgh, PA 15213, USA. [email protected]
This article briefly reviews the novel atypical second-generation antipsychotic
drugs iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®), all
of which have been approved by the U.S. Food and Drug Administration since 2009.
Each is indicated for the treatment of schizophrenia, and asenapine has an
additional indication for bipolar disorder. Very little information is available
on their use in other disorders, pediatric and geriatric patients, and during
pregnancy and breastfeeding. Their overall efficacy is no different than other
antipsychotic drugs, but they do have different side effect profiles. Because of
their unique pharmacologies and different tolerability profiles, they may be a
more effective alternative for patients who do not respond to or cannot tolerate
other antipsychotic drugs.
Copyright 2011, SLACK Incorporated.
DOI: 10.3928/02793695-20110311-99
PMID: 21446639 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22364325
|
1. Expert Rev Neurother. 2012 Mar;12(3):265-73. doi: 10.1586/ern.12.7.
Lurasidone for schizophrenia: what's different?
Kantrowitz JT(1), Citrome L.
Author information:
(1)Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
[email protected]
Lurasidone is one of several antipsychotics approved in the recent past by the
US FDA for the treatment of schizophrenia. Several Phase II and III studies have
established that lurasidone is more efficacious than placebo. There are no
available adequately powered head-to-head comparisons of efficacy of lurasidone
with other antipsychotics. However, in contrast to some other antipsychotics,
lurasidone is associated with minimal weight gain and no clinically meaningful
alterations in glucose, lipids, or the ECG QT interval. As per the product
label, the recommended starting dose is 40 mg/day and the maximum recommended
dose is 80 mg/day. Higher doses do not appear to be more efficacious, and may be
associated with increases in adverse effects, such as somnolence and akathisia;
however, this tolerability issue was not observed in one recently conducted
6-week study when lurasidone was administered at a dose of 160 mg/day. It is
recommended that lurasidone be administered once daily with at least 350
calories of food. Additional studies are desirable to directly compare and
contrast lurasidone with other antipsychotic agents.
DOI: 10.1586/ern.12.7
PMID: 22364325 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29962579
|
1. Indian J Psychol Med. 2018 Mar-Apr;40(2):191-192. doi:
10.4103/IJPSYM.IJPSYM_374_17.
Lurasidone Induced Thrombocytopenia: Is it a Signal of Drug Induced
Myelosuppression?
Rafi M(1), Goyal C(1), Reddy P(1), Reddy S(2).
Author information:
(1)Department of Pharmacology, Sri Aurobindo Medical College and PGI, Indore,
Madhya Pradesh, India.
(2)Department of Psychiatry, Sri Aurobindo Medical College and PGI, Indore,
Madhya Pradesh, India.
The U.S. Food and Drug Administration (FDA) has approved a supplemental new drug
application Lurasidone (Latuda, Sunovion Pharmaceuticals), an atypical
antipsychotic, for the treatment of schizophrenia in adolescents 13-17 years of
age. Lurasidone was previously indicated in the U.S. for the treatment of adults
with schizophrenia and major depressive episodes with bipolar I disorder as
monotherapy. We present a case of a 29-year-old male patient who was
hospitalized with thrombocytopenia (WHO grade-3 toxicity) (unlabeled) along with
extrapyramidal disorder, gastritis, and hyperprolactinemia within 2-3 months of
initiation of tablet lurasidone 80 mg/day (Lurasid, Intas Pharmaceuticals) in
bipolar depression. Dechallenge was found to be positive in three reactions
except hyperprolactinemia (outcome unknown) during hospital stay. The terms
anemia and leukopenia are well labeled/listed with the drug literatures of
lurasidone. Thus, this case presents a strong probability of lurasidone to cause
myelosuppression/bone marrow depression.
DOI: 10.4103/IJPSYM.IJPSYM_374_17
PMCID: PMC6009006
PMID: 29962579
Conflict of interest statement: There are no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/32124704
|
1. CNS Neurol Disord Drug Targets. 2020;19(2):109-114. doi:
10.2174/1871527319666200303120147.
Risk Analysis of Lurasidone in Patients with Schizophrenia and Bipolar
Depression.
Modugula H(1), Kumar A(1).
Author information:
(1)Department of Pharmacology and Toxicology, National Institute of
Pharmaceutical Education and Research, Raebareli (NIPER-R), Lucknow (UP)
-226002, India.
Lurasidone was approved by the United States Food and Drug Administration (FDA)
for the treatment of schizophrenia, as well as for the treatment of bipolar
depression. However, emerging reports have indicated various adverse drug
reactions with the use of lurasidone. Thus, in this article, we have analyzed
the risk profile of lurasidone in the established therapeutic indication. A
total of 419 studies were published from October 2010-July 2019 regarding
lurasidone. After the inclusion and exclusion criteria, 17 studies were selected
for the analysis of risk. The adverse drug reactions (ADRs) of these studies
were categorized as per the innovator summary of product characteristics (SmPC).
Finally, the unlisted ADRs were analyzed by using the Naranjo probability
algorithm. Telogen effluvium, thrombocytopenia, restless leg syndrome and
hypersexuality were found with the use of lurasidone and fall under the unlisted
category. The causality assessment has shown a probable correlation of
lurasidone with hypersexuality, restless leg syndrome, thrombocytopenia and
possible relation with telogen effluvium. In conclusion, lurasidone is a novel
and efficacious pharmacological treatment for bipolar depression and
schizophrenia. However, more data regarding the safety of this drug in a large
population is needed.
Copyright© Bentham Science Publishers; For any queries, please email at
[email protected].
DOI: 10.2174/1871527319666200303120147
PMID: 32124704 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26316760
|
1. Neuropsychiatr Dis Treat. 2015 Aug 19;11:2143-52. doi: 10.2147/NDT.S50961.
eCollection 2015.
Lurasidone for the treatment of bipolar depression: an evidence-based review.
Franklin R(1), Zorowitz S(1), Corse AK(1), Widge AS(2), Deckersbach T(1).
Author information:
(1)Division of Neurotherapeutics, Department of Psychiatry, Massachusetts
General Hospital, Harvard Medical School, Charlestown, MA, USA.
(2)Picower Institute for Learning and Memory, Massachusetts Institute of
Technology, Cambridge, MA, USA.
Bipolar disorder (BD) is a debilitating and difficult-to-treat psychiatric
disease that presents a serious burden to patients' lives as well as health care
systems around the world. The essential diagnostic criterion for BD is episodes
of mania or hypomania; however, the patients report that the majority of their
time is spent in a depressive phase. Current treatment options for this
component of BD have yet to achieve satisfactory remission rates. Lurasidone is
a drug in the benzisothiazole class approved by the US Food and Drug
Administration in June 2013 for the acute treatment of bipolar depression. Its
pharmacological profile features high-affinity antagonism at D2, 5-HT2A, and
5-HT7 receptors; moderate-affinity antagonism at α2C-adrenergic receptors; low-
to very low-affinity antagonism at α1A-adrenergic, α2A-adrenergic, H1, M1, and
5-HT2C receptors; and high-affinity partial agonism at 5-HT1A. Preliminary
findings from two recent double-blinded clinical trials suggest that lurasidone
is efficacious in treating bipolar I depression, with clinical effects
manifesting as early as the first 2-3 weeks of treatment (as measured by the
Montgomery-Åsberg Depression Rating Scale and Clinical Global Impressions Scale
for use in bipolar illness). Its therapeutic benefit appears to be comparable to
the current US Food and Drug Administration-indicated treatments: quetiapine and
olanzapine-fluoxetine, according to a measure of effect size known as number
needed to treat. These studies reported relatively limited extrapyramidal and
metabolic side effects as a result of treatment with lurasidone, with the most
common side effect being nausea. Safety data drawn from these studies, as well
as a more extensive body of schizophrenia research, indicate that in comparison
with other atypical antipsychotics, treatment with lurasidone is less likely to
result in metabolic side effects such as weight gain or disturbances of serum
glucose or lipid levels. Lurasidone holds clinical potential as a novel,
efficacious pharmacological treatment for bipolar depression. However, current
data on its use for the treatment of BD are limited, and more extensive
research, both longer in duration as well as independently conducted, is needed.
DOI: 10.2147/NDT.S50961
PMCID: PMC4547662
PMID: 26316760
|
http://www.ncbi.nlm.nih.gov/pubmed/22146224
|
1. Drugs Today (Barc). 2011 Nov;47(11):807-16. doi:
10.1358/dot.2011.47.11.1708832.
Lurasidone: a new treatment option for schizophrenia.
Owen RT(1).
Author information:
(1)Crewe, Cheshire, UK. [email protected]
Lurasidone is a novel benzoisothiazol antipsychotic that has recently been
approved for the treatment of schizophrenia in the U.S. Like many other
second-generation antipsychotics, it has a high affinity for dopamine D(2) and
serotonin 5-HT(2A) receptors as well as a high affinity for 5-HT(7) receptors.
It has negligible affinity for α(1)-adrenoceptors, histamine H(1) receptors or
muscarinic acetylcholine M(1) receptors. It has demonstrated efficacy in
short-term trials versus placebo, two of which included an active comparator
(olanzapine, quetiapine) assay arm. A short-term, head-to-head trial of
lurasidone versus ziprasidone in chronic stable schizophrenia was also
conducted. A long-term, 12-month risperidone-controlled study and open-label
studies primarily investigated the safety and tolerability of lurasidone.
Limited evidence of procognitive and antidepressant effects was seen although
these need further corroboration. The incidence of extrapyramidal symptoms
(excluding akathisia/restlessness) was greater with lurasidone (14.7%) than
placebo (5.1%). Akathisia and somnolence were dose-related adverse events.
Lurasidone appears to have relatively little effect on weight, plasma glucose or
lipids to date. No evidence of QTc prolongation was seen and orthostatic
hypotension was uncommon. Raised prolactin levels in short-term studies were
dose-dependent, greater in females and occurred overall in 3.7 and 0.7% of
lurasidone and placebo recipients, respectively.
Copyright 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
DOI: 10.1358/dot.2011.47.11.1708832
PMID: 22146224 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25852975
|
1. Innov Clin Neurosci. 2015 Jan-Feb;12(1-2):21-3.
Lurasidone: a new treatment option for bipolar depression-a review.
