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http://www.ncbi.nlm.nih.gov/pubmed/20041827 | 1. Curr Pharm Des. 2010;16(8):988-1001. doi: 10.2174/138161210790883480.
Splice modification to restore functional dystrophin synthesis in Duchenne
muscular dystrophy.
Wilton SD(1), Fletcher S.
Author information:
(1)Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, 4th Floor A Block, QE II Medical Centre, Nedlands, Western Australia,
Australia. swilton@meddent.uwa.edu.au
In little more than a decade, induced exon skipping as a therapy to treat
Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro,
to pre-clinical evaluation in mouse and dog models, and recent completion of
Phase I clinical trials in man. There is no longer any doubt that antisense
oligomers can redirect dystrophin gene processing and by-pass protein truncating
mutations after direct injection into muscle. Proof-of-concept has been
demonstrated in human dystrophic muscle, with trials in Leiden and London
showing that two different oligomer chemistries can restore the reading-frame in
selected DMD patients by excising dystrophin exon 51. Systemic delivery of both
oligomer types into DMD patients has commenced with promising results but it
remains to be established if this therapy will have measurable clinical
benefits. Targeted removal of exon 51 will only be directly applicable to about
one in ten DMD individuals, and the immediate challenges include development of
appropriate and effective delivery regimens, and extending splice-switching
therapies to other dystrophin gene lesions. The success of induced exon skipping
has spawned a number of "fusion therapies", including vector-mediated dystrophin
exon skipping and ex vivo viral delivery of splice-switching antisense molecules
into myogenic stem cells, followed by implantation, which may address long term
oligomer delivery issues. This review summarizes the pivotal events leading to
the completion of the first proof-of-concept trials and speculates on some of
the scientific, ethical, regulatory and commercial challenges facing targeted
exon skipping for the treatment of DMD.
DOI: 10.2174/138161210790883480
PMID: 20041827 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23609411 | 1. Nat Rev Genet. 2013 Jun;14(6):373-8. doi: 10.1038/nrg3460. Epub 2013 Apr 23.
Therapy for Duchenne muscular dystrophy: renewed optimism from genetic
approaches.
Fairclough RJ(1), Wood MJ, Davies KE.
Author information:
(1)Department of Physiology, Anatomy and Genetics, University of Oxford, Parks
Road, Oxford OX1 3PT, UK.
Duchenne muscular dystrophy (DMD) is a devastating progressive disease for which
there is currently no effective treatment except palliative therapy. There are
several promising genetic approaches, including viral delivery of the missing
dystrophin gene, read-through of translation stop codons, exon skipping to
restore the reading frame and increased expression of the compensatory utrophin
gene. The lessons learned from these approaches will be applicable to many other
disorders.
DOI: 10.1038/nrg3460
PMID: 23609411 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17217326 | 1. Annu Rev Med. 2007;58:75-88. doi: 10.1146/annurev.med.58.011706.144703.
New approaches in the therapy of cardiomyopathy in muscular dystrophy.
McNally EM(1).
Author information:
(1)Department of Medicine, The University of Chicago, Chicago, Illinois 60637,
USA. emcnally@medicine.bsd.uchicago.edu
Cardiomyopathy is a frequent occurrence in muscular dystrophy, and heart disease
in muscular dystrophy can contribute to both morbidity and mortality. A number
of novel therapies are being developed for muscular dystrophy, and the efficacy
of these therapies for heart disease is unknown. The most common X-linked
recessive disease is Duchenne muscular dystrophy (DMD), which arises from
defects in the dystrophin gene. Therapy specifically aimed at DMD is reviewed in
the context of its projected effect on cardiomyopathy associated with DMD.
Additionally, novel therapies are being pursued to treat specifically the
cardiomyopathy of DMD. There is substantial genetic heterogeneity underlying the
muscular dystrophies, and not all muscular dystrophy patients develop
cardiomyopathy. A subset of muscular dystrophies may place patients at
significantly greater risk of developing cardiomyopathy and cardiac rhythm
disturbances. These disorders are discussed, highlighting recent studies and
recommendations for therapy.
DOI: 10.1146/annurev.med.58.011706.144703
PMID: 17217326 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19527108 | 1. Expert Opin Biol Ther. 2009 Jul;9(7):849-66. doi: 10.1517/14712590903029164.
Gene therapy for muscular dystrophy: current progress and future prospects.
Trollet C(1), Athanasopoulos T, Popplewell L, Malerba A, Dickson G.
