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http://www.ncbi.nlm.nih.gov/pubmed/21243716 | 1. Chembiochem. 2011 Jan 24;12(2):290-8. doi: 10.1002/cbic.201000438. Epub 2010
Nov 24.
KAT(ching) metabolism by the tail: insight into the links between lysine
acetyltransferases and metabolism.
Albaugh BN(1), Arnold KM, Denu JM.
Author information:
(1)Department of Biomolecular Chemistry, School of Medicine and Public Health,
University of Wisconsin, Madison, WI 53706, USA.
Post-translational modifications of histones elicit structural and functional
changes within chromatin that regulate various epigenetic processes. Epigenetic
mechanisms rely on enzymes whose activities are driven by coenzymes and
metabolites from intermediary metabolism. Lysine acetyltransferases (KATs)
catalyze the transfer of acetyl groups from acetyl-CoA to epsilon amino groups.
Utilization of this critical metabolite suggests these enzymes are modulated by
the metabolic status of the cell. This review highlights studies linking KATs to
metabolism. We cover newly identified acyl modifications (propionylation and
butyrylation), discuss the control of KAT activity by cellular acetyl-CoA
levels, and provide insights into how acetylation regulates metabolic proteins.
We conclude with a discussion of the current approaches to identifying novel
KATs and their metabolic substrates.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/cbic.201000438
PMCID: PMC3327878
PMID: 21243716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29261229 | 1. Curr Protoc Pharmacol. 2017 Dec 20;79:3.14.1-3.14.16. doi: 10.1002/cpph.31.
In Vitro Histone Acetylation Assay.
Brown JAL(1).
Author information:
(1)Discipline of Surgery, Lambe Institute for Translational Research, School of
Medicine, National University of Ireland, Galway, Ireland.
Acetylation is a core cellular process involved in maintaining genomic
integrity, gene regulation, and metabolism. Histone acetyltransferases (HATs)
are an enzyme family that regulates these processes by catalyzing the transfer
of an acetyl moiety onto target proteins. Perturbations of cellular acetylation
profiles have been associated with a variety of disease states, including
cancer. Changes in acetylation profiles can be achieved by mechanisms associated
with acetyltransferases, such as gene down-regulation or alterations in the
activity of key acetyltransferase enzymes. An important set of tools for
quantifying enzyme activity are in vitro histone acetylation assays, using
either endogenous or tagged overexpressed proteins. Detailed in this unit is an
in vitro acetylation assay used to quantify HAT activity. © 2017 by John Wiley &
Sons, Inc.
Copyright © 2017 John Wiley & Sons, Inc.
DOI: 10.1002/cpph.31
PMID: 29261229 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30069049 | 1. Nature. 2018 Aug;560(7717):253-257. doi: 10.1038/s41586-018-0387-5. Epub 2018
Aug 1.
Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest
tumour growth.
Baell JB(1)(2), Leaver DJ(3), Hermans SJ(4), Kelly GL(5)(6), Brennan MS(5)(6),
Downer NL(5), Nguyen N(3), Wichmann J(5)(6), McRae HM(5)(6), Yang Y(5)(6),
Cleary B(3), Lagiakos HR(3)(7), Mieruszynski S(5)(6), Pacini G(5), Vanyai
HK(5)(6), Bergamasco MI(5)(6), May RE(5), Davey BK(5)(7), Morgan KJ(5)(6),
Sealey AJ(5)(6), Wang B(5)(6)(8), Zamudio N(5)(6), Wilcox S(5)(6), Garnham
AL(5)(6), Sheikh BN(5)(6), Aubrey BJ(5)(6), Doggett K(5)(6), Chung MC(4), de
Silva M(5)(7), Bentley J(9), Pilling P(9), Hattarki M(9), Dolezal O(9), Dennis
ML(9), Falk H(5)(6)(7), Ren B(9), Charman SA(10), White KL(10), Rautela J(5)(6),
Newbold A(11), Hawkins ED(5)(6), Johnstone RW(11), Huntington ND(5)(6), Peat
TS(9), Heath JK(5)(6), Strasser A(5)(6), Parker MW(4)(12), Smyth GK(5)(13),
Street IP(5)(6)(7), Monahan BJ(5)(6)(7), Voss AK(14)(15), Thomas T(16)(17).
Author information:
(1)Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria, Australia. [email protected].
(2)School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China.
[email protected].
(3)Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria, Australia.
(4)ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical
Research, Fitzroy, Victoria, Australia.
(5)The Walter and Eliza Hall Institute of Medical Research, Parkville,
Melbourne, Victoria, Australia.
(6)Department of Medical Biology, University of Melbourne, Parkville, Victoria,
Australia.
(7)Cancer Therapeutics CRC, Parkville, Victoria, Australia.
(8)School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
(9)Commonwealth Scientific and Industrial Research Organisation (CSIRO),
Biomedical Program, Parkville, Victoria, Australia.
(10)Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical
Sciences, Monash University, Parkville, Victoria, Australia.
(11)The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
(12)Department of Biochemistry and Molecular Biology, Bio21 Molecular Science
and Biotechnology Institute, University of Melbourne, Parkville, Victoria,
Australia.
(13)Department of Mathematics and Statistics, University of Melbourne,
Parkville, Victoria, Australia.
(14)The Walter and Eliza Hall Institute of Medical Research, Parkville,
Melbourne, Victoria, Australia. [email protected].
(15)Department of Medical Biology, University of Melbourne, Parkville, Victoria,
Australia. [email protected].
(16)The Walter and Eliza Hall Institute of Medical Research, Parkville,
Melbourne, Victoria, Australia. [email protected].
(17)Department of Medical Biology, University of Melbourne, Parkville, Victoria,
Australia. [email protected].
Acetylation of histones by lysine acetyltransferases (KATs) is essential for
chromatin organization and function1. Among the genes coding for the MYST family
of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also
known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic
stem cells4-6 and is the target of recurrent chromosomal translocations, causing
acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have
been identified in diverse cancers8. KAT6A suppresses cellular senescence
through the regulation of suppressors of the CDKN2A locus9,10, a function that
requires its KAT activity10. Loss of one allele of KAT6A extends the median
survival of mice with MYC-induced lymphoma from 105 to 413 days11. These
findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic
benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A
and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies
demonstrate that these compounds are reversible competitors of acetyl coenzyme A
and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell
cycle exit and cellular senescence without causing DNA damage. Senescence is
INK4A/ARF-dependent and is accompanied by changes in gene expression that are
typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced
senescence in vitro and in a zebrafish model of hepatocellular carcinoma.
WM-1119, which has increased bioavailability, arrests the progression of
lymphoma in mice. We anticipate that this class of inhibitors will help to
accelerate the development of therapeutics that target gene transcription
regulated by histone acetylation.
DOI: 10.1038/s41586-018-0387-5
PMID: 30069049 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33130515 | 1. Drug Resist Updat. 2020 Dec;53:100729. doi: 10.1016/j.drup.2020.100729. Epub
2020 Oct 7.
The key roles of the lysine acetyltransferases KAT6A and KAT6B in physiology and
pathology.
Wiesel-Motiuk N(1), Assaraf YG(2).
Author information:
(1)The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology,
Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
(2)The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology,
Technion-Israel Institute of Technology, Haifa, 3200003, Israel. Electronic
address: [email protected].
Histone modifications and more specifically ε-lysine acylations are key
epigenetic regulators that control chromatin structure and gene transcription,
thereby impacting on various important cellular processes and phenotypes.
Furthermore, lysine acetylation of many non-histone proteins is involved in key
cellular processes including transcription, DNA damage repair, metabolism,
cellular proliferation, mitosis, signal transduction, protein folding, and
autophagy. Acetylation affects protein functions through multiple mechanisms
including regulation of protein stability, enzymatic activity, subcellular
localization, crosstalk with other post-translational modifications as well as
regulation of protein-protein and protein-DNA interactions. The paralogous
lysine acetyltransferases KAT6A and KAT6B which belong to the MYST family of
acetyltransferases, were first discovered approximately 25 years ago. KAT6
acetyltransferases acylate both histone H3 and non-histone proteins. In this
respect, KAT6 acetyltransferases play key roles in regulation of transcription,
various developmental processes, maintenance of hematopoietic and neural stem
cells, regulation of hematopoietic cell differentiation, cell cycle progression
as well as mitosis. In the current review, we discuss the physiological
functions of the acetyltransferases KAT6A and KAT6B as well as their functions
under pathological conditions of aberrant expression, leading to several
developmental syndromes and cancer. Importantly, both upregulation and
downregulation of KAT6 proteins was shown to play a role in cancer formation,
progression, and therapy resistance, suggesting that they can act as oncogenes
or tumor suppressors. We also describe reciprocal regulation of expression
between KAT6 proteins and several microRNAs as well as their involvement in
cancer formation, progression and resistance to therapy.
Copyright © 2020. Published by Elsevier Ltd.
DOI: 10.1016/j.drup.2020.100729
PMID: 33130515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15959560 | 1. Biochem Cell Biol. 2005 Jun;83(3):344-53. doi: 10.1139/o05-041.
Role of histone acetylation in the control of gene expression.
Verdone L(1), Caserta M, Di Mauro E.
Author information:
(1)Dipartimento di Genetica e Biologia Molecolare, Università La Sapienza, Rome,
Italy.
Histone proteins play structural and functional roles in all nuclear processes.
They undergo different types of covalent modifications, defined in their
ensemble as epigenetic because changes in DNA sequences are not involved.
Histone acetylation emerges as a central switch that allows interconversion
between permissive and repressive chromatin domains in terms of transcriptional
competence. The mechanisms underlying the histone acetylation-dependent control
of gene expression include a direct effect on the stability of nucleosomal
arrays and the creation of docking sites for the binding of regulatory proteins.
Histone acetyltransferases and deacetylases are, respectively, the enzymes
devoted to the addition and removal of acetyl groups from lysine residues on the
histone N-terminal tails. The enzymes exert fundamental roles in developmental
processes and their deregulation has been linked to the progression of diverse
human disorders, including cancer.
DOI: 10.1139/o05-041
PMID: 15959560 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11395403 | 1. Annu Rev Biochem. 2001;70:81-120. doi: 10.1146/annurev.biochem.70.1.81.
Histone acetyltransferases.
Roth SY(1), Denu JM, Allis CD.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, USA. [email protected]
Transcriptional regulation in eukaryotes occurs within a chromatin setting and
is strongly influenced by nucleosomal barriers imposed by histone proteins.
Among the well-known covalent modifications of histones, the reversible
acetylation of internal lysine residues in histone amino-terminal domains has
long been positively linked to transcriptional activation. Recent biochemical
and genetic studies have identified several large, multisubunit enzyme complexes
responsible for bringing about the targeted acetylation of histones and other
factors. This review discusses our current understanding of histone
acetyltransferases (HATs) or acetyltransferases (ATs): their discovery,
substrate specificity, catalytic mechanism, regulation, and functional links to
transcription, as well as to other chromatin-modifying activities. Recent
studies underscore unexpected connections to both cellular regulatory processes
underlying normal development and differentiation, as well as abnormal processes
that lead to oncogenesis. Although the functions of HATs and the mechanisms by
which they are regulated are only beginning to be understood, these fundamental
processes are likely to have far-reaching implications for human biology and
disease.
DOI: 10.1146/annurev.biochem.70.1.81
PMID: 11395403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12185447 | 1. J Mol Med (Berl). 2002 Aug;80(8):463-74. doi: 10.1007/s00109-002-0341-7. Epub
2002 May 22.
Histone acetyl transferases: a role in DNA repair and DNA replication.
Hasan S(1), Hottiger MO.
Author information:
(1)Institute of Veterinary Biochemistry and Molecular Biology, University of
Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
In eukaryotic cells DNA is associated with proteins to form a complex known as
chromatin. The dominant proteins within this chromatin complex are the histones,
which are subject to a wide variety of covalent and reversible posttranslational
modifications such as acetylation. A specialized family of enzymes, the histone
acetyl transferases, catalyzes the transfer of acetyl groups from their
cosubstrate acetyl-coenzyme A to lysine residues of histones. Acetylation of
histone N-terminal lysine residues induces chromosomal changes and results in
the loss of chromosomal repression that allows the successful transcription of
the underlying genes. Analogously, in DNA repair and also DNA replication the
chromosomal repression is thought to be relieved by such mechanisms. Recently
several publications have provided evidence that histone acetyl transferases
also modify nonhistone proteins and thereby regulate their activities. This
review discusses various aspects of histone acetyl transferases and summarizes
recent findings which suggest a role for histone acetyl transferases in DNA
repair and DNA replication.
DOI: 10.1007/s00109-002-0341-7
PMID: 12185447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30059156 | 1. Allergy. 2019 Jun;74(6):1081-1089. doi: 10.1111/all.13582. Epub 2019 Mar 19.
Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of
Hereditary angioedema.
Qiu T(1)(2), Chiuchiolo MJ(1), Whaley AS(1), Russo AR(1), Sondhi D(1), Kaminsky
SM(1), Crystal RG(1), Pagovich OE(1).
Author information:
(1)Department of Genetic Medicine, Weill Cornell Medical College, New York,
New York.
(2)Department of Respiratory Medicine, KunShan Hospital of Traditional Chinese
Medicine, Kunshan, China.
BACKGROUND: Hereditary angioedema (HAE) is a life-threatening, autosomal
dominant disorder characterized by unpredictable, episodic swelling of the face,
upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract.
Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting
in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine
protease inhibitor that normally inhibits proteases in the contact, complement,
and fibrinolytic systems. Current treatment of HAE includes long-term
prophylaxis with attenuated androgens or human plasma-derived C1EI and
management of acute attacks with human plasma-derived or recombinant C1EI,
bradykinin, and kallikrein inhibitors, each of which requires repeated
administration. As an approach to effectively treat HAE with a single treatment,
we hypothesized that a one-time intravenous administration of an
adeno-associated virus (AAV) gene transfer vector expressing the genetic
sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide
sustained circulating C1EI levels sufficient to prevent angioedema episodes.
METHODS: To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology
to create a heterozygote C1EI-deficient mouse model (S63±) that shares
characteristics associated with HAE in humans including decreased plasma C1EI
and C4 levels. Phenotypically, these mice have increased vascular permeability
of skin and internal organs.
RESULTS: Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in
sustained human C1EI activity levels above the predicted therapeutic levels and
correction of the vascular leak in skin and internal organs.
CONCLUSION: A single treatment with AAVrh.10hC1EI has the potential to provide
long-term protection from angioedema attacks in affected individuals.
© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
DOI: 10.1111/all.13582
PMCID: PMC6752709
PMID: 30059156 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts statement. Cornell University has
licensed the patent disclosure relating to gene therapy for C1EI deficiency to
Adverum Biotechnologies. RGC is a shareholder and a consultant to Adverum. OP,
MC and RGC are inventors on the patent disclosure. TQ, ASW, ARR, DS and SMK have
no conflicts |
http://www.ncbi.nlm.nih.gov/pubmed/33861387 | 1. Drugs. 2021 May;81(7):875-879. doi: 10.1007/s40265-021-01512-2. Epub 2021 Apr
16.
Casimersen: First Approval.
Shirley M(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. [email protected].
Casimersen (Amondys 45™) is an antisense oligonucleotide of the
phosphorodiamidate morpholino oligomer subclass developed by Sarepta
Therapeutics for the treatment of Duchenne muscular dystrophy (DMD) in patients
who have a mutation in the DMD gene that is amenable to exon 45 skipping.
Administered by intravenous infusion, casimersen is designed to bind to exon 45
of the DMD gene pre-mRNA, resulting in skipping of this exon during mRNA
processing, intended to allow for production of an internally truncated but
functional dystrophin protein in patients with DMD. Casimersen received its
first approval on 25 February 2021, in the USA, for the treatment of DMD in
patients who have a confirmed mutation of the DMD gene that is amenable to
exon 45 skipping. The approval, granted under the US FDA Accelerated Approval
Program, was based on an observed increase in dystrophin production in skeletal
muscle in patients treated with casimersen. Casimersen is continuing in
phase III development for the treatment of DMD in several other countries
worldwide. This article summarises the milestones in the development of
casimersen leading to this first approval for DMD. As with other approvals under
the Accelerated Approval Program, continued approval for this indication may be
contingent upon verification of a clinical benefit in confirmatory trials.
DOI: 10.1007/s40265-021-01512-2
PMID: 33861387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34105177 | 1. Muscle Nerve. 2021 Sep;64(3):285-292. doi: 10.1002/mus.27347. Epub 2021 Jun
29.
Safety, tolerability, and pharmacokinetics of casimersen in patients with
Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized,
double-blind, placebo-controlled, dose-titration trial.
Wagner KR(1)(2), Kuntz NL(3), Koenig E(4), East L(5), Upadhyay S(6), Han B(7),
Shieh PB(8).
Author information:
(1)Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore,
Maryland, USA.
(2)Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine,
Baltimore, Maryland, USA.
(3)Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois, USA.
(4)Clinical Development, Sarepta Therapeutics, Inc, Cambridge, Massachusetts,
USA.
(5)Clinical Pharmacology, Sarepta Therapeutics, Inc, Cambridge, Massachusetts,
USA.
(6)Pharmacovigilance, Sarepta Therapeutics, Inc, Cambridge, Massachusetts, USA.
(7)Biostatistics, Sarepta Therapeutics, Inc, Cambridge, Massachusetts, USA.
(8)Department of Neurology, University of California, Los Angeles, California,
USA.
INTRODUCTION/AIMS: Duchenne muscular dystrophy (DMD) is caused by mutations in
the DMD gene resulting in the absence of dystrophin. Casimersen is a
phosphorodiamidate morpholino oligomer designed to bypass frameshift DMD
mutations and produce internally truncated, yet functional, dystrophin protein
in patients amenable to exon 45 skipping. Our primary study objective was to
evaluate safety and tolerability of casimersen; the secondary objective was to
characterize the plasma pharmacokinetics.
METHODS: This multicenter, phase 1/2 trial enrolled 12 participants (aged
7-21 years, who had limited ambulation or were nonambulatory) and comprised a
12-week, double-blind dose titration, then an open-label extension for up to
132 weeks. During dose titration, participants were randomized 2:1 to weekly
casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks
per dose), or placebo.
RESULTS: Participants received casimersen for a mean 139.6 weeks.
Treatment-emergent adverse events (TEAEs) occurred in all casimersen- and
placebo-treated participants and were mostly mild (over 91.4%) and unrelated to
casimersen or its dose. There were no deaths, dose reductions, abnormalities in
laboratory parameters or vital signs, or casimersen-related serious AEs.
Casimersen plasma concentration increased with dose and declined similarly for
all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were
similar at weeks 7 and 60.
DISCUSSION: Casimersen was well tolerated in participants with DMD amenable to
exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen.
Plasma exposure was dose proportional with no suggestion of plasma accumulation.
These results support further studies of casimersen in this population.
© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
DOI: 10.1002/mus.27347
PMCID: PMC9290993
PMID: 34105177 [Indexed for MEDLINE]
Conflict of interest statement: K.R.W. has served as a paid consultant for
Asklepios BioPharmaceutical, Inc, Dynacure, Dyne Therapeutics, PTC Therapeutics,
F. Hoffmann‐LaRoche, Ltd, Sarepta Therapeutics, Inc, and Vita Therapeutics.
N.L.K. has served as a paid consultant on advisory boards for Audentes, AveXis,
Biogen, Cytokinetics, PTC Therapeutics, Roche, and Sarepta Therapeutics, Inc.
E.K., L.E., S.U., and B.H. are employees of Sarepta Therapeutics, Inc, and may
own stock/options in the company. P.B.S. has served as a paid consultant on ad
hoc advisory boards for Alexion, AveXis, Biogen, and Sarepta Therapeutics, Inc,
and has served on speakers’ bureaus for Alexion, AveXis, Biogen, CSL Behring,
Genentech, and Grifols. |
http://www.ncbi.nlm.nih.gov/pubmed/34403681 | 1. Pharmacol Ther. 2022 Feb;230:107967. doi: 10.1016/j.pharmthera.2021.107967.
Epub 2021 Aug 14.
Deliver the promise: RNAs as a new class of molecular entities for therapy and
vaccination.
Yu AM(1), Tu MJ(2).
Author information:
(1)Department of Biochemistry and Molecular Medicine, UC Davis School of
Medicine, Sacramento, CA 95817, USA. Electronic address: [email protected].
(2)Department of Biochemistry and Molecular Medicine, UC Davis School of
Medicine, Sacramento, CA 95817, USA.
The concepts of developing RNAs as new molecular entities for therapies have
arisen again and again since the discoveries of antisense RNAs, direct
RNA-protein interactions, functional noncoding RNAs, and RNA-directed gene
editing. The feasibility was demonstrated with the development and utilization
of synthetic RNA agents to selectively control target gene expression, modulate
protein functions or alter the genome to manage diseases. Rather, RNAs are
labile to degradation and cannot cross cell membrane barriers, making it hard to
develop RNA medications. With the development of viable RNA technologies, such
as chemistry and pharmaceutics, eight antisense oligonucleotides (ASOs)
(fomivirsen, mipomersen, eteplirsen, nusinersen, inotersen, golodirsen,
viltolarsen and casimersen), one aptamer (pegaptanib), and three small
interfering RNAs (siRNAs) (patisiran, givosiran and lumasiran) have been
approved by the United States Food and Drug Administration (FDA) for therapies,
and two mRNA vaccines (BNT162b2 and mRNA-1273) under Emergency Use Authorization
for the prevention of COVID-19. Therefore, RNAs have become a great addition to
small molecules, proteins/antibodies, and cell-based modalities to improve the
public health. In this article, we first summarize the general characteristics
of therapeutic RNA agents, including chemistry, common delivery strategies,
mechanisms of actions, and safety. By overviewing individual RNA medications and
vaccines approved by the FDA and some agents under development, we illustrate
the unique compositions and pharmacological actions of RNA products. A new era
of RNA research and development will likely lead to commercialization of more
RNA agents for medical use, expanding the range of therapeutic targets and
increasing the diversity of molecular modalities.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pharmthera.2021.107967
PMCID: PMC9477512
PMID: 34403681 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
are named inventors of issued and pending patents related to RNA bioengineering
technology and use that are owned by the University of California, Davis; and
Dr. Yu is a founder of AimRNA, Inc. that intends to license the intellectual
property. |
http://www.ncbi.nlm.nih.gov/pubmed/35652612 | 1. Cancer Discov. 2022 Jul 6;12(7):1603-1604. doi:
10.1158/2159-8290.CD-NB2022-0040.
Tiragolumab Results Cast Shadow on TIGIT Pipeline.
[No authors listed]
Genentech's TIGIT-targeted antibody tiragolumab missed its endpoints in two
late-stage lung cancer trials, raising doubts about one of the most widely
studied next-generation checkpoint targets in immuno-oncology. But numerical
signs of benefit among certain patients with metastatic non-small cell lung
cancer suggest that TIGIT blockade still has potential-if drug developers can
successfully identify the best indications, drug combinations, or patient
populations.
©2022 American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-NB2022-0040
PMID: 35652612 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35576957 | 1. Lancet Oncol. 2022 Jun;23(6):781-792. doi: 10.1016/S1470-2045(22)00226-1. Epub
2022 May 13.
Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line
treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and
follow-up analyses of a randomised, double-blind, phase 2 study.
Cho BC(1), Abreu DR(2), Hussein M(3), Cobo M(4), Patel AJ(5), Secen N(6), Lee
KH(7), Massuti B(8), Hiret S(9), Yang JCH(10), Barlesi F(11), Lee DH(12), Ares
LP(13), Hsieh RW(14), Patil NS(14), Twomey P(14), Yang X(14), Meng R(14),
Johnson ML(15).
Author information:
(1)Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South
Korea. Electronic address: [email protected].
(2)Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain.
(3)SCRI Florida Cancer Specialists, Leesburg, FL, USA.
(4)Unidad de Gestión Clínica Intercentros, Medical Oncology, Hospitales
Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.
(5)SCRI Florida Cancer Specialists, Sarasota, FL, USA.
(6)Institute of Lung Diseases Vojvodina, Sremska Kamenica, Serbia.
(7)Chungbuk National University Hospital, Cheongju, South Korea.
(8)Hospital Universitario de Alicante-ISABIAL, Alicante, Spain.
(9)Institute de Cancerologie de l'Ouest, Saint Herblain, France.
(10)National Taiwan University Cancer Centre, Taipei, Taiwan.
(11)Aix Marseille University, CNRS, INSERM, CRCM, Marseille, France; Gustave
Roussy Cancer Campus, Villejuif, France.
(12)Asan Medical Center, Seoul, South Korea.
(13)Hospital Universitario Doce de Octubre, Madrid, Spain.
(14)Genentech, South San Francisco, CA, USA.
(15)Sarah Cannon Research Institute-Tennessee Oncology, Nashville, TN, USA.
Comment in
Nat Rev Clin Oncol. 2022 Jul;19(7):428. doi: 10.1038/s41571-022-00650-0.
Lancet Oncol. 2022 Jun;23(6):695-697. doi: 10.1016/S1470-2045(22)00261-3.
BACKGROUND: Targeted inhibition of the PD-L1-PD-1 pathway might be further
amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT
inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE
trial, we aimed to assess the preliminary efficacy and safety of tiragolumab
plus atezolizumab (anti-PD-L1) therapy as first-line treatment for
non-small-cell lung cancer (NSCLC).
METHODS: CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled
trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour
proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako,
Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with
measurable disease, Eastern Cooperative Oncology Group performance status of 0
or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe,
Asia, and the USA. Patients were randomly assigned (1:1), via an interactive
voice or web-based response system, to receive tiragolumab (600 mg) plus
atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3
weeks. Investigators and patients were masked to treatment assignment. The
co-primary endpoints were investigator-assessed objective response rate and
progression-free survival as per Response Evaluation Criteria in Solid Tumors
version 1.1 in the intention-to-treat population, analysed after approximately
80 progression-free survival events had been observed in the primary population.
Safety was assessed in all patients who received at least one dose of study
drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is
ongoing.
FINDINGS: Patients were enrolled between Aug 10, 2018, and March 20, 2019. At
data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients
assessed for eligibility were randomly assigned to receive tiragolumab plus
atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary
analysis, after a median follow-up of 5·9 months (4·6-7·6, in the
intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the
tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the
placebo plus atezolizumab group had an objective response (p=0·031). Median
progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the
tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo
plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90],
p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%)
patients receiving placebo plus atezolizumab had serious treatment-related
adverse events. The most frequently reported grade 3 or worse treatment-related
adverse event was lipase increase (in six [9%] patients in the tiragolumab plus
atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two
treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab
plus atezolizumab group.