Bawa R(1), Scarff JR(1).
Author information:
(1)Dr. Bawa is with Lehman College, the City University of New York, Bronx, New
York; and Dr. Scarff is with Veterans Affairs Outpatient Clinic, Spartanburg,
South Carolina.
Depressive episodes in bipolar disorder contribute to significant morbidity and
mortality. Until recently, only quetiapine and an olanzapine-fluoxetine
combination were approved to treat bipolar depression. Recently, lurasidone was
approved to treat bipolar depression either as monotherapy or adjunctively with
lithium or valproate. Lurasidone was well- tolerated, and commonly observed
adverse reactions (incidence ≥5% and at least twice the rate for placebo) were
akathisia, extrapyramidal symptoms, and somnolence. There were no significant
metabolic or electrocardiogram abnormalities. It is taken with food to ensure
maximal absorption, and dose should be adjusted in patients who receive moderate
CYP450 inhibitors or inducers and in patients with renal disease.
PMCID: PMC4382136
PMID: 25852975
|
http://www.ncbi.nlm.nih.gov/pubmed/34304240
|
1. Am J Case Rep. 2021 Jul 25;22:e933003. doi: 10.12659/AJCR.933003.
BNT162b2 mRNA Vaccine Interference with Co-Administration of Tdap Vaccine.
Chilimuri S(1), Mantri N(1), Shrestha E(1), Sun H(1), Gongati S(1), Zahid M(1),
Kelly P(2).
Author information:
(1)Department of Medicine, Bronx Care Health System, Affiliated with Icahn
School of Medicine at Mount Sinai, Bronx, NY, USA.
(2)BronxCare Center for Travel Medicine, Bronx Care Health System, Affiliated
with Icahn School of Medicine at Mount Sinai, Bronx, NY, USA.
BACKGROUND It is unknown if the efficacy of the coronavirus disease-19
(COVID-19) vaccine is affected by the co-administration of other vaccines. The
Centers for Disease Control and Prevention (CDC) has shifted their
recommendations recently, allowing for the co-administration of the currently
available COVID-19 vaccines with other vaccines. This is based on the experience
with non-COVID-19 vaccines, where the immunogenicity and adverse event profiles
were generally similar when vaccines are administered simultaneously or alone.
CASE REPORT We present a case of a 29-year-old Asian woman who received the
first dose of BNT162b2 mRNA vaccine and the tetanus toxoid, reduced diphtheria
toxoid, and acellular pertussis (Tdap) vaccine at around the same time. BNT162b2
mRNA vaccine and Tdap vaccine were administered into the deltoid region of the
left arm and right arm, respectively. We then monitored for immunogenicity. We
observed a delay in the development of SARS-CoV-2 Spike (S1) protein antibodies
at around 8 weeks after the second dose. CONCLUSIONS Unless warranted, it is
important to adhere to current CDC recommendations with regards to the
co-administration of vaccines. Although the administration of Tdap with COVID-19
vaccine in our case caused delay in immunogenicity, it did not negate the
ability of the BNT162B2 mRNA vaccine to elicit an adequate immune response. The
reason for delay in immune response with co-administration of COVID-19 vaccines
with other vaccines is unknown and further studies are needed.
DOI: 10.12659/AJCR.933003
PMCID: PMC8317582
PMID: 34304240 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None declared Conflict of
Interest None declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/21177242
|
1. Clin Schizophr Relat Psychoses. 2011 Jan;4(4):251-7.
Lurasidone for schizophrenia: a brief review of a new second-generation
antipsychotic.
Citrome L(1).
Author information:
(1)Department of Psychiatry, New York University School of Medicine, New York,
NY, USA. [email protected]
Lurasidone is a second-generation antipsychotic newly approved by the U.S. Food
and Drug Administration for the treatment of schizophrenia. Similar to most
other second-generation antipsychotics, lurasidone is a full antagonist at
dopamine D2 and serotonin 5HT2A receptors. Efficacy within the dose range of
40-120 mg/d was established in four 6-week, randomized, controlled trials. The
recommended starting dose is 40 mg/d and the maximum recommended dose is 80
mg/d. Doses above 80 mg/d do not appear to confer added benefit and may be
associated with a dose-related increase in certain adverse reactions such as
somnolence and akathisia. Lurasidone is administered once daily with at least
350 calories of food in order to optimize bioavailability. Lurasidone is
primarily metabolized in the liver through the CYP3A4 enzyme system, and
coadministration with drugs that are strong inhibitors of CYP3A4 (such as
ketoconazole) or strong inducers (such as rifampin) are contraindicated.
Lurasidone is associated with minimal weight gain and no clinically meaningful
alterations in glucose, lipids, or the ECG QT interval.
PMID: 21177242 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34534629
|
1. Int J Pharm. 2021 Oct 25;608:121098. doi: 10.1016/j.ijpharm.2021.121098. Epub
2021 Sep 14.
Harnessing the potential of nanostructured formulations to mimic the food effect
of lurasidone.
Meola TR(1), Joyce P(1), Wignall A(1), Bremmell KE(1), Prestidge CA(2).
Author information:
(1)UniSA Clinical and Health Sciences, University of South Australia, Adelaide,
South Australia 5000, Australia; ARC Centre for Excellence in Bio-Nano Science
and Technology, Adelaide, South Australia 5000, Australia.
(2)UniSA Clinical and Health Sciences, University of South Australia, Adelaide,
South Australia 5000, Australia; ARC Centre for Excellence in Bio-Nano Science
and Technology, Adelaide, South Australia 5000, Australia. Electronic address:
[email protected].
Lurasidone is an important antipsychotic drug indicated for the treatment of
schizophrenia and bipolar disorder, with an oral bioavailability of 9-19% owing
to its poor aqueous solubility. Additionally, lurasidone exhibits a 2-fold
positive food effect, such that patients must administer their medication with a
meal, leading to significant non-compliance. The aim of this research was to
evaluate the in vitro and in vivo performance of lurasidone when engineered as
nanostructured systems. Specifically, a nanosuspension, nano-emulsion and
silica-lipid hybrid (SLH) microparticles were formulated and the influence of
composition and nanostructure on the mechanism of solubilisation was compared.
Formulations were shown to enhance fasted state solubilisation levels in vitro
by up to 5.9-fold, compared to pure drug. Fed- and fasted-state solubilisation
profiles revealed that in contrast to the nanosuspension and nano-emulsion,
lurasidone SLH mitigated the positive pharmaceutical effect of lurasidone. In
vivo pharmacokinetic evaluations revealed that the nanosuspension, nano-emulsion
and SLH enhanced the bioavailability of lurasidone by 3-fold, 2.4-fold and
8.8-fold, respectively, compared to pure drug after oral administration. For
lurasidone, the combination of lipid-based nanostructure and porous silica
nanostructure (SLH) led to optimal fasted state bioavailability which can
ultimately result in enhanced treatment efficacy, easier dosing regimens and
improved patient outcomes.
Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ijpharm.2021.121098
PMID: 34534629 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26755968
|
1. BJPsych Bull. 2015 Oct;39(5):237-41. doi: 10.1192/pb.bp.114.048793.
Lurasidone: a novel antipsychotic agent for the treatment of schizophrenia and
bipolar depression.
Loebel A(1), Citrome L(2).
Author information:
(1)Sunovion Pharmaceuticals, Fort Lee, New Jersey, USA.
(2)New York Medical College, Valhalla, New York, USA.
Lurasidone is a novel antipsychotic agent approved for the treatment of
schizophrenia in a number of countries including the UK, and is also approved in
the USA and Canada for the treatment of major depressive episodes associated
with bipolar I disorder as either a monotherapy or adjunctive therapy with
lithium or valproate. In addition to full antagonist activity at dopamine D2 (K
i(D2) = 1 nM) and serotonin 5-HT2A (K i(5-HT2A) = 0.5 nM) receptors, the
pharmacodynamic profile of lurasidone is notable for its high affinity for
serotonin 5-HT7 receptors (K i(5-HT7) = 0.5 nM) and its partial agonist activity
at 5-HT1A receptors (K i(5-HT1A) = 6.4 nM). Long-term treatment of schizophrenia
with lurasidone has been shown to reduce the risk of relapse. Lurasidone appears
associated with minimal effects on body weight and low risk for clinically
meaningful alterations in glucose, lipids or electrocardiogram parameters.
DOI: 10.1192/pb.bp.114.048793
PMCID: PMC4706192
PMID: 26755968
Conflict of interest statement: Declaration of interest A.L. is a full-time
employee of Sunovion Pharmaceuticals. In the past 12 months, L.C. was a
consultant for, has received honoraria from, or has conducted clinical research
supported by: Actavis (Forest Laboratories), Alexza Pharmaceuticals, Alkermes,
AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Company, Forum Pharmaceuticals,
Genentech, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Medivation,
Merck Worldwide, Mylan Laboratories, Novartis Pharmaceuticals, Noven
Pharmaceuticals, Otsuka Pharmaceutical Group, Pfizer, Reckitt Benckiser, Reviva
Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company,
and Teva Pharmaceutical Industries
|
http://www.ncbi.nlm.nih.gov/pubmed/35417663
|
1. Hum Vaccin Immunother. 2022 Nov 30;18(5):2049169. doi:
10.1080/21645515.2022.2049169. Epub 2022 Apr 13.
Willingness toward COVID-19 vaccination, coadministration with other vaccines
and receive a COVID-19 vaccine booster: a cross-sectional study on the guardians
of children in China.
Ma L(1)(2)(3), Yang J(1), Zhang T(1)(2), Han X(1), Huang Q(1), Yang Y(4), Feng
L(1)(2), Yang W(1)(2), Wang C(5).
Author information:
(1)School of Population Medicine and Public Health, Chinese Academy of Medical
Sciences & Peking Union Medical College, Beijing, China.
(2)Institute of pharmaceutical and medical devices supervision, National Medical
Products Administration-Chinese Academy of Medical Sciences, Beijing, China.
(3)Department of Respiratory and Critical Care Medicine, Affiliated Hospital of
Guilin Medical University, Guilin, China.