Author information:
(1)School of Biological Sciences, Royal Holloway-University of London, Egham,
TW20 0EX, Surrey, UK.
Muscular dystrophies refer to a group of inherited disorders characterized by
progressive muscle weakness, wasting and degeneration. So far, there is no
effective treatment but new gene-based therapies are currently being developed
with particular noted advances in using conventional gene replacement
strategies, RNA-based approaches, or cell-based gene therapy with a main focus
on Duchenne muscular dystrophy (DMD). DMD is the most common and severe form of
muscular dystrophy and current treatments are far from adequate. However,
genetic and cell-based therapies, in particular exon skipping induced by
antisense strategies, and corrective gene therapy via functionally engineered
dystrophin genes hold great promise, with several clinical trials ongoing.
Proof-of-concept of exon skipping has been obtained in animal models, and most
recently in clinical trials; this approach represents a promising therapy for a
subset of patients. In addition, gene-delivery-based strategies exist both for
antisense-induced reading frame restoration, and for highly efficient delivery
of functional dystrophin mini- and micro-genes to muscle fibres in vivo and
muscle stem cells ex-vivo. In particular, AAV-based vectors show efficient
systemic gene delivery to skeletal muscle directly in vivo, and lentivirus-based
vectors show promise of combining ex vivo gene modification strategies with
cell-mediated therapies.
DOI: 10.1517/14712590903029164
PMID: 19527108 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23387802 | 1. FEBS J. 2013 Sep;280(17):4263-80. doi: 10.1111/febs.12178. Epub 2013 Mar 4.
Repair or replace? Exploiting novel gene and cell therapy strategies for
muscular dystrophies.
Benedetti S(1), Hoshiya H, Tedesco FS.
Author information:
(1)Department of Cell and Developmental Biology, University College London, UK.
Muscular dystrophies are genetic disorders characterized by skeletal muscle
wasting and weakness. Although there is no effective therapy, a number of
experimental strategies have been developed over recent years and some of them
are undergoing clinical investigation. In this review, we highlight recent
developments and key challenges for strategies based upon gene replacement and
gene/expression repair, including exon-skipping, vector-mediated gene therapy
and cell therapy. Therapeutic strategies for different forms of muscular
dystrophy are discussed, with an emphasis on Duchenne muscular dystrophy, given
the severity and the relatively advanced status of clinical studies for this
disease.
© 2013 The Authors Journal compilation © 2013 FEBS.
DOI: 10.1111/febs.12178
PMID: 23387802 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35939579 | 1. N Engl J Med. 2022 Jul 28;387(4):332-344. doi: 10.1056/NEJMoa2117872.
Germline Mutations in CIDEB and Protection against Liver Disease.
Verweij N(1), Haas ME(1), Nielsen JB(1), Sosina OA(1), Kim M(1), Akbari P(1), De
T(1), Hindy G(1), Bovijn J(1), Persaud T(1), Miloscio L(1), Germino M(1),
Panagis L(1), Watanabe K(1), Mbatchou J(1), Jones M(1), LeBlanc M(1),
Balasubramanian S(1), Lammert C(1), Enhörning S(1), Melander O(1), Carey DJ(1),
Still CD(1), Mirshahi T(1), Rader DJ(1), Parasoglou P(1), Walls JR(1), Overton
JD(1), Reid JG(1), Economides A(1), Cantor MN(1), Zambrowicz B(1), Murphy AJ(1),
Abecasis GR(1), Ferreira MAR(1), Smagris E(1), Gusarova V(1), Sleeman M(1),
Yancopoulos GD(1), Marchini J(1), Kang HM(1), Karalis K(1), Shuldiner AR(1),
Della Gatta G(1), Locke AE(1), Baras A(1), Lotta LA(1).
Author information:
(1)From the Regeneron Genetics Center (N.V., M.E.H., J.B.N., O.A.S., M.K., P.A.,
T.D., G.H., J.B., T.P., L.M., K.W., J. Mbatchou, M.J., M.L., S.B., J.D.O.,
J.G.R., A.E., M.N.C., G.R.A., M.A.R.F., J. Marchini, H.M.K., K.K., A.R.S.,
G.D.G., A.E.L., A.B., L.A.L.), Regeneron Pharmaceuticals (M.G., L.P., P.P.,
J.R.W., B.Z., A.J.M., E.S., V.G., M.S., G.D.Y.), Tarrytown, NY; Indiana
University School of Medicine, Indianapolis