INTERPRETATION: Tiragolumab plus atezolizumab showed a clinically meaningful
improvement in objective response rate and progression-free survival compared
with placebo plus atezolizumab in patients with chemotherapy-naive,
PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was
well tolerated, with a safety profile generally similar to that of atezolizumab
alone. These findings demonstrate that tiragolumab plus atezolizumab is a
promising immunotherapy combination for the treatment of previously untreated,
locally advanced unresectable or metastatic NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00226-1
PMID: 35576957 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests BCC reports research
funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions
Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie,
Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio
Convergence; royalties from Champions Oncology; and consulting fees from
Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono,
Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, and Blueprint
Medicines; participates on a scientific advisory board for KANAPH Therapeutic,
Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, and Joseah BIO; is
on the Board of Directors for Interpark Bio Convergence and Gencurix; holds
stock in TheraCanVac, Gencurix, Bridgebio Therapeutics, KANAPH Therapeutic,
Cyrus Therapeutics, and Interpark Bio Convergence; and is the founder of DAAN
Biotherapeutics. DRA reports personal payment or honoraria from Roche,
AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Pfizer, and
Novartis; and institutional support for attending meetings or travel from Roche,
Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. MH reports consulting or
advisory fees from IntegraConnect, Coherus Biosciences, Athenex, Karyopharm
Therapeutics, Bristol-Myers Squibb, AstraZeneca, and Mirati Therapeutics. AJP is
on the Executive Board of Florida Cancer Specialists. KHL reports consulting
fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Pfizer, and
AstraZeneca. BM reports consulting fees from Roche, Bristol-Myers Squibb, Merck
Sharp & Dohme, and Takeda; payment or honoraria from Boehringer Ingelheim,
Bristol-Myers Squibb, and AstraZeneca; support for attending meetings or travel
from Merck Sharp & Dohme and AstraZeneca; and a leadership or fiduciary role in
the Spanish Lung Cancer Group. SH is a consultant–advisor to AstraZeneca and
Takeda. JCHY reports grants from AstraZeneca; personal fees from Amgen,
AstraZeneca, Bayer, Boehringrer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo,
Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer,
Roche–Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; and institutional
fees for advisory or consulting services from Amgen, AstraZeneca, Bayer,
Boehringrer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck
KGaA, Merck Sharp & Dohme, Novartis, Roche–Genentech, Takeda Oncology, Yuhan
Pharmaceuticals, and Johnson and Johnson. FB reports personal consulting fees
from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly
Oncology, F Hoffmann-La Roche, Novartis, Merck, Mirati, Merck Sharp & Dohme,
Pierre Fabre, Pfizer, Seattle Genetics, and Takeda; and institutional consulting
fees from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb,
Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F Hoffmann-La Roche, Genentech,
Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, Merck Sharp &
Dohme, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda. DHL reports personal
fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CJ
Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, Merck Sharp & Dohme,
Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie,
Takeda, Genexine, Menarini, and BC Pharma; and non-financial support from Takeda
and Blueprint Medicine. LPA reports grants or contracts from Merck Sharp &
Dohme, AstraZeneca, Pfizer, and Bristol-Myers Squibb; consulting fees from
Lilly, Bristol-Myers Squibb, Roche, Pharmamar, Merck, AstraZeneca, Novartis,
Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb,
and Mirati; payment or honoraria from AstraZeneca, Janssen, Merck, Mirati and
Sanofi; and a leadership or fiduciary role in Genomica and Altum Sequency. RWH
reports stock and stock options with F Hoffmann-La Roche, and is an employee of
Genentech. NSP is an employee of Genentech. PT reports stock and stock options
with F Hoffmann-La Roche. XY is an employee of Genentech. RM is an employee of
Genentech and reports stock with Genentech. MLJ reports grants from AbbVie,
Amgen, Apexigen, Arcus Biosciences, Array Biopharma, Artios Pharma, AstraZeneca,
Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences,
Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo,
Dracen Pharmaceuticals, Dynavax, Lilly, EMD Serono, Genentech–Roche, Genmab,
Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health,
Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics,
Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics,
Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals,
Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi, Seven and Eight
Biopharmaceuticals–Birdie Biopharmaceuticals, Shattuck Labs, Silicon
Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals,
Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and
WindMIL; and institutional fees for consulting services from AbbVie, Amgen,
AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint
Therapeutics, CytomX, Daiichi Sankyo, EMD Serono, Genentech–Roche,
GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo
Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics,
Sanofi, WindMIL, Achilles Therapeutics, Bristol-Myers Squibb, Editas Medicine,
Eisai, G1 Therapeutics, Ideaya Biosciences, Lilly, and Association of Community
Cancer Centers. MC, NS, and XY declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35292828 | 1. Cancer Immunol Immunother. 2022 Oct;71(10):2549-2563. doi:
10.1007/s00262-022-03182-9. Epub 2022 Mar 16.
Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in
human colorectal cancer.
Thibaudin M(1)(2)(3)(4), Limagne E(1)(2)(3)(4), Hampe L(1)(2)(3)(4), Ballot
E(1)(2)(3)(4), Truntzer C(1)(2)(3)(4), Ghiringhelli F(5)(6)(7)(8)(9).
Author information:
(1)Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer
Center-UNICANCER, 1 rue du Professeur Marion, 21000, Dijon, France.
(2)UMR INSERM 1231, 7 Boulevard Jeanne d'Arc, 21000, Dijon, France.
(3)Genomic and Immunotherapy Medical Institute, Dijon University Hospital, 14
rue Paul Gaffarel, 21000, Dijon, France.
(4)University of Burgundy-Franche Comté, Maison de l'université Esplanade
Erasme, 21000, Dijon, France.
(5)Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer
Center-UNICANCER, 1 rue du Professeur Marion, 21000, Dijon, France.
[email protected].
(6)UMR INSERM 1231, 7 Boulevard Jeanne d'Arc, 21000, Dijon, France.
[email protected].
(7)Genomic and Immunotherapy Medical Institute, Dijon University Hospital, 14
rue Paul Gaffarel, 21000, Dijon, France. [email protected].
(8)University of Burgundy-Franche Comté, Maison de l'université Esplanade
Erasme, 21000, Dijon, France. [email protected].
(9)Department of Medical Oncology, Georges François Leclerc Cancer
Center-UNICANCER, 1 rue du Professeur Marion, Dijon, 21000, Dijon, France.
[email protected].
Microsatellite stable colorectal cancers (MSS-CRC) are resistant to
anti-PD-1/PD-L1 therapy but the combination of immune checkpoints inhibitors
(ICI) could be a clue to reverse resistance. Our aim was to evaluate ex vivo the
capacity of the combination of atezolizumab (anti-PD-L1) and tiragolumab
(anti-TIGIT) to reactivate the immune response of tumor infiltrating lymphocytes
(TILs) in MSS-CRC. We analysed CRC tumor tissue and the associated blood sample
in parallel. For each patient sample, extensive immunomonitoring and cytokine
production were tested. We generated an ex vivo assay to study immune reactivity
following immune stimulation with checkpoint inhibitors of tumor cell
suspensions. Three microsatellite instable (MSI) and 13 MSS-CRC tumors were
analysed. To generalize our observations, bioinformatics analyses were performed
on public data of single cell RNA sequencing of CRC TILs and RNA sequencing data
of TCGA. Atezolizumab alone could only reactivate T cells from MSI tumors.
Atezolizumab and tiragolumab reactivated T cells in 46% of MSS-CRC samples.
Reactivation by ICK was observed in patients with higher baseline frequency of
Th1 and Tc1 cells, and was also associated with higher baseline T cell
polyfunctionality and higher CD96 expression. We showed that a high frequency of
CD96 expression on T cells could be a surrogate marker of atezolizumab and
tiragolumab efficacy. Together these data suggest that the association of
atezolizumab and tiragolumab could restore function of CD4 and CD8 TILs in
MSS-CRC and could be tested in a clinical trial in colorectal cancer patients
with MSS status.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,
part of Springer Nature.
DOI: 10.1007/s00262-022-03182-9
PMCID: PMC10992601
PMID: 35292828 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there is no potential
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31425702 | 1. Surv Ophthalmol. 2020 Jan-Feb;65(1):12-17. doi:
10.1016/j.survophthal.2019.08.001. Epub 2019 Aug 16.
Optic neuritis in the era of biomarkers.
Chen JJ(1), Pittock SJ(2), Flanagan EP(2), Lennon VA(3), Bhatti MT(4).
Author information:
(1)Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester,
Minnesota, USA; Department of Neurology, Mayo Clinic College of Medicine,
Rochester, Minnesota, USA. Electronic address: [email protected].
(2)Department of Neurology, Mayo Clinic College of Medicine, Rochester,
Minnesota, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic
College of Medicine, Rochester, Minnesota, USA; Center for Multiple Sclerosis
and Autoimmune Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota,
USA.
(3)Department of Neurology, Mayo Clinic College of Medicine, Rochester,
Minnesota, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic
College of Medicine, Rochester, Minnesota, USA; Center for Multiple Sclerosis
and Autoimmune Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota,
USA; Department of Immunology, Mayo Clinic College of Medicine, Rochester,
Minnesota, USA.
(4)Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester,
Minnesota, USA; Department of Neurology, Mayo Clinic College of Medicine,
Rochester, Minnesota, USA.
The Optic Neuritis Treatment Trial, a landmark study completed in 1991,
stratified the risk of multiple sclerosis in patients with optic neuritis. Since
that time, unique biomarkers for optic neuritis have been found. The antibody
against aquaporin-4 (AQP4)-immunoglobulin G (IgG) discovered in 2004 was found
to be both the pathologic cause and a reliable biomarker for neuromyelitis
optica spectrum disorders. This finding enabled an expanded definition of the
phenotype of neuromyelitis optica spectrum disorder and improved treatment of
the disease. Subsequently, myelin oligodendrocyte glycoprotein (MOG) IgG was
recognized to be a marker for MOG-IgG-associated disorder, a central
demyelinating disease characterized by recurrent optic neuritis, prominent disk
edema, and perineural optic nerve enhancement on magnetic resonance imaging.
Most multiple sclerosis disease-modifying agents are ineffective for
AQP4-IgG-positive neuromyelitis optica spectrum disorder and MOG-IgG-associated
disorder. Because there are crucial differences in treatment and prognosis
between multiple sclerosis, AQP4-IgG-positive neuromyelitis optica spectrum
disorder, and MOG-IgG-associated disorder, ophthalmologists should be aware of
these new biomarkers of optic neuritis and incorporate their testing in all
patients with atypical optic neuritis.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.survophthal.2019.08.001
PMID: 31425702 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34212756 | 1. Mult Scler. 2022 Apr;28(4):512-521. doi: 10.1177/13524585211024978. Epub 2021
Jul 2.
Longitudinal follow-up of serum biomarkers in patients with neuromyelitis optica
spectrum disorder.
Kim H(1), Lee EJ(2), Kim S(3), Choi LK(4), Kim HJ(3), Kim HW(5), Chung K(5), Seo
D(5), Moon S(5), Kim KK(5), Lim YM(5).
Author information:
(1)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea Graduate School of Medical Science and Engineering,
Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
(2)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea Department of Convergence Medicine, Asan Medical
Institute of Convergence Science and Technology, Seoul, South Korea.
(3)Department of Convergence Medicine, Asan Medical Institute of Convergence
Science and Technology, Seoul, South Korea.
(4)Graduate School of Medical Science and Engineering, Korea Advanced Institute
of Science and Technology, Daejeon, South Korea.
(5)Department of Neurology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea.
BACKGROUND: Recently, several serum biomarkers have been proposed in
Neuromyelitis Optica Spectrum Disorders (NMOSD) to monitor disease activity.
OBJECTIVE: The objective of the study is to evaluate the longitudinal clinical
value of serum biomarkers in patients with NMOSD.
METHODS: We prospectively recruited consecutive NMOSD patients with
anti-aquaporin-4 antibody and obtained serum samples at enrollment, after
6-12 months of follow-up (main period), and at attacks. Using single-molecule
array assays, we evaluated longitudinal changes of serum neurofilament light
chain (NfL), glial fibrillary acidic protein (GFAP), and GFAP/NfL levels.
RESULTS: Overall, 64 patients (58 women) were enrolled (age: 51 years, disease
duration: 6.7 years) and 133 samples were obtained. Among patients who did not
develop new attacks during the main period (n = 62), serum levels of NfL, GFAP,
and GFAP/NfL were significantly decreased over time in patients with attacks
(<2 months) at enrollment (n = 14 (23%)), whereas serum NfL and GFAP levels
gradually increased in the others (n = 48 (77%)). During the study, five (8%)
patients developed new attacks; only serum GFAP levels increased consistently
upon these events compared with baseline levels. To differentiate attacks from
remissions, serum GFAP levels showed the largest area under the receiver
operating characteristic curve (0.876, 95% confidence interval: 0.801-0.951).
CONCLUSION: Among NfL, GFAP, and GFAP/NfL, serum GFAP might be the most
appropriate for monitoring NMOSD longitudinally, which warrants future
confirming studies.
DOI: 10.1177/13524585211024978
PMID: 34212756 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35635574 | 1. Semin Immunopathol. 2022 Sep;44(5):599-610. doi: 10.1007/s00281-022-00941-9.
Epub 2022 May 30.
Immuno-pathogenesis of neuromyelitis optica and emerging therapies.
Chihara N(1), Yamamura T(2).
Author information:
(1)Division of Neurology, Kobe University Graduate School of Medicine, Kobe,
Japan.
(2)Department of Immunology, National Institute of Neuroscience, National Center
of Neurology and Psychiatry, Tokyo, Japan. [email protected].
Neuromyelitis optica (NMO) is an inflammatory disease that resembles MS in the
relapsing clinical course of optic neuritis and myelitis. Two decades of studies
have revealed that autoantibodies, reactive to the water channel protein
aquaporin 4 (AQP4) are detected in the core group of patients. These
autoantibodies play a crucial role in the inflammatory pathology of NMO,
involving proinflammatory cytokines, chemokines, and various inflammatory cells
such as Th17 cells. Anti-AQP4 antibody-positive NMO differs fundamentally from
MS, particularly in the responsiveness to therapies and the neuropathology
accompanying destruction of astrocytes. Research into the immunological
mechanism has led to the identification of possible targets of therapy,
including complement pathway and interleukin-6 (IL-6) receptor signaling. Recent
randomized controlled clinical trials have shown the remarkable efficacy of
antibodies specific for complement C5, IL-6 receptor, and CD19+ B cells in
prevention of NMO spectrum disorder relapses, although no such effects were
found in anti-AQP4 antibody-negative patients. These results imply that
anti-AQP4 antibody is a biomarker predicting the efficacy of therapies, and
indicate the future direction towards "precision medicine."
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,
part of Springer Nature.
DOI: 10.1007/s00281-022-00941-9
PMID: 35635574 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35938660 | 1. Continuum (Minneap Minn). 2022 Aug 1;28(4):1131-1170. doi:
10.1212/CON.0000000000001168.
Neuromyelitis Optica Spectrum Disorders.
Costello F.
Erratum in
Continuum (Minneap Minn). 2022 Dec 1;28(6):1859. doi:
10.1212/CON.0000000000001271.
PURPOSE OF REVIEW: This article reviews the cardinal clinical features, distinct
immunopathology, current diagnostic criteria, relapse-related risk factors,
emerging biomarkers, and evolving treatment strategies pertaining to
neuromyelitis optica spectrum disorders (NMOSD).
RECENT FINDINGS: The discovery of the pathogenic aquaporin-4 (AQP4)-IgG
autoantibody and characterization of NMOSD as an autoimmune astrocytopathy have
spearheaded the identification of key immunologic therapeutic targets in this
disease, including but not limited to the complement system, the interleukin 6
(IL-6) receptor, and B cells. Accordingly, four recent randomized controlled
trials have demonstrated the efficacy of three new NMOSD therapies, namely
eculizumab, satralizumab, and inebilizumab.
SUMMARY: Currently, NMOSD poses both diagnostic and treatment challenges. It is
debated whether individuals who are seropositive for myelin oligodendrocyte
glycoprotein (MOG)-IgG belong within the neuromyelitis optica spectrum. This
discussion is fueled by disparities in treatment responses between patients who
are AQP4-IgG seropositive and seronegative, suggesting different
immunopathologic mechanisms may govern these conditions. As our understanding
regarding the immune pathophysiology of NMOSD expands, emerging biomarkers,
including serum neurofilament light chain and glial fibrillary acidic protein
(GFAP), may facilitate earlier relapse detection and inform long-term treatment
decisions. Future research focal points should include strategies to optimize
relapse management, restorative treatments that augment neurologic recovery, and
practical solutions that promote equitable access to approved therapies for all
patients with NMOSD.
Copyright © 2022 American Academy of Neurology.
DOI: 10.1212/CON.0000000000001168
PMID: 35938660 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35898513 | 1. Front Immunol. 2022 Jul 11;13:853891. doi: 10.3389/fimmu.2022.853891.
eCollection 2022.
Plasma Complement 3 and Complement 4 Are Promising Biomarkers for Distinguishing
NMOSD From MOGAD and Are Associated With the Blood-Brain-Barrier Disruption in
NMOSD.
Lin L(1), Wu Y(1), Hang H(1), Lu J(1), Ding Y(1).
Author information:
(1)Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical
University, Nanjing, China.
BACKGROUND AND OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) and
myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease
(MOGAD) are autoimmune inflammatory demyelinating diseases of the central
nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD,
diagnostic confusion exists between the two diseases. To better discriminate
NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3)
and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks
of the diseases. We sought to determine whether C3 or C4 has an influence on the
features of NMOSD.
METHODS: In this observational study, data from 73 aquaporin-4 antibodies
(AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were
collected retrospectively. Demographics, clinical characteristics, plasma
parameters, and cerebrospinal fluid (CSF) findings will be analyzed for
comparability between the two groups. Immunoglobulin-G (IgG) and albumin were
measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and
compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The
correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.
RESULTS: The ages of onset were later in the AQP4-IgG positive NMOSD group and
females predominated, which differed from the MOGAD group, whose ages were
younger and with a slight male preponderance. The AQP4-IgG positive NMOSD
patients presented with the clinical symptoms of optic neuritis (ON) and
transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in
MOGAD patients. CSF analysis shows that slight but not significantly higher
white cell count (WCC) and protein were observed in the MOGAD group than in the
AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are
significantly lower (p = 0.027) than in NMOSD patients. On the contrary, the
plasma levels of albumin in MOGAD were higher than in NMOSD, which reached
statistical significance (p = 0.039). Both the plasma C3 and C4 levels in the
NMOSD group were significantly lower than in MOGAD and HC. The receiver
operating characteristic (ROC) curve of the prediction model comprises C3 and C4
to distinguish NMOSD from MOGAD [area under the curve (AUC): 0.731, 0.645],
which are considered to have discriminatory values. The results of Spearman's
analysis revealed that there was a significant positive correlation between the
plasma C3 and the CSF WCC (r = 0.383, p = 0.040). There was an inverse
correlation between plasma C4 and plasma IgG (r = -0.244, p = 0.038). Plasma C3
or C4 was significantly positively correlated with CSF albumin and Q-Alb, which
is considered a measure of blood-brain barrier (BBB) disruption.
CONCLUSION: During the acute phase of NMOSD and MOGAD, plasma C3 and C4 may
become potential biomarkers for distinguishing the two diseases and reflecting
the NMOSD BBB damage.
Copyright © 2022 Lin, Wu, Hang, Lu and Ding.
DOI: 10.3389/fimmu.2022.853891
PMCID: PMC9309329
PMID: 35898513 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33724534 | 1. Ann Neurol. 2021 May;89(5):895-910. doi: 10.1002/ana.26067. Epub 2021 Mar 30.
Serum Glial Fibrillary Acidic Protein: A Neuromyelitis Optica Spectrum Disorder
Biomarker.
Aktas O(1), Smith MA(2), Rees WA(2), Bennett JL(3), She D(2), Katz E(2), Cree
BAC(4); N-MOmentum scientific group and the N-MOmentum study investigators.
Collaborators: Fujihara K, Paul F, Hartung HP, Marignier R, Kim HJ, Weinshenker
BG, Pittock SJ, Wingerchuk DM, Cutter GR, Green AJ, Mealy MA, Drappa J.
Author information:
(1)Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
(2)Viela Bio, Gaithersburg, MD.
(3)School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora,
CO.
(4)Department of Neurology, UCSF Weill Institute for Neurosciences, University
of California San Francisco, San Francisco, CA.
OBJECTIVE: Blood tests to monitor disease activity, attack severity, or
treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been
developed. This study investigated the relationship between serum glial
fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed
the impact of inebilizumab treatment.
METHODS: N-MOmentum was a prospective, multicenter, double-blind,
placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels
were measured by single-molecule arrays (SIMOA) in 1,260 serial and
attack-related samples from 215 N-MOmentum participants (92% aquaporin
4-immunoglobulin G-seropositive) and in control samples (from healthy donors and
patients with relapsing-remitting multiple sclerosis).
RESULTS: At baseline, 62 participants (29%) exhibited high sGFAP concentrations
(≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and
were more likely to experience an adjudicated attack than participants with
lower baseline concentrations (hazard ratio [95% confidence interval], 3.09
[1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations
increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml;
attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with
attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR
= 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This
attack-related increase in sGFAP occurred primarily in placebo-treated
participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in
inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five
participants (28%) with elevated baseline sGFAP reported neurological symptoms
leading to nonadjudicated attack assessments.
INTERPRETATION: Serum GFAP may serve as a biomarker of NMOSD activity, attack
risk, and treatment effects. ANN NEUROL 2021;89:895-910.
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on
behalf of American Neurological Association.
DOI: 10.1002/ana.26067
PMCID: PMC8252046
PMID: 33724534 [Indexed for MEDLINE]
Conflict of interest statement: Viela Bio and MedImmune funded the N‐MOmentum
study. Viela Bio is the owner of inebilizumab. Mitsubishi Tanabe Pharma
Corporation and Hansoh Pharmaceutical Group Co. Ltd. have partnerships with
Viela Bio to develop and commercialize inebilizumab for NMOSD (and other
potential indications) in Asia. O.A. serves on a steering committee for Viela
Bio and has received funding for travel and fees from Viela Bio. M.A.S., W.R.,
D.S., and E.K. are employees of Viela Bio. J.L.B. reports payment for study
design/consultation from Viela Bio and personal fees from Mitsubishi Tanabe
Pharma Corporation. B.A.C.C. has nothing to report. |
http://www.ncbi.nlm.nih.gov/pubmed/31471502 | 1. Neurology. 2019 Sep 24;93(13):e1299-e1311. doi: 10.1212/WNL.0000000000008160.
Epub 2019 Aug 30.
Serum GFAP and neurofilament light as biomarkers of disease activity and
disability in NMOSD.
Watanabe M(1), Nakamura Y(1), Michalak Z(1), Isobe N(1), Barro C(1), Leppert
D(1), Matsushita T(1), Hayashi F(1), Yamasaki R(1), Kuhle J(1), Kira JI(2).
Author information:
(1)From the Departments of Neurology (M.W., Y.N., T.M., F.H., R.Y., J.-i.K.) and
Neurological Therapeutics (N.I.), Neurological Institute, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan; and Neurology (Z.M., C.B.,
D.L., J.K.), Departments of Medicine, Biomedicine and Clinical Research,
University Hospital Basel, University of Basel, Switzerland.
(2)From the Departments of Neurology (M.W., Y.N., T.M., F.H., R.Y., J.-i.K.) and
Neurological Therapeutics (N.I.), Neurological Institute, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan; and Neurology (Z.M., C.B.,
D.L., J.K.), Departments of Medicine, Biomedicine and Clinical Research,
University Hospital Basel, University of Basel, Switzerland.
[email protected] [email protected].
OBJECTIVE: To test the hypothesis that serum levels of glial fibrillary acidic
protein (GFAP) and neurofilament light chain (NfL), which are an intermediate
astrocyte and neuron filaments, respectively, are clinically useful biomarkers
of disease activity and disability in neuromyelitis optica spectrum disorders
(NMOSD).
METHODS: Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in
CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples),
patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with
multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive
single-molecule array assays. Association of sGFAP and sNfL levels with clinical
parameters was determined.
RESULTS: For both GFAP and NfL, CSF and serum levels were strongly correlated.
Both were higher in the serum of patients with NMOSD than in HCs (both p <
0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1
pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse
(540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP
and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p
= 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse
differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of
75.8%.
CONCLUSIONS: sGFAP and sNfL are likely to be good biomarkers of disease activity
and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic
marker for NMOSD.
© 2019 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000008160
PMID: 31471502 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34278578 | 1. J Neurochem. 2021 Dec;159(5):913-922. doi: 10.1111/jnc.15478. Epub 2021 Jul
28.
Serum neurofilament light chain and glial fibrillary acidic protein in
AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and multiple
sclerosis: A cohort study.
Liu C(1)(2), Lu Y(3), Wang J(1), Chang Y(1), Wang Y(1), Chen C(1), Liu Z(3),
Kermode AG(1)(4), Zhang Y(2), Qiu W(1).
Author information:
(1)Neurology Department, The Third Affiliated Hospital, Sun Yat-sen University,
Guangzhou, China.
(2)Emergency Department, The Third Affiliated Hospital of Sun Yat-sen
University, Guangzhou, China.
(3)Clinical Data Center, The Third Affiliated Hospital of Sun Yat-Sen
University, Guangzhou, China.
(4)Perron Institute, University of Western Australia, Perth, WA, Australia.
We investigated the serum neurofilament light chain (sNfL) and glial fibrillary
acidic protein (sGFAP) levels in a cohort of Chinese patients with neuromyelitis
optica spectrum disorders (NMOSD) and multiple sclerosis (MS) in relation to
clinical disease course and treatment. sNfL and sGFAP levels were determined by
ultrasensitive single molecule array (Simoa) assay in patients with NMOSD
(n = 102) and MS (n = 98) and healthy controls (HCs; n = 84). Notably, 13
patients with NMOSD and 27 patients with MS were enrolled in the 1-year
follow-up cohort. Levels were compared with data such as clinical course,
disease duration, Expanded Disability Status Scale (EDSS) score, and lesions on
MRI. Higher levels of sNfL and sGFAP were found in subjects with NMOSD and MS
than in HCs (sNfL, median 12.11, 17.5 vs. 8.88 pg/ml, p < .05; sGFAP, median
130.2, 160.4 vs. 80.01 pg/ml, p < .05). Moreover, sNfL levels were higher in the
relapse phase of MS than in the relapse phase of NMOSD (30.02 vs. 14.57 pg/ml,
p < .05); sGFAP levels were higher in the remission phase of MS than in the
remission phase of NMOSD (159.8 vs. 124.5 pg/ml, p < .01). A higher sGFAP/sNfL
quotient at relapse differentiated NMOSD from MS. Multivariate analyses
indicated that sGFAP levels were associated with the EDSS score in NMOSD
(p < .05). At the 1-year follow-up, sNfL and sGFAP levels were both decreased in
NMOSD patients in remission, while only sNfL levels were decreased in MS
patients in remission. sGFAP and sNfL are potential blood biomarkers for
diagnosing and monitoring NMOSD and MS.
© 2021 International Society for Neurochemistry.
DOI: 10.1111/jnc.15478
PMID: 34278578 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33586113 | 1. J Thromb Thrombolysis. 2021 Apr;51(3):595-607. doi:
10.1007/s11239-021-02394-7. Epub 2021 Feb 14.
Thrombotic complications in 2928 patients with COVID-19 treated in intensive
care: a systematic review.
Jenner WJ(1), Kanji R(2)(1), Mirsadraee S(2)(3), Gue YX(1)(4), Price S(2)(3),
Prasad S(2)(3), Gorog DA(5)(6)(7).
Author information:
(1)Cardiology Department, East and North Hertfordshire NHS Trust, Stevenage,
Hertfordshire, UK.
(2)Faculty of Medicine, National Heart and Lung Institute, Imperial College,
London, UK.
(3)Cardiology Department, Royal Brompton and Harefield NHS Foundation Trust,
London, UK.
(4)School of Life and Medical Sciences, Postgraduate Medical School, University
of Hertfordshire, Hatfield, UK.
(5)Faculty of Medicine, National Heart and Lung Institute, Imperial College,
London, UK. [email protected].
(6)Cardiology Department, East and North Hertfordshire NHS Trust, Stevenage,
Hertfordshire, UK. [email protected].
(7)School of Life and Medical Sciences, Postgraduate Medical School, University
of Hertfordshire, Hatfield, UK. [email protected].
A prothrombotic state is reported with severe COVID-19 infection, which can
manifest in venous and arterial thrombotic events. Coagulopathy is reflective of
more severe disease and anticoagulant thromboprophylaxis is recommended in
hospitalized patients. However, the prevalence of thrombosis on the intensive
care unit (ICU) remains unclear, including whether this is sufficiently
addressed by conventional anticoagulant thromboprophylaxis. We aimed to identify
the rate of thrombotic complications in ICU-treated patients with COVID-19, to
inform recommendations for diagnosis and management. A systematic review was
conducted to assess the incidence of thrombotic complications in ICU-treated
patients with COVID-19. Observational studies and registries reporting
thrombotic complications in ICU-treated patients were included. Information
extracted included patient demographics, use of thromboprophylaxis or
anticoagulation, method of identifying thrombotic complications, and reported
patient outcomes. In 28 studies including 2928 patients, thrombotic
complications occurred in 34% of ICU-managed patients, with deep venous
thrombosis reported in 16.1% and pulmonary embolism in 12.6% of patients,
despite anticoagulant thromboprophylaxis, and were associated with high
mortality. Studies adopting systematic screening for venous thrombosis with
Duplex ultrasound reported a significantly higher incidence of venous thrombosis
compared to those relying on clinical suspicion (56.3% vs. 11.0%, p < 0.001).
Despite thromboprophylaxis, there is a very high incidence of thrombotic
complications in patients with COVID-19 on the ICU. Systematic screening
identifies many thrombotic complications that would be missed by relying on
clinical suspicion and should be employed, with consideration given to increased
dose anticoagulant thromboprophylaxis, whilst awaiting results of prospective
trials of anticoagulation in this cohort.
DOI: 10.1007/s11239-021-02394-7
PMCID: PMC7882250
PMID: 33586113 [Indexed for MEDLINE]
Conflict of interest statement: The author declares that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33074525 | 1. Cardiovasc Drugs Ther. 2021 Apr;35(2):215-229. doi:
10.1007/s10557-020-07084-9. Epub 2020 Oct 19.
Thrombotic Complications in Patients with COVID-19: Pathophysiological
Mechanisms, Diagnosis, and Treatment.
Gąsecka A(#)(1), Borovac JA(#)(2), Guerreiro RA(3), Giustozzi M(4), Parker W(5),
Caldeira D(6)(7), Chiva-Blanch G(8)(9).