(4)Division of Infectious Diseases, Chinese Center for Disease Control and
Prevention, Beijing, China.
(5)Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China.
This study aimed to investigate the changes in the willingness of guardians to
administer the COVID-19 vaccine to their children, allow the coadministration of
other vaccines, and administer the COVID-19 vaccine booster dose. This was a
follow-up study conducted 6 months after a similar previous study. The
self-administered questionnaire was distributed through the "Xiao Dou Miao" app
and 9424 guardians with access to this app participated in the survey that was
conducted from September 15 to October 8, 2021. Of all the participating
guardians, 86.68% were willing to vaccinate their children with the COVID-19
vaccine, which was approximately 16% more than those in our previous study.
Guardians aged ≥40 years, healthcare workers, and those with children aged
≥3 years were more willing to vaccinate their children. Approximately 77% of the
guardians were willing toward the coadministration of COVID-19 and influenza
vaccines. Approximately 64% of the guardians were willing toward the
coadministration of other nonimmunization program vaccines with the COVID-19
vaccine for their children. The primary reasons for reluctance toward the
coadministration of vaccines were concerns about vaccine safety and
effectiveness. If necessary, 92% of the guardians were willing to receive a
COVID-19 vaccine booster and 82% were willing to vaccinate their children with a
COVID-19 vaccine booster. We hope that this research will facilitate the
formulation of successful strategies for the implementation of COVID-19
vaccinations, covaccinations, and COVID-19 booster doses, particularly for
children aged <6 years.
DOI: 10.1080/21645515.2022.2049169
PMCID: PMC9196675
PMID: 35417663 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported
by the author(s).
|
http://www.ncbi.nlm.nih.gov/pubmed/34774197
|
1. Lancet. 2021 Dec 18;398(10318):2277-2287. doi: 10.1016/S0140-6736(21)02329-1.
Epub 2021 Nov 11.
Safety and immunogenicity of concomitant administration of COVID-19 vaccines
(ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK
(ComFluCOV): a multicentre, randomised, controlled, phase 4 trial.
Lazarus R(1), Baos S(2), Cappel-Porter H(2), Carson-Stevens A(3), Clout M(2),
Culliford L(2), Emmett SR(4), Garstang J(5), Gbadamoshi L(4), Hallis B(6),
Harris RA(2), Hutton D(2), Jacobsen N(7), Joyce K(2), Kaminski R(8), Libri V(9),
Middleditch A(10), McCullagh L(10), Moran E(11), Phillipson A(12), Price E(13),
Ryan J(14), Thirard R(2), Todd R(2), Snape MD(15), Tucker D(16), Williams
RL(11), Nguyen-Van-Tam JS(17), Finn A(18), Rogers CA(2); ComfluCOV Trial Group.
Collaborators: Adams K, Alaee S, Aley PK, Allum E, Anthony S, Ashton K, Awal T,
Barnett L, Barratt A, Barron C, Baum H, Beard C, Bennett L, Bird S, Bishop S,
Bisset J, Bodalia P, Bowles J, Bowyer C, Bradburn K, Bray JJH, Bressington C,
Brimfield M, Broad L, Brown P, Brydon-Hill R, Burge S, Carmichael D, Chohan G,
Clark T, Close A, Coleman T, Cowley C, Cranfield C, Cross E, D'Agostino A,
D'Arcangelo S, David Otter A, Davies K, Davies C, Davies R, Davies L, Driver K,
Eglinton C, Ekblad C, Eldridge E, Evans T, Evans M, Evans I, F Mujadidi Y,
Farrow A, Faulkner B, Feltham S, Figueirido S, Ford J, Foxwell D, Frayling S,
Gardiner S, Gooch KE, Goodwin J, Halliday A, Hamal S, Harrhy S, Harris A, Haxton
L, Haynes M, Hazell M, Hembrough T, Hewson J, Hicks B, Higgins T, Hill M, Hills
A, Hilton Z, Hitchings B, Hua C, Iftikhar H, Iqbal A, Jones L, Jones N, Kellett
Wright J, Kidd S, Kirby A, Knibbs L, Lamb J, Langton H, Leach R, Lewis-Clarke P,
Lloyd A, Maclean K, Manning N, Marriott A, McFadzean IJ, McLaughlin M, McQueen
A, Mills B, Naik G, Nicholls L, Norman C, Northcott K, Nyland K, Oliver C,
Oliver E, Oliver J, Owen D, Paterson J, Pearce L, Pegler S, Price Z, Pynsent WB,
Ramos L, Rampling T, Rea D, Regan K, Riaz T, Ricamara M, Rice D, Rich M, Roots
M, Ryan KA, Sakagami Y, Salem A, Salter-Hewitt J, Samuels M, Santoloce S, Seaman
S, Seneviratne M, Shankland S, Silva L, Smart K, Smith RM, Smith J, Stringer R,
Talbot H, Tarling T, Taylor SL, Thomas A, Tilzey G, Townley G, Trembath L,
Turkentine K, Turner K, Tyler J, Ugoji J, Wale K, Walker-Smith T, Walton M,
Warnes B, Whittley S, Williams J, Williams G, Williamson K, Yim YTN, Youlden N.
Author information:
(1)University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
Electronic address: [email protected].
(2)Bristol Trials Centre, University of Bristol, Bristol, UK.
(3)Division of Population Medicine, School of Medicine, Cardiff University,
Cardiff, UK.
(4)Royal United Hospitals NHS Foundation Trust, Bath, UK.
(5)Knowle House Surgery, Plymouth, UK.
(6)Porton Down, Public Health England, Salisbury, UK.
(7)Newquay Health Centre, North Coast Medical, Newquay, UK.
(8)Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.
(9)University College Hospitals NHS Foundation Trust, London, UK.
(10)University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
(11)North Bristol NHS Trust, Bristol, UK.
(12)Rotherham Doncaster and South Humber NHS Foundation Trust, Doncaster, UK.
(13)Great Western Hospitals NHS Foundation Trust, Swindon, UK.
(14)The Alverton Practice, Atlantic Medical, Penzance, UK.
(15)Oxford Vaccine Group, Department of Paediatrics, University of Oxford,
Oxford, UK; Oxford NIHR-Biomedical Research Centre, Oxford University Hospitals
NHS Foundation Trust, Oxford, UK.
(16)Royal Cornwall Hospitals NHS Trust, Truro, UK.
(17)Division of Epidemiology and Public Health, University of Nottingham School
of Medicine, Nottingham, UK.
(18)Bristol Vaccine Centre, Bristol Medical School, Bristol Population Health
Sciences and School of Cellular and Molecular Medicine, University of Bristol,
Bristol, UK.
BACKGROUND: Concomitant administration of COVID-19 and influenza vaccines could
reduce burden on health-care systems. We aimed to assess the safety of
concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate
influenza vaccine.
METHODS: In this multicentre, randomised, controlled, phase 4 trial, adults in
receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and
randomly assigned (1:1) to receive concomitant administration of either an
age-appropriate influenza vaccine or placebo alongside their second dose of
COVID-19 vaccine. 3 weeks later the group who received placebo received the
influenza vaccine, and vice versa. Participants were followed up for 6 weeks.
The influenza vaccines were three seasonal, inactivated vaccines (trivalent,
MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine).
Participants and investigators were masked to the allocation. The primary
endpoint was one or more participant-reported solicited systemic reactions in
the 7 days after first trial vaccination(s), with a difference of less than 25%
considered non-inferior. Analyses were done on an intention-to-treat basis.
Local and unsolicited systemic reactions and humoral responses were also
assessed. The trial is registered with ISRCTN, ISRCTN14391248.
FINDINGS: Between April 1 and June 26, 2021, 679 participants were recruited to
one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza
vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1
plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C
adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant
quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent
influenza vaccine. 340 participants were assigned to concomitant administration
of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo
at day 21, and 339 participants were randomly assigned to concomitant
administration of placebo and a second dose of COVID-19 vaccine at day 0
followed by influenza vaccine at day 21. Non-inferiority was indicated in four
cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk
difference for influenza vaccine minus placebos -1·29%, 95% CI -14·7 to 12·1),
BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, -6·27 to 18·6),
BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (-12·9%, -34·2 to
8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, -13·3
to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the
0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza
vaccine 10·3%, -5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza
vaccine 6·75%, -11·8 to 25·3). Most systemic reactions to vaccination were mild
or moderate. Rates of local and unsolicited systemic reactions were similar
between the randomly assigned groups. One serious adverse event, hospitalisation
with severe headache, was considered related to the trial intervention. Immune
responses were not adversely affected.
INTERPRETATION: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an
age-appropriate influenza vaccine raises no safety concerns and preserves
antibody responses to both vaccines. Concomitant vaccination with both COVID-19
and influenza vaccines over the next immunisation season should reduce the
burden on health-care services for vaccine delivery, allowing for timely vaccine
administration and protection from COVID-19 and influenza for those in need.
FUNDING: National Institute for Health Research Policy Research Programme.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..
All rights reserved.
DOI: 10.1016/S0140-6736(21)02329-1
PMCID: PMC8585490
PMID: 34774197 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests RL reports grants from
the National Institute for Health Research (NIHR) during the conduct of the
trial, and grants from Elizabeth Blackwell Institute, AstraZeneca, Janssen, and
Valneva outside the submitted work. CAR reports grants from NIHR, during the
conduct of the trial. JSN-V-T reports that he is seconded to the Department of
Health and Social Care, England. AF reports grants from Pfizer during the
conduct of the trial, and grants from Elizabeth Blackwell Institute, Sanofi
Pasteur, VBI Vaccines, Pfizer, Janssen, GSK, MedImmune, Novavax, and Valneva
outside the submitted work. AM reports grants from NIHR during the conduct of
the trial, and grants from AstraZeneca, Janssen, and Valneva outside the
submitted work. MDS acts on behalf of the University of Oxford as an
investigator on studies funded or sponsored by vaccine manufacturers, including
AstraZeneca, GSK, Pfizer, Novavax, Pfizer, Janssen, Medimmune, and MCM. All
other authors declare no competing interests.
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http://www.ncbi.nlm.nih.gov/pubmed/34919292
|
1. Acta Paediatr. 2022 Mar;111(3):478-489. doi: 10.1111/apa.16222. Epub 2022 Jan
31.
Clinical benefits of music-based interventions on preterm infants' health: A
systematic review of randomised trials.
Costa VS(1), Bündchen DC(1), Sousa H(2), Pires LB(3), Felipetti FA(1).
Author information:
(1)Department of Health Sciences, Federal University of Santa Catarina (UFSC),
Araranguá, Brazil.
(2)Department of Education and Psychology, Center for Health Technology and
Services Research (CINTESIS.UA), University of Aveiro, Aveiro, Portugal.
(3)Espaço Envolver, Florianópolis, Brazil.
AIM: This systematic review aimed to differentiate and isolate the results of
different music-based interventions used with preterm infants in the neonatal
intensive care unit and explore their clinical benefits.
METHODS: The last search was performed on 5 July 2021 on Web of Science, Scopus,
EMBASE, PsycINFO, CINAHL, LILACS and CENTRAL. Only randomised clinical trials
that explored the health benefits of music-based interventions were considered.
RESULTS: A total of 39 studies were included. All music-based interventions were
divided into music medicine and music therapy. The overall results suggested
that music medicine interventions were associated with a significant improvement
in pain relief; in turn, improvements in cardiac and respiratory function,
weight gain, eating behaviour, and quiet alert and sleep states were more
consistent in studies that followed a music therapy approach with the presence
of a music therapist.
CONCLUSION: This review supports the beneficial effects of music-based
interventions on the health of preterm infants in a neonatal intensive care
unit; however, it also offers suggestions for future studies in order to
increase the number of interventions with music therapists, since the results of
music therapy approaches were more consistent for physiological and behavioural
outcomes.
© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
DOI: 10.1111/apa.16222
PMID: 34919292 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/32499082
|
1. Therapie. 2020 Sep-Oct;75(5):397-406. doi: 10.1016/j.therap.2020.05.007. Epub
2020 May 18.
Prolonged-release buprenorphine formulations: Perspectives for clinical
practice.
Chappuy M(1), Trojak B(2), Nubukpo P(3), Bachellier J(4), Bendimerad P(5),
Brousse G(6), Rolland B(7).
Author information:
(1)Service universitaire d'addictologie de Lyon (SUAL), centre hospitalier Le
Vinatier, 69500 Bron, France; Service d'addictologie, groupement hospitalier
centre, Hospices Civils de Lyon, 69003 Lyon, France; Centre de soins,
d'accompagnement et de prévention en addictologie, groupement hospitalier nord,
Hospices Civils de Lyon, 69004 Lyon, France. Electronic address:
[email protected].
(2)Service hospitalo-universitaire d'addictologie, CHU de Dijon, 21079 Dijon,
France; INSERM U1093 cognition, action et plasticité sensorimotrice, UFR staps,
université de Bourgogne Franche-Comté, 21078 Dijon, France.
(3)Service universitaire d'addictologie, centre hospitalier Esquirol, 87000
Limoges, France; INSERM UMR 1094 neuroépidémiologie tropicale, université de
Limoges, 87000 Limoges, France.
(4)Service universitaire d'addictologie de Tours, CHU Bretonneau, 37000 Tours,
France.
(5)Service d'addictologie, groupe hospitalier de La Rochelle-Ré-Aunis, 17000 La
Rochelle, France; Service de psychiatrie, groupe hospitalier de La
Rochelle-Ré-Aunis, 17000 La Rochelle, France.
(6)Service de psychiatrie B et d'addictologie, CHU de Clermont-Ferrand, 63000
Clermont-Ferrand, France; Équipe d'accueil 7280, unité de formation et de
recherche de médecine, université Clermont Auvergne, Clermont-Ferrand, France.
(7)Service universitaire d'addictologie de Lyon (SUAL), centre hospitalier Le
Vinatier, 69500 Bron, France; Service d'addictologie, groupement hospitalier
centre, Hospices Civils de Lyon, 69003 Lyon, France; Université de Lyon, UCBL1,
INSERM, INSERM U1028, CNRS UMR 5292, CRNL, 69500 Bron, France.
Buprenorphine and methadone are the two main opioid agonist treatments approved
for opioid use disorder. Buprenorphine is a partial agonist of the mu opioid
receptors, which has been merely available through sublingual form until now. In
practice, the use of buprenorphine is smoother than that of methadone, and it
induces reduced risks of overdose. However, sublingual buprenorphine also
exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily
intake). Three new galenic formulations of prolonged-release buprenorphine (PRB)
are being commercialized and should allow some improvements in patients' comfort
and safety. This narrative review aims to describe the main technical features
and efficacy and safety data of these PRBs, as well as patients' and
professionals' expectancies and concerns, using data of the scientific
literature and the regulatory texts. PRBs consist of one subcutaneous implant
and two subcutaneous injection depots. Sixmo®/Probuphine® is a six-month-long
implant which needs to be surgically placed and removed and is approved for
subjects previously treated with a maximum daily dose of 8mg of sublingual
buprenorphine, and can be used only for two successive periods of six months
before the subject needs to be switched back to sublingual form. Sublocade® is a
one-month-long depot formulation that is indicated in switch from sublingual
buprenorphine, and which proposes only two dose schemes, i.e., 100 and 300mg
monthly. Buvidal®/Brixadi® is a one-week- or one-month-long depot formulation
with multiple dosages, which can be used in initiation or in switched from
sublingual formulations. While opioid users report some concerns with a risk of
coercive use of long-acting forms of buprenorphine, both users and professionals
deem that these new specialties could be particularly appreciated in stabilized
patients bothered with the daily intake of the treatments, or specific
situations at risk of treatment dropout (e.g., following hospital discharge or
prison release).
Copyright © 2020 Société française de pharmacologie et de thérapeutique.
Published by Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.therap.2020.05.007
PMID: 32499082 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/31532835
|
1. Acta Paediatr. 2020 Mar;109(3):511-517. doi: 10.1111/apa.15018. Epub 2019 Oct
18.
No effect of a musical intervention on stress response to venepuncture in a
neonatal population.
Howard C(1), Powell AS(1), Pavlidis E(2), Pavel A(1)(2), Finn D(2), Allen A(3),
Olavarria-Ramirez L(3), Clarke G(2)(3)(4), Livingstone V(2), Boylan GB(1)(2),
Dempsey EM(1)(2).
Author information:
(1)Department of Paediatrics and Child Health, Neonatal Intensive Care Unit,
Cork University Maternity Hospital, Cork, Ireland.
(2)INFANT, Irish Centre for Fetal and Neonatal Translational Research,
University College Cork, Cork, Ireland.
(3)APC Microbiome Ireland, Biosciences Institute, University College Cork, Cork,
Ireland.
(4)Department of Psychiatry and Neurobehavioural Science, University College
Cork, Cork, Ireland.
AIM: To investigate the effect of a musical intervention on neonatal stress
response to venepuncture as measured by salivary cortisol levels and pain
profile scores.
METHODS: In a randomised control crossover trial, participants were randomised
to both a control arm (sucrose) and intervention arm (sucrose and music) for
routine venepuncture procedures. Salivary swabs were collected at baseline,
20 minutes post-venepuncture and 4 hours post-venepuncture. Pain levels were
assessed using the Premature Infant Pain Profile (PIPP). A total of 16 preterm
neonates participated in both arms to complete the study.
RESULTS: Cortisol values were elevated at all timepoints in the intervention arm
(baseline, 20 minutes, and 4 hours post-procedure) but not significantly so
(P = .056, P = .3, and P = .575, respectively). Median change in cortisol values
from baseline was +128.48 pg/mL (-47.66 to 517.02) at 20 minutes and
+393.52 pg/mL (47.88-1221.34) at 4 hours post-procedure in the control arm
compared to -69.564 pg/mL (-860.96 to 397.289) and +100.48 pg/mL (-560.46 to
842.99) at 20 minutes and 4 hours post-procedure in the intervention arm. There
was no statistically significant difference observed between groups (P = .311 at
20 minutes, and P = .203 at 4 hours post-procedure). PIPP scores were not
significantly different between study arms.
CONCLUSION: Our findings did not support the additional benefit of music
intervention on neonatal stress response to venepuncture in preterm infants.
© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
DOI: 10.1111/apa.15018
PMID: 31532835 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/25467598
|
1. Midwifery. 2015 Mar;31(3):365-72. doi: 10.1016/j.midw.2014.11.001. Epub 2014
Nov 11.
Pain relief effect of breast feeding and music therapy during heel lance for
healthy-term neonates in China: a randomized controlled trial.
Zhu J(1), Hong-Gu H(2), Zhou X(3), Wei H(4), Gao Y(5), Ye B(6), Liu Z(7), Chan
SW(8).
Author information:
(1)Department of Nursing, School of Medicine, Xiamen University, Xiamen, China.
Electronic address: [email protected].
(2)Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore. Electronic address:
[email protected].
(3)Department of Obstetrics and Gynecology, The First Affiliated Hospital of
Xiamen University, Xiamen, China. Electronic address: [email protected].
(4)BSc (Nursing) Programme, Department of Nursing, School of Medicine, Xiamen
University, China. Electronic address: [email protected].
(5)BSc (Nursing) Programme, Department of Nursing, School of Medicine, Xiamen
University, China. Electronic address: [email protected].
(6)Department of Nursing, School of Medicine, Xiamen University, Xiamen, China.
Electronic address: [email protected].
(7)School of Medicine, Xiamen University, Xiangan Campus, Xiamen 361102, China.
Electronic address: [email protected].
(8)School of Nursing and Midwifery, Faculty of Health and Medicine, The
University of Newcastle, Australia. Electronic address:
[email protected].
OBJECTIVES: to test the effectiveness of breast feeding (BF), music therapy
(MT), and combined breast feeding and music therapy (BF+MT) on pain relief in
healthy-term neonates during heel lance.
DESIGN: randomised controlled trial.
SETTING: in the postpartum unit of one university-affiliated hospital in China
from August 2013 to February 2014.