Author information:
(1)1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw,
Poland. [email protected].
(2)Department of Pathophysiology, University of Split School of Medicine, Split,
Croatia.
(3)Cardiology Department, Hospital do Espírito Santo, Évora, Portugal.
(4)Internal Vascular and Emergency Medicine and Stroke Unit, University of
Perugia, Perugia, Italy.
(5)Cardiovascular Research Unit, University of Sheffield, Sheffield, UK.
(6)Centro Cardiovascular da Universidade de Lisboa (CCUL), Faculdade de
Medicina, Univerisdade de Lisboa, Lisbon, Portugal.
(7)Cardiology Department, Hospital Universitário de Santa Maria (CHULN), Avenida
Professor Egas Moniz, 1649-028, Lisbon, Portugal.
(8)Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical
Research Institute (IDIBAPS), Hospital Clínic of Barcelona, Barcelona, Spain.
(9)Spanish Biomedical Research Network in Physiopathology of Obesity and
Nutrition (CIBEROBN), ISCIII, Madrid, Spain.
(#)Contributed equally
INTRODUCTION: Emerging evidence points to an association between severe clinical
presentation of COVID-19 and increased risk of thromboembolism. One-third of
patients hospitalized due to severe COVID-19 develops macrovascular thrombotic
complications, including venous thromboembolism, myocardial injury/infarction
and stroke. Concurrently, the autopsy series indicate multiorgan damage pattern
consistent with microvascular injury.
PROPHYLAXIS, DIAGNOSIS AND TREATMENT: COVID-19 associated coagulopathy has
distinct features, including markedly elevated D-dimers concentration with
nearly normal activated partial thromboplastin time, prothrombin time and
platelet count. The diagnosis may be challenging due to overlapping features
between pulmonary embolism and severe COVID-19 disease, such as dyspnoea, high
concentration of D-dimers, right ventricle with dysfunction or enlargement, and
acute respiratory distress syndrome. Both macro- and microvascular complications
are associated with an increased risk of in-hospital mortality. Therefore, early
recognition of coagulation abnormalities among hospitalized COVID-19 patients
are critical measures to identify patients with poor prognosis, guide
antithrombotic prophylaxis or treatment, and improve patients' clinical
outcomes.
RECOMMENDATIONS FOR CLINICIANS: Most of the guidelines and consensus documents
published on behalf of professional societies focused on thrombosis and
hemostasis advocate the use of anticoagulants in all patients hospitalized with
COVID-19, as well as 2-6 weeks post hospital discharge in the absence of
contraindications. However, since there is no guidance for deciding the
intensity and duration of anticoagulation, the decision-making process should be
made in individual-case basis.
CONCLUSIONS: Here, we review the mechanistic relationships between inflammation
and thrombosis, discuss the macrovascular and microvascular complications and
summarize the prophylaxis, diagnosis and treatment of thromboembolism in
patients affected by COVID-19.
DOI: 10.1007/s10557-020-07084-9
PMCID: PMC7569200
PMID: 33074525 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there are no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34083499 | 1. Blood Res. 2021 Jun 30;56(2):61-64. doi: 10.5045/br.2021.2021011.
Association of hypercoagulation with severe acute respiratory syndrome
coronavirus 2 infection.
Nuthalapati P(1), Ghanta MK(2), Natesh NS(3), L V K S B(4).
Author information:
(1)Sri Ramachandra Medical College and Research Institute, Chennai, India.
(2)MVJ Medical College and Research Hospital, Hoskote, India.
(3)Sathyabama Institute of Science and Technology, Chennai, India.
(4)Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India.
The coronavirus disease 2019 (COVID-19) pandemic has emerged as a major threat
to all healthcare systems across the globe, and it was declared a public health
emergency of international concern by the World Health Organization (WHO). The
novel coronavirus affects the respiratory system, producing symptoms such as
fever, cough, dyspnea, and pneumonia. The association between COVID-19 and
coagulation has been previously reported. Due to several inflammatory changes
that occur in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infections such as alterations in the levels of clotting factors, platelet
activation leads to thrombus formation in coronary and cerebral vessels, leading
to myocardial infarction and cerebrovascular accidents, respectively.
Unfortunately, the progression of hypercoagulability in COVID-19 is rapid in
patients with and without comorbidities. Hence, the proper monitoring of
thrombotic complications in patients with COVID-19 is essential to avoid further
complications. The implementation of guidelines for antithrombotic treatments
based on the presentation of the disease is recommended. This review discusses
the symptoms and mechanisms of upregulated coagulation in patients with
COVID-19.
DOI: 10.5045/br.2021.2021011
PMCID: PMC8246040
PMID: 34083499
Conflict of interest statement: Authors’ Disclosures of Potential Conflicts of
Interest No potential conflicts of interest relevant to this article were
reported. |
http://www.ncbi.nlm.nih.gov/pubmed/32492712 | 1. Blood. 2020 Jul 23;136(4):489-500. doi: 10.1182/blood.2020006520.
COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2
infection.
Al-Samkari H(1)(2), Karp Leaf RS(1)(2), Dzik WH(1)(2), Carlson JCT(1)(2),
Fogerty AE(1)(2), Waheed A(1)(2), Goodarzi K(1)(2), Bendapudi PK(1)(2),
Bornikova L(1)(2), Gupta S(2)(3), Leaf DE(2)(3), Kuter DJ(1)(2), Rosovsky
RP(1)(2).
Author information:
(1)Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA.
(2)Harvard Medical School, Boston, MA; and.
(3)Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.
Comment in
Blood. 2020 Jul 23;136(4):381-383. doi: 10.1182/blood.2020007335.
Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels.
Early reports describe high venous thromboembolism (VTE) and disseminated
intravascular coagulation (DIC) rates, but data are limited. This multicenter
retrospective study describes the rate and severity of hemostatic and thrombotic
complications of 400 hospital-admitted COVID-19 patients (144 critically ill)
primarily receiving standard-dose prophylactic anticoagulation. Coagulation and
inflammatory parameters were compared between patients with and without
coagulation-associated complications. Multivariable logistic models examined the
utility of these markers in predicting coagulation-associated complications,
critical illness, and death. The radiographically confirmed VTE rate was 4.8%
(95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication
rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8%
(95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically
ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI,
3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial
presentation was predictive of coagulation-associated complications during
hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis,
6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]),
critical illness, and death. Additional markers at initial presentation
predictive of thrombosis during hospitalization included platelet count >450 ×
109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100
mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate
(ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen,
ferritin, and procalcitonin were higher in patients with thrombotic
complications than in those without. DIC, clinically relevant thrombocytopenia,
and reduced fibrinogen were rare and were associated with significant bleeding
manifestations. Given the observed bleeding rates, randomized trials are needed
to determine any potential benefit of intensified anticoagulant prophylaxis in
COVID-19 patients.
© 2020 by The American Society of Hematology.
DOI: 10.1182/blood.2020006520
PMCID: PMC7378457
PMID: 32492712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32367170 | 1. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x.
Epub 2020 May 4.
High risk of thrombosis in patients with severe SARS-CoV-2 infection: a
multicenter prospective cohort study.
Helms J(1)(2), Tacquard C(3), Severac F(4), Leonard-Lorant I(5), Ohana M(5),
Delabranche X(3), Merdji H(1)(6), Clere-Jehl R(1)(2), Schenck M(7), Fagot Gandet
F(7), Fafi-Kremer S(2)(8), Castelain V(7), Schneider F(7), Grunebaum L(9),
Anglés-Cano E(10), Sattler L(9), Mertes PM(3), Meziani F(11)(12); CRICS
TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for
Global Evaluation and Research in Sepsis).
Author information:
(1)Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux
universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex,
France.
(2)ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre
de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération
Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle
de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France.
(3)Service d'Anesthésie-Réanimation, Nouvel Hôpital Civil, Hôpitaux
universitaires de Strasbourg, Strasbourg, France.
(4)Groupe Méthodes en Recherche Clinique (GMRC), Hôpital Civil, Hôpitaux
universitaires de Strasbourg, Strasbourg, France.
(5)Radiology Department, Nouvel Hôpital Civil, Strasbourg University Hospital,
Strasbourg, France.
(6)UMR 1260, Regenerative Nanomedicine (RNM), FMTS, INSERM (French National
Institute of Health and Medical Research), Strasbourg, France.
(7)Service de Médecine Intensive Réanimation, Hautepierre, Hôpitaux
universitaires de Strasbourg, Strasbourg, France.
(8)Laboratoire de Virologie Médicale, Hôpitaux universitaires de Strasbourg,
Strasbourg, France.
(9)Laboratoire de d'Hématologie, Hautepierre, Hôpitaux universitaires de
Strasbourg, Strasbourg, France.
(10)Innovative Therapies in Haemostasis, INSERM UMR_S 1140, Université de Paris,
75006, Paris, France.
(11)Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux
universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex,
France. [email protected].
(12)UMR 1260, Regenerative Nanomedicine (RNM), FMTS, INSERM (French National
Institute of Health and Medical Research), Strasbourg, France.
[email protected].
Comment in
Intensive Care Med. 2020 Jul;46(7):1500-1501. doi:
10.1007/s00134-020-06081-8.
J Thromb Haemost. 2020 Oct;18(10):2778. doi: 10.1111/jth.14937.
Cardiol J. 2020;27(5):481-484. doi: 10.5603/CJ.2020.0153.
PURPOSE: Little evidence of increased thrombotic risk is available in COVID-19
patients. Our purpose was to assess thrombotic risk in severe forms of
SARS-CoV-2 infection.
METHODS: All patients referred to 4 intensive care units (ICUs) from two centers
of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due
to COVID-19 between March 3rd and 31st 2020 were included. Medical history,
symptoms, biological data and imaging were prospectively collected. Propensity
score matching was performed to analyze the occurrence of thromboembolic events
between non-COVID-19 ARDS and COVID-19 ARDS patients.
RESULTS: 150 COVID-19 patients were included (122 men, median age 63 [53; 71]
years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic
complications were diagnosed in 150 patients, mainly pulmonary embolisms
(16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy
experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of
centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients
(> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated
intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII
were considerably increased, and 50/57 tested patients (87.7%) had positive
lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145)
confirmed that COVID-19 ARDS patients (n = 77) developed significantly more
thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p < 0.008).
Coagulation parameters significantly differed between the two groups.
CONCLUSION: Despite anticoagulation, a high number of patients with ARDS
secondary to COVID-19 developed life-threatening thrombotic complications.
Higher anticoagulation targets than in usual critically ill patients should
therefore probably be suggested.
DOI: 10.1007/s00134-020-06062-x
PMCID: PMC7197634
PMID: 32367170 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interest to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/32291094 | 1. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub
2020 Apr 10.
Incidence of thrombotic complications in critically ill ICU patients with
COVID-19.
Klok FA(1), Kruip MJHA(2), van der Meer NJM(3), Arbous MS(4), Gommers DAMPJ(5),
Kant KM(6), Kaptein FHJ(7), van Paassen J(4), Stals MAM(7), Huisman MV(7),
Endeman H(5).
Author information:
(1)Department of Thrombosis and Hemostasis, Leiden University Medical Center,
Leiden, the Netherlands. Electronic address: [email protected].
(2)Department of Haematology, Erasmus University Medical Center, Rotterdam, the
Netherlands.
(3)Department of Anesthesiology and Critical Care, Amphia Hospital Breda and
Oosterhout the Netherlands and TIAS/Tilburg University, Tilburg, the
Netherlands.
(4)Department of Intensive Care Medicine, Leiden University Medical Center,
Leiden, the Netherlands.
(5)Department of Adult Intensive Care, Erasmus Medical Center, Rotterdam, the
Netherlands.
(6)Department of Intensive Care, Amphia Hospital, Breda, the Netherlands.
(7)Department of Thrombosis and Hemostasis, Leiden University Medical Center,
Leiden, the Netherlands.
Comment in
Thromb Res. 2020 Jun;190:102. doi: 10.1016/j.thromres.2020.04.021.
Thromb Res. 2020 Jul;191:29. doi: 10.1016/j.thromres.2020.04.023.
Thromb Res. 2020 Jul;191:36-37. doi: 10.1016/j.thromres.2020.04.022.
Thromb Res. 2020 Jul;191:152. doi: 10.1016/j.thromres.2020.04.045.
Thromb Res. 2020 Jul;191:151. doi: 10.1016/j.thromres.2020.04.042.
Thromb Res. 2020 Jul;191:56. doi: 10.1016/j.thromres.2020.04.032.
Thromb Res. 2020 Jul;191:76-77. doi: 10.1016/j.thromres.2020.04.028.
Thromb Res. 2020 Aug;192:75-77. doi: 10.1016/j.thromres.2020.05.025.
Intern Emerg Med. 2020 Aug;15(5):893-895. doi: 10.1007/s11739-020-02393-1.
Thromb Res. 2020 Sep;193:77. doi: 10.1016/j.thromres.2020.06.006.
Thromb Res. 2020 Sep;193:78. doi: 10.1016/j.thromres.2020.05.019.
Curr Cardiol Rep. 2020 Jun 17;22(7):53. doi: 10.1007/s11886-020-01328-8.
Swiss Med Wkly. 2020 Jun 22;150:w20304. doi: 10.4414/smw.2020.20304.
J Clin Anesth. 2020 Dec;67:109976. doi: 10.1016/j.jclinane.2020.109976.
Thromb Res. 2020 Dec;196:1-3. doi: 10.1016/j.thromres.2020.07.035.
JCO Oncol Pract. 2021 Sep;17(9):522-523. doi: 10.1200/OP.21.00359.
Thromb Res. 2022 Feb;210:6-11. doi: 10.1016/j.thromres.2021.12.015.
Dataset use reported in
Thromb Res. 2020 Jul;191:153-155. doi: 10.1016/j.thromres.2020.04.046.
INTRODUCTION: COVID-19 may predispose to both venous and arterial
thromboembolism due to excessive inflammation, hypoxia, immobilisation and
diffuse intravascular coagulation. Reports on the incidence of thrombotic
complications are however not available.
METHODS: We evaluated the incidence of the composite outcome of symptomatic
acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial
infarction or systemic arterial embolism in all COVID-19 patients admitted to
the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.
RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23
died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU
on April 5th 2020. All patients received at least standard doses
thromboprophylaxis. The cumulative incidence of the composite outcome was 31%
(95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI
17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most
frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR)
1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous
prolongation of the prothrombin time > 3 s or activated partial thromboplastin
time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic
complications.
CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with
COVID-19 infections is remarkably high. Our findings reinforce the
recommendation to strictly apply pharmacological thrombosis prophylaxis in all
COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing
the prophylaxis towards high-prophylactic doses, even in the absence of
randomized evidence.
Copyright © 2020. Published by Elsevier Ltd.
DOI: 10.1016/j.thromres.2020.04.013
PMCID: PMC7146714
PMID: 32291094 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures Frederikus Klok reports research
grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo,
MSD and Actelion, the Dutch Heart foundation and the Dutch Thrombosis
association, all outside the submitted work. Menno Huisman reports grants from
ZonMW Dutch Healthcare Fund, and grants and personal fees from
Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen, Daiichi-Sankyo, all
outside the submitted work. Marieke Kruip reports unrestricted research grants
from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer, Sobi, and The
Netherlands Organisation for Health Research and Development (ZonMW). The other
authors having nothing to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/34231186 | 1. Neurocrit Care. 2022 Feb;36(1):259-265. doi: 10.1007/s12028-021-01297-y. Epub
2021 Jul 6.
Intracerebral Hemorrhage and Coronavirus Disease 2019 in a Cohort of 282,718
Hospitalized Patients.
Qureshi AI(1), Baskett WI(2), Huang W(1), Myers D(3), Lobanova I(4), Ishfaq
MF(1), Naqvi SH(5), French BR(1), Chandrasekaran PN(1), Siddiq F(6), Gomez
CR(1), Shyu CR(2)(5)(7).
Author information:
(1)Zeenat Qureshi Stroke Insititutes and Department of Neurology, University of
Missouri, One Hospital Dr. CE507, Columbia, MO, USA.
(2)Institute for Data Science and Informatics, University of Missouri, Columbia,
MO, USA.
(3)Tiger Institute for Health Innovation, Cerner Corporation, Columbia, MO, USA.
(4)Zeenat Qureshi Stroke Insititutes and Department of Neurology, University of
Missouri, One Hospital Dr. CE507, Columbia, MO, USA. [email protected].
(5)Department of Medicine, University of Missouri, Columbia, MO, USA.
(6)Division of Neurosurgery, University of Missouri, Columbia, MO, USA.
(7)Department of Electrical Engineering and Computer Science, University of
Missouri, Columbia, MO, USA.
BACKGROUND: To identify whether the risk of intracerebral hemorrhage is higher
in patients with coronavirus disease 2019 (COVID-19), we compared the risk
factors, comorbidities, and outcomes in patients intracerebral hemorrhage and
COVID-19 and those without COVID-19.
METHODS: We analyzed the data from the Cerner deidentified COVID-19 data set
derived from 62 health care facilities. The data set included patients with an
emergency department or inpatient encounter with discharge diagnoses codes that
could be associated with suspicion of or exposure to COVID-19 or confirmed
COVID-19.
RESULTS: There were a total of 154 (0.2%) and 667 (0.3%) patients with
intracerebral hemorrhage among 85,645 patients with COVID-19 and 197,073
patients without COVID-19, respectively. In the multivariate model, there was a
lower risk of intracerebral hemorrhage in patients with COVID-19 (odds ratio
0.5; 95% confidence interval 0.5-0.6; p < .0001) after adjustment for sex, age
strata, race/ethnicity, hypertension, diabetes mellitus, nicotine
dependence/tobacco use, hyperlipidemia, atrial fibrillation, congestive heart
failure, long-term anticoagulant use, and alcohol abuse. The proportions of
patients who developed pneumonia (58.4% versus 22.5%; p < .0001), acute kidney
injury (48.7% versus 31.0%; p < .0001), acute myocardial infarction (11% versus
6.4%; p = .048), sepsis (41.6% versus 22.5%; p < .0001), and respiratory failure
(61.7% versus 42.3%; p < .0001) were significantly higher among patients with
intracerebral hemorrhage and COVID-19 compared with those without COVID-19. The
in-hospital mortality among patients with intracerebral hemorrhage and COVID-19
was significantly higher compared with that among those without COVID-19 (40.3%
versus 19.0%; p < .0001).
CONCLUSIONS: Our analysis does not suggest that rates of intracerebral
hemorrhage are higher in patients with COVID-19. The higher mortality in
patients with intracerebral hemorrhage and COVID-19 compared with those without
COVID-19 is likely mediated by higher frequency of comorbidities and adverse
in-hospital events.
© 2021. Springer Science+Business Media, LLC, part of Springer Nature and
Neurocritical Care Society.
DOI: 10.1007/s12028-021-01297-y
PMCID: PMC8260011
PMID: 34231186 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34047936 | 1. J Thromb Thrombolysis. 2022 Jan;53(1):231-234. doi:
10.1007/s11239-021-02461-z. Epub 2021 May 28.
Increased incidence of massive hemorrhage at uncommon sites after initiation of
systemic anticoagulation in critically ill patients with coronavirus disease
2019 (COVID-19) infection.
Koubaissi SA(1), Daou MAZ(1), Mohamad R(1), Husari A(2).
Author information:
(1)Pulmonary and Critical Care Division, Department of Internal Medicine,
American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236,
Beirut, 1107 2020, Lebanon.
(2)Pulmonary and Critical Care Division, Department of Internal Medicine,
American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-236,
Beirut, 1107 2020, Lebanon. [email protected].
BACKGROUND: The management of the Coronavirus disease 2019 (COVID-19) infected
patients continues to be challenging. Critically ill COVID patients are at
increased risk of serious thrombotic events and hence increased mortality. On
the other side, COVID-19 patients are also showing major life-threatening
bleeds, especially when systemic anticoagulation is used. Pro-coagulant
propensity in critically ill COVID-19 patients have been published, but very few
have described the incidence of major bleeding and its characteristics.
METHODS: In this study, we retrospectively observed the incidence of major bleed
in 25 critically ill COVID-19 patients admitted to the Intensive Care Unit at
the American University of Beirut Medical Center. Six cases were identified and
described together with their outcome.
RESULTS: Major bleeding occurred in six of the 25 studied patients. Four
patients were on therapeutic anticoagulation at the onset of the bleed, two
required embolization for bleeding control and one died from hemorrhagic shock.
Half of the described cases had unusual sites of bleeding including gluteal and
abdominal wall muscles.
CONCLUSIONS: A high rate of major bleeding was witnessed in our sample of
critically ill patients with COVID-19 infection, with the majority being on
therapeutic anticoagulation. This rate may be higher than previously reported,
necessitating additional attention from the treating physician when considering
empiric therapeutic anticoagulation. Moreover, the uncommon sites of bleeding
shed the light on the need for additional studies in our population to identify
the predisposing risk factors and mechanisms behind it.
© 2021. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s11239-021-02461-z
PMCID: PMC8159717
PMID: 34047936 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial and
non-financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/32948243 | 1. Crit Care. 2020 Sep 18;24(1):561. doi: 10.1186/s13054-020-03260-3.
Thrombotic and haemorrhagic complications in critically ill patients with
COVID-19: a multicentre observational study.
Shah A(1)(2), Donovan K(3), McHugh A(4), Pandey M(5), Aaron L(3), Bradbury
CA(6), Stanworth SJ(7)(8), Alikhan R(9), Von Kier S(10), Maher K(10), Curry
N(8)(11), Shapiro S(8)(11), Rowland MJ(3)(12), Thomas M(4), Mason R(4), Holland
M(4), Holmes T(5), Ware M(5), Gurney S(13), McKechnie SR(3).
Author information:
(1)Radcliffe Department of Medicine, Level 4 Academic Block, University of
Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
[email protected].
(2)Adult Intensive Care Unit, John Radcliffe Hospital, Oxford University
Hospitals NHS Foundation Trust, Oxford, UK. [email protected].
(3)Adult Intensive Care Unit, John Radcliffe Hospital, Oxford University
Hospitals NHS Foundation Trust, Oxford, UK.
(4)Intensive Care Unit, North Bristol NHS Trust, Bristol, UK.
(5)Adult Intensive Care Unit, University Hospital of Wales, Cardiff, Wales, UK.
(6)Faculty of Health Sciences, University of Bristol, Bristol, UK.
(7)Radcliffe Department of Medicine, Level 4 Academic Block, University of
Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
(8)Haematology Theme, NIHR Oxford Biomedical Research Centre, Oxford, UK.
(9)Haemostasis and Thrombosis, Department of Haematology, University Hospital of
Wales, Cardiff, UK.
(10)Blood Management and Conservation Service, Oxford University Hospitals NHS
Foundation Trust, Oxford, UK.
(11)Oxford Haemophilia & Thrombosis Centre, Department of Haematology, Churchill
Hospital, Oxford University Hospitals NHS Foundation, Oxford, UK.
(12)Kadoorie Centre for Critical Care Research, Nuffield Department of Clinical
Neurosciences, University of Oxford, Oxford, UK.
(13)Intensive Care Unit, Bristol Royal Infirmary, University Hospitals Bristol
NHS Trust, Bristol, UK.
BACKGROUND: Optimal prophylactic and therapeutic management of thromboembolic
disease in patients with COVID-19 remains a major challenge for clinicians. The
aim of this study was to define the incidence of thrombotic and haemorrhagic
complications in critically ill patients with COVID-19. In addition, we sought
to characterise coagulation profiles using thromboelastography and explore
possible biological differences between patients with and without thrombotic
complications.
METHODS: We conducted a multicentre retrospective observational study evaluating
all the COVID-19 patients received in four intensive care units (ICUs) of four
tertiary hospitals in the UK between March 15, 2020, and May 05, 2020. Clinical
characteristics, laboratory data, thromboelastography profiles and clinical
outcome data were evaluated between patients with and without thrombotic
complications.
RESULTS: A total of 187 patients were included. Their median (interquartile
(IQR)) age was 57 (49-64) years and 124 (66.3%) patients were male. Eighty-one
(43.3%) patients experienced one or more clinically relevant thrombotic
complications, which were mainly pulmonary emboli (n = 42 (22.5%)). Arterial
embolic complications were reported in 25 (13.3%) patients. ICU length of stay
was longer in patients with thrombotic complications when compared with those
without. Fifteen (8.0%) patients experienced haemorrhagic complications, of
which nine (4.8%) were classified as major bleeding. Thromboelastography
demonstrated a hypercoagulable profile in patients tested but lacked
discriminatory value between those with and without thrombotic complications.
Patients who experienced thrombotic complications had higher D-dimer, ferritin,
troponin and white cell count levels at ICU admission compared with those that
did not.
CONCLUSION: Critically ill patients with COVID-19 experience high rates of
venous and arterial thrombotic complications. The rates of bleeding may be
higher than previously reported and re-iterate the need for randomised trials to
better understand the risk-benefit ratio of different anticoagulation
strategies.
DOI: 10.1186/s13054-020-03260-3
PMCID: PMC7499016
PMID: 32948243 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/32381264 | 1. Thromb Res. 2020 Jul;191:148-150. doi: 10.1016/j.thromres.2020.04.041. Epub
2020 Apr 30.
Confirmation of the high cumulative incidence of thrombotic complications in
critically ill ICU patients with COVID-19: An updated analysis.
Klok FA(1), Kruip MJHA(2), van der Meer NJM(3), Arbous MS(4), Gommers D(5), Kant
KM(6), Kaptein FHJ(7), van Paassen J(4), Stals MAM(7), Huisman MV(7), Endeman
H(5).
Author information:
(1)Department of Thrombosis and Hemostasis, Leiden University Medical Center,
Leiden, the Netherlands. Electronic address: [email protected].
(2)Department of Hematology, Erasmus University Medical Center, Rotterdam, the
Netherlands.
(3)Department of Anesthesiology and Critical Care, Amphia Hospital Breda,
Oosterhout, the Netherlands; TIAS/Tilburg University Tilburg, the Netherlands.
(4)Department of Intensive Care Medicine, Leiden University Medical Center,
Leiden, the Netherlands.
(5)Department of Adult Intensive Care, Erasmus Medical Center, Rotterdam, the
Netherlands.
(6)Department of Intensive Care, Amphia Hospital, Breda, the Netherlands.
(7)Department of Thrombosis and Hemostasis, Leiden University Medical Center,
Leiden, the Netherlands.
Comment in
Thromb Res. 2020 Sep;193:22-24. doi: 10.1016/j.thromres.2020.05.050.
Am J Respir Crit Care Med. 2020 Aug 1;202(3):455-457. doi:
10.1164/rccm.202005-1654LE.
Thromb Res. 2020 Sep;193:77. doi: 10.1016/j.thromres.2020.06.006.
Thromb Res. 2020 Sep;193:78. doi: 10.1016/j.thromres.2020.05.019.
INTRODUCTION: We recently reported a high cumulative incidence of thrombotic
complications in critically ill patients with COVID-19 admitted to the intensive
care units (ICUs) of three Dutch hospitals. In answering questions raised
regarding our study, we updated our database and repeated all analyses.
METHODS: We re-evaluated the incidence of the composite outcome of symptomatic
acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial
infarction and/or systemic arterial embolism in all COVID-19 patients admitted
to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from
ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.
RESULTS: We studied the same 184 ICU patients as reported on previously, of whom
a total of 41 died (22%) and 78 were discharged alive (43%). The median
follow-up duration increased from 7 to 14 days. All patients received
pharmacological thromboprophylaxis. The cumulative incidence of the composite
outcome, adjusted for competing risk of death, was 49% (95% confidence interval
[CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the
competing risk model, chronic anticoagulation therapy at admission was
associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29,
95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at
higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic
anticoagulation was not associated with all-cause death (HR 0.79, 95%CI
0.35-1.8).
CONCLUSION: In this updated analysis, we confirm the very high cumulative
incidence of thrombotic complications in critically ill patients with COVID-19
pneumonia.
Copyright © 2020. Published by Elsevier Ltd.
DOI: 10.1016/j.thromres.2020.04.041
PMCID: PMC7192101
PMID: 32381264 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest Frederikus
Klok reports research grants from Bayer, Bristol-Myers Squibb,
Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart
foundation and the Dutch Thrombosis association, all outside the submitted work.
Menno Huisman reports grants from ZonMW Dutch Healthcare Fund, and grants and
personal fees from Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen,
Daiichi-Sankyo, all outside the submitted work. Marieke Kruip reports
unrestricted research grants from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo,
Pfizer, Sobi, and The Netherlands Organisation for Health Research and
Development (ZonMW). The other authors having nothing to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/33036855 | 1. Am J Emerg Med. 2021 Jan;39:213-218. doi: 10.1016/j.ajem.2020.09.065. Epub
2020 Oct 1.
Thrombotic complications of COVID-19.