PARTICIPANTS: among 288 healthy-term neonates recruited, 250 completed the
trial. All neonates were undergoing heel lancing for metabolic screening, were
breast fed, and had not been fed for the previous 30 minutes.
INTERVENTIONS: all participants were randomly assigned into four groups - BF,
MT, BF+MT, and no intervention - with 72 neonates in each group. Neonates in the
control group received routine care. Neonates in the other three intervention
groups received corresponding interventions five minutes before the heel lancing
and throughout the whole procedure.
MEASUREMENTS: Neonatal Infant Pain Scale (NIPS), latency to first cry, and
duration of first crying.
FINDINGS: mean changes in NIPS scores from baseline over time was dependent on
the interventions given. Neonates in the BF and combined BF+MT groups had
significantly longer latency to first cry, shorter duration of first crying, and
lower pain mean score during and one minute after heel lance, compared to the
other two groups. No significant difference in pain response was found between
BF groups with or without music therapy. The MT group did not achieve a
significantly reduced pain response in all outcome measures.
CONCLUSIONS: BF could significantly reduce pain response in healthy-term
neonates during heel lance. MT did not enhance the effect of pain relief of BF.
IMPLICATIONS FOR PRACTICE: healthy-term neonates should be breast fed to
alleviate pain during heel lance. There is no need for the additional input of
classical music on breast feeding in clinic to relieve procedural pain. Nurses
should encourage breast feeding to relieve pain during heel lance.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.midw.2014.11.001
PMID: 25467598 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35637252
|
1. Blood Cancer J. 2022 May 30;12(5):84. doi: 10.1038/s41408-022-00677-7.
Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute
myeloid leukemia treated with gilteritinib who received prior midostaurin or
sorafenib.
Perl AE(1), Hosono N(2), Montesinos P(3), Podoltsev N(4), Martinelli G(5),
Panoskaltsis N(6), Recher C(7), Smith CC(8), Levis MJ(9), Strickland S(10),
Röllig C(11), Groß-Langenhoff M(12), Chou WC(13), Lee JH(14), Yokoyama
H(15)(16), Hasabou N(17), Lu Q(17), Tiu RV(17), Altman JK(18).
Author information:
(1)Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
[email protected].
(2)University of Fukui, Fukui, Japan.
(3)Hospital Universitario y Politécnico La Fe, Valencia, Spain.
(4)Yale School of Medicine, New Haven, CT, USA.
(5)Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRST S. r. l,
Meldola, Italy.
(6)Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA,
USA.
(7)Cancer Research Center of Toulouse, Toulouse, France.
(8)University of California-San Francisco, San Francisco, CA, USA.
(9)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,
Baltimore, MD, USA.
(10)Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
(11)Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
(12)Astellas Pharma GmbH, Munich, Germany.
(13)National Taiwan University Hospital, Taipei, Taiwan.
(14)Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
(15)Sendai Medical Center, National Hospital Organization, Sendai, Japan.
(16)Tohoku University, National Hospital Organization, Sendai, Japan.
(17)Astellas Pharma US, Northbrook, IL, USA.
(18)Robert H. Lurie Comprehensive Cancer Center, Northwestern University
Feinberg School of Medicine, Chicago, IL, USA.
The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for
relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on
its observed superior response and survival outcomes compared with salvage
chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs)
midostaurin and sorafenib may contribute to cross-resistance to single-agent
gilteritinib in the R/R AML setting but has not been well characterized. To
clarify the potential clinical impact of prior TKI use, we retrospectively
compared clinical outcomes in patients with R/R FLT3-mutated AML in the
CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against
those without prior FLT3 TKI exposure. Similarly high rates of composite
complete remission (CRc) were observed in patients who received a FLT3 TKI
before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3
TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior
FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median
overall survival was observed in the gilteritinib arm versus the SC arm
(CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210).
Remission duration was shorter with prior FLT3 TKI exposure. These findings
support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or
midostaurin.
© 2022. The Author(s).
DOI: 10.1038/s41408-022-00677-7
PMCID: PMC9151663
PMID: 35637252 [Indexed for MEDLINE]
Conflict of interest statement: AE Perl reports grants, personal fees and
non-financial support from Astellas, during the conduct of the study; grants,
personal fees, and non-financial support from FujiFilm; grants, personal fees,
and non-financial support from Daiichi Sankyo; grants and personal fees from
Abbvie and Actinium Pharmaceuticals; personal fees from Agios, Loxo, LLS/Beat
AML, and Forma; non-financial support from Arog; personal fees and non-financial
support from New Link Genetics, Novartis, Takeda, and Jazz; and grants from
Bayer and Biomed Valley Discoveries, outside the submitted work. N Hosono
reports no relevant conflicts of interest to disclose. P Montesinos reports
research support from Pfizer, Abbvie, and Daiichi Sankyo; consultancy from
Celgene, Pfizer, and Abbvie; and speakers bureau from Astellas, Novartis, and
Janssen. N Podoltsev reports consultancy fees from Pfizer, Celgene, Agios
Pharmaceuticals, Blueprint Medicines, Incyte, Novartis, Bristol-Myers Squibb,
CTI Biopharma, PharmaEssentia, Constellation Pharmaceuticals, Cogent
BioSciences, and AbbVie; and institutional research funding from Pfizer,
Celgene, CTI Biopharma, Boehringer Ingelheim, Astellas, Daiichi Sankyo, Sunesis
Pharmaceuticals, Jazz Pharmaceuticals, Astex Pharmaceuticals, Genentech, AI
Therapeutics, Samus Therapeutics, Arog Therapeutics, and Kartos Therapeutics. G
Martinelli reports grant funding and consultancy fees from Amgen, Ariad, Incyte,
Pfizer, Roche, Celgene, Janssen, AbbVie, and Novartis. N Panoskaltsis reports no
relevant conflicts of interest to disclose. C Recher reports grant funding and
personal fees from Celgene, Sunesis, Amgen, and Novartis and personal fees from
Incyte, Jazz Pharmaceuticals, AbbVie, Astellas, Macrogenics, and Otsuka. C Smith
reports research funding from Abbvie, Revolution Medicines, Celgene, FujiFilm;
consulting fees from Astellas, Daichi Sanyko, and Genentech to attend an
advisory board meeting; and reports being a stockolder at Ligacept, LLC. MJ
Levis reports grants and personal fees from Astellas and FujiFilm and personal
fees from Daiichi Sankyo, Amgen, and Menarini. S Strickland reports consulting
or advisory fees from Abbvie, Astellas Pharma, Jazz Pharmaceuticals, Kite, a
Gilead company, Novartis, and Pfizer and research funding at an institutional
level from Abbvie, Astellas Pharma, Inc, Celator/Jazz, Celgene, Daiichi Sankyo,
Karyopharm Therapeutics, Menarini, Novartis, and Sunesis Pharmaceuticals. C
Röllig has received grants from AbbVie, Novartis, and Pfizer; consulting fees
from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Janssen,
Jazz, Novartis, Pfizer, and Roche; and honoraria for speaker engagements from
AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Janssen, Jazz,
Novartis, Pfizer, and Roche. WC Chou reports no relevant conflicts of interest
to disclose. H Lee has received honoraria for speaker engagements from AbbVie
Korea and Astellas Korea, participated in and advisory board for AbbVie and
Astellas, and is President of The Korean Society of Hematology. H Yokoyama
reports having received honoraria from Astellas for speaking engagements. Q Lu,
N Hasabou, M Groß-Langenhoff are employees of Astellas. R Tiu is a former
employee of Astellas. JK Altman reports advisory or consulting fees from AbbVie,
Amgen, Astellas, Daiichi Sankyo, Kura Oncology, Syros, and Theradex;
institutional research funding for trials conducted by ALX Oncology, Amgen,
Aptos, Astellas, Aprea, BioSight, Bristol-Myers Squibb, Boehringer Ingelheim,
Celgene, FujiFilm, Immunogen, Kartos, Kura Oncology, and Loxo; reimbursement for
travel from BioSight; and serves on a data monitoring committee for
GlycoMimetics.
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http://www.ncbi.nlm.nih.gov/pubmed/35997897
|
1. BioDrugs. 2022 Sep;36(5):549-571. doi: 10.1007/s40259-022-00549-3. Epub 2022
Aug 23.
Therapeutic siRNA: State-of-the-Art and Future Perspectives.
Friedrich M(1)(2), Aigner A(3).
Author information:
(1)Faculty of Leipzig, Institute of Clinical Immunology,
Max-Bürger-Forschungszentrum (MBFZ), University of Leipzig, Leipzig, Germany.
(2)Department of Vaccines and Infection Models, Fraunhofer Institute for Cell
Therapy and Immunology IZI, Leipzig, Germany.
(3)Rudolf-Boehm Institute for Pharmacology and Toxicology, Clinical
Pharmacology, University of Leipzig, Haertelstrasse 16-18, 04107, Leipzig,
Germany. [email protected].
The highly specific induction of RNA interference-mediated gene knockdown, based
on the direct application of small interfering RNAs (siRNAs), opens novel
avenues towards innovative therapies. Two decades after the discovery of the RNA
interference mechanism, the first siRNA drugs received approval for clinical use
by the US Food and Drug Administration and the European Medicines Agency between
2018 and 2022. These are mainly based on an siRNA conjugation with a targeting
moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of
acute hepatic porphyria, transthyretin-mediated amyloidosis,
hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development
of siRNA therapeutics faces several challenges and issues, including the
definition of optimal siRNAs in terms of target, sequence, and chemical
modifications, siRNA delivery to its intended site of action, and the absence of
unspecific off-target effects. Further siRNA drugs are in clinical studies,
based on different delivery systems and covering a wide range of different
pathologies including metabolic diseases, hematology, infectious diseases,
oncology, ocular diseases, and others. This article reviews the knowledge on
siRNA design and chemical modification, as well as issues related to siRNA
delivery that may be addressed using different delivery systems. Details on the
mode of action and clinical status of the various siRNA therapeutics are
provided, before giving an outlook on issues regarding the future of siRNA drugs
and on their potential as one emerging standard modality in pharmacotherapy.
Notably, this may also cover otherwise un-druggable diseases, the definition of
non-coding RNAs as targets, and novel concepts of personalized and combination
treatment regimens.
© 2022. The Author(s).
DOI: 10.1007/s40259-022-00549-3
PMCID: PMC9396607
PMID: 35997897 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interest to
declare.
|
http://www.ncbi.nlm.nih.gov/pubmed/35867041
|
1. Nucleic Acid Ther. 2022 Dec;32(6):507-512. doi: 10.1089/nat.2022.0010. Epub
2022 Jul 22.
Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated
siRNAs.
Boianelli A(1), Aoki Y(1), Ivanov M(2), Dahlén A(3), Gennemark P(1)(4).
Author information:
(1)Drug Metabolism and Pharmacokinetics, Research and Early Development,
Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D,
AstraZeneca, Gothenburg, Sweden.
(2)Quantitative Biology SE, Data Sciences and Quantitative Biology, Discovery
Sciences, AstraZeneca, Gothenburg, Sweden.
(3)Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D,
AstraZeneca, Gothenburg, Sweden.
(4)Department of Biomedical Engineering, Linköping University, Linköping,
Sweden.
Small interfering RNAs (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation
for improved liver uptake represent an emerging class of drugs to treat liver
diseases. Understanding how pharmacokinetics and pharmacodynamics translate is
pivotal for in vivo study design and human dose prediction. However, the
literature is sparse on translational data for this modality, and
pharmacokinetics in the liver is seldom measured. To overcome these
difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in
various species and applied the kinetic-pharmacodynamic modeling approach to
estimate the biophase (liver) half-life and the potency. Our analysis indicates
that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and
1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8
times longer in human than in mouse, and generally 1-3 times longer in human
than in monkey. The analysis indicates that the siRNAs are more potent in human
than in mouse and monkey.
DOI: 10.1089/nat.2022.0010
PMCID: PMC9784597
PMID: 35867041 [Indexed for MEDLINE]
Conflict of interest statement: Authors are employed by AstraZeneca AB.
|
http://www.ncbi.nlm.nih.gov/pubmed/35625776
|
1. Biomedicines. 2022 Apr 30;10(5):1038. doi: 10.3390/biomedicines10051038.
Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated
Acute Myeloid Leukemia Reduced Blast Viability.
Cao H(1)(2), Tadros V(3), Hiramoto B(3), Leeper K(3), Hino C(1), Xiao J(3), Pham
B(1), Kim DH(3), Reeves ME(1)(2), Chen CS(1)(2), Zhong JF(4), Zhang KK(5)(6),
Xie L(5), Wasnik S(3), Baylink DJ(3), Xu Y(1)(2)(3).
Author information:
(1)Division of Hematology and Oncology, Department of Medicine, Loma Linda
University, Loma Linda, CA 92354, USA.
(2)Loma Linda University Cancer Center, Loma Linda, CA 92354, USA.
(3)Division of Regenerative Medicine, Department of Medicine, Loma Linda
University, Loma Linda, CA 92354, USA.
(4)Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354,
USA.
(5)Department of Nutrition, Texas A&M University, College Station, TX 77030,
USA.
(6)Center for Epigenetics & Disease Prevention, Institute of Biosciences &
Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
Disease relapse is a common cause of treatment failure in FMS-like tyrosine
kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify
therapeutic targets responsible for the survival and proliferation of leukemic
cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation
tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of
cytokine release and in vitro/ex vivo studies to investigate their associated
signaling pathways and transcriptional regulation. Here, we report that
macrophage migration inhibition factor (MIF) was significantly increased in the
supernatant of GILT-treated blasts when compared to untreated controls.
Additionally, the GILT-treated blasts that survived were found to exhibit higher
expressions of the CXCR2 gene and protein, a common receptor for MIF and
pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated
blasts revealed a group of CD44High+ cells that might be responsible for the
relapse. Furthermore, we identified the highly activated non-classical NFKB2
pathway after GILT-treatment. The siRNA transient knockdown of NFKB2
significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally,
treatments of AML patient samples ex vivo demonstrated that the combination of a
pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress
primary blasts' secretion of tumor-promoting cytokines, such as CXCL1/5/8. In
summary, we provide the first evidence that targeting treatment-activated
compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel
therapeutic strategy to overcome TKI-resistance and effectively treat AML
patients with FLT3 mutations.
DOI: 10.3390/biomedicines10051038
PMCID: PMC9138861
PMID: 35625776
Conflict of interest statement: The authors declare that they have no competing
interest.
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http://www.ncbi.nlm.nih.gov/pubmed/34350585
|
1. Br J Haematol. 2022 Jan;196(2):316-328. doi: 10.1111/bjh.17746. Epub 2021 Aug
4.
Updates on targeted therapies for acute myeloid leukaemia.
Kayser S(1)(2), Levis MJ(3).
Author information:
(1)Medical Clinic and Policlinic I, Hematology and Cellular Therapy, University
Hospital Leipzig, Leipzig, Germany.
(2)NCT Trial Center, National Center of Tumor Diseases, German Cancer Research
Center (DKFZ), Heidelberg, Germany.
(3)Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,
Baltimore, MD, USA.
In the past few years research in the underlying pathogenic mechanisms of acute
myeloid leukaemia (AML) has led to remarkable advances in our understanding of
the disease. Cytogenetic and molecular aberrations are the most important
factors in determining response to chemotherapy as well as long-term outcome,
but beyond prognostication are potential therapeutic targets. Our increased
understanding of the pathogenesis of AML facilitated by next-generation
sequencing has spurred the development of new compounds in the treatment of AML,
particularly the creation of small molecules that target the disease on a
molecular level. Many of the hopeful predictions outlined in our AML review of
2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3
inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib),
CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be
(quizartinib, APR246 magrolimab, menin inhibitors). The wealth of positive data
allows reconsideration of what might soon be new standards of care in younger
and older patients with AML. In this review we give an overview of recently
approved therapies in AML and address present and future research directions.
© 2021 The Authors. British Journal of Haematology published by British Society
for Haematology and John Wiley & Sons Ltd.
DOI: 10.1111/bjh.17746
PMID: 34350585 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/34154993
|
1. Drug Metab Dispos. 2022 Jun;50(6):781-797. doi: 10.1124/dmd.121.000428. Epub
2021 Jun 21.
The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of
N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable
and Build Confidence in Translation to Human.
McDougall R(1), Ramsden D(1), Agarwal S(1), Agarwal S(1), Aluri K(1), Arciprete
M(1), Brown C(1), Castellanos-Rizaldos E(1), Charisse K(1), Chong S(1), Cichocki
J(1), Fitzgerald K(1), Goel V(1), Gu Y(1), Guenther D(1), Habtemariam B(1),
Jadhav V(1), Janas M(1), Jayaraman M(1), Kurz J(1), Li J(1), Liu J(1), Liu X(1),
Liou S(1), Maclauchlin C(1), Maier M(1), Manoharan M(1), Nair JK(1), Robbie
G(1), Schmidt K(1), Smith P(1), Theile C(1), Vaishnaw A(1), Waldron S(1), Xu
Y(1), Zhang X(1), Zlatev I(1), Wu JT(2).
Author information:
(1)Alnylam Pharmaceuticals, Cambridge, Massachusetts.
(2)Alnylam Pharmaceuticals, Cambridge, Massachusetts [email protected].
Conjugation of oligonucleotide therapeutics, including small interfering RNAs
(siRNAs) or antisense oligonucleotides, to N-acetylgalactosamine (GalNAc)
ligands has become the primary strategy for hepatocyte-targeted delivery, and
with the recent approvals of GIVLAARI (givosiran) for the treatment of acute
hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary
hyperoxaluria, and Leqvio (inclisiran) for the treatment of
hypercholesterolemia, the technology has been well validated clinically.
Although much knowledge has been gained over decades of development, there is a
paucity of published literature on the drug metabolism and pharmacokinetic
properties of GalNAc-siRNA. With this in mind, the goals of this minireview are
to provide an aggregate analysis of these nonclinical absorption, distribution,
metabolism, and excretion (ADME) data to build confidence on the translation of
these properties to human. Upon subcutaneous administration, GalNAc-conjugated
siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic
(PK) properties that reflect rapid elimination through asialoglycoprotein
receptor-mediated uptake from circulation into hepatocytes. These studies
confirm that liver PK, including half-life and, most importantly, siRNA levels
in RNA-induced silencing complex in hepatocytes, are better predictors of
pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical
studies were conducted to characterize the ADME properties of GalNAc-conjugated
siRNAs. These studies demonstrate that the PK/PD and ADME properties of
GalNAc-conjugated siRNAs are highly conserved across species, are largely
predictable, and can be accurately scaled to human, allowing us to identify
efficacious and safe clinical dosing regimens in the absence of human liver PK
profiles. SIGNIFICANCE STATEMENT: Several nonclinical ADME studies have been
conducted in order to provide a comprehensive overview of the disposition and
elimination of GalNAc-conjugated siRNAs and the pharmacokinetic/pharmacodynamic
translation between species. These studies demonstrate that the ADME properties
of GalNAc-conjugated siRNAs are well correlated and predictable across species,
building confidence in the ability to extrapolate to human.
Copyright © 2022 by The Author(s).
DOI: 10.1124/dmd.121.000428
PMID: 34154993 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36250252
|
1. Br J Pharmacol. 2023 Nov;180(21):2697-2720. doi: 10.1111/bph.15972. Epub 2022
Nov 13.
Small interfering RNA: Discovery, pharmacology and clinical development-An
introductory review.
Ranasinghe P(1)(2), Addison ML(2), Dear JW(2), Webb DJ(2).
Author information:
(1)Department of Pharmacology, Faculty of Medicine, University of Colombo,
Colombo, Sri Lanka.
(2)University/British Heart Foundation Centre for Cardiovascular Science, The
University of Edinburgh, Edinburgh, UK.