Avila J(1), Long B(2), Holladay D(3), Gottlieb M(4).
Author information:
(1)Department of Emergency Medicine University of Kentucky, United States of
America.
(2)Department of Emergency Medicine Brooke Army Medical Center, United States of
America.
(3)Department of Emergency Medicine Rush University Medical Center, United
States of America.
(4)Department of Emergency Medicine Rush University Medical Center, United
States of America. Electronic address: [email protected].
INTRODUCTION: The novel coronavirus disease of 2019 (COVID-19) is associated
with significant morbidity and mortality. The impact of thrombotic complications
has been increasingly recognized as an important component of this disease.
OBJECTIVE: This narrative review summarizes the thrombotic complications
associated with COVID-19 with an emphasis on information for Emergency Medicine
clinicians.
DISCUSSION: Thrombotic complications from COVID-19 are believed to be due to a
hyperinflammatory response caused by the virus. Several complications have been
described in the literature. These include acute limb ischemia, abdominal and
thoracic aortic thrombosis, mesenteric ischemia, myocardial infarction, venous
thromboembolism, acute cerebrovascular accident, and disseminated intravascular
coagulation.
CONCLUSION: It is important for Emergency Medicine clinicians to be aware of the
thrombotic complications of COVID-19. Knowledge of these components are
essential to rapidly recognize and treat to reduce morbidity and mortality in
these patients.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ajem.2020.09.065
PMCID: PMC7528743
PMID: 33036855 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/33577800 | 1. Am Heart J. 2021 May;235:12-23. doi: 10.1016/j.ahj.2021.02.001. Epub 2021 Feb
9.
Rationale and design for the study of rivaroxaban to reduce thrombotic events,
hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.
Capell WH(1), Barnathan ES(2), Piazza G(3), Spyropoulos AC(4), Hsia J(5), Bull
S(2), Lipardi C(2), Sugarmann C(2), Suh E(2), Rao JP(6), Hiatt WR(5), Bonaca
MP(5).
Author information:
(1)CPC Clinical Research, Aurora, CO; Division of Endocrinology, Diabetes, and
Metabolism, Department of Medicine, University of Colorado Anschutz Medical
Campus, Aurora, CO. Electronic address: [email protected].
(2)Janssen Research and Development LLC, Raritan, NJ.
(3)Division of Cardiovascular Medicine, Department of Medicine, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA.
(4)Donald and Barbara Zucker School of Medicine at Hofstra/Northwell,
Huntington, NY; Institute for Health Innovation and Outcomes Research, Feinstein
Institutes for Medical Research, Manhasset, NY; Department of Medicine,
Northwell Health at Lenox Hill Hospital, New York, NY.
(5)CPC Clinical Research, Aurora, CO; Division of Cardiology, Department of
Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
(6)REDCap Cloud, Encinitas, CA.
BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic
complications. While prophylactic anticoagulation is now widely recommended for
hospitalized patients with COVID-19, the effectiveness and safety of
thromboprophylaxis in outpatients with COVID-19 has not been established.
STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic,
event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in
symptomatic outpatients with laboratory-confirmed COVID-19 at risk for
thrombotic events, hospitalization, and death. Several challenges posed by the
pandemic have necessitated innovative approaches to clinical trial design,
start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by
time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or
placebo for 35 days. The primary efficacy end point is a composite of
symptomatic venous thromboembolism, myocardial infarction, ischemic stroke,
acute limb ischemia, non-central nervous system systemic embolization, all-cause
hospitalization, and all-cause mortality. The primary safety end point is fatal
and critical site bleeding according to the International Society on Thrombosis
and Haemostasis definition. Enrollment began in August 2020 and is expected to
enroll approximately 4,000 participants to yield the required number of end
point events.
CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety
of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce
major venous and arterial thrombotic events, hospitalization, and mortality
associated with COVID-19.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ahj.2021.02.001
PMCID: PMC7871775
PMID: 33577800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32586214 | 1. Circ Res. 2020 Jul 31;127(4):571-587. doi: 10.1161/CIRCRESAHA.120.317447. Epub
2020 Jun 26.
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic
Implications.
McFadyen JD(#)(1)(2)(3), Stevens H(#)(1)(2)(3), Peter K(4)(3).
Author information:
(1)From the Atherothrombosis and Vascular Biology Program, Baker Heart and
Diabetes Institute, Melbourne, Victoria, Australia (J.D.M., H.S., K.P.).
(2)Clinical Hematology Department (J.D.M., H.S.), Alfred Hospital, Melbourne,
Victoria, Australia.
(3)Department of Medicine, Monash University, Melbourne, Victoria, Australia
(J.D.M., H.S., K.P.).
(4)Department of Cardiology (K.P.), Alfred Hospital, Melbourne, Victoria,
Australia.
(#)Contributed equally
The recent emergence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of
unprecedented magnitude. Recent clinical data has highlighted that coronavirus
disease 2019 (COVID-19) is associated with a significant risk of thrombotic
complications ranging from microvascular thrombosis, venous thromboembolic
disease, and stroke. Importantly, thrombotic complications are markers of severe
COVID-19 and are associated with multiorgan failure and increased mortality. The
evidence to date supports the concept that the thrombotic manifestations of
severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells
via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the
endothelial cell surface. However, in patients with COVID-19 the subsequent
endothelial inflammation, complement activation, thrombin generation, platelet,
and leukocyte recruitment, and the initiation of innate and adaptive immune
responses culminate in immunothrombosis, ultimately causing (micro)thrombotic
complications, such as deep vein thrombosis, pulmonary embolism, and stroke.
Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer)
and thrombocytopenia have emerged as prognostic markers in COVID-19. Given
thrombotic complications are central determinants of the high mortality rate in
COVID-19, strategies to prevent thrombosis are of critical importance. Several
antithrombotic drugs have been proposed as potential therapies to prevent
COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic
drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic
anti-inflammatory or antiviral effects. The growing awareness and mechanistic
understanding of the prothrombotic state of COVID-19 patients are driving
efforts to more stringent diagnostic screening for thrombotic complications and
to the early institution of antithrombotic drugs, for both the prevention and
therapy of thrombotic complications. The shifting paradigm of diagnostic and
treatment strategies holds significant promise to reduce the burden of
thrombotic complications and ultimately improve the prognosis for patients with
COVID-19.
DOI: 10.1161/CIRCRESAHA.120.317447
PMCID: PMC7386875
PMID: 32586214 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33296828 | 1. Clin Imaging. 2021 Apr;72:178-182. doi: 10.1016/j.clinimag.2020.11.030. Epub
2020 Nov 14.
Acute myocardial infarction secondary to COVID-19 infection: A case report and
review of the literature.
Capaccione KM(1), Leb JS(2), D'souza B(2), Utukuri P(2), Salvatore MM(2).
Author information:
(1)Department of Radiology, Columbia University Irving Medical Center, New York,
NY, United States of America. Electronic address: [email protected].
(2)Department of Radiology, Columbia University Irving Medical Center, New York,
NY, United States of America.
BACKGROUND: Thrombotic complications of COVID-19 infection have become
increasingly apparent as the disease has infected a growing number of
individuals. Although less common than upper respiratory symptoms, thrombotic
complications are not infrequent and may result in severe and long-term
sequelae. Common thrombotic complications include pulmonary embolism, cerebral
infarction, or venous thromboembolism; less commonly seen are acute myocardial
injury, renal artery thrombosis, and mesenteric ischemia. Several case reports
and case series have described acute myocardial injury in patients with COVID-19
characterized by elevations in serum biomarkers.
CASE REPORT: Here, we report the first case to our knowledge of a patient with
acute coronary syndrome confirmed on catheter angiography and cardiac MRI. This
patient was found to additionally have a left ventricular thrombus and
ultimately suffered an acute cerebral infarction. Recognition of thrombotic
complications in the setting of COVID-19 infection is essential for initiating
appropriate therapy.
CONCLUSIONS: In acute myocardial injury, given the different treatment
strategies for myocarditis versus acute myocardial infarction secondary to
coronary artery thrombus, imaging can play a key role in clinical decision
making for patients.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.clinimag.2020.11.030
PMCID: PMC7666611
PMID: 33296828 [Indexed for MEDLINE]
Conflict of interest statement: Mary M. Salvatore - Speaker and consultant:
Genentech, Boehringer Ingelheim. Grant funding: Genentech, Boehringer Ingelheim.
The remaining authors have no conflicts to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/32924567 | 1. J Cardiovasc Pharmacol Ther. 2021 Jan;26(1):12-24. doi:
10.1177/1074248420958973. Epub 2020 Sep 14.
COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and
Thromboembolism/Prophylactic and Therapeutic Management.
Manolis AS(1), Manolis TA(2), Manolis AA(3), Papatheou D(4), Melita H(4).
Author information:
(1)First Department of Cardiology, Athens University School of Medicine, Athens,
Greece.
(2)Red Cross Hospital, Athens, Greece.
(3)Patras University School of Medicine, Patras, Greece.
(4)Onassis Cardiac Surgery Center, Athens, Greece.
Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous
thrombosis commonly complicating the clinical course of hospitalized patients
and attributed to the inflammatory state, endothelial dysfunction, platelet
activation and blood stasis. This viral coagulopathy may occur despite
thromboprophylaxis and raises mortality; the risk appears highest among
critically ill inpatients monitored in the intensive care unit. The prevalence
of venous thromboembolism in COVID-19 patients has been reported to reach
∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic
complication is pulmonary embolism, which though may occur in the absence of a
recognizable deep venous thrombosis and may be due to pulmonary arterial
thrombosis rather than embolism, resulting in thrombotic occlusion of small- to
mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This
micro-thrombotic pattern seems more specific for COVID-19 and is associated with
an intense immuno-inflammatory reaction that results in diffuse occlusive
thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis.
Furthermore, thrombosis has also been observed in various arterial sites,
including coronary, cerebral and peripheral arteries. Biomarkers related to
coagulation, platelet activation and inflammation have been suggested as useful
diagnostic and prognostic tools for COVID-19-associated coagulopathy; among
them, D-dimer remains a key biomarker employed in clinical practice. Various
medical societies have issued guidelines or consensus statements regarding
thromboprophylaxis and treatment of these thrombotic complications specifically
adapted to COVID-19 patients. All these issues are detailed in this review, data
from meta-analyses and current guidelines are tabulated, while the relevant
mechanisms of this virus-associated coagulopathy are pictorially illustrated.
DOI: 10.1177/1074248420958973
PMCID: PMC7492826
PMID: 32924567 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/32947478 | 1. Cardiol Rev. 2021 Jan/Feb;29(1):43-47. doi: 10.1097/CRD.0000000000000347.
Thrombotic Complications of COVID-19 Infection: A Review.
Castro RA(1), Frishman WH(2).
Author information:
(1)From the New York Medical College, Valhalla, NY.
(2)Department of Medicine, New York Medical College/Westchester Medical Center,
Valhalla, NY.
The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]),
also known as COVID-19, is a single-stranded enveloped RNA virus that created a
Public Health Emergency of International Concern in January 2020, with a global
case burden of over 15 million in just 7 months. Infected patients develop a
wide range of clinical manifestations-typically presenting with fever, cough,
myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory
distress syndrome, acute heart injuries, neurological manifestations, or
complications due to secondary infections. These critically ill patients are
also found to have disrupted coagulation function, predisposing them to
consumptive coagulopathies, and both venous and thromboembolic complications.
Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin
degradation products, and fibrinogen, all of which have been associated with
greater disease severity. Many cases of pulmonary embolism have been noted,
along with deep vein thrombosis, ischemic stroke, myocardial infarction, and
systemic arterial embolism. The pathogenesis of coronavirus has not been
completely elucidated, but the virus is known to cause excessive inflammation,
endothelial injury, hypoxia, and disseminated intravascular coagulation, all of
which contribute to thrombosis formation. These patients are also faced with
prolonged immobilization while staying in the hospital or intensive care unit.
It is important to have a high degree of suspicion for thrombotic complications
as patients may rapidly deteriorate in severe cases. Evidence suggests that
prophylaxis with anticoagulation may lead to a lower risk of mortality, although
it does not eliminate the possibility. The risks and benefits of anticoagulation
treatment should be considered in each case. Patients should be regularly
evaluated for bleeding risks and thrombotic complications.
DOI: 10.1097/CRD.0000000000000347
PMID: 32947478 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35957796 | 1. Clin Case Rep. 2022 Aug 8;10(8):e6143. doi: 10.1002/ccr3.6143. eCollection
2022 Aug.
Coronavirus disease 19 (COVID-19) and Cerebral venous sinus thrombosis (CVST): A
case series and review of the literature.
Kallel N(1), Saidani A(1), Kotti A(1), Moussa N(1), Maddeh S(1), Gargouri R(1),
Msaad S(1), Feki W(1).
Author information:
(1)Department of Pneumology, Hedi Chaker University Hospital Sfax Tunisia.
A large proportion of patients with coronavirus disease 19 (COVID-19) suffer
from excessive coagulation activation and coagulopathy which predisposes them to
a wide spectrum of thrombotic events including in situ pulmonary thrombosis,
deep-vein thrombosis, and associated pulmonary embolism, as well as arterial
thrombotic events. Cerebral venous sinus thrombosis (CVST) have also been
reported but in a very small number of cases. This report aims to increase
awareness about CVST as a potential neurological thromboembolic complication in
patients with coronavirus disease. We report three COVID-19 patients presenting
with CVTS. We also review all previously described cases and present an overview
of their demographic, clinical, and diagnostic data. We describe three patients
with concomitant coronavirus disease and CVST among 1000 hospitalized COVID-19
patients (2 males, 1female, and mean age of 37 years). One patient was
previously healthy, while the two others had a history of chronic anemia and
ulcerative colitis, respectively. CVST symptoms including seizure in two
patients and headache in one patient occurred day to weeks after the onset of
COVID-19 symptoms. Three months of anticoagulant therapy was given for all three
patients with favorable outcomes. No neurological sequelae and no recurrence
occurred within 6 months after hospital discharge. Our search identified 33
cases of COVID-19 complicated by CVST. The mean age was 45.3 years, there was a
slight male predominance (60%), and more than half of cases were diagnosed in
previously healthy individuals. All cases of CVT were clinically symptomatic and
were observed in patients with a different spectrum of coronavirus disease
severity. Headache was the most common complaint, reported by just less than
half of patients. There was a high mortality rate (30.3%). CVT is a very rare,
but potentially life-threatening complication in patients with COVID-19. It's
mainly reported in relatively young individuals with no or little comorbid
disease and can occur even in patients who do not display severe respiratory
symptoms. Atypical clinical presentations may pose a challenge to the early
diagnosis and treatment. High suspicion is necessary as early diagnosis and
prompt treatment with anticoagulation in all patients with COVID-19 and CVT
could contain the mortality rate and improve neurological outcomes in these
patients.
© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
DOI: 10.1002/ccr3.6143
PMCID: PMC9359113
PMID: 35957796
Conflict of interest statement: The authors do not have any conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36289613 | 1. Biomedicines. 2022 Sep 21;10(10):2354. doi: 10.3390/biomedicines10102354.
Arterial Thrombotic Complications in COVID-19: A Case of Renal Infarction.
Mancini M(1)(2), Randazzo G(1)(2), Piazza G(3), Dal Moro F(1)(2).
Author information:
(1)Urological Clinic, University Hospital of Padova, 35121 Padova, Italy.
(2)Department of Surgical, Oncological and Gastroenterological Sciences,
University of Padova, 35121 Padova, Italy.
(3)Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA 02115, USA.
COVID-19 infection has been associated with thrombotic complications, especially
venous thromboembolism. Although arterial thrombotic complications are rarely
seen in these patients, we report the case of a 43-year-old patient who
developed thrombosis of the main branch of the left renal artery, causing
partial infarction of the left kidney associated with severe pain. He had no
risk factors for thrombosis except for COVID-19 infection. We excluded any
possible condition usually associated with renal artery thrombosis/embolism
(i.e., cardiovascular, oncological, hematological, or rheumatic). The thrombosis
resolved after a combination of anticoagulant and anti-platelet therapy. This
case highlights the importance of the risk of recurrence of thrombosis in
patients with a recent history of COVID-19, even after hospital discharge,
improvement of the initial thrombotic event, and clearance of SARS-CoV-2
infection.
DOI: 10.3390/biomedicines10102354
PMCID: PMC9598528
PMID: 36289613
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33074732 | 1. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620962853. doi:
10.1177/1076029620962853.
COVID-19 and Hypercoagulability: A Review.
Kichloo A(1)(2), Dettloff K(2), Aljadah M(3), Albosta M(2), Jamal S(1)(2), Singh
J(4), Wani F(5), Kumar A(6), Vallabhaneni S(7), Khan MZ(8).
Author information:
(1)St. Mary's of Saginaw Hospital, Saginaw, MI, USA.
(2)Central Michigan University College of Medicine, Saginaw, MI, USA.
(3)Medical College of Wisconsin Affiliated Hospitals, Milwaukee, WI, USA.
(4)Geisinger Commonwealth School of Medicine, Scranton, PA, USA.
(5)Samaritan Medical Center, Watertown, NY, USA.
(6)University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
(7)St. Luke's University School of Medicine, Bethlehem, PA, USA.
(8)West Virginia University School of Medicine, Morgantown, WV, USA.
Thrombotic complications of the novel coronavirus (COVID-19) are a concerning
aspect of the disease, due to the high incidence in critically ill patients and
poor clinical outcomes. COVID-19 predisposes patients to a hypercoagulable
state, however, the pathophysiology behind the thrombotic complications seen in
this disease is not well understood. Several mechanisms have been proposed and
the pathogenesis likely involves a host immune response contributing to vascular
endothelial cell injury, inflammation, activation of the coagulation cascade via
tissue factor expression, and shutdown of fibrinolysis. Treatments targeting
these pathways may need to be considered to improve clinical outcomes and
decrease overall mortality due to thrombotic complications. In this review, we
will discuss the proposed pathophysiologic mechanisms for thrombotic
complications in COVID-19, as well as treatment strategies for these
complications based on the current literature available.
DOI: 10.1177/1076029620962853
PMCID: PMC7592310
PMID: 33074732 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/33659138 | 1. Cureus. 2021 Jan 30;13(1):e13007. doi: 10.7759/cureus.13007.
Diagnosis of Stroke on Neuroimaging of COVID-19 Patients in Coma: A Case Series.
Vegunta R(1), Vegunta R(2), Rokkam VR(3), Kutti Sridharan G(4)(5).
Author information:
(1)Internal Medicine, Westchester Medical Center, Valhalla, USA.
(2)Oncology, University of North Dakota, Fargo, USA.
(3)Inpatient Medicine, Banner University Medical Center, University of Arizona,
Tucson, USA.
(4)Internal Medicine, Banner University Medical Center, University of Arizona,
Tucson, USA.
(5)Internal Medicine, University of Arizona, Tucson, USA.
Patients with severe coronavirus disease 2019 (COVID-19) disease suffer from
many thrombotic complications including deep vein thrombosis, pulmonary
embolism, myocardial infarction (MI), and stroke. Large vessel strokes have been
reported in young patients with COVID-19 disease. We report four cases of stroke
diagnosed based on CT scan in critically ill individuals treated in the medical
intensive care unit in a health facility in New York. All patients were
receiving supportive treatment and mechanical ventilation at the time of
diagnosis. All patients had impaired consciousness and were unable to wake up
after sedation had worn off, prompting further workup. The pathogenesis of
stroke could be secondary to the embolic phenomenon vs. hypercoagulopathy in our
patients. Stroke should be considered in all COVID-19 patients who present with
altered mental status. Severe COVID-19 patients with risk factors of stroke may
benefit from therapeutic anticoagulation.
Copyright © 2021, Vegunta et al.
DOI: 10.7759/cureus.13007
PMCID: PMC7919759
PMID: 33659138
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/35584541 | 1. Expert Rev Hematol. 2022 Jun;15(6):539-546. doi:
10.1080/17474086.2022.2080051. Epub 2022 May 26.
Post-COVID-19 hematologic complications: a systematic review.
Alahyari S(1), Moradi M(1), Rajaeinejad M(2), Jalaeikhoo H(2).
Author information:
(1)Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran,
Iran.
(2)AJA Cancer Epidemiology Research and Treatment Center (AJA- CERTC), AJA
University of Medical Sciences, Tehran, Iran.
INTRODUCTION: COVID-19 crisis continues around the world. Some patients
developed complications after the disease, which have been reported in limited
studies. The aim of this study is to comprehensively assess the post-COVID
hematologic complications in patients.
AREAS COVERED: We searched PubMed, Scopus, and Google Scholar between January
2020 and August 2021 using related keywords. Evaluation of the article was
performed by two independent researchers. The extracted data included the number
of patients, age, type of hematological complication, duration of follow-up,
response to treatment and prognosis.
EXPERT OPINION: Sixty-five articles reported post-COVID hematologic
complications. The most frequent hematologic complication in COVID-19 patients
is thromboembolic events, which often occur in two forms: deep vein thrombosis
(DVT) and pulmonary embolism (PE). In a group of patients after the diagnosis of
COVID-19, a significant decrease in platelets was observed, which was attributed
to the ITP induced by COVID-19. Hemolytic anemia and aplastic anemia have also
been reported rarely in patients. Finally, post-COVID hematologic complications
appear to go beyond thromboembolic events. Although these complications have
rarely been reported, searching for methods to identify susceptible patients and
prevent these complications could be the subject of future research.
DOI: 10.1080/17474086.2022.2080051
PMID: 35584541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32474145 | 1. Ann Vasc Surg. 2020 Aug;67:10-13. doi: 10.1016/j.avsg.2020.05.031. Epub 2020
May 29.
COVID-19-Related Aortic Thrombosis: A Report of Four Cases.
Gomez-Arbelaez D(1), Ibarra-Sanchez G(1), Garcia-Gutierrez A(1),
Comanges-Yeboles A(1), Ansuategui-Vicente M(1), Gonzalez-Fajardo JA(2).
Author information:
(1)Division of Vascular Surgery, Hospital Universitario 12 de Octubre, Madrid,
Spain.
(2)Division of Vascular Surgery, Hospital Universitario 12 de Octubre, Madrid,
Spain. Electronic address: [email protected].
COVID-19 may predispose patients to an increased risk of thrombotic
complications through various pathophysiological mechanisms. Most of the reports
on a high incidence of thrombotic complications are in relation to deep vein
thrombosis and pulmonary embolism, while the evidence about arterial thrombosis
in patients with COVID-19 is limited. We describe 4 cases of aortic thrombosis
and associated ischemic complications in patients with severe SARS-CoV-2
infection.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.avsg.2020.05.031
PMCID: PMC7256515
PMID: 32474145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35967591 | 1. JACC Adv. 2022 Aug;1(3):100057. doi: 10.1016/j.jacadv.2022.100057. Epub 2022
Aug 10.
Cardiovascular Complications of Pregnancy-Associated COVID-19 Infections.
Briller JE(1), Aggarwal NR(2), Davis MB(3), Hameed AB(4), Malhamé I(5), Mahmoud
Z(6), McDonald EG(5), Moraes de Oliveira G(7), Quesada O(8)(9), Scott
NS(10)(11), Sharma J(12); American College of Cardiology Cardiovascular Disease
in Women Committee.
Author information:
(1)Division of Cardiology, Department of Medicine and Department of Obstetrics
and Gynecology, University of Illinois at Chicago, Chicago, Illinois, USA.
(2)Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota,
USA.
(3)Division of Cardiovascular Medicine, Department of Medicine, University of
Michigan, Ann Arbor, Michigan, USA.
(4)Department of Obstetrics and Gynecology and Division of Cardiology,
Department of Medicine, University of California, Irvine Medical Center, Orange,
California, USA.
(5)Division of General Internal Medicine, Department of Medicine, McGill
University Health Centre, Montreal, Quebec, Canada.
(6)Cardiovascular Division, Department of Medicine, Washington University School
of Medicine, St Louis, Missouri, USA.
(7)Internal Medicine Department, Univiersidade Federal do Rio de Janeiro, Rio de
Janeiro, Brazil.
(8)Women's Heart Center, The Christ Hospital Heart and Vascular Institute,
Cincinnati, Ohio, USA.
(9)The Carl and Edyth Lindner Center for Research and Education, The Christ
Hospital, Cincinnati, Ohio, USA.
(10)Department of Medicine, Cardiology Division, Massachusetts General Hospital,
Boston, Massachusetts, USA.
(11)Department of Medicine, Cardiology Division, Harvard Medical School, Boston,
Massachusetts, USA.
(12)Division of Cardiology, Piedmont Heart Institute, Atlanta, Georgia, USA.
Cardiovascular complications are frequently present in coronavirus-2019
(COVID-19) infection. These include microvascular and macrovascular thrombotic
complications such as arterial and venous thromboembolism, myocardial injury or
inflammation resulting in infarction, heart failure, and arrhythmias. Data
suggest increased risk of adverse outcomes in pregnant compared with nonpregnant
women of reproductive age with COVID-19 infection, including need for intensive
care unit admission, mechanical ventilation, and extracorporeal membrane
oxygenation utilization. Current statements addressing COVID-19-associated
cardiac complications do not include pregnancy complications that may mimic
COVID-19 complications such as peripartum cardiomyopathy, spontaneous coronary
artery dissection, and preeclampsia. Unique to pregnancy, COVID-19 complications
can result in preterm delivery and modify management of the pregnancy. Moreover,
pregnancy has often been an exclusion criterion for enrollment in research
studies. In this review, we summarize what is known about pregnancy-associated
COVID-19 cardiovascular complications.
© 2022 The Authors.
DOI: 10.1016/j.jacadv.2022.100057
PMCID: PMC9364954
PMID: 35967591
Conflict of interest statement: Dr Quesada has received external funding of
10.13039/100000002NIH, United States K23HL151867 award for investigation on
hypertensive disorders of pregnancy. Drs Malhamé and Gibson McDonald hold Fonds
de Recherche du Quebec-Santé (FRQS), Canada Career awards. Dr Gibson McDonald is
a site investigator and member of steering committee for the ATTACC study. The
sponsors for the ATTACC study had no role in interpretation of data for this
study. Dr Briller is on the steering committee and a site investigator for the
REBIRTH trial. All other authors have reported they have no relationships
relevant to the content of this paper to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/34938638 | 1. RETRACTED ARTICLE
Cureus. 2021 Nov 20;13(11):e19763. doi: 10.7759/cureus.19763. eCollection 2021
Nov.
Cerebral Venous Infarct After Recovery From COVID-19 Pneumonia.
Alfahhad MF(1), Alghamdi SS(2), Alzahrani OA(2), Aldakhil SK(3), Algarni AA(3),
Juraybi IA(4), Alsalmi TM(5), Alsulaihebi AS(6), Yousef MK(1), Almuhaisen AS(7),
Alfawzan HM(8), Alsalehi FM(9), Alsaeed RN(10), Alharthi HH(6), Al-Hawaj F(11).
Author information:
(1)College of Medicine, King Abdulaziz University, Jeddah, SAU.
(2)College of Medicine, Al-Baha University, Al-Baha, SAU.
(3)College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU.
(4)College of Medicine, Jazan University, Jazan, SAU.
(5)College of Medicine, Taif University, Taif, SAU.
(6)College of Medicine, Umm Al-Qura University, Mecca, SAU.
(7)College of Medicine, King Faisal University, Al-Ahsa, SAU.
(8)College of Medicine, King Saud Bin Abdulaziz University For Health Sciences,
Riyadh, SAU.
(9)College of Medicine, Dammam Medical Complex, Dammam, SAU.
(10)College of Medicine, Alfaisal University, Riyadh, SAU.
(11)College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU.
Retraction in
Cureus. 2024 Jan 25;16(1):r100. doi: 10.7759/cureus.r100.
Expression of concern in
Cureus. 2022 Apr 7;14(4):x22. doi: 10.7759/cureus.x22.
The coronavirus disease 2019 (COVID-19) may have multisystem organ involvement.
Thrombotic events are well-recognized complications of COVID-19. Such
complications may include the pulmonary, renal, and other organs vasculature.
The risk of coagulopathy is usually related to the severity of COVID-19
pneumonia. Few cases suggested that the coagulopathy risk may persist for some
period after the recovery from COVID-19. We report the case of a middle-aged man
with severe COVID-19 pneumonia that required seven days of endotracheal
intubation and mechanical ventilation who presented with headache and left-sided
weakness that occurred three days after his discharge. A computed tomography
scan was performed to rule out intracranial hemorrhage before initiating the
thrombolytic therapy. The scan demonstrated hemorrhage in the right temporal
lobe with surrounding vasogenic edema along with density in the right transverse
sinus. Subsequently, computed tomography venography was performed and
demonstrated the filling defect representing right sigmoid venous sinus
thrombosis. The patient received conservative measures in the form of
intravenous hydration, anticoagulation, analgesics, and anticonvulsants. During
the hospital stay, the patient had improvement in his symptom and mild
neurological deficit persisted. The case highlighted that risk of thrombotic
complications in COVID-19 pneumonia may persist for some period after the
recovery from the disease. Hence, thromboprophylaxis may be indicated in
selected patients with a risk of thrombotic events after their recovery from
severe COVID-19.