Post-transcriptional gene silencing targets and degrades mRNA transcripts,
silencing the expression of specific genes. RNA interference technology, using
synthetic structurally well-defined short double-stranded RNA (small interfering
RNA [siRNA]), has advanced rapidly in recent years. This introductory review
describes the utility of siRNA, by exploring the underpinning biology,
pharmacology, recent advances and clinical developments, alongside potential
limitations and ongoing challenges. Mediated by the RNA-induced silencing
complex, siRNAs bind to specific complementary mRNAs, which are subsequently
degraded. siRNA therapy offers advantages over other therapeutic approaches,
including ability of specifically designed siRNAs to potentially target any mRNA
and improved patient adherence through infrequent administration associated with
a very long duration of action. Key pharmacokinetic and pharmacodynamic
challenges include targeted administration, poor tissue penetration, nuclease
inactivation, rapid renal elimination, immune activation and off-target effects.
These have been overcome by chemical modification of siRNA and/or by utilising a
range of delivery systems, increasing bioavailability and stability to allow
successful clinical translation. Patisiran (hereditary transthyretin-mediated
amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic
porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial
hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for
effective liver-directed delivery. Others are currently under development for
indications varying from rare genetic diseases to common chronic
non-communicable diseases (hypertension, cancer). Technological advances are
paving the way for broader clinical use. Ongoing challenges remain in targeting
organs beyond the liver and reaching special sites (e.g., brain). By overcoming
these barriers, siRNA therapy has the potential to substantially widen its
therapeutic impact.
© 2022 The Authors. British Journal of Pharmacology published by John Wiley &
Sons Ltd on behalf of British Pharmacological Society.
DOI: 10.1111/bph.15972
PMID: 36250252 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25434769
|
1. J Am Chem Soc. 2014 Dec 10;136(49):16958-61. doi: 10.1021/ja505986a. Epub 2014
Dec 1.
Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and
elicits robust RNAi-mediated gene silencing.
Nair JK(1), Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, Hoekstra M,
Kandasamy P, Kel'in AV, Milstein S, Taneja N, O'Shea J, Shaikh S, Zhang L, van
der Sluis RJ, Jung ME, Akinc A, Hutabarat R, Kuchimanchi S, Fitzgerald K,
Zimmermann T, van Berkel TJ, Maier MA, Rajeev KG, Manoharan M.
Author information:
(1)Alnylam Pharmaceuticals , 300 Third Street, Cambridge, Massachusetts 02142,
United States.
Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor
ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery
of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from
GalNAc are compatible with solid-phase oligonucleotide synthesis and
deprotection conditions, with synthesis yields comparable to those of standard
oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates
resulted in robust RNAi-mediated gene silencing in liver. Refinement of the
siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design
in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose.
This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically
relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing
resulted in sustained dose-dependent gene silencing for over 9 months with no
adverse effects in rodents. The optimally chemically modified siRNA-GalNAc
conjugates are hepatotropic and long-acting and have the potential to treat a
wide range of diseases involving liver-expressed genes.
DOI: 10.1021/ja505986a
PMID: 25434769 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35505960
|
1. Mol Ther Nucleic Acids. 2022 Apr 2;28:423-434. doi:
10.1016/j.omtn.2022.04.003. eCollection 2022 Jun 14.
RAB18 is a key regulator of GalNAc-conjugated siRNA-induced silencing in Hep3B
cells.
Lu J(1), Swearingen E(1), Hardy M(1), Collins P(1), Wu B(1), Yuan E(1), Lu D(1),
Li CM(1), Wang S(1), Ollmann M(1).
Author information:
(1)Genome Analysis Unit, Amgen Global Research, 1120 Veteran Blvd, ASF1, South
San Francisco, CA 94080, USA.
Small interfering RNA (siRNA) therapeutics have developed rapidly in recent
years, despite the challenges associated with delivery of large, highly charged
nucleic acids. Delivery of siRNA therapeutics to the liver has been established,
with conjugation of siRNA to N-acetylgalactosamine (GalNAc) providing durable
gene knockdown in hepatocytes following subcutaneous injection. GalNAc binds the
asialoglycoprotein receptor (ASGPR) that is highly expressed on hepatocytes and
exploits this scavenger receptor to deliver siRNA across the plasma membrane by
endocytosis. However, siRNA needs to access the RNA-induced silencing complex
(RISC) in the cytoplasm to provide effective gene knockdown, and the entire
siRNA delivery process is very inefficient, likely because of steps required for
endosomal escape, intracellular trafficking, and stability of siRNA. To reveal
the cellular factors limiting delivery of siRNA therapeutics, we performed a
genome-wide pooled knockout screen on the basis of delivery of GalNAc-conjugated
siRNA targeting the HPRT1 gene in the human hepatocellular carcinoma line Hep3B.
Our primary genome-wide pooled knockout screen identified candidate genes that
when knocked out significantly enhanced siRNA efficacy in Hep3B cells. Follow-up
studies indicate that knockout of RAB18 improved the efficacy of siRNA delivered
by GalNAc, cholesterol, or antibodies, but not siRNA delivered by Lipofectamine
transfection, suggesting a role for RAB18 in siRNA delivery and intracellular
trafficking.
© 2022 The Authors.
DOI: 10.1016/j.omtn.2022.04.003
PMCID: PMC9035644
PMID: 35505960
Conflict of interest statement: All authors have the following conflicts of
interest to declare: J.L., E.S., B.W., E.Y., D.L., C.-M.L., and S.W. are
employees of Amgen Inc. M.O., P.C., and M.H. were employed by Amgen Inc. while
working on the study. All authors owned Amgen shares when the study was carried
out. However, these do not alter the authors’ adherence to all journal policies
on sharing data and materials. None of the authors serves as a current editorial
team member for this journal.
|
http://www.ncbi.nlm.nih.gov/pubmed/25786782
|
1. Chembiochem. 2015 Apr 13;16(6):903-8. doi: 10.1002/cbic.201500023. Epub 2015
Mar 18.
Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic
trivalent N-acetylgalactosamine elicits robust gene silencing in vivo.
Rajeev KG(1), Nair JK, Jayaraman M, Charisse K, Taneja N, O'Shea J, Willoughby
JL, Yucius K, Nguyen T, Shulga-Morskaya S, Milstein S, Liebow A, Querbes W,
Borodovsky A, Fitzgerald K, Maier MA, Manoharan M.
Author information:
(1)Alnylam. Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142
(USA). [email protected].
We recently demonstrated that siRNAs conjugated to triantennary
N-acetylgalactosamine (GalNAc) induce robust RNAi-mediated gene silencing in the
liver, owing to uptake mediated by the asialoglycoprotein receptor (ASGPR).
Novel monovalent GalNAc units, based on a non-nucleosidic linker, were developed
to yield simplified trivalent GalNAc-conjugated oligonucleotides under
solid-phase synthesis conditions. Synthesis of oligonucleotide conjugates using
monovalent GalNAc building blocks required fewer synthetic steps compared to the
previously optimized triantennary GalNAc construct. The redesigned trivalent
GalNAc ligand maintained optimal valency, spatial orientation, and distance
between the sugar moieties for proper recognition by ASGPR. siRNA conjugates
were synthesized by sequential covalent attachment of the trivalent GalNAc to
the 3'-end of the sense strand and resulted in a conjugate with in vitro and in
vivo potency similar to that of the parent trivalent GalNAc conjugate design.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/cbic.201500023
PMID: 25786782 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25730476
|
1. ACS Chem Biol. 2015 May 15;10(5):1181-7. doi: 10.1021/cb501028c. Epub 2015 Mar
2.
siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine
linked through nucleosides elicit robust gene silencing in vivo in hepatocytes.
Matsuda S(1), Keiser K(1), Nair JK(1), Charisse K(1), Manoharan RM(1),
Kretschmer P(1), Peng CG(1), V Kel'in A(1), Kandasamy P(1), Willoughby JL(1),
Liebow A(1), Querbes W(1), Yucius K(1), Nguyen T(1), Milstein S(1), Maier MA(1),
Rajeev KG(1), Manoharan M(1).
Author information:
(1)Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142,
United States.
Asialoglycoprotein receptor (ASGPR) mediated delivery of triantennary
N-acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) to
hepatocytes is a promising paradigm for RNAi therapeutics. Robust and durable
gene silencing upon subcutaneous administration at therapeutically acceptable
dose levels resulted in the advancement of GalNAc-conjugated
oligonucleotide-based drugs into preclinical and clinical developments. To
systematically evaluate the effect of display and positioning of the GalNAc
moiety within the siRNA duplex on ASGPR binding and RNAi activity, nucleotides
carrying monovalent GalNAc were designed. Evaluation of clustered and dispersed
incorporation of GalNAc units to the sense (S) strand indicated that sugar
proximity is critical for ASGPR recognition, and location of the clustered
ligand impacts the intrinsic potency of the siRNA. An array of nucleosidic
GalNAc monomers resembling a trivalent ligand at or near the 3' end of the S
strand retained in vitro and in vivo siRNA activity, similar to the parent
conjugate design. This work demonstrates the utility of simple,
nucleotide-based, cost-effective siRNA-GalNAc conjugation strategies.
DOI: 10.1021/cb501028c
PMID: 25730476 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34413198
|
1. J Pharmacol Exp Ther. 2021 Nov;379(2):134-146. doi: 10.1124/jpet.121.000805.
Epub 2021 Aug 19.
Minimal Physiologically Based Pharmacokinetic-Pharmacodynamic (mPBPK-PD) Model
of N-Acetylgalactosamine-Conjugated Small Interfering RNA Disposition and Gene
Silencing in Preclinical Species and Humans.
Ayyar VS(1), Song D(2), Zheng S(2), Carpenter T(2), Heald DL(2).
Author information:
(1)Clinical Pharmacology & Pharmacometrics (V.S.A., D.S.) and Janssen
BioTherapeutics (V.S.A., S.Z., T.C., D.L.H.), Janssen Research and Development,
Spring House, Pennsylvania [email protected].
(2)Clinical Pharmacology & Pharmacometrics (V.S.A., D.S.) and Janssen
BioTherapeutics (V.S.A., S.Z., T.C., D.L.H.), Janssen Research and Development,
Spring House, Pennsylvania.