Copyright © 2021, Alfahhad et al.
DOI: 10.7759/cureus.19763
PMCID: PMC8686011
PMID: 34938638
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34271813 | 1. J Coll Physicians Surg Pak. 2021 Jul;31(Supp. 2):S130-S131. doi:
10.29271/jcpsp.2021.Supp2.S130.
COVID-19-related Abdominal Aortic Thrombosis.
Güven C(1).
Author information:
(1)Department of Cardiovascular Surgery, Adiyaman University School of Medicine,
Adıyaman, Turkey.
Thrombotic complications increase in novel coronavirus disease 2019 (COVID-19)
patients. Most of these complications are associated with venous thromboembolism
and pulmonary embolism; and arterial thrombosis is rare. Usually, arterial
thrombosis affects peripheral arteries. The involvement of large vessels, such
as aorta, is rare in the literature. Major artery thrombosis manifests with
different additional complications. Contrast-enhanced abdominal computed
tomography angiography (CTA) was performed on a patient, who was followed-up
with COVID-19 due to gastrointestinal symptoms. Supra-celiac aortic thrombosis
and splenic infarction were detected. This case is reported to share experience
regarding our treatment approach in the light of the literature data. Key Words:
Arterial thrombosis, Acute aortic thrombosis, COVID-19.
DOI: 10.29271/jcpsp.2021.Supp2.S130
PMID: 34271813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35999833 | 1. Ann Med Surg (Lond). 2022 Sep;81:104445. doi: 10.1016/j.amsu.2022.104445. Epub
2022 Aug 19.
An acute lower limb ischemia revealing a covid-19 infection: A case report.
El Mesnaoui R(1), Nikiema S(2), Massimbo D(3), El Mesnaoui A(1).
Author information:
(1)Ibn Sina Hospital, Department of Vascular Surgery, Mohammed V University,
Morocco.
(2)Ibn Sina Hospital, Department of Cardiology, Department of Cardiology B,
Mohammed V University, Morocco.
(3)Mohammed V Military Instruction Hospital, Department of Cardiology, Morocco.
INTRODUCTION: Covid-19 is associated with thrombo-embolic events. These
complications are either veinous or arterial. By this case report, we aim to
highlight the physiopathology and the epidemiology of covid-19 related
thromboembolic complications.
CASE REPORT: We report a case of a 65 years old patient who was admitted fo
lower limb ischemia complicating a covid-19 infection. Computed tomography of
the aorta and lower limbs showed thrombosis of the femoral artery extended to
the popliteal artery and leg arteries. Despite a surgical embolectomy the
patient rethromboses twice leading to a thigh amputation.
DISCUSSION: Several hypotheses have been put forward to explain Covid 19-related
thromboembolic events. About 3% of patients develop arterial thrombosis.
Raffaello Bellosta and al. reported the incidence of acute limb ischemia has
significantly increased during the COVID-19 pandemic in the Italian Lombardy
region.
CONCLUSION: The coagulopathy responsible for venous and arterial thrombosis is a
well-established complication of COVID-19. Arterial thromboembolic complications
can be either stroke, acute coronary syndrome or peripheral acute ischemia.
Therefore, patients with covid19 should be monitored more closely for
thromboembolic complications.
© 2022 The Authors.
DOI: 10.1016/j.amsu.2022.104445
PMCID: PMC9389520
PMID: 35999833
Conflict of interest statement: No conflict interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35643053 | 1. J Infect Public Health. 2022 Jun;15(6):689-702. doi:
10.1016/j.jiph.2022.05.003. Epub 2022 May 14.
Venous and arterial thrombosis in COVID-19: An updated narrative review.
Duhailib ZA(1), Oczkowski S(2), Polok K(3), Fronczek J(3), Szczeklik W(3),
Piticaru J(4), Mammen MJ(5), Alshamsi F(6), Eikelboom J(7), Belley-Cote E(7),
Alhazzani W(8).
Author information:
(1)Department of Critical Care Medicine, King Faisal Specialist Hospital and
Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University,
Riyadh, Saudi Arabia. Electronic address: [email protected].
(2)Department of Health Research Methods, Evidence, and Impact, McMaster
University, Canada; Department of Medicine, McMaster University, Hamilton,
Ontario, Canada.
(3)Centre for Intensive Care and Perioperative Medicine, Jagiellonian University
Medical College, Krakow, Poland.
(4)Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
(5)Department of Medicine, Division of Pulmonary and Critical Care Medicine,
University of Rochester, USA.
(6)Department of Internal Medicine, College of Medicine and Health Sciences,
United Arab Emirates University, Al Ain, United Arab Emirates.
(7)Population Health Research Institute, Hamilton, Ontario, Canada; Department
of Medicine, McMaster University, Hamilton, Ontario, Canada.
(8)Department of Health Research Methods, Evidence, and Impact, McMaster
University, Canada; Department of Medicine, McMaster University, Hamilton,
Ontario, Canada; Department of Critical Care, College of Medicine, King Saud
University, Riyadh, Saudi Arabia.
Hospitalized patients with coronavirus disease 2019 (COVID-19), particularly
those admitted to the intensive care unit (ICU) are at high risk of morbidity
and mortality. Several observational studies have described hemostatic
derangements and thrombotic complications in patients with COVID-19. The aim of
this review article is to summarize the current evidence on pathologic findings,
pathophysiology, coagulation and hemostatic abnormalities, D-dimer's role in
prognostication epidemiology and risk factors of thrombotic complications, and
the role of prophylactic and therapeutic anticoagulation in patients with
COVID-19. While existing evidence is limited in quality, COVID-19 appears to
increase micro-and macro-vascular thrombosis rates in hospitalized and
critically ill patients, which may contribute to the burden of disease. D-dimer
can be used for risk stratification of hospitalized patients, but its role to
guide anticoagulation therapy remains unclear. Evidence of higher quality is
needed to address the role of therapeutic anticoagulation or high-intensity
venous thromboembolism prophylaxis in COVID-19 patients. TAKE-HOME POINTS.
Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.jiph.2022.05.003
PMCID: PMC9106398
PMID: 35643053 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32353746 | 1. Thromb Res. 2020 Jul;191:9-14. doi: 10.1016/j.thromres.2020.04.024. Epub 2020
Apr 23.
Venous and arterial thromboembolic complications in COVID-19 patients admitted
to an academic hospital in Milan, Italy.
Lodigiani C(1), Iapichino G(2), Carenzo L(2), Cecconi M(3), Ferrazzi P(4),
Sebastian T(5), Kucher N(5), Studt JD(6), Sacco C(4), Bertuzzi A(7), Sandri
MT(8), Barco S(9); Humanitas COVID-19 Task Force.
Author information:
(1)Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and
Research Hospital, Rozzano, Milano, Italy; Department of Medical Sciences,
Humanitas University, Milano, Italy. Electronic address:
[email protected].
(2)Department of Anaestesia and Intensive Care, Humanitas Clinical and Research
Center, Rozzano, Milano, Italy.
(3)Department of Medical Sciences, Humanitas University, Milano, Italy;
Department of Anaestesia and Intensive Care, Humanitas Clinical and Research
Center, Rozzano, Milano, Italy.
(4)Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and
Research Hospital, Rozzano, Milano, Italy.
(5)Clinic for Angiology, University Hospital Zurich, Zurich, Switzerland.
(6)Division of Medical Oncology and Hematology, University Hospital Zurich,
Zurich, Switzerland.
(7)Humanitas Clinical and Research Center - IRCCS, Humanitas Cancer Center, via
Manzoni 56, 20089 Rozzano, Milan, Italy.
(8)Laboratory Medicine Division, Humanitas Clinical and Research Hospital,
Rozzano, Milano, Italy.
(9)Clinic for Angiology, University Hospital Zurich, Zurich, Switzerland; Center
for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg
University Mainz, Mainz, Germany.
Comment in
J Formos Med Assoc. 2020 Jul;119(7):1230-1231. doi:
10.1016/j.jfma.2020.05.005.
Thromb Res. 2020 Aug;192:1. doi: 10.1016/j.thromres.2020.05.004.
BACKGROUND: Few data are available on the rate and characteristics of
thromboembolic complications in hospitalized patients with COVID-19.
METHODS: We studied consecutive symptomatic patients with laboratory-proven
COVID-19 admitted to a university hospital in Milan, Italy
(13.02.2020-10.04.2020). The primary outcome was any thromboembolic
complication, including venous thromboembolism (VTE), ischemic stroke, and acute
coronary syndrome (ACS)/myocardial infarction (MI). Secondary outcome was overt
disseminated intravascular coagulation (DIC).
RESULTS: We included 388 patients (median age 66 years, 68% men, 16% requiring
intensive care [ICU]). Thromboprophylaxis was used in 100% of ICU patients and
75% of those on the general ward. Thromboembolic events occurred in 28 (7.7% of
closed cases; 95%CI 5.4%-11.0%), corresponding to a cumulative rate of 21%
(27.6% ICU, 6.6% general ward). Half of the thromboembolic events were diagnosed
within 24 h of hospital admission. Forty-four patients underwent VTE imaging
tests and VTE was confirmed in 16 (36%). Computed tomography pulmonary
angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total,
and pulmonary embolism was confirmed in 10 (33% of CTPA). The rate of ischemic
stroke and ACS/MI was 2.5% and 1.1%, respectively. Overt DIC was present in 8
(2.2%) patients.
CONCLUSIONS: The high number of arterial and, in particular, venous
thromboembolic events diagnosed within 24 h of admission and the high rate of
positive VTE imaging tests among the few COVID-19 patients tested suggest that
there is an urgent need to improve specific VTE diagnostic strategies and
investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19
patients.
Copyright © 2020. Published by Elsevier Ltd.
DOI: 10.1016/j.thromres.2020.04.024
PMCID: PMC7177070
PMID: 32353746 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest Corrado
Lodigiani received congress and travel payments from Bayer HealthCare,
Daiichi-Sankyo and Boehringer Ingelheim, NovoNordisk, Takeda, and honoraria from
Daiichi-Sankyo, Takeda, NovoNordisk, Boehringer Ingelheim, Bayer HealthCare,
Aspen, Italfarmaco. Stefano Barco has received congress and travel payments from
Daiichi-Sankyo and Bayer HealthCare, and honoraria from Bayer HealthCare and
LeoPharma. The other authors do not disclose any potential conflict of interest.
The present study was not funded. |
http://www.ncbi.nlm.nih.gov/pubmed/21942916 | 1. BioDrugs. 2011 Oct 1;25(5):317-27. doi: 10.2165/11208390-000000000-00000.
Nanofiltered human C1 inhibitor concentrate (Cinryze®): in hereditary
angioedema.
Lyseng-Williamson KA(1).
Author information:
(1)Adis, a Wolters Kluwer Business, Auckland, New Zealand. [email protected]
Intravenous nanofiltered human C1 inhibitor (C1-INH NF) concentrate (Cinryze®)
is used as a direct replacement of deficient levels of plasma C1 inhibitor in
patients with hereditary angioedema (HAE). In the EU, C1-INH NF concentrate
1000 U is indicated in the treatment, pre-procedural prevention, and routine
prevention of angioedema attacks in adults and adolescents with HAE. Intravenous
C1-INH NF concentrate 1000 U effectively relieved angioedema attacks in patients
with HAE. In a randomized, double-blind trial in pediatric and adult patients,
the median time to onset of unequivocal relief from an attack was significantly
shorter with C1-INH NF concentrate than with placebo. In an open-label trial,
both unequivocal relief and clinical relief were shown in the majority of
attacks within 1 and 4 hours of infusion of C1-INH NF concentrate, regardless of
the site (i.e. gastrointestinal, cutaneous, laryngeal, or genitourinary) of the
defining symptom. When administered prior to a procedure, open-label intravenous
C1-INH NF concentrate 1000 U reduced the incidence of angioedema attacks during
and after a variety of dental, surgical, or interventional diagnostic procedures
in pediatric and adult patients with HAE. Routine preventative treatment with
intravenous C1-INH NF concentrate 1000 U every 3 or 4 days reduced the number of
angioedema attacks. In a randomized, double-blind, crossover trial in pediatric
and adult patients with HAE, the mean normalized number of attacks per 12-week
period was significantly lower during routine prevention with C1-INH NF
concentrate than with placebo. Routine prevention with C1-INH NF concentrate
reduced the median monthly attack rate from baseline in an open-label trial.
Intravenous C1-INH NF concentrate was well tolerated in clinical trials in
patients with HAE. No cases of viral transmission were reported.
DOI: 10.2165/11208390-000000000-00000
PMID: 21942916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36227551 | 1. Methods Mol Biol. 2023;2553:325-393. doi: 10.1007/978-1-0716-2617-7_16.
Machine Learning Methods for Survival Analysis with Clinical and Transcriptomics
Data of Breast Cancer.
Doan LMT(1), Angione C(1)(2)(3)(4), Occhipinti A(5)(6)(7).
Author information:
(1)School of Computing, Engineering and Digital Technologies, Teesside
University, Middlesbrough, UK.
(2)Centre for Digital Innovation, Teesside University, Middlesbrough, UK.
(3)Healthcare Innovation Centre, Teesside University, Middlesbrough, UK.
(4)National Horizons Centre, Teesside University, Darlington, UK.
(5)School of Computing, Engineering and Digital Technologies, Teesside
University, Middlesbrough, UK. [email protected].
(6)Centre for Digital Innovation, Teesside University, Middlesbrough, UK.
[email protected].
(7)National Horizons Centre, Teesside University, Darlington, UK.
[email protected].
Breast cancer is one of the most common cancers in women worldwide, which causes
an enormous number of deaths annually. However, early diagnosis of breast cancer
can improve survival outcomes enabling simpler and more cost-effective
treatments. The recent increase in data availability provides unprecedented
opportunities to apply data-driven and machine learning methods to identify
early-detection prognostic factors capable of predicting the expected survival
and potential sensitivity to treatment of patients, with the final aim of
enhancing clinical outcomes. This tutorial presents a protocol for applying
machine learning models in survival analysis for both clinical and
transcriptomic data. We show that integrating clinical and mRNA expression data
is essential to explain the multiple biological processes driving cancer
progression. Our results reveal that machine-learning-based models such as
random survival forests, gradient boosted survival model, and survival support
vector machine can outperform the traditional statistical methods, i.e., Cox
proportional hazard model. The highest C-index among the machine learning models
was recorded when using survival support vector machine, with a value 0.688,
whereas the C-index recorded using the Cox model was 0.677. Shapley Additive
Explanation (SHAP) values were also applied to identify the feature importance
of the models and their impact on the prediction outcomes.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2617-7_16
PMID: 36227551 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29920226 | 1. Am J Ophthalmol. 2018 Sep;193:71-79. doi: 10.1016/j.ajo.2018.06.007. Epub 2018
Jun 18.
Detection of Longitudinal Visual Field Progression in Glaucoma Using Machine
Learning.
Yousefi S(1), Kiwaki T(2), Zheng Y(2), Sugiura H(2), Asaoka R(3), Murata H(3),
Lemij H(4), Yamanishi K(2).
Author information:
(1)Department of Ophthalmology, Department of Genetics, Genomics, and
Informatics, University of Tennessee Health Science Center, Memphis, Tennessee,
USA; Graduate School of Information Science and Technology, The University of
Tokyo, Tokyo, Japan. Electronic address: [email protected].
(2)Graduate School of Information Science and Technology, The University of
Tokyo, Tokyo, Japan.
(3)Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.
(4)Rotterdam Eye Hospital, Rotterdam, Netherlands.
PURPOSE: Global indices of standard automated perimerty are insensitive to
localized losses, while point-wise indices are sensitive but highly variable.
Region-wise indices sit in between. This study introduces a machine
learning-based index for glaucoma progression detection that outperforms global,
region-wise, and point-wise indices.
DESIGN: Development and comparison of a prognostic index.
METHOD: Visual fields from 2085 eyes of 1214 subjects were used to identify
glaucoma progression patterns using machine learning. Visual fields from 133
eyes of 71 glaucoma patients were collected 10 times over 10 weeks to provide a
no-change, test-retest dataset. The parameters of all methods were identified
using visual field sequences in the test-retest dataset to meet fixed 95%
specificity. An independent dataset of 270 eyes of 136 glaucoma patients and
survival analysis were used to compare methods.
RESULTS: The time to detect progression in 25% of the eyes in the longitudinal
dataset using global mean deviation (MD) was 5.2 (95% confidence interval,
4.1-6.5) years; 4.5 (4.0-5.5) years using region-wise, 3.9 (3.5-4.6) years using
point-wise, and 3.5 (3.1-4.0) years using machine learning analysis. The time
until 25% of eyes showed subsequently confirmed progression after 2 additional
visits were included were 6.6 (5.6-7.4) years, 5.7 (4.8-6.7) years, 5.6
(4.7-6.5) years, and 5.1 (4.5-6.0) years for global, region-wise, point-wise,
and machine learning analyses, respectively.
CONCLUSIONS: Machine learning analysis detects progressing eyes earlier than
other methods consistently, with or without confirmation visits. In particular,
machine learning detects more slowly progressing eyes than other methods.
Copyright © 2018 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ajo.2018.06.007
PMID: 29920226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33858811 | 1. Eur Urol Focus. 2022 Mar;8(2):623-630. doi: 10.1016/j.euf.2021.04.001. Epub
2021 Apr 12.
Survival Analysis Using Surgeon Skill Metrics and Patient Factors to Predict
Urinary Continence Recovery After Robot-assisted Radical Prostatectomy.
Trinh L(1), Mingo S(2), Vanstrum EB(2), Sanford DI(2), Aastha(1), Ma R(2),
Nguyen JH(2), Liu Y(1), Hung AJ(3).
Author information:
(1)Computer Science Department, Viterbi School of Engineering, University of
Southern California, Los Angeles, CA, USA.
(2)Center for Robotic Simulation & Education, Catherine & Joseph Aresty
Department of Urology, USC Institute of Urology, University of Southern
California, Los Angeles, CA, USA.
(3)Center for Robotic Simulation & Education, Catherine & Joseph Aresty
Department of Urology, USC Institute of Urology, University of Southern
California, Los Angeles, CA, USA. Electronic address: [email protected].
Comment in
Eur Urol Focus. 2022 Sep;8(5):1553. doi: 10.1016/j.euf.2021.06.011.
Eur Urol Focus. 2022 Sep;8(5):1186. doi: 10.1016/j.euf.2021.05.011.
BACKGROUND: It has been shown that metrics recorded for instrument kinematics
during robotic surgery can predict urinary continence outcomes.
OBJECTIVE: To evaluate the contributions of patient and treatment factors,
surgeon efficiency metrics, and surgeon technical skill scores, especially for
vesicourethral anastomosis (VUA), to models predicting urinary continence
recovery following robot-assisted radical prostatectomy (RARP).
DESIGN, SETTING, AND PARTICIPANTS: Automated performance metrics (APMs;
instrument kinematics and system events) and patient data were collected for
RARPs performed from July 2016 to December 2017. Robotic Anastomosis Competency
Evaluation (RACE) scores during VUA were manually evaluated. Training datasets
included: (1) patient factors; (2) summarized APMs (reported over RARP steps);
(3) detailed APMs (reported over suturing phases of VUA); and (4) technical
skills (RACE). Feature selection was used to compress the dimensionality of the
inputs.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The study outcome was urinary
continence recovery, defined as use of 0 or 1 safety pads per day. Two
predictive models (Cox proportional hazards [CoxPH] and deep learning survival
analysis [DeepSurv]) were used.
RESULTS AND LIMITATIONS: Of 115 patients undergoing RARP, 89 (77.4%) recovered
their urinary continence and the median recovery time was 166 d (interquartile
range [IQR] 82-337). VUAs were performed by 23 surgeons. The median RACE score
was 28/30 (IQR 27-29). Among the individual datasets, technical skills (RACE)
produced the best models (C index: CoxPH 0.695, DeepSurv: 0.708). Among summary
APMs, posterior/anterior VUA yielded superior model performance over other RARP
steps (C index 0.543-0.592). Among detailed APMs, metrics for needle driving
yielded top-performing models (C index 0.614-0.655) over other suturing phases.
DeepSurv models consistently outperformed CoxPH; both approaches performed best
when provided with all the datasets. Limitations include feature selection,
which may have excluded relevant information but prevented overfitting.
CONCLUSIONS: Technical skills and "needle driving" APMs during VUA were most
contributory. The best-performing model used synergistic data from all datasets.
PATIENT SUMMARY: One of the steps in robot-assisted surgical removal of the
prostate involves joining the bladder to the urethra. Detailed information on
surgeon performance for this step improved the accuracy of predicting recovery
of urinary continence among men undergoing this operation for prostate cancer.
Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All
rights reserved.
DOI: 10.1016/j.euf.2021.04.001
PMCID: PMC8505550
PMID: 33858811 [Indexed for MEDLINE]
Conflict of interest statement: Financial disclosures: Andrew J. Hung certifies
that all conflicts of interest, including specific financial interests and
relationships and affiliations relevant to the subject matter or materials
discussed in the manuscript (eg, employment/affiliation, grants or funding,
consultancies, honoraria, stock ownership or options, expert testimony,
royalties, or patents filed, received, or pending), are the following: Andrew J.
Hung has received consultant fees from Quantgene, Mimic Technologies, and
Johnson & Johnson. |
http://www.ncbi.nlm.nih.gov/pubmed/20153956 | 1. Artif Intell Med. 2010 May;49(1):33-42. doi: 10.1016/j.artmed.2010.01.002.
Epub 2010 Feb 13.
A machine learning-based approach to prognostic analysis of thoracic
transplantations.
Delen D(1), Oztekin A, Kong ZJ.
Author information:
(1)Oklahoma State University, Tulsa, 74106, USA. [email protected]
OBJECTIVE: The prediction of survival time after organ transplantations and
prognosis analysis of different risk groups of transplant patients are not only
clinically important but also technically challenging. The current studies,
which are mostly linear modeling-based statistical analyses, have focused on
small sets of disparate predictive factors where many potentially important
variables are neglected in their analyses. Data mining methods, such as machine
learning-based approaches, are capable of providing an effective way of
overcoming these limitations by utilizing sufficiently large data sets with many
predictive factors to identify not only linear associations but also highly
complex, non-linear relationships. Therefore, this study is aimed at exploring
risk groups of thoracic recipients through machine learning-based methods.
METHODS AND MATERIAL: A large, feature-rich, nation-wide thoracic
transplantation dataset (obtained from the United Network for Organ
Sharing-UNOS) is used to develop predictive models for the survival time
estimation. The predictive factors that are most relevant to the survival time
identified via, (1) conducting sensitivity analysis on models developed by the
machine learning methods, (2) extraction of variables from the published
literature, and (3) eliciting variables from the medical experts and other
domain specific knowledge bases. A unified set of predictors is then used to
develop a Cox regression model and the related prognosis indices. A comparison
of clustering algorithm-based and conventional risk grouping techniques is
conducted based on the outcome of the Cox regression model in order to identify
optimal number of risk groups of thoracic recipients. Finally, the Kaplan-Meier
survival analysis is performed to validate the discrimination among the
identified various risk groups.
RESULTS: The machine learning models performed very effectively in predicting
the survival time: the support vector machine model with a radial basis Kernel
function produced the best fit with an R(2) value of 0.879, the artificial
neural network (multilayer perceptron-MLP-model) came the second with an R(2)
value of 0.847, and the M5 algorithm-based regression tree model came last with
an R(2) value of 0.785. Following the proposed method, a consolidated set of
predictive variables are determined and used to build the Cox survival model.
Using the prognosis indices revealed by the Cox survival model along with a
k-means clustering algorithm, an optimal number of "three" risk groups is
identified. The significance of differences among these risk groups are also
validated using the Kaplan-Meier survival analysis.
CONCLUSIONS: This study demonstrated that the integrated machine learning method
to select the predictor variables is more effective in developing the Cox
survival models than the traditional methods commonly found in the literature.
The significant distinction among the risk groups of thoracic patients also
validates the effectiveness of the methodology proposed herein. We anticipate
that this study (and other AI based analytic studies like this one) will lead to
more effective analyses of thoracic transplant procedures to better understand
the prognosis of thoracic organ recipients. It would potentially lead to new
medical and biological advances and more effective allocation policies in the
field of organ transplantation.
2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.artmed.2010.01.002
PMID: 20153956 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34910160 | 1. Int J Epidemiol. 2022 Jun 13;51(3):931-944. doi: 10.1093/ije/dyab258.
Predicting cardiovascular risk from national administrative databases using a
combined survival analysis and deep learning approach.
Barbieri S(1), Mehta S(2), Wu B(2), Bharat C(3), Poppe K(2), Jorm L(1), Jackson
R(2).
Author information:
(1)Centre for Big Data Research in Health, University of New South Wales,
Sydney, NSW, Australia.
(2)Section of Epidemiology and Biostatistics, University of Auckland, Auckland,
New Zealand.
(3)National Drug and Alcohol Research Centre, University of New South Wales,
Sydney, NSW, Australia.
Comment in
Int J Epidemiol. 2022 Jun 13;51(3):931-933. doi: 10.1093/ije/dyac064.
BACKGROUND: Machine learning-based risk prediction models may outperform
traditional statistical models in large datasets with many variables, by
identifying both novel predictors and the complex interactions between them.
This study compared deep learning extensions of survival analysis models with
Cox proportional hazards models for predicting cardiovascular disease (CVD) risk
in national health administrative datasets.
METHODS: Using individual person linkage of administrative datasets, we
constructed a cohort of all New Zealanders aged 30-74 who interacted with public
health services during 2012. After excluding people with prior CVD, we developed
sex-specific deep learning and Cox proportional hazards models to estimate the
risk of CVD events within 5 years. Models were compared based on the proportion
of explained variance, model calibration and discrimination, and hazard ratios
for predictor variables.
RESULTS: First CVD events occurred in 61 927 of 2 164 872 people. Within the
reference group, the largest hazard ratios estimated by the deep learning models
were for tobacco use in women (2.04, 95% CI: 1.99, 2.10) and chronic obstructive
pulmonary disease with acute lower respiratory infection in men (1.56, 95% CI:
1.50, 1.62). Other identified predictors (e.g. hypertension, chest pain,
diabetes) aligned with current knowledge about CVD risk factors. Deep learning
outperformed Cox proportional hazards models on the basis of proportion of
explained variance (R2: 0.468 vs 0.425 in women and 0.383 vs 0.348 in men),
calibration and discrimination (all P <0.0001).
CONCLUSIONS: Deep learning extensions of survival analysis models can be applied
to large health administrative datasets to derive interpretable CVD risk
prediction equations that are more accurate than traditional Cox proportional
hazards models.
© The Author(s) 2021. Published by Oxford University Press on behalf of the
International Epidemiological Association.
DOI: 10.1093/ije/dyab258
PMCID: PMC9189958
PMID: 34910160 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35179504 | 1. JMIR Med Inform. 2022 Feb 18;10(2):e33440. doi: 10.2196/33440.
The Application and Comparison of Machine Learning Models for the Prediction of
Breast Cancer Prognosis: Retrospective Cohort Study.
Xiao J(1)(2)(3), Mo M(2)(3), Wang Z(2)(3), Zhou C(2)(3), Shen J(2)(3), Yuan
J(2)(3), He Y(1)(2), Zheng Y(2)(3)(4).
Author information:
(1)Department of Epidemiology, School of Public Health, Fudan University,
Shanghai, China.
(2)Department of Cancer Prevention, Fudan University Shanghai Cancer Center,
Shanghai, China.
(3)Department of Oncology, Shanghai Medical College, Fudan University, Shanghai,
China.
(4)Shanghai Engineering Research Center of Artificial Intelligence Technology
for Tumor Diseases, Shanghai, China.
BACKGROUND: Over the recent years, machine learning methods have been
increasingly explored in cancer prognosis because of the appearance of improved
machine learning algorithms. These algorithms can use censored data for
modeling, such as support vector machines for survival analysis and random
survival forest (RSF). However, it is still debated whether traditional (Cox
proportional hazard regression) or machine learning-based prognostic models have
better predictive performance.
OBJECTIVE: This study aimed to compare the performance of breast cancer
prognostic prediction models based on machine learning and Cox regression.
METHODS: This retrospective cohort study included all patients diagnosed with
breast cancer and subsequently hospitalized in Fudan University Shanghai Cancer
Center between January 1, 2008, and December 31, 2016. After all exclusions, a
total of 22,176 cases with 21 features were eligible for model development. The
data set was randomly split into a training set (15,523 cases, 70%) and a test
set (6653 cases, 30%) for developing 4 models and predicting the overall
survival of patients diagnosed with breast cancer. The discriminative ability of
models was evaluated by the concordance index (C-index), the time-dependent area
under the curve, and D-index; the calibration ability of models was evaluated by
the Brier score.
RESULTS: The RSF model revealed the best discriminative performance among the 4
models with 3-year, 5-year, and 10-year time-dependent area under the curve of
0.857, 0.838, and 0.781, a D-index of 7.643 (95% CI 6.542, 8.930) and a C-index
of 0.827 (95% CI 0.809, 0.845). The statistical difference of the C-index was
tested, and the RSF model significantly outperformed the Cox-EN (elastic net)
model (C-index 0.816, 95% CI 0.796, 0.836; P=.01), the Cox model (C-index 0.814,
95% CI 0.794, 0.835; P=.003), and the support vector machine model (C-index
0.812, 95% CI 0.793, 0.832; P<.001). The 4 models' 3-year, 5-year, and 10-year
Brier scores were very close, ranging from 0.027 to 0.094 and less than 0.1,
which meant all models had good calibration. In the context of feature
importance, elastic net and RSF both indicated that TNM staging, neoadjuvant
therapy, number of lymph node metastases, age, and tumor diameter were the top 5
important features for predicting the prognosis of breast cancer. A final online
tool was developed to predict the overall survival of patients with breast
cancer.
CONCLUSIONS: The RSF model slightly outperformed the other models on
discriminative ability, revealing the potential of the RSF method as an
effective approach to building prognostic prediction models in the context of
survival analysis.
©Jialong Xiao, Miao Mo, Zezhou Wang, Changming Zhou, Jie Shen, Jing Yuan, Yulian
He, Ying Zheng. Originally published in JMIR Medical Informatics
(https://medinform.jmir.org), 18.02.2022.
DOI: 10.2196/33440
PMCID: PMC8900909
PMID: 35179504
Conflict of interest statement: Conflicts of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35358302 | 1. Cancer Res. 2022 May 3;82(9):1832-1843. doi: 10.1158/0008-5472.CAN-21-3074.
Comprehensive Evaluation of Machine Learning Models and Gene Expression
Signatures for Prostate Cancer Prognosis Using Large Population Cohorts.
Li R(1)(2), Zhu J(3), Zhong WD(4)(5)(6), Jia Z(1)(2).
Author information:
(1)Department of Botany and Plant Sciences, University of California, Riverside,
California.
(2)Graduate Program in Genetics, Genomics, and Bioinformatics, University of
California, Riverside, California.
(3)Department of Urology, Guizhou Provincial People's Hospital, Guizhou, China.
(4)Department of Urology, Guangdong Key Laboratory of Clinical Molecular
Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine,
South China University of Technology, Guangzhou, China.
(5)Guangdong Key Laboratory of Urology, The First Affiliated Hospital of
Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
(6)Macau Institute for Applied Research in Medicine and Health, Macau University
of Science and Technology, Macau, China.
Overtreatment remains a pervasive problem in prostate cancer management due to
the highly variable and often indolent course of disease. Molecular signatures
derived from gene expression profiling have played critical roles in guiding
prostate cancer treatment decisions. Many gene expression signatures have been
developed to improve the risk stratification of prostate cancer and some of them
have already been applied to clinical practice. However, no comprehensive
evaluation has been performed to compare the performance of these signatures. In
this study, we conducted a systematic and unbiased evaluation of 15 machine
learning (ML) algorithms and 30 published prostate cancer gene expression-based
prognostic signatures leveraging 10 transcriptomics datasets with 1,558 primary
patients with prostate cancer from public data repositories. This analysis
revealed that survival analysis models outperformed binary classification models
for risk assessment, and the performance of the survival analysis methods-Cox
model regularized with ridge penalty (Cox-Ridge) and partial least squares (PLS)
regression for Cox model (Cox-PLS)-were generally more robust than the other
methods. Based on the Cox-Ridge algorithm, several top prognostic signatures
displayed comparable or even better performance than commercial panels. These
findings will facilitate the identification of existing prognostic signatures
that are promising for further validation in prospective studies and promote the
development of robust prognostic models to guide clinical decision-making.
Moreover, this study provides a valuable data resource from large primary
prostate cancer cohorts, which can be used to develop, validate, and evaluate
novel statistical methodologies and molecular signatures to improve prostate
cancer management.
SIGNIFICANCE: This systematic evaluation of 15 machine learning algorithms and
30 published gene expression signatures for the prognosis of prostate cancer
will assist clinical decision-making.
©2022 American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-21-3074
PMID: 35358302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31147687 | 1. Bioinformatics. 2019 Dec 15;35(24):5137-5145. doi:
10.1093/bioinformatics/btz446.
Path2Surv: Pathway/gene set-based survival analysis using multiple kernel
learning.
Dereli O(1), Oğuz C(2), Gönen M(2)(3)(4).
Author information:
(1)Graduate School of Sciences and Engineering, İstanbul 34450, Turkey.
(2)Department of Industrial Engineering, College of Engineering, İstanbul 34450,
Turkey.
(3)School of Medicine, Koc¸ University, İstanbul 34450, Turkey.
(4)Department of Biomedical Engineering, School of Medicine, Oregon Health &
Science University, Portland, OR 97239, USA.
MOTIVATION: Survival analysis methods that integrate pathways/gene sets into
their learning model could identify molecular mechanisms that determine survival
characteristics of patients. Rather than first picking the predictive
pathways/gene sets from a given collection and then training a predictive model
on the subset of genomic features mapped to these selected pathways/gene sets,
we developed a novel machine learning algorithm (Path2Surv) that conjointly
performs these two steps using multiple kernel learning.
RESULTS: We extensively tested our Path2Surv algorithm on 7655 patients from 20
cancer types using cancer-specific pathway/gene set collections and gene
expression profiles of these patients. Path2Surv statistically significantly
outperformed survival random forest (RF) on 12 out of 20 datasets and obtained
comparable predictive performance against survival support vector machine (SVM)
using significantly fewer gene expression features (i.e. less than 10% of what
survival RF and survival SVM used).
AVAILABILITY AND IMPLEMENTATION: Our implementations of survival SVM and
Path2Surv algorithms in R are available at
https://github.com/mehmetgonen/path2surv together with the scripts that
replicate the reported experiments.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author(s) 2019. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: [email protected].
DOI: 10.1093/bioinformatics/btz446
PMID: 31147687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30632193 | 1. Stat Med. 2019 May 30;38(12):2139-2156. doi: 10.1002/sim.8090. Epub 2019 Jan
10.
Extreme learning machine Cox model for high-dimensional survival analysis.
Wang H(1), Li G(2).
Author information:
(1)School of Mathematics and Statistics, Central South University, Changsha,
China.
(2)Department of Biostatistics, UCLA Fielding School of Public Health,
University of California, Los Angeles, California.
Some interesting recent studies have shown that neural network models are useful
alternatives in modeling survival data when the assumptions of a classical
parametric or semiparametric survival model such as the Cox (1972) model are
seriously violated. However, to the best of our knowledge, the plausibility of
adapting the emerging extreme learning machine (ELM) algorithm for
single-hidden-layer feedforward neural networks to survival analysis has not
been explored. In this paper, we present a kernel ELM Cox model regularized by
an L0 -based broken adaptive ridge (BAR) penalization method. Then, we
demonstrate that the resulting method, referred to as ELMCoxBAR, can outperform
some other state-of-art survival prediction methods such as L1 - or L2
-regularized Cox regression, random survival forest with various splitting
rules, and boosted Cox model, in terms of its predictive performance using both
simulated and real world datasets. In addition to its good predictive
performance, we illustrate that the proposed method has a key computational
advantage over the above competing methods in terms of computation time
efficiency using an a real-world ultra-high-dimensional survival data.
© 2019 John Wiley & Sons, Ltd.
DOI: 10.1002/sim.8090
PMCID: PMC6498851
PMID: 30632193 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31896241 | 1. Genomics Inform. 2019 Dec;17(4):e41. doi: 10.5808/GI.2019.17.4.e41. Epub 2019
Dec 20.
Review of statistical methods for survival analysis using genomic data.
Lee S(1), Lim H(2).
Author information:
(1)Department of Mathematics and Statistics, Sejong University, Seoul 05006,
Korea.
(2)Department of Statistics, University of Connecticut, Storrs, CT 06269, USA.
Survival analysis mainly deals with the time to event, including death, onset of
disease, and bankruptcy. The common characteristic of survival analysis is that
it contains "censored" data, in which the time to event cannot be completely
observed, but instead represents the lower bound of the time to event. Only the
occurrence of either time to event or censoring time is observed. Many
traditional statistical methods have been effectively used for analyzing
survival data with censored observations. However, with the development of
high-throughput technologies for producing "omics" data, more advanced
statistical methods, such as regularization, should be required to construct the
predictive survival model with high-dimensional genomic data. Furthermore,
machine learning approaches have been adapted for survival analysis, to fit
nonlinear and complex interaction effects between predictors, and achieve more
accurate prediction of individual survival probability. Presently, since most
clinicians and medical researchers can easily assess statistical programs for
analyzing survival data, a review article is helpful for understanding
statistical methods used in survival analysis. We review traditional survival
methods and regularization methods, with various penalty functions, for the
analysis of high-dimensional genomics, and describe machine learning techniques
that have been adapted to survival analysis.
DOI: 10.5808/GI.2019.17.4.e41
PMCID: PMC6944043
PMID: 31896241
Conflict of interest statement: Conflicts of Interest No potential conflict of
interest relevant to this article was reported. |
http://www.ncbi.nlm.nih.gov/pubmed/30409119 | 1. BMC Cancer. 2018 Nov 8;18(1):1084. doi: 10.1186/s12885-018-4985-2.
Spatially varying effects of predictors for the survival prediction of
nonmetastatic colorectal Cancer.
Tian Y(1), Li J(2), Zhou T(3), Tong D(1), Chi S(1), Kong X(2), Ding K(2), Li
J(1).
Author information:
(1)Engineering Research Center of EMR and Intelligent Expert System, Ministry of
Education, Collaborative Innovation Center for Diagnosis and Treatment of
Infectious Diseases, College of Biomedical Engineering and Instrument Science,
Zhejiang University, No. 38 Zheda Road, Hangzhou, 310027, Zhejiang Province,
China.
(2)Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang
University School of Medicine, No. 88 Jiefang Road, Hangzhou, 31009, Zhejiang
Province, China.
(3)Engineering Research Center of EMR and Intelligent Expert System, Ministry of
Education, Collaborative Innovation Center for Diagnosis and Treatment of
Infectious Diseases, College of Biomedical Engineering and Instrument Science,
Zhejiang University, No. 38 Zheda Road, Hangzhou, 310027, Zhejiang Province,
China. [email protected].
BACKGROUND: An increasing number of studies have identified spatial differences
in colorectal cancer survival. However, little is known about the spatially
varying effects of predictors in survival prediction modeling studies of
colorectal cancer that have focused on estimating the absolute survival risk for
patients from a wide range of populations. This study aimed to demonstrate the
spatially varying effects of predictors of survival for nonmetastatic colorectal
cancer patients.
METHODS: Patients diagnosed with nonmetastatic colorectal cancer from 2004 to
2013 who were followed up through the end of 2013 were extracted from the
Surveillance Epidemiology End Results registry (Patients: 128061). The log-rank
test and the restricted mean survival time were used to evaluate survival
outcome differences among spatial clusters corresponding to a widely used
clinical predictor: stage determined by AJCC 7th edition staging system. The
heterogeneity test, which is used in meta-analyses, revealed the spatially
varying effects of single predictors. Then, considering the above predictors in
a standard survival prediction model based on spatially clustered data, the
spatially varying coefficients of these models revealed that some covariate
effects may not be constant across the geographic regions of the study. Then,
two types of survival prediction models (a statistical model and a machine
learning model) were built; these models considered the predictors and enabled
survival prediction for patients from a wide range of geographic regions.
RESULTS: Based on univariate and multivariate analysis, some prognostic factors,
such as "TNM stage", "tumor size" and "age at diagnosis," have significant
spatially varying effects among different regions. When considering these
spatially varying effects, machine learning models have fewer assumption
constraints (such as proportional hazard assumptions) and better predictive
performance compared with statistical models. Upon comparing the concordance
indexes of these two models, the machine learning model was found to be more
accurate (0.898[0.895,0.902]) than the statistical model (0.732 [0.726, 0.738]).
CONCLUSIONS: Based on this study, it's recommended that the spatially varying
effect of predictors should be considered when building survival prediction
models involving large-scale and multicenter research data. Machine learning
models that are not limited by the requirement of a statistical hypothesis are
promising alternative models.
DOI: 10.1186/s12885-018-4985-2
PMCID: PMC6225720
PMID: 30409119 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/35617368 | 1. PLoS Med. 2022 May 26;19(5):e1003953. doi: 10.1371/journal.pmed.1003953.
eCollection 2022 May.
Safety and immunogenicity of heterologous boost immunization with an adenovirus
type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001):
A randomized, observer-blinded, placebo-controlled trial.
Jin P(1), Guo X(1), Chen W(2), Ma S(3), Pan H(1), Dai L(4), Du P(5)(6), Wang
L(3), Jin L(7), Chen Y(1), Shi F(1), Liu J(1), Xu X(5), Zhang Y(2), Gao GF(4),
Chen C(2), Feng J(8), Li J(1)(8)(9), Zhu F(1)(8)(9).
Author information:
(1)NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Province
Center for Disease Control and Prevention, Nanjing, PR China.
(2)Anhui Zhifei Longcom Biopharmaceutical, Hefei, PR China.
(3)Guanyun County Center for Disease Control and Prevention, Guanyun County, PR
China.
(4)CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of
Microbiology, Chinese Academy of Sciences, Beijing, PR China.
(5)Vazyme Biotech, Nanjing, PR China.
(6)Basic Medical Science School, Zhengzhou University, Zhengzhou, PR China.
(7)School of Public Health, Southeast University, Nanjing, PR China.
(8)School of Public Health, Nanjing Medical University, Nanjing, PR China.
(9)Institute of Global Health and Emergency Pharmacy, China Pharmaceutical
University, Nanjing, PR China.
BACKGROUND: Heterologous boost vaccination has been proposed as an option to
elicit stronger and broader, or longer-lasting immunity. We assessed the safety
and immunogenicity of heterologous immunization with a recombinant adenovirus
type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia,
hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine
(ZF2001, hereafter referred to as ZF).
METHODS AND FINDINGS: We conducted a randomized, observer-blinded,
placebo-controlled trial, in which healthy adults aged 18 years or older, who
have received 1 dose of Convidecia, with no history of Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China.
Sixty participants were randomly assigned (2:1) to receive either 1 dose of
ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV))
administered at 28 days after priming, and received the third injection with
ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5)
regimen, respectively. Sixty participants were randomly assigned (2:1) to
receive either 1 dose of ZF2001 or TIV administered at 56 days after priming,
and received the third injection with ZF2001 at 6 months, referred to as
CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and
investigators were masked to the vaccine received but not to the boosting
interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing
antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions.
The primary analysis was done in the intention-to-treat population. Between
April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned
to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months
post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days
and 6 months post priming. Of them, 7 participants did not receive the third
injection with ZF2001. A total of 26 participants (21.7%) reported solicited
adverse reactions within 7 days post boost vaccinations, and all the reported
adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7
(35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen,
and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first
boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days
and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to
39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8
to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing
antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen
and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of
CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that
elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0,
200.9), respectively. Study limitations include the absence of vaccine
effectiveness in a real-world setting and current lack of immune persistence
data.
CONCLUSIONS: Heterologous boosting with ZF2001 following primary vaccination
with Convidecia is more immunogenic than a single dose of Convidecia and is not
associated with safety concerns. These results support flexibility in
cooperating viral vectored and recombinant protein vaccines.
TRIAL REGISTRATION: Study on Heterologous Prime-boost of Recombinant COVID-19
Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov
NCT04833101.
DOI: 10.1371/journal.pmed.1003953
PMCID: PMC9187065
PMID: 35617368 [Indexed for MEDLINE]
Conflict of interest statement: I have read the journal’s policy and the authors
of this manuscript have the following competing interests: JL reports grants
from National Natural Science Foundation of China (grant number 82173584). FZ
reports grants from Jiangsu Provincial Key Research and Development Program
(grant number BE2021738). LD is an inventor of the patent for the protein
subunit vaccine ZF2001. WC, YZ and CC are the employees of Anhui Zhifei Longcom
Biopharmaceutical. All other authors declare no competing interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35596222 | 1. Virol J. 2022 May 20;19(1):86. doi: 10.1186/s12985-022-01818-x.
Effective protection of ZF2001 against the SARS-CoV-2 Delta variant in lethal
K18-hACE2 mice.
Bian L(#)(1), Bai Y(#)(1), Gao F(1), Liu M(1), He Q(1), Wu X(1), Mao Q(1), Xu
M(2), Liang Z(3).
Author information:
(1)Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of
Research on Quality and Standardization of Biotech Products, and NMPA Key
Laboratory for Quality Research and Evaluation of Biological Products, Institute
of Biological Products, National Institutes for Food and Drug Control, Beijing,
China.
(2)Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of
Research on Quality and Standardization of Biotech Products, and NMPA Key
Laboratory for Quality Research and Evaluation of Biological Products, Institute
of Biological Products, National Institutes for Food and Drug Control, Beijing,
China. [email protected].
(3)Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of
Research on Quality and Standardization of Biotech Products, and NMPA Key
Laboratory for Quality Research and Evaluation of Biological Products, Institute
of Biological Products, National Institutes for Food and Drug Control, Beijing,
China. [email protected].
(#)Contributed equally
To investigate the protective efficacy and mechanism of ZF2001 (a protein
subunit vaccine with conditional approval in China) to SARS-CoV-2 Delta
variant-induced severe pneumonia, the lethal challenge model of K18-hACE2
transgenic mice was used in this study. An inactivated-virus vaccine at the
research and development stage (abbreviated as RDINA) was compared to ZF2001. We
found that ZF2001 and RDINA could provide the protective effect against Delta
variant-induced severe cases, as measured by the improved survival rates, the
reduced virus loads, the alleviated lung histopathology and the high
neutralizing antibody geomean titers, compared to aluminum adjuvant group. To
prevent and control Omicron or other variant epidemics, further improvements in
vaccine design and compatibilities with the novel adjuvant are required to
achieve better immunogenicity.
© 2022. The Author(s).
DOI: 10.1186/s12985-022-01818-x
PMCID: PMC9122244
PMID: 35596222 [Indexed for MEDLINE]
Conflict of interest statement: All authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35634276 | 1. Front Immunol. 2022 May 13;13:855311. doi: 10.3389/fimmu.2022.855311.
eCollection 2022.
Safety and Immunogenicity of Inactivated and Recombinant Protein SARS-CoV-2
Vaccines in Patients With Thyroid Cancer.
Han Y(1), Yang J(1), He D(1), Feng Y(1), Liu X(1), Min Y(1), Fan S(1), Yin G(1),
Hu D(1).
Author information:
(1)Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of
Chongqing Medical University, Chongqing, China.
BACKGROUND: This study aimed at assessing the safety and immunogenicity of
SARS-CoV-2 vaccines in patients with thyroid cancer.
METHODS: This observational study included thyroid cancer patients between April
1, 2021, and November 31, 2021, in the Second Affiliated Hospital of Chongqing
Medical University. All participants received at least one dose of the
SARS-CoV-2 vaccine. SARS-CoV-2 IgG was tested, and the interval time between the
last dose and humoral response test ranged from <1 to 8 months. The
complications after SARS-CoV-2 vaccines were recorded.
RESULTS: A total of 115 participants at least received one dose of SARS-CoV-2
vaccines with a 67.0% IgG-positive rate. Among them, 98 cases had completed
vaccination, and the positivity of SARS-CoV-2 IgG antibodies was 96% (24/25)
with three doses of ZF2001. SARS-CoV-2 IgG antibodies' positivity was 63.0%
(46/73) of two doses of CoronaVac or BBIBP-CorV vaccine. Additionally, after 4
months of the last-dose vaccination, the IgG-positive rate (31.6%, 6/19)
significantly decreased in thyroid cancer patients. The IgG-positive rate
(81.0%, 64/79) was satisfactory within 3 months of the last-dose vaccination.
Ten (10.2%) patients had side effects after SARS-CoV-2 vaccination. Among them,
two (2.0%) patients had a fever, five (5.1%) patients had injection site pain,
one (1.0%) patient felt dizzy, and one patient felt dizzy and had injection site
pain at the same time.
CONCLUSION: SARS-CoV-2 vaccines (CoronaVac, BBIBP-CorV, and ZF2001) are safe in
thyroid cancer patients. The regression time of SARS-CoV-2 IgG is significantly
shorter in thyroid cancer patients than in healthy adults. Therefore, a booster
vaccination dose may be earlier than the systematic strategy for thyroid cancer
patients.
Copyright © 2022 Han, Yang, He, Feng, Liu, Min, Fan, Yin and Hu.
DOI: 10.3389/fimmu.2022.855311
PMCID: PMC9139473
PMID: 35634276 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35568034 | 1. Cell. 2022 Jun 23;185(13):2265-2278.e14. doi: 10.1016/j.cell.2022.04.029. Epub
2022 Apr 27.
Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against
SARS-CoV-2.
Xu K(1), Gao P(2), Liu S(3), Lu S(4), Lei W(5), Zheng T(6), Liu X(7), Xie Y(8),
Zhao Z(2), Guo S(9), Tang C(4), Yang Y(4), Yu W(4), Wang J(4), Zhou Y(4), Huang
Q(4), Liu C(10), An Y(11), Zhang R(10), Han Y(11), Duan M(12), Wang S(2), Yang
C(2), Wu C(13), Liu X(13), She G(13), Liu Y(14), Zhao X(15), Xu K(5), Qi J(15),
Wu G(16), Peng X(17), Dai L(18), Wang P(19), Gao GF(20).
Author information:
(1)Research Network of Immunity and Health (RNIH), Beijing Institutes of Life
Science, Chinese Academy of Sciences, Beijing 100101, China.
(2)CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of
Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of
Chinese Academy of Sciences, Beijing 100049, China.
(3)Cryo-EM Center, Southern University of Science and Technology, Shenzhen
518055, China.
(4)National Kunming High-level Biosafety Primate Research Center, Institute of
Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Kunming 650031, China.
(5)NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control
and Prevention, Chinese Center for Disease Control and Prevention, Beijing
102206, China.
(6)Zhejiang University School of Medicine, Hangzhou 310058, China.
(7)School of Public Health, Cheeloo College of Medicine, Shandong University,
Jinan 250012, China.
(8)Department of Basic Medical Sciences, School of Medicine, Tsinghua
University, Beijing 100084, China.
(9)Faculty of Health Sciences, University of Macau, Macau, SAR 999078, China.
(10)State Key Laboratory for Conservation and Utilization of Subtropical
Agro-Bioresources, Guangxi University, Nanning 530004, China.
(11)Savaid Medical School, University of Chinese Academy of Sciences, Beijing
101408, China.
(12)School of Life Sciences, Yunnan University, Kunming 650091, China.
(13)Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, Hefei 230088, China.
(14)Chongqing Medleader Bio-Pharm, Chongqing 401338, China.
(15)CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of
Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
(16)NHC Key Laboratory of Biosafety, National Institute for Viral Disease
Control and Prevention, Chinese Center for Disease Control and Prevention,
Beijing 102206, China. Electronic address: [email protected].
(17)National Kunming High-level Biosafety Primate Research Center, Institute of
Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Kunming 650031, China; State Key Laboratory of Medical Molecular
Biology, Department of Molecular Biology and Biochemistry, Institute of Basic
Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese
Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical
College, Beijing 100005, China. Electronic address: [email protected].
(18)CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of
Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of
Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
[email protected].
(19)Cryo-EM Center, Southern University of Science and Technology, Shenzhen
518055, China. Electronic address: [email protected].
(20)Research Network of Immunity and Health (RNIH), Beijing Institutes of Life
Science, Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory
of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese
Academy of Sciences, Beijing 100101, China; University of Chinese Academy of
Sciences, Beijing 100049, China; Savaid Medical School, University of Chinese
Academy of Sciences, Beijing 101408, China. Electronic address: [email protected].
Breakthrough infections by SARS-CoV-2 variants become the global challenge for
pandemic control. Previously, we developed the protein subunit vaccine ZF2001
based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2.
Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2
variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the
resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine
elicited broader sera neutralization of variants and conferred better protection
in mice. The protection of the chimeric vaccine was further verified in
macaques. This approach was generalized to develop Delta-Omicron chimeric
RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine
elicited broader sera neutralization of SARS-CoV-2 variants and conferred better
protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The
chimeric approach is applicable for rapid updating of immunogens, and our data
supported the use of variant-adapted multivalent vaccine against circulating and
emerging variants.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2022.04.029
PMCID: PMC9042943
PMID: 35568034 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests Kun Xu, Y.A., L.D., and
G.F.G. are listed in the patent as the inventors of the prototype RBD-dimer as
coronavirus vaccines. Kun Xu, P.G., Z.Z., Y.A., L.D., and G.F.G. are listed in
the patent as the inventors of chimeric prototype-Beta RBD-dimer as coronavirus
vaccines. Kun Xu, T.Z., L.D., and G.F.G. are listed in the patent as the
inventors of chimeric Delta-Omicron RBD-dimer as coronavirus vaccine. All other
authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/29706521 | 1. Curr Biol. 2018 May 7;28(9):1344-1356.e5. doi: 10.1016/j.cub.2018.03.023. Epub
2018 Apr 26.
Chromosome Segregation Is Biased by Kinetochore Size.
Drpic D(1), Almeida AC(2), Aguiar P(3), Renda F(4), Damas J(5), Lewin HA(6),
Larkin DM(5), Khodjakov A(7), Maiato H(8).
Author information:
(1)Chromosome Instability & Dynamics Laboratory, Instituto de Biologia Molecular
e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto,
Portugal; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do
Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Graduate Program in
Areas of Basic and Applied Biology (GABBA), Instituto de Ciências Biomédicas
Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313
Porto, Portugal.
(2)Chromosome Instability & Dynamics Laboratory, Instituto de Biologia Molecular
e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto,
Portugal; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do
Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
(3)Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto,
Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto Nacional de
Engenharia Biomédica (INEB), Universidade do Porto, Rua Alfredo Allen 208,
4200-135 Porto, Portugal.
(4)Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA.
(5)Department of Comparative Biomedical Sciences, Royal Veterinary College,
University of London, London NW1 0TU, UK.
(6)Department of Evolution and Ecology, University of California, Davis, Davis,
CA 95616, USA.
(7)Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA;
Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
(8)Chromosome Instability & Dynamics Laboratory, Instituto de Biologia Molecular
e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto,
Portugal; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do
Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Cell Division Group,
Experimental Biology Unit, Department of Biomedicine, Faculdade de Medicina,
Universidade do Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto,
Portugal. Electronic address: [email protected].
Comment in
Curr Biol. 2018 Jun 4;28(11):R665-R667. doi: 10.1016/j.cub.2018.04.036.
Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and
the main cause of prenatal death in humans. The gain or loss of specific
chromosomes is thought to be random, with cell viability being essentially
determined by selection. Several established pathways including centrosome
amplification, sister-chromatid cohesion defects, or a compromised spindle
assembly checkpoint can lead to chromosome missegregation. However, how specific
intrinsic features of the kinetochore-the critical chromosomal interface with
spindle microtubules-impact chromosome segregation remains poorly understood.
Here we used the unique cytological attributes of female Indian muntjac, the
mammal with the lowest known chromosome number (2n = 6), to characterize and
track individual chromosomes with distinct kinetochore size throughout mitosis.
We show that centromere and kinetochore functional layers scale proportionally
with centromere size. Measurement of intra-kinetochore distances, serial-section
electron microscopy, and RNAi against key kinetochore proteins confirmed a
standard structural and functional organization of the Indian muntjac
kinetochores and revealed that microtubule binding capacity scales with
kinetochore size. Surprisingly, we found that chromosome segregation in this
species is not random. Chromosomes with larger kinetochores bi-oriented more
efficiently and showed a 2-fold bias to congress to the equator in a
motor-independent manner. Despite robust correction mechanisms during
unperturbed mitosis, chromosomes with larger kinetochores were also strongly
biased to establish erroneous merotelic attachments and missegregate during
anaphase. This bias was impervious to the experimental attenuation of polar
ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a.
Thus, kinetochore size is an important determinant of chromosome segregation
fidelity.
Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.cub.2018.03.023
PMCID: PMC5954971
PMID: 29706521 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35385739 | 1. Cell Rep. 2022 Apr 5;39(1):110610. doi: 10.1016/j.celrep.2022.110610.
Augmin-dependent microtubule self-organization drives kinetochore fiber
maturation in mammals.
Almeida AC(1), Soares-de-Oliveira J(1), Drpic D(1), Cheeseman LP(1), Damas J(2),
Lewin HA(3), Larkin DM(4), Aguiar P(5), Pereira AJ(1), Maiato H(6).
Author information:
(1)Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto,
Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Biologia Molecular
e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto,
Portugal.
(2)Department of Comparative Biomedical Sciences, Royal Veterinary College,
University of London, London NW1 0TU, UK; Department of Evolution and Ecology,
University of California, Davis, CA 95616, USA.
(3)Department of Evolution and Ecology, University of California, Davis, CA
95616, USA.
(4)Department of Comparative Biomedical Sciences, Royal Veterinary College,
University of London, London NW1 0TU, UK.
(5)Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto,
Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto Nacional de
Engenharia Biomédica (INEB), Universidade do Porto, Rua Alfredo Allen 208,
4200-135 Porto, Portugal.
(6)Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto,
Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Biologia Molecular
e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto,
Portugal; Cell Division Group, Department of Biomedicine, Faculdade de Medicina,
Universidade do Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto,
Portugal. Electronic address: [email protected].
Chromosome segregation in mammals relies on the maturation of a thick bundle of
kinetochore-attached microtubules known as k-fiber. How k-fibers mature from
initial kinetochore microtubule attachments remains a fundamental question. By
combining molecular perturbations and phenotypic analyses in Indian muntjac
fibroblasts containing the lowest known diploid chromosome number in mammals
(2N = 6) and distinctively large kinetochores, with fixed/live-cell
super-resolution coherent-hybrid stimulated emission depletion (CH-STED)
nanoscopy and laser microsurgery, we demonstrate a key role for augmin in
kinetochore microtubule self-organization and maturation, regardless of pioneer
centrosomal microtubules. In doing so, augmin promotes kinetochore and
interpolar microtubule turnover and poleward flux. Tracking of microtubule
growth events within individual k-fibers reveals a wide angular dispersion,
consistent with augmin-mediated branched microtubule nucleation. Augmin
depletion reduces the frequency of kinetochore microtubule growth events and
hampers efficient repair after acute k-fiber injury by laser microsurgery.
Together, these findings underscore the contribution of augmin-mediated
microtubule amplification for k-fiber self-organization and maturation in
mammals.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2022.110610
PMCID: PMC8994134
PMID: 35385739 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33613099 | 1. Pattern Anal Appl. 2021;24(3):993-1005. doi: 10.1007/s10044-021-00958-0. Epub
2021 Feb 15.
Coronavirus disease 2019 (COVID-19): survival analysis using deep learning and
Cox regression model.
Atlam M(1), Torkey H(1), El-Fishawy N(1), Salem H(2).
Author information:
(1)Computer Science & Engineering Department, Faculty of Electronic Engineering,
Menoufia University, Menouf, Egypt.
(2)Faculty of Engineering, Delta University for Science and Technology, Gamasa,
Egypt.
Coronavirus (COVID-19) is one of the most serious problems that has caused
stopping the wheel of life all over the world. It is widely spread to the extent
that hospital places are not available for all patients. Therefore, most
hospitals accept patients whose recovery rate is high. Machine learning
techniques and artificial intelligence have been deployed for computing
infection risks, performing survival analysis and classification. Survival
analysis (time-to-event analysis) is widely used in many areas such as
engineering and medicine. This paper presents two systems, Cox_COVID_19 and
Deep_ Cox_COVID_19 that are based on Cox regression to study the survival
analysis for COVID-19 and help hospitals to choose patients with better chances
of survival and predict the most important symptoms (features) affecting
survival probability. Cox_COVID_19 is based on Cox regression and
Deep_Cox_COVID_19 is a combination of autoencoder deep neural network and Cox
regression to enhance prediction accuracy. A clinical dataset for COVID-19
patients is used. This dataset consists of 1085 patients. The results show that
applying an autoencoder on the data to reconstruct features, before applying Cox
regression algorithm, would improve the results by increasing concordance,
accuracy and precision. For Deep_ Cox_COVID_19 system, it has a concordance of
0.983 for training and 0.999 for testing, but for Cox_COVID_19 system, it has a
concordance of 0.923 for training and 0.896 for testing. The most important
features affecting mortality are, age, muscle pain, pneumonia and throat pain.
Both Cox_COVID_19 and Deep_ Cox_COVID_19 prediction systems can predict the
survival probability and present significant symptoms (features) that
differentiate severe cases and death cases. But the accuracy of
Deep_Cox_Covid_19 outperforms that of Cox_Covid_19. Both systems can provide
definite information for doctors about detection and intervention to be taken,
which can reduce mortality.
© The Author(s), under exclusive licence to Springer-Verlag London Ltd. part of
Springer Nature 2021.
DOI: 10.1007/s10044-021-00958-0
PMCID: PMC7883884
PMID: 33613099 |
http://www.ncbi.nlm.nih.gov/pubmed/31879909 | 1. Methods Mol Biol. 2020;2101:247-266. doi: 10.1007/978-1-0716-0219-5_16.
Functional Dissection of Mitosis Using Immortalized Fibroblasts from the Indian
Muntjac, a Placental Mammal with Only Three Chromosomes.
Almeida AC(1)(2)(3), Drpic D(1)(2), Okada N(1)(2), Bravo J(4), Madureira M(4),
Maiato H(5)(6)(7).
Author information:
(1)Chromosome Instability & Dynamics Laboratory, IBMC - Instituto de Biologia
Molecular e Celular, Universidade do Porto, Porto, Portugal.
(2)i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal.
(3)Graduate Program in Biomedicine, Faculdade de Medicina, Universidade do
Porto, Porto, Portugal.
(4)Graduate Program in Areas of Basic and Applied Biology (GABBA), Instituto de
Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
(5)Chromosome Instability & Dynamics Laboratory, IBMC - Instituto de Biologia
Molecular e Celular, Universidade do Porto, Porto, Portugal. [email protected].
(6)i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto,
Porto, Portugal. [email protected].
(7)Experimental Biology Unit, Faculdade de Medicina, Cell Division Group,
Department of Biomedicine, Universidade do Porto, Porto, Portugal.
[email protected].
During cell division in eukaryotes a microtubule-based network undergoes drastic
changes and remodeling to assemble a mitotic spindle competent to segregate
chromosomes. Several model systems have been widely used to dissect the
molecular and structural mechanisms behind mitotic spindle assembly and
function. These include budding and fission yeasts, which are ideal for genetic
and molecular approaches, but show limitations in high-resolution live-cell
imaging, while being evolutionarily distant from humans. On the other hand,
systems that were historically used for their exceptional properties for
live-cell imaging of mitosis (e.g., newt lung cells and Haemanthus endosperm
cells) lack the necessary genomic tools for molecular studies. In a CRISPR-Cas9
era, human cultured cells have conquered the privilege to be positioned among
the most powerful genetically manipulatable systems, but their high chromosome
number remains a significant bottleneck for the molecular dissection of mitosis
in mammals. We believe that we can significantly broaden this scenario by
establishing a unique placental mammal model system that combines the powerful
genetic tools and low chromosome number of fission yeast and Drosophila
melanogaster, with the exceptional cytological features of a rat kangaroo cell.
This system is based on hTERT-immortalized fibroblasts from a female Indian
muntjac, a placental mammal with the lowest known chromosome number (n = 3).
Here we describe a series of methodologies established in our laboratory for the
study of mitosis in Indian muntjac. These include standard techniques such as
immunofluorescence, western blotting, and FISH, but also several
state-of-the-art methodologies, including live-cell imaging, cell confinement,
RNAi, super-resolution STED microscopy, and laser microsurgery.
DOI: 10.1007/978-1-0716-0219-5_16
PMID: 31879909 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16791631 | 1. Chromosoma. 2006 Dec;115(6):427-36. doi: 10.1007/s00412-006-0066-4. Epub 2006
Jun 22.
Comparative genomic analysis links karyotypic evolution with genomic evolution
in the Indian muntjac (Muntiacus muntjak vaginalis).
Zhou Q(1), Huang L, Zhang J, Zhao X, Zhang Q, Song F, Chi J, Yang F, Wang W.
Author information:
(1)CAS-Max Planck Junior Research Group, Key Laboratory of Cellular and
Molecular Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences,
Kunming, Yunnan, 650223, People's Republic of China.
The karyotype of Indian muntjacs (Muntiacus muntjak vaginalis) has been greatly
shaped by chromosomal fusion, which leads to its lowest diploid number among the
extant known mammals. We present, here, comparative results based on draft
sequences of 37 bacterial artificial clones (BAC) clones selected by chromosome
painting for this special muntjac species. Sequence comparison on these BAC
clones uncovered sequence syntenic relationships between the muntjac genome and
those of other mammals. We found that the muntjac genome has peculiar features
with respect to intron size and evolutionary rates of genes. Inspection of more
than 80 pairs of orthologous introns from 15 genes reveals a significant
reduction in intron size in the Indian muntjac compared to that of human, mouse,
and dog. Evolutionary analysis using 19 genes indicates that the muntjac genes
have evolved rapidly compared to other mammals. In addition, we identified and
characterized sequence composition of the first BAC clone containing a
chromosomal fusion site. Our results shed new light on the genome architecture
of the Indian muntjac and suggest that chromosomal rearrangements have been
accompanied by other salient genomic changes.
DOI: 10.1007/s00412-006-0066-4
PMID: 16791631 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/5444269 | 1. Science. 1970 Jun 12;168(3937):1364-6. doi: 10.1126/science.168.3937.1364.
Indian muntjac, Muntiacus muntjak: a deer with a low diploid chromosome number.
Wurster DH, Benirschke K.
The Indian muntjac (Muntiacus muntjak) has a diploid chromosome number of 7 in
the male and 6 in the female, the lowest number yet described in a mammal. Its
near relative, Reeve's muntjac (Muntiacus reevesi) has a diploid number of 46,
and the karyotypes of the two, species are very different.
DOI: 10.1126/science.168.3937.1364
PMID: 5444269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8485991 | 1. Cytogenet Cell Genet. 1993;63(3):156-9. doi: 10.1159/000133525.
Interstitial localization of telomeric DNA sequences in the Indian muntjac
chromosomes: further evidence for tandem chromosome fusions in the karyotypic
evolution of the Asian muntjacs.
Lee C(1), Sasi R, Lin CC.
Author information:
(1)Department of Laboratory Medicine and Pathology, University of Alberta,
Edmonton, Canada.
The Indian muntjac is believed to have the lowest chromosome number in mammals
(2n = 6 in females and 2n = 7 in males). It has been suggested that a series of
tandem chromosome fusions from an ancestral Chinese muntjac-like species (2n =
46) may have occurred during the karyotypic evolution of the Indian muntjac. In
an earlier study, hybridization signals generated by the Chinese muntjac
centromeric heterochromatin DNA probe (C5) were found to be distributed
interstitially in the chromosomes of the Indian muntjac, providing supportive
evidence for the tandem chromosome fusion theory. In this study, the highly
conserved human telomeric DNA sequence (TTAGGG)n was localized by fluorescence
in situ hybridization (FISH) on the metaphase chromosomes of three Cervidae
species: the Indian muntjac, Chinese muntjac, and woodland caribou. As expected,
hybridization signals were observed at the termini of almost every chromosome in
all three species. In addition, interstitial hybridization signals were detected
in chromosomes 1 and 2 of the Indian muntjac. The observed interstitial
telomeric signals appeared to correspond to specific interstitial centromeric
heterochromatin sites. These interstitial telomeric signals could represent
remnant DNA sequences from the ancestral species telomeres, further supporting
the tandem chromosome fusion theory. Furthermore, these observations permit the
elucidation of the chromosome sites where breakage and fusion most likely
occurred during the restructuring of the ancestral Chinese muntjac-like
chromosomes to form the present day Indian muntjac karyotype.
DOI: 10.1159/000133525
PMID: 8485991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8513693 | 1. Cytometry. 1993;14(4):362-8. doi: 10.1002/cyto.990140404.
DNA content measurements and an improved idiogram for the Indian muntjac.
Levy HP(1), Schultz RA, Ordonez JV, Cohen MM.
Author information:
(1)Department of Obstetrics and Gynecology, University of Maryland, Baltimore
21201.
The Indian muntjac, an asiatic deer, has the lowest diploid chromosome number
among mammals (female 2N = 6; male 2N = 7). Using flow cytometric quantification
of propidium iodide-stained cells, we determined the DNA content of muntjac
cells to be 94% that of human. This suggests that the muntjac may serve as a
model for investigation of karyotypic evolution and rearrangement. In order to
facilitate future comparative gene mapping studies, computer-aided analysis of
digitized metaphase chromosomes allowed development of a detailed Indian muntjac
G-banded idiogram incorporating both ISCN-type nomenclature and quantitative
estimates of the size of each band and position.
DOI: 10.1002/cyto.990140404
PMID: 8513693 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10611321 | 1. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14967-72. doi:
10.1073/pnas.96.26.14967.
Methylation of histone H3 at lysine 4 is highly conserved and correlates with
transcriptionally active nuclei in Tetrahymena.
Strahl BD(1), Ohba R, Cook RG, Allis CD.
Author information:
(1)Department of Biochemistry, University of Virginia Health Science Center,
Charlottesville, VA 22908, USA.
Studies into posttranslational modifications of histones, notably acetylation,
have yielded important insights into the dynamic nature of chromatin structure
and its fundamental role in gene expression. The roles of other covalent histone
modifications remain poorly understood. To gain further insight into histone
methylation, we investigated its occurrence and pattern of site utilization in
Tetrahymena, yeast, and human HeLa cells. In Tetrahymena, transcriptionally
active macronuclei, but not transcriptionally inert micronuclei, contain a
robust histone methyltransferase activity that is highly selective for H3.
Microsequence analyses of H3 from Tetrahymena, yeast, and HeLa cells indicate
that lysine 4 is a highly conserved site of methylation, which to date, is the
major site detected in Tetrahymena and yeast. These data document a nonrandom
pattern of H3 methylation that does not overlap with known acetylation sites in
this histone. In as much as H3 methylation at lysine 4 appears to be specific to
macronuclei in Tetrahymena, we suggest that this modification pattern plays a
facilitatory role in the transcription process in a manner that remains to be
determined. Consistent with this possibility, H3 methylation in yeast occurs
preferentially in a subpopulation of H3 that is preferentially acetylated.
DOI: 10.1073/pnas.96.26.14967
PMCID: PMC24756
PMID: 10611321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11893494 | 1. Curr Opin Genet Dev. 2002 Apr;12(2):198-209. doi:
10.1016/s0959-437x(02)00287-3.
Histone methylation in transcriptional control.
Kouzarides T(1).
Author information:
(1)Wellcome/CRC Institute and Department of Pathology, University of Cambridge,
Tennis Court Road, Cambridge CB2 1QR, UK. [email protected]
Erratum in
Curr Opin Genet Dev 2002 Jun;12(3):371.
Over the past year or so, methylation of histones has come to be recognised as a
major player in the regulation of gene activity. This notion follows the
discovery of lysine and arginine methyltransferases and proteins that recognise
the methyl-lysine 'mark' on histones. Methylated histones have been implicated
in heterochromatic repression, promoter regulation and the propagation of a
repressed state via DNA methylation.
DOI: 10.1016/s0959-437x(02)00287-3
PMID: 11893494 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15248813 | 1. Crit Rev Eukaryot Gene Expr. 2004;14(3):147-69. doi:
10.1615/critreveukaryotgeneexpr.v14.i3.10.
Structure and function of histone methyltransferases.
Trievel RC(1).
Author information:
(1)University of Michigan Medical School, Department of Biological Chemistry,
Ann Arbor, MI 48109-0606, USA. [email protected]
Histones are the major protein constituent of chromatin in the eukaryotic
nucleus. These proteins undergo a host of different post-translational
modifications, including phosphorylation, acetylation, and methylation, which
have profound effects on the remodeling of chromatin. Histone modifications can
function either individually or combinatorially to govern such processes as
transcription, replication, DNA repair, and apoptosis. Recent studies have
focused on histone arginine and lysine methylation and the roles of these
modifications in transcriptional regulation and the establishment of
heterochromatin. Concomitantly, several families of histone methyltransferases
(HMTs) have been identified that catalyze the methylation of specific arginines
or lysines in histones H3 and H4. Not surprisingly, many of these
methyltransferase genes had been previously identified as important genetic
regulators in organisms such as yeast and Drosophila, which underscores the
importance of histone methylation in transcriptional control and chromatin
remodeling. Structures of several representatives of these HMT families have
recently been determined, yielding insight into their catalytic mechanism and
histone substrate specificity. The focus of this review is to briefly summarize
the roles of histone methylation in chromatin remodeling and to discuss the
structures, substrate specificities, and mechanisms of the different classes of
HMTs.
DOI: 10.1615/critreveukaryotgeneexpr.v14.i3.10
PMID: 15248813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23892751 | 1. Appl Environ Microbiol. 2013 Oct;79(19):6102-9. doi: 10.1128/AEM.01578-13.
Epub 2013 Jul 26.
Distinct amino acids of histone H3 control secondary metabolism in Aspergillus
nidulans.
Nützmann HW(1), Fischer J, Scherlach K, Hertweck C, Brakhage AA.
Author information:
(1)Department of Molecular and Applied Microbiology.
Chromatin remodelling events play an important role in the secondary metabolism
of filamentous fungi. Previously, we showed that a bacterium, Streptomyces
rapamycinicus, is able to reprogram the histone-modifying
Spt-Ada-Gcn5-acetyltransferase/ADA (SAGA/ADA) complex of the model fungus
Aspergillus nidulans. Consequently, the histone H3 amino acids lysine 9 and
lysine 14 at distinct secondary metabolism genes were specifically acetylated
during the bacterial fungal interaction, which, furthermore, was associated with
the activation of the otherwise silent orsellinic acid gene cluster. To
investigate the importance of the histone modifications for distinct gene
expression profiles in fungal secondary metabolism, we exchanged several amino
acids of histone H3 of A. nidulans. These amino acids included lysine residues
9, 14, 18, and 23 as well as serine 10 and threonine 11. Lysine residues were
replaced by arginine or glutamine residues, and serine/threonine residues were
replaced by alanine. All generated mutant strains were viable, allowing direct
analysis of the consequences of missing posttranslational histone modifications.
In the mutant strains, major changes in the expression patterns at both the
transcriptional and metabolite levels of the penicillin, sterigmatocystin, and
orsellinic acid biosynthesis gene clusters were detected. These effects were due
mainly to the substitution of the acetylatable lysine 14 of histone H3 and were
enhanced in a lysine 14/lysine 9 double mutant of histone H3. Taken together,
our findings show a causal linkage between the acetylation of lysine residue 14
of histone H3 and the transcription and product formation of secondary
metabolite gene clusters.
DOI: 10.1128/AEM.01578-13
PMCID: PMC3811361
PMID: 23892751 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24068969 | 1. PLoS Genet. 2013;9(9):e1003805. doi: 10.1371/journal.pgen.1003805. Epub 2013
Sep 19.
N-alpha-terminal acetylation of histone H4 regulates arginine methylation and
ribosomal DNA silencing.
Schiza V(1), Molina-Serrano D, Kyriakou D, Hadjiantoniou A, Kirmizis A.
Author information:
(1)Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
Post-translational modifications of histones play a key role in DNA-based
processes, like transcription, by modulating chromatin structure. N-terminal
acetylation is unique among the numerous histone modifications because it is
deposited on the N-alpha amino group of the first residue instead of the
side-chain of amino acids. The function of this modification and its interplay
with other internal histone marks has not been previously addressed. Here, we
identified N-terminal acetylation of H4 (N-acH4) as a novel regulator of
arginine methylation and chromatin silencing in Saccharomyces cerevisiae. Lack
of the H4 N-alpha acetyltransferase (Nat4) activity results specifically in
increased deposition of asymmetric dimethylation of histone H4 arginine 3
(H4R3me2a) and in enhanced ribosomal-DNA silencing. Consistent with this, H4
N-terminal acetylation impairs the activity of the Hmt1 methyltransferase
towards H4R3 in vitro. Furthermore, combinatorial loss of N-acH4 with internal
histone acetylation at lysines 5, 8 and 12 has a synergistic induction of
H4R3me2a deposition and rDNA silencing that leads to a severe growth defect.
This defect is completely rescued by mutating arginine 3 to lysine (H4R3K),
suggesting that abnormal deposition of a single histone modification, H4R3me2a,
can impact on cell growth. Notably, the cross-talk between N-acH4 and H4R3me2a,
which regulates rDNA silencing, is induced under calorie restriction conditions.
Collectively, these findings unveil a molecular and biological function for H4
N-terminal acetylation, identify its interplay with internal histone
modifications, and provide general mechanistic implications for N-alpha-terminal
acetylation, one of the most common protein modifications in eukaryotes.
DOI: 10.1371/journal.pgen.1003805
PMCID: PMC3778019
PMID: 24068969 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/18603028 | 1. Biochim Biophys Acta. 2009 Jan;1789(1):45-57. doi:
10.1016/j.bbagrm.2008.06.005. Epub 2008 Jun 14.
Chemical mechanisms of histone lysine and arginine modifications.
Smith BC(1), Denu JM.
Author information:
(1)Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin
53706, USA.
Histone lysine and arginine residues are subject to a wide array of
post-translational modifications including methylation, citrullination,
acetylation, ubiquitination, and sumoylation. The combinatorial action of these
modifications regulates critical DNA processes including replication, repair,
and transcription. In addition, enzymes that modify histone lysine and arginine
residues have been correlated with a variety of human diseases including
arthritis, cancer, heart disease, diabetes, and neurodegenerative disorders.
Thus, it is important to fully understand the detailed kinetic and chemical
mechanisms of these enzymes. Here, we review recent progress towards determining
the mechanisms of histone lysine and arginine modifying enzymes. In particular,
the mechanisms of S-adenosyl-methionine (AdoMet) dependent methyltransferases,
FAD-dependent demethylases, iron dependent demethylases, acetyl-CoA dependent
acetyltransferases, zinc dependent deacetylases, NAD(+) dependent deacetylases,
and protein arginine deiminases are covered. Particular attention is paid to the
conserved active-site residues necessary for catalysis and the individual
chemical steps along the catalytic pathway. When appropriate, areas requiring
further work are discussed.
DOI: 10.1016/j.bbagrm.2008.06.005
PMCID: PMC2642981
PMID: 18603028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22923743 | 1. J Biochem. 2012 Nov;152(5):453-62. doi: 10.1093/jb/mvs093. Epub 2012 Aug 25.
Inhibition of acetyltransferase alters different histone modifications: probed
by small molecule inhibitor plumbagin.
Dalvoy Vasudevarao M(1), Dhanasekaran K, Selvi RB, Kundu TK.
Author information:
(1)Transcription and Disease Laboratory, Jawaharlal Nehru Centre for Advanced
Scientific Research, Jakkur, Bangalore-560064, India.
Histone modifications; acetylation, methylation (both Lysine and Arginine) etc.,
at different positions regulates the chromatin fluidity and function in a
combinatorial manner, which could be referred as an epigenetic language. In the
context of transcription, histone acetylation, methylation and phosphorylation
at specific sites, especially at the N-terminal tails of histones play very
important roles in activation and/or repression. While acetylation of histones
is generally important for transcriptional activation, methylation and
phosphorylation could also be involved in repression, depending on the context.
Here, we have investigated the crosstalk of histone modifications on a gross
scale over histone H3, using a small molecule inhibitor of lysine
acetyltransferase KAT3B/p300, Plumbagin, to analyze the histone modification
profile upon inhibition of acetylation. In addition to the inhibition of
acetylation, there was a concomitant decrease of transcriptional activation
mark, H3 lysine 4 trimethylation (H3K4me3) in the cellular context. The histone
H3 Serine 10 Phosphorylation (H3S10p) also decreased upon inhibition of
acetylation. However, there were no changes observed with transcriptional
repressive marks like H3 Lysine 9 di/trimethylation (H3K9me2/me3) suggesting
that transcriptional activation marks were selectively targeted. These data
suggest that Plumbagin induces a distinct modification profile involving
transcriptional activation marks H3K4me3 and H3S10 phosphorylation in the
context of histone acetylation brought about by KAT3B/ p300.
DOI: 10.1093/jb/mvs093
PMID: 22923743 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30940741 | 1. Essays Biochem. 2019 Apr 23;63(1):97-107. doi: 10.1042/EBC20180061. Print 2019
Apr 23.
Acetylation & Co: an expanding repertoire of histone acylations regulates
chromatin and transcription.
Barnes CE(1), English DM(1), Cowley SM(2).
Author information:
(1)Department of Molecular and Cell Biology, University of Leicester, Leicester,
U.K.
(2)Department of Molecular and Cell Biology, University of Leicester, Leicester,
U.K. [email protected].
Packaging the long and fragile genomes of eukaryotic species into nucleosomes is
all well and good, but how do cells gain access to the DNA again after it has
been bundled away? The solution, in every species from yeast to man, is to
post-translationally modify histones, altering their chemical properties to
either relax the chromatin, label it for remodelling or make it more compact
still. Histones are subject to a myriad of modifications: acetylation,
methylation, phosphorylation, ubiquitination etc. This review focuses on histone
acylations, a diverse group of modifications which occur on the ε-amino group of
Lysine residues and includes the well-characterised Lysine acetylation. Over the
last 50 years, histone acetylation has been extensively characterised, with the
discovery of histone acetyltransferases (HATs) and histone deacetylases (HDACs),
and global mapping experiments, revealing an association of hyperacetylated
histones with accessible, transcriptionally active chromatin. More recently,
there has been an explosion in the number of unique short chain 'acylations'
identified by MS, including: propionylation, butyrylation, crotonylation,
succinylation, malonylation and 2-hydroxyisobutyrylation. These novel
modifications add a range of chemical environments to histones, and similar to
acetylation, appear to accumulate at transcriptional start sites and correlate
with gene activity.
© 2019 The Author(s).
DOI: 10.1042/EBC20180061
PMCID: PMC6484784
PMID: 30940741 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there are no competing
interests associated with the manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/11395403 | 1. Annu Rev Biochem. 2001;70:81-120. doi: 10.1146/annurev.biochem.70.1.81.
Histone acetyltransferases.
Roth SY(1), Denu JM, Allis CD.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, USA. [email protected]
Transcriptional regulation in eukaryotes occurs within a chromatin setting and
is strongly influenced by nucleosomal barriers imposed by histone proteins.
Among the well-known covalent modifications of histones, the reversible
acetylation of internal lysine residues in histone amino-terminal domains has
long been positively linked to transcriptional activation. Recent biochemical
and genetic studies have identified several large, multisubunit enzyme complexes
responsible for bringing about the targeted acetylation of histones and other
factors. This review discusses our current understanding of histone
acetyltransferases (HATs) or acetyltransferases (ATs): their discovery,
substrate specificity, catalytic mechanism, regulation, and functional links to
transcription, as well as to other chromatin-modifying activities. Recent
studies underscore unexpected connections to both cellular regulatory processes
underlying normal development and differentiation, as well as abnormal processes
that lead to oncogenesis. Although the functions of HATs and the mechanisms by
which they are regulated are only beginning to be understood, these fundamental
processes are likely to have far-reaching implications for human biology and
disease.
DOI: 10.1146/annurev.biochem.70.1.81
PMID: 11395403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28450737 | 1. Exp Mol Med. 2017 Apr 28;49(4):e324. doi: 10.1038/emm.2017.11.
Writing, erasing and reading histone lysine methylations.
Hyun K(1), Jeon J(1), Park K(1), Kim J(1).
Author information:
(1)Laboratory of Eukaryotic Transcription, Department of Biological Sciences,
Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Histone modifications are key epigenetic regulatory features that have important
roles in many cellular events. Lysine methylations mark various sites on the
tail and globular domains of histones and their levels are precisely balanced by
the action of methyltransferases ('writers') and demethylases ('erasers'). In
addition, distinct effector proteins ('readers') recognize specific
methyl-lysines in a manner that depends on the neighboring amino-acid sequence
and methylation state. Misregulation of histone lysine methylation has been
implicated in several cancers and developmental defects. Therefore, histone
lysine methylation has been considered a potential therapeutic target, and
clinical trials of several inhibitors of this process have shown promising
results. A more detailed understanding of histone lysine methylation is
necessary for elucidating complex biological processes and, ultimately, for
developing and improving disease treatments. This review summarizes enzymes
responsible for histone lysine methylation and demethylation and how histone
lysine methylation contributes to various biological processes.