Conjugation of small interfering RNA (siRNA) to tris N-acetylgalactosamine
[(GalNAc)3] can enable highly selective, potent, and durable knockdown of
targeted proteins in the liver. However, potential knowledge gaps between in
vitro experiments, preclinical species, and clinical scenarios remain. A minimal
physiologically based pharmacokinetic-pharmacodynamic model for
GalNAc-conjugated siRNA (GalNAc-siRNA) was developed using published data for
fitusiran (ALN-AT3), an investigational compound targeting liver antithrombin
(AT), to delineate putative determinants governing the whole-body-to-cellular
pharmacokinetic (PK) and pharmacodynamic (PD) properties of GalNAc-siRNA and
facilitate preclinical-to-clinical translation. The model mathematically linked
relevant mechanisms: 1) hepatic biodistribution, 2) tris-GalNAc binding to
asialoglycoprotein receptors (ASGPRs) on hepatocytes, 3) ASGPR endocytosis and
recycling, 4) endosomal transport and escape of siRNA, 5) cytoplasmic
RNA-induced silencing complex (RISC) loading, 6) degradation of target mRNA by
bound RISC, and 7) knockdown of protein. Physiologic values for 36 out of 48
model parameters were obtained from the literature. Kinetic parameters governing
(GalNAc)3-ASGPR binding and internalization were derived from published studies
of uptake in hepatocytes. The proposed model well characterized reported
pharmacokinetics, RISC dynamics, and knockdown of AT mRNA and protein by ALN-AT3
in mice. The model bridged multiple PK-PD data sets in preclinical species
(mice, rat, monkey) and successfully captured reported plasma pharmacokinetics
and AT knockdown in a phase I ascending-dose study. Estimates of in vivo potency
were similar (∼2-fold) across species. Subcutaneous absorption and serum AT
degradation rate constants scaled across species by body weight with allometric
exponents of -0.29 and -0.22. The proposed mechanistic modeling framework
characterizes the unique PK-PD properties of GalNAc-siRNA. SIGNIFICANCE
STATEMENT: Tris N-acetylgalactosamine (GalNAc)3-conjugated small interfering RNA
(siRNA) therapeutics enable liver-targeted gene therapy and precision medicine.
Using a translational and systems-based minimal physiologically based
pharmacokinetic-pharmacodynamic (mPBPK-PD) modeling approach, putative
determinants influencing GalNAc-conjugated siRNA (GalNAc-siRNA) functionality in
three preclinical species and humans were investigated. The developed model
successfully integrated and characterized relevant published in vitro-derived
biomeasures, mechanistic PK-PD profiles in animals, and observed clinical PK-PD
responses for an investigational GalNAc-siRNA (fitusiran). This modeling effort
delineates the disposition and liver-targeted pharmacodynamics of GalNAc-siRNA.
Copyright © 2021 by The American Society for Pharmacology and Experimental
Therapeutics.
DOI: 10.1124/jpet.121.000805
PMID: 34413198 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34091052
|
1. Mol Ther. 2021 Oct 6;29(10):2910-2919. doi: 10.1016/j.ymthe.2021.06.002. Epub
2021 Jun 4.
Ligand conjugate SAR and enhanced delivery in NHP.
Holland RJ(1), Lam K(1), Ye X(1), Martin AD(1), Wood MC(1), Palmer L(1), Fraser
D(1), McClintock K(1), Majeski S(1), Jarosz A(1), Lee ACH(2), Thi EP(2), Judge
A(1), Heyes J(3).
Author information:
(1)Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada.
(2)Arbutus Biopharma Corporation, Warminster, PA 18974, USA.
(3)Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada. Electronic
address: [email protected].
Comment in
Mol Ther. 2021 Oct 6;29(10):2893-2894. doi: 10.1016/j.ymthe.2021.09.006.
N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a
leading RNA interference (RNAi) platform allowing targeted inhibition of
disease-causing genes in hepatocytes. More than a decade of development has
recently resulted in the first approvals for this class of drugs. While
substantial effort has been made to improve nucleic acid modification patterns
for better payload stability and efficacy, relatively little attention has been
given to the GalNAc targeting ligand. In addition, the lack of an intrinsic
endosomal release mechanism has limited potency. Here, we report a stepwise
analysis of the structure activity relationships (SAR) of the components
comprising these targeting ligands. We show that there is relatively little
difference in biological performance between bi-, tri-, and tetravalent ligand
structures while identifying other features that affect their biological
activity more significantly. Further, we demonstrate that subcutaneous
co-administration of a GalNAc-functionalized, pH responsive endosomal release
agent markedly improved the activity and duration of effect for siRNA
conjugates, without compromising tolerability, in non-human primates. These
findings could address a significant bottleneck for future siRNA ligand
conjugate development.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2021.06.002
PMCID: PMC8531135
PMID: 34091052 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors are
employees or consultants of Genevant Sciences Corporation or Arbutus Biopharma
Corporation as noted in the author affiliations and own shares or stock options
in their respective companies.
|
http://www.ncbi.nlm.nih.gov/pubmed/29792572
|
1. Nucleic Acid Ther. 2018 Jun;28(3):109-118. doi: 10.1089/nat.2018.0736. Epub
2018 May 24.
GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics.
Springer AD(1), Dowdy SF(1).
Author information:
(1)Department of Cellular and Molecular Medicine, University of California San
Diego , La Jolla, California.
Short-interfering RNA (siRNA)-induced RNAi responses have great potential to
treat a wide variety of human diseases from cancer to pandemic viral outbreaks
to Parkinson's Disease. However, before siRNAs can become drugs, they must
overcome a billion years of evolutionary defenses designed to keep invading RNAs
on the outside cells from getting to the inside of cells. Not surprisingly,
significant effort has been placed in developing a wide array of delivery
technologies. Foremost of these has been the development of
N-acetylgalactosamine (GalNAc) siRNA conjugates for delivery to liver.
Tris-GalNAc binds to the Asialoglycoprotein receptor that is highly expressed on
hepatocytes resulting in rapid endocytosis. While the exact mechanism of escape
across the endosomal lipid bilayer membrane remains unknown, sufficient amounts
of siRNAs enter the cytoplasm to induce robust, target selective RNAi responses
in vivo. Multiple GalNAc-siRNA conjugate clinical trials, including two phase
III trials, are currently underway by three biotech companies to treat a wide
variety of diseases. GalNAc-siRNA conjugates are a simple solution to the siRNA
delivery problem for liver hepatocytes and have shown the RNAi (and antisense
oligonucleotide) field the path forward for targeting other tissue types.
DOI: 10.1089/nat.2018.0736
PMCID: PMC5994659
PMID: 29792572 [Indexed for MEDLINE]
Conflict of interest statement: S.F.D. is a founder of Solstice Biologics.
A.D.S. declares no competing financial interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/36281788
|
1. Clin Pharmacol Ther. 2023 Feb;113(2):328-338. doi: 10.1002/cpt.2774. Epub 2022
Nov 14.
Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA
Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.
Gosselin NH(1), Schuck VJA(1), Barriere O(1), Kulmatycki K(2), Margolskee A(2),
Smith P(1), He Y(2).
Author information:
(1)Certara, Cambridge, Massachusetts, USA.
(2)Novartis Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated
small-interfering ribonucleic acid (siRNA) therapy designed to specifically
target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver
for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment
results in a rapid uptake into the liver, and thus a short plasma half-life, but
long duration of effects on PCSK9 inhibition and low-density lipoprotein
cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent
LDL-C reduction are sustained for more than 6 months following a single
subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only
for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to
characterize inclisiran's dose-related LDL-C lowering effects and to evaluate
the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate
the long duration of action, the K-PD model incorporated an effect compartment
which represents the liver. Inclisiran concentration in the liver leads to
decreased production of the PCSK9 protein and allow recycling of more LDL-C
receptors on the hepatocyte cell surface, which results in a reduction of
circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C
baseline levels as important factors for the effects of LDL-C lowering.
Observations and modeling and simulation results demonstrated that PCSK9 and
LDL-C reductions are achieved rapidly after dosing and sustained when patients
are treated with a 300 mg s.c. dose once every 6 months.
© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society
for Clinical Pharmacology and Therapeutics.
DOI: 10.1002/cpt.2774
PMID: 36281788 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32170309
|
1. Nucleic Acids Res. 2020 May 7;48(8):4028-4040. doi: 10.1093/nar/gkaa125.
Chimeric siRNAs with chemically modified pentofuranose and hexopyranose
nucleotides: altritol-nucleotide (ANA) containing GalNAc-siRNA conjugates: in
vitro and in vivo RNAi activity and resistance to 5'-exonuclease.
Kumar P(1), Degaonkar R(1), Guenther DC(1), Abramov M(2), Schepers G(2),
Capobianco M(1), Jiang Y(1), Harp J(3), Kaittanis C(1), Janas MM(1), Castoreno
A(1), Zlatev I(1), Schlegel MK(1), Herdewijn P(2), Egli M(3), Manoharan M(1).
Author information:
(1)Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA.
(2)Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven,
Herestraat 49, 3000 Leuven, Belgium.
(3)Department of Biochemistry, School of Medicine, Vanderbilt University,
Nashville, TN 37232, USA.
In this report, we investigated the hexopyranose chemical modification Altriol
Nucleic Acid (ANA) within small interfering RNA (siRNA) duplexes that were
otherwise fully modified with the 2'-deoxy-2'-fluoro and 2'-O-methyl
pentofuranose chemical modifications. The siRNAs were designed to silence the
transthyretin (Ttr) gene and were conjugated to a trivalent
N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes.
Sense and antisense strands of the parent duplex were synthesized with single
ANA residues at each position on the strand, and the resulting siRNAs were
evaluated for their ability to inhibit Ttr mRNA expression in vitro. Although
ANA residues were detrimental at the 5' end of the antisense strand, the siRNAs
with ANA at position 6 or 7 in the seed region had activity comparable to the
parent. The siRNA with ANA at position 7 in the seed region was active in a
mouse model. An Oligonucleotide with ANA at the 5' end was more stable in the
presence of 5'-exonuclease than an oligonucleotide of the same sequence and
chemical composition without the ANA modification. Modeling studies provide
insight into the origins of regiospecific changes in potency of siRNAs and the
increased protection against 5'-exonuclease degradation afforded by the ANA
modification.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkaa125
PMCID: PMC7192627
PMID: 32170309 [Indexed for MEDLINE]
|
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