DOI: 10.1038/emm.2017.11
PMCID: PMC6130214
PMID: 28450737 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32890768 | 1. Biochim Biophys Acta Gene Regul Mech. 2021 Feb;1864(2):194629. doi:
10.1016/j.bbagrm.2020.194629. Epub 2020 Sep 2.
The Ada2/Ada3/Gcn5/Sgf29 histone acetyltransferase module.
Espinola-Lopez JM(1), Tan S(2).
Author information:
(1)Center for Eukaryotic Gene Regulation, Department of Biochemistry and
Molecular Biology, The Pennsylvania State University, University Park, PA 16802,
USA.
(2)Center for Eukaryotic Gene Regulation, Department of Biochemistry and
Molecular Biology, The Pennsylvania State University, University Park, PA 16802,
USA. Electronic address: [email protected].
Histone post-translational modifications are essential for the regulation of
gene expression in eukaryotes. Gcn5 (KAT2A) is a histone acetyltransferase that
catalyzes the post-translational modification at multiple positions of histone
H3 through the transfer of acetyl groups to the free amino group of lysine
residues. Gcn5 catalyzes histone acetylation in the context of a HAT module
containing the Ada2, Ada3 and Sgf29 subunits of the parent megadalton SAGA
transcriptional coactivator complex. Biochemical and structural studies have
elucidated mechanisms for Gcn5's acetyl- and other acyltransferase activities on
histone substrates, for histone H3 phosphorylation and histone H3 methylation
crosstalks with histone H3 acetylation, and for how Ada2 increases Gcn5's
histone acetyltransferase activity. Other studies have identified Ada2 isoforms
in SAGA-related complexes and characterized variant Gcn5 HAT modules containing
these Ada2 isoforms. In this review, we highlight biochemical and structural
studies of Gcn5 and its functional interactions with Ada2, Ada3 and Sgf29.
Copyright © 2020 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2020.194629
PMCID: PMC8351874
PMID: 32890768 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24781734 | 1. J Physiol Pharmacol. 2014 Apr;65(2):247-55.
Social isolation-induced epigenetic changes in midbrain of adult mice.
Siuda D(1), Wu Z, Chen Y, Guo L, Linke M, Zechner U, Xia N, Reifenberg G,
Kleinert H, Forstermann U, Li H.
Author information:
(1)Department of Pharmacology, University Medical Center, Johannes Gutenberg
University, Mainz, Germany. [email protected].
Social isolation and loneliness increase the risk of death as much as
well-established risk factors for mortality such as cigarette smoking and
alcohol consumption. The underlying molecular mechanisms are poorly understood.
In the present study, 3 months old male C57BL/6 mice were socially isolated by
individual housing for another 3 months. At the age of 6 months, epigenetic
changes were analyzed in midbrain. Social isolation of male adult mice led to an
increased global DNA methylation, which was associated with enhanced activity of
DNA methyltransferase. Di- and trimethylation of global histone H3 lysine 4
(H3K4) were increased in midbrain of socially isolated mice, accompanied by
enhanced H3K4 histone methyltransferase activity. In addition, social isolation
of adult mice led to activation of histone acetyltransferases as well as of
histone deacetylases (HDAC) resulting in a net enhancement of histone H3 lysine
9 (H3K9) acetylation. Gene-specific effects were observed for Hdac1, Hdac3 and
the serotonin transporter Slc6a4. Social isolation led to an up-regulation of
Hdac1 and Hdac3, associated with decreased DNA methylation in the CpG island of
the respective genes. On the contrary, the Slc6a4 gene was down-regulated, which
was associated with enhanced DNA methylation. Collectively, the results from the
present study demonstrate for the first time that social isolation of adult mice
leads to a wide range of global epigenetic changes and these effects may have
profound impact on gene expression pattern and phenotype of the socially
isolated animals.
PMID: 24781734 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21273441 | 1. Mol Endocrinol. 2011 Mar;25(3):433-44. doi: 10.1210/me.2010-0482. Epub 2011
Jan 27.
Lysine methylation and functional modulation of androgen receptor by Set9
methyltransferase.
Ko S(1), Ahn J, Song CS, Kim S, Knapczyk-Stwora K, Chatterjee B.
Author information:
(1)Department of Molecular Medicine/Institute Biotechnology, The University of
Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio,
Texas 78245, USA.
Lysine methyltransferases modulate activities of transcription factors and
transcription coregulators by methylating specific lysine residue(s). We report
that the androgen receptor (AR) is methylated at lysine-630 by Set9, which was
originally identified as a histone H3K4 monomethyltransferase. Alanine
substitution of lysine-630 prevented AR methylation in vitro and in vivo. Set9
methylated the nuclear and cytoplasmic AR utilizing the cofactor
S-adenosyl-methionine. A pan-methyllysine antibody recognized endogenous AR, and
Set9 coimmunoprecipitated with nuclear and cytoplasmic AR. Set9 overexpression
potentiated AR-mediated transactivation of the probasin promoter, whereas Set9
depletion inhibited AR activity and target gene expression. Similar to AR,
chromatin occupancy of Set9 at androgen response elements (AREs) was androgen
dependent, and associated with methylated histone H3K4 chromatin activation
marks and p300/CBP associated factor acetyltransferase recruitment. Set9
depletion increased the histone H3K9-dimethyl repressive mark at AREs and
reduced histone activation marks and occupancy of p300/CBP associated factor.
K630A mutation reduced amino- and carboxy-terminal (N-C) interaction in
Set9-intact cells, whereas N-C interaction for wild-type AR was reduced upon
Set9 depletion. The K630A mutant was resistant to loss of activity from Set9
silencing and to increase of activity from Set9 overexpression. The K630
dependence of Set9-regulated N-C interaction and AR activity suggests that Set9
directly acts on AR at the amino acid level. Chromatin recruitment of Set9 to
AREs is suggestive of its additional role as a transcriptional coactivator.
Because the cellular metabolic state determines the level of
S-adenosylmethionine and consequently the activity of Set9, the enhanced
activity of methylated AR may have special significance in certain metabolic
contexts.
DOI: 10.1210/me.2010-0482
PMCID: PMC3045741
PMID: 21273441 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32420474 | 1. Heliyon. 2020 May 12;6(5):e03864. doi: 10.1016/j.heliyon.2020.e03864.
eCollection 2020 May.
Protein arginine methyltransferase 6 mediates cardiac hypertrophy by
differential regulation of histone H3 arginine methylation.
Raveendran VV(1), Al-Haffar K(1), Kunhi M(1), Belhaj K(2), Al-Habeeb W(3),
Al-Buraiki J(3), Eyjolsson A(4), Poizat C(1)(5).
Author information:
(1)Cardiovascular Research Program, King Faisal Specialist Hospital and Research
Center, Riyadh, Saudi Arabia.
(2)College of Medicine, Al Faisal University, PO Box 50927, Riyadh 11211, Saudi
Arabia.
(3)King Saud University, Riyadh, Saudi Arabia.
(4)Heart Centre, King Faisal Specialist Hospital and Research Center, Riyadh,
Saudi Arabia.
(5)Masonic Medical Research Institute, Utica, NY 13501, USA.
Heart failure remains a major cause of hospitalization and death worldwide.
Heart failure can be caused by abnormalities in the epigenome resulting from
dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing
lysine acetylation and methylation of histones have been the topic of many
investigations, the role of arginine methyltransferases has been overlooked. In
an effort to understand regulatory mechanisms implicated in cardiac hypertrophy
and heart failure, we assessed the expression of protein arginine
methyltransferases (PRMTs) in the left ventricle of failing human hearts and
control hearts. Our results show a significant up-regulation of protein arginine
methyltransferase 6 (PRMT6) in failing human hearts compared to control hearts,
which also occurs in the early phase of cardiac hypertrophy in mouse hearts
subjected to pressure overload hypertrophy induced by trans-aortic constriction
(TAC), and in neonatal rat ventricular myocytes (NRVM) stimulated with the
hypertrophic agonist phenylephrine (PE). These changes are associated with a
significant increase in arginine 2 asymmetric methylation of histone H3
(H3R2Me2a) and reduced lysine 4 tri-methylation of H3 (H3K4Me3) observed both in
NRVM and in vivo. Importantly, forced expression of PRMT6 in NRVM enhances the
expression of the hypertrophic marker, atrial natriuretic peptide (ANP).
Conversely, specific silencing of PRMT6 reduces ANP protein expression and cell
size, indicating that PRMT6 is critical for the PE-mediated hypertrophic
response. Silencing of PRMT6 reduces H3R2Me2a, a mark normally associated with
transcriptional repression. Furthermore, evaluation of cardiac contractility and
global ion channel activity in live NRVM shows a striking reduction of
spontaneous beating rates and prolongation of extra-cellular field potentials in
cells expressing low-level PRMT6. Altogether, our results indicate that PRMT6 is
a critical regulator of cardiac hypertrophy, implicating H3R2Me2a as an
important histone modification. This study identifies PRMT6 as a new epigenetic
regulator and suggests a new point of control in chromatin to inhibit
pathological cardiac remodeling.
© 2020 The Author(s).
DOI: 10.1016/j.heliyon.2020.e03864
PMCID: PMC7218648
PMID: 32420474 |
http://www.ncbi.nlm.nih.gov/pubmed/34877957 | 1. Org Biomol Chem. 2021 Dec 22;20(1):173-181. doi: 10.1039/d1ob02191e.
Amide-derived lysine analogues as substrates and inhibitors of histone lysine
methyltransferases and acetyltransferases.
Hintzen JCJ(1), Merx J(2), Maas MN(1), Langens SGHA(2), White PB(2), Boltje
TJ(2), Mecinović J(1).
Author information:
(1)Department of Physics, Chemistry and Pharmacy, University of Southern
Denmark, Campusvej 55, 5230 Odense, Denmark. [email protected].
(2)Institute for Molecules and Materials, Radboud University, Heyendaalseweg
135, 6525AJ, Nijmegen, The Netherlands. [email protected].
Histone lysine methyltransferases and acetyltransferases are two classes of
epigenetic enzymes that play pivotal roles in human gene regulation. Although
they both recognise and posttranslationally modify lysine residues in histone
proteins, their difference in histone peptide-based substrates and inhibitors
remains to be firmly established. Here, we have synthesised lysine mimics that
posses an amide bond linker in the side chain, incorporated them into histone H3
tail peptides, and examined synthetic histone peptides as substrates and
inhibitors for human lysine methyltransferases and acetyltransferases. This work
demonstrates that histone lysine methyltransferases G9a and GLP do catalyse
methylation of the most similar lysine mimic, whereas they typically do not
tolerate more sterically demanding side chains. In contrast, histone lysine
acetyltransferases GCN5 and PCAF do not catalyse acetylation of the same panel
of lysine analogues. Our results also identify potent H3-based inhibitors of GLP
methyltransferase, providing a basis for development of peptidomimetics for
targeting KMT enzymes.
DOI: 10.1039/d1ob02191e
PMID: 34877957 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20054610 | 1. Plant Mol Biol. 2010 Apr;72(6):585-95. doi: 10.1007/s11103-009-9594-7.
Genome-wide profiling of histone H3 lysine 9 acetylation and dimethylation in
Arabidopsis reveals correlation between multiple histone marks and gene
expression.
Zhou J(1), Wang X, He K, Charron JB, Elling AA, Deng XW.
Author information:
(1)National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun
Life Science Park, 102206 Beijing, People's Republic of China.
[email protected]
Lysine residue 9 of histone H3 can either be acetylated or mono-, di-, or
tri-methylated. These epigenetic states have a diverse impact on regulating gene
transcriptional activity and chromatin organization. H3K9ac is invariably
correlated with transcriptional activation, whereas H3K9me2 has been reported to
be mainly located in constitutive heterochromatin in Arabidopsis. Here, we
present epigenetic landscapes for histone H3 lysine 9 acetylation (H3K9ac) and
dimethylation (H3K9me2) in Arabidopsis seedlings. The results show that H3K9ac
targeted 5,206 non-transposable element (non-TE) genes and 321 transposable
elements (TEs), whereas H3K9me2 targeted 2,281 TEs and 1,112 non-TE genes.
H3K9ac was biased towards the 5' end of genes and peaked at the ATG position,
while H3K9me2 tended to span the entire gene body. H3K9ac correlated with high
gene expression, while H3K9me2 correlated with low expression. Analyses of
H3K9ac and H3K9me2 with the available datasets of H3K27me3 and DNA methylation
revealed a correlation between the occurrence of multiple epigenetic
modifications and gene expression. Genes with H3K9ac alone were actively
transcribed, while genes that were also modified by either H3K27me3 or DNA
methylation showed a lower expression level, suggesting that a combination of
repressive marks weakened the positive regulatory effect of H3K9ac. Furthermore,
we observed a significant increase of the H3K9ac modification level of selected
target genes in hda19 (histone deacetylase 19) mutant seedlings, which indicated
that HDA19 plays an important role in regulating the level of H3K9ac and thereby
influencing the transcriptional activity in young seedlings.
DOI: 10.1007/s11103-009-9594-7
PMID: 20054610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19358899 | 1. Biochim Biophys Acta. 2009 May;1789(5):395-402. doi:
10.1016/j.bbagrm.2009.03.004. Epub 2009 Apr 7.
Functional connection between histone acetyltransferase Gcn5p and
methyltransferase Hmt1p.
Kuo MH(1), Xu XJ, Bolck HA, Guo D.
Author information:
(1)Department of Biochemistry and Molecular Biology, Programs in Cell and
Molecular Biology and in Genetics, Michigan State University, East Lansing, MI
48824, USA. [email protected]
Histone acetylation and methylation are linked to a variety of nuclear
activities, most notably transcriptional regulation. Both synergistic and
antagonistic relationships between these two modifications have been reported in
different systems. Here we show that the budding yeast histone H4 arginine 3
(R3) methyltransferase Hmt1p binds acetylated histones H3 and H4, and
importantly, that acetylated H4 is a significantly better methylation substrate
for Hmt1p. Kinetic studies show that acetylation at any of the four acetylatable
lysine residues of histone H4 results in more efficient methylation. Among the
four, K8 acetylation imposes the strongest effect on reducing K(M), consistent
with the observed acetylation-stimulated interaction. In vivo, hmt1Delta cells
rescue the transcriptional defect caused by GCN5 deletion, indicating that one
of the functions of Gcn5p is to neutralize the negative effect of Hmt1p.
Mutating either K8 or R3 to alanine causes similar growth defects in selective
histone and gcn5 mutant background, suggesting that these two residues function
in the same pathway for optimal vegetative growth. Together, these results
reveal a functional connection between histone acetylation, methylation, and two
of the responsible enzymes, Gcn5p and Hmt1p.
DOI: 10.1016/j.bbagrm.2009.03.004
PMCID: PMC2791397
PMID: 19358899 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30466474 | 1. Clin Epigenetics. 2018 Nov 22;10(1):145. doi: 10.1186/s13148-018-0583-z.
Tackling malignant melanoma epigenetically: histone lysine methylation.
Orouji E(1)(2)(3), Utikal J(4)(5).
Author information:
(1)Department of Genomic Medicine, University of Texas MD Anderson Cancer
Center, 1901 East Rd. South Campus Research Building 4, Houston, TX, 77054, USA.
[email protected].
(2)Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
[email protected].
(3)Department of Dermatology, Venereology and Allergology, University Medical
Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
[email protected].
(4)Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
(5)Department of Dermatology, Venereology and Allergology, University Medical
Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
Post-translational histone modifications such as acetylation and methylation can
affect gene expression. Histone acetylation is commonly associated with
activation of gene expression whereas histone methylation is linked to either
activation or repression of gene expression. Depending on the site of histone
modification, several histone marks can be present throughout the genome. A
combination of these histone marks can shape global chromatin architecture, and
changes in patterns of marks can affect the transcriptomic landscape.
Alterations in several histone marks are associated with different types of
cancers, and these alterations are distinct from marks found in original normal
tissues. Therefore, it is hypothesized that patterns of histone marks can change
during the process of tumorigenesis.This review focuses on histone methylation
changes (both removal and addition of methyl groups) in malignant melanoma, a
deadly skin cancer, and the implications of specific inhibitors of these
modifications as a combinatorial therapeutic approach.
DOI: 10.1186/s13148-018-0583-z
PMCID: PMC6249913
PMID: 30466474 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/19829087 | 1. Epigenetics. 2009 Oct 1;4(7):429-33. doi: 10.4161/epi.4.7.9787. Epub 2009 Oct
10.
Methylation, a new epigenetic mark for protein stability.
Yang XD(1), Lamb A, Chen LF.
Author information:
(1)Department of Biochemistry, College of Medicine, University of Illinois at
Urbana-Champaign, Urbana, IL, USA.
Recent studies on the lysine methylation of histones have moved rapidly thanks
to the discoveries of a variety of histone lysine methyltransferases. Histone
lysine methylation is known to either activate or repress gene expression
depending upon the position and status of the methylated lysine residue.
Recently, an increasing number of lysine methyltransferases have been identified
to modify non-histone proteins. Among those enzymes, the most extensively
studied is Set9, a SET domain-containing lysine methyltransferase. Set9 was
initially found to target histone H3 lysine 4 for monomethylation and was
subsequently shown to target a variety of non-histone proteins, especially
transcription-related factors. Functional studies revealed that Set9-mediated
methylation of different non-histone proteins leads to distinct biological
consequences, most of which point to protein stability. Here we summarize the
latest findings on the effects of Set9-mediated lysine methylation on the
stability of non-histone proteins.
DOI: 10.4161/epi.4.7.9787
PMID: 19829087 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18800048 | 1. Nat Chem Biol. 2008 Oct;4(10):590-7. doi: 10.1038/nchembio.111.
Chemical probes for histone-modifying enzymes.
Cole PA(1).
Author information:
(1)Department of Pharmacology and Molecular Sciences, Johns Hopkins
UniversitySchool of Medicine, 75 N. Wolfe Street, Baltimore, Maryland 21205,
USA. [email protected]
The histone-modifying enzymes that catalyze reversible lysine acetylation and
methylation are central to the epigenetic regulation of chromatin remodeling.
From the early discovery of histone deacetylase inhibitors to the more recent
identification of histone demethylase blockers, chemical approaches offer
increasingly sophisticated tools for the investigation of the structure and
function of these lysine-modifying enzymes. This review summarizes progress to
date on compounds identified from screens or by design that can modulate the
activity of classical histone deacetylases, sirtuins, histone
acetyltransferases, histone methyltransferases and histone demethylases. We
highlight applications of compounds to mechanistic and functional studies
involving these enzymes and discuss future challenges regarding target
specificity and general utility.
DOI: 10.1038/nchembio.111
PMCID: PMC2908280
PMID: 18800048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18003914 | 1. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44. doi:
10.1073/pnas.0707292104. Epub 2007 Nov 14.
Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27
demethylases.
Hong S(1), Cho YW, Yu LR, Yu H, Veenstra TD, Ge K.
Author information:
(1)Nuclear Receptor Biology Section, Clinical Endocrinology Branch, National
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, MD 20892, USA.
Covalent modifications of histones, such as acetylation and methylation, play
important roles in the regulation of gene expression. Histone lysine methylation
has been implicated in both gene activation and repression, depending on the
specific lysine (K) residue that becomes methylated and the state of methylation
(mono-, di-, or trimethylation). Methylation on K4, K9, and K36 of histone H3
has been shown to be reversible and can be removed by site-specific
demethylases. However, the enzymes that antagonize methylation on K27 of histone
H3 (H3K27), an epigenetic mark important for embryonic stem cell maintenance,
Polycomb-mediated gene silencing, and X chromosome inactivation have been
elusive. Here we show the JmjC domain-containing protein UTX (ubiquitously
transcribed tetratricopeptide repeat, X chromosome), as well as the related
JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27
in vitro. Further, the demethylase activity of UTX requires a catalytically
active JmjC domain. Finally, overexpression of UTX and JMJD3 leads to reduced
di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may
function as H3K27 demethylases in vivo. The identification of UTX and JMJD3 as
H3K27-specific demethylases provides direct evidence to indicate that similar to
methylation on K4, K9, and K36 of histone H3, methylation on H3K27 is also
reversible and can be dynamically regulated by site-specific histone
methyltransferases and demethylases.
DOI: 10.1073/pnas.0707292104
PMCID: PMC2141795
PMID: 18003914 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/21423664 | 1. PLoS Genet. 2011 Mar;7(3):e1001325. doi: 10.1371/journal.pgen.1001325. Epub
2011 Mar 10.
The SUVR4 histone lysine methyltransferase binds ubiquitin and converts H3K9me1
to H3K9me3 on transposon chromatin in Arabidopsis.
Veiseth SV(1), Rahman MA, Yap KL, Fischer A, Egge-Jacobsen W, Reuter G, Zhou MM,
Aalen RB, Thorstensen T.
Author information:
(1)Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
Chromatin structure and gene expression are regulated by posttranslational
modifications (PTMs) on the N-terminal tails of histones. Mono-, di-, or
trimethylation of lysine residues by histone lysine methyltransferases
(HKMTases) can have activating or repressive functions depending on the position
and context of the modified lysine. In Arabidopsis, trimethylation of lysine 9
on histone H3 (H3K9me3) is mainly associated with euchromatin and transcribed
genes, although low levels of this mark are also detected at transposons and
repeat sequences. Besides the evolutionarily conserved SET domain which is
responsible for enzyme activity, most HKMTases also contain additional domains
which enable them to respond to other PTMs or cellular signals. Here we show
that the N-terminal WIYLD domain of the Arabidopsis SUVR4 HKMTase binds
ubiquitin and that the SUVR4 product specificity shifts from di- to
trimethylation in the presence of free ubiquitin, enabling conversion of H3K9me1
to H3K9me3 in vitro. Chromatin immunoprecipitation and immunocytological
analysis showed that SUVR4 in vivo specifically converts H3K9me1 to H3K9me3 at
transposons and pseudogenes and has a locus-specific repressive effect on the
expression of such elements. Bisulfite sequencing indicates that this repression
involves both DNA methylation-dependent and -independent mechanisms. Transcribed
genes with high endogenous levels of H3K4me3, H3K9me3, and H2Bub1, but low
H3K9me1, are generally unaffected by SUVR4 activity. Our results imply that
SUVR4 is involved in the epigenetic defense mechanism by trimethylating H3K9 to
suppress potentially harmful transposon activity.
DOI: 10.1371/journal.pgen.1001325
PMCID: PMC3053343
PMID: 21423664 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/27397541 | 1. Acta Pharmacol Sin. 2016 Sep;37(10):1273-1280. doi: 10.1038/aps.2016.64. Epub
2016 Jul 11.
Histone lysine methyltransferases as anti-cancer targets for drug discovery.
Liu Q(1)(2)(3), Wang MW(1)(2)(3).
Author information:
(1)The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203, China.
(2)The National Center for Drug Screening, Shanghai 201203, China.
(3)School of Pharmacy, Fudan University, Shanghai 201203, China.
Post-translational epigenetic modification of histones is controlled by a number
of histone-modifying enzymes. Such modification regulates the accessibility of
DNA and the subsequent expression or silencing of a gene. Human histone
methyltransferases (HMTs)constitute a large family that includes histone lysine
methyltransferases (HKMTs) and histone/protein arginine methyltransferases
(PRMTs). There is increasing evidence showing a correlation between HKMTs and
cancer pathogenesis. Here, we present an overview of representative HKMTs,
including their biological and biochemical properties as well as the profiles of
small molecule inhibitors for a comprehensive understanding of HKMTs in drug
discovery.
DOI: 10.1038/aps.2016.64
PMCID: PMC5057236
PMID: 27397541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28364192 | 1. Cell Mol Life Sci. 2017 Sep;74(18):3305-3315. doi: 10.1007/s00018-017-2515-z.
Epub 2017 Mar 31.
Protein arginine methylation: a prominent modification and its demethylation.
Wesche J(1), Kühn S(1), Kessler BM(2), Salton M(3), Wolf A(4).
Author information:
(1)Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum
München-German Research Center for Environmental Health, Ingolstädter
Landstrasse 1, 85764, Neuherberg, Germany.
(2)Nuffield Department of Medicine, Target Discovery Institute, University of
Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK.
(3)Department of Biochemistry and Molecular Biology, The Institute for Medical
Research Israel-Canada, Hebrew University-Hadassah Medical School, 91120,
Jerusalem, Israel.
(4)Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum
München-German Research Center for Environmental Health, Ingolstädter
Landstrasse 1, 85764, Neuherberg, Germany. [email protected].
Arginine methylation of histones is one mechanism of epigenetic regulation in
eukaryotic cells. Methylarginines can also be found in non-histone proteins
involved in various different processes in a cell. An enzyme family of nine
protein arginine methyltransferases catalyses the addition of methyl groups on
arginines of histone and non-histone proteins, resulting in either mono- or
dimethylated-arginine residues. The reversibility of histone modifications is an
essential feature of epigenetic regulation to respond to changes in
environmental factors, signalling events, or metabolic alterations. Prominent
histone modifications like lysine acetylation and lysine methylation are
reversible. Enzyme family pairs have been identified, with each pair of lysine
acetyltransferases/deacetylases and lysine methyltransferases/demethylases
operating complementarily to generate or erase lysine modifications. Several
analyses also indicate a reversible nature of arginine methylation, but the
enzymes facilitating direct removal of methyl moieties from arginine residues in
proteins have been discussed controversially. Differing reports have been seen
for initially characterized putative candidates, like peptidyl arginine
deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most
recent cellular, biochemical, and mass spectrometry work on arginine methylation
and its reversible nature with a special focus on putative arginine
demethylases, including the enzyme superfamily of Fe(II) and
2-oxoglutarate-dependent oxygenases.
DOI: 10.1007/s00018-017-2515-z
PMCID: PMC11107486
PMID: 28364192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26718039 | 1. Enzymes. 2006;24:123-53. doi: 10.1016/S1874-6047(06)80007-7. Epub 2010 Nov 8.
5 Methylation and demethylation of his tone arg and lys residues in chromatin
structure and function.
Wang Y(1).
Author information:
(1)Department of Biochemistry and Molecular Biology Pennsylvania State
University 108 Althouse Lab University Park, PA 16802, USA.
Chromatin is the physiological template of all eukaryotic genomic activities.
Histone proteins are the fundamental building elements of chromatin, which are
the subject of various posttranslational modifications, including methylation.
Adding and removing the methyl moieties from histones plays an important
epigenetic role to ensure the release of the appropriate genetic information.
Both Lys and Arg residues in histones can be dynamically methylated and
demethylated by different enzymes. The processes of adding and removing methyl
groups on histone Lys residues are catalyzed by histone Lys methyltransferases
(HKMTs) and histone-Lys-specific demethylase (LSD), respectively. Protein Arg
methyltransferases (PRMTs) add methyl groups to histone Arg residues. On the
other hand, peptidy-larginine deiminases remove the methyl groups in conjunction
with the amine group, leaving the citrulline aminoacid in histones. The fate of
citrulline residues in histone is currently unknown. Importantly, methylation
has been implicated as playing a major role in regulating gene expression to
control normal cell growth, proliferation, and differentiation. The steady-state
balance of histone methylation is important for the normal development and the
health of an organism.
Copyright © 2006 Elsevier Inc. All rights reserved.
DOI: 10.1016/S1874-6047(06)80007-7
PMID: 26718039 |
http://www.ncbi.nlm.nih.gov/pubmed/22122749 | 1. Epigenomics. 2010 Feb;2(1):119-37. doi: 10.2217/epi.09.39.
Arginine/lysine-methyl/methyl switches: biochemical role of histone arginine
methylation in transcriptional regulation.
Migliori V(1), Phalke S, Bezzi M, Guccione E.
Author information:
(1)Institute of Molecular and Cell Biology, Singapore.
Post-translational modifications (PTMs) are commonly used to modify protein
function. Modifications such as phosphorylation, acetylation and methylation can
influence the conformation of the modified protein and its interaction with
other proteins or DNA. In the case of histones, PTMs on specific residues can
influence chromatin structure and function by modifying the biochemical
properties of key amino acids. Histone methylation events, especially on
arginine- and lysine-residues, are among the best-characterized PTMs, and many
of these modifications have been linked to downstream effects. The addition of a
methyl group to either residue results in a slight increase in hydrophobicity,
in the loss of a potential hydrogen-bond donor site and, in the alteration of
the protein interaction surface. Thus far, a number of protein domains have been
demonstrated to directly bind to methylated lysine residues. However, the
biochemical mechanisms linking histone arginine methylation to downstream
biological outputs remain poorly characterized. This review will focus on the
role of histone arginine methylation in transcriptional regulation and on the
crosstalk between arginine methylation and other PTMs. We will discuss the
mechanisms by which differentially methylated arginines on histones modulate
transcriptional outcomes and contribute to the complexity of the 'histone code'.
DOI: 10.2217/epi.09.39
PMID: 22122749 [Indexed for MEDLINE] |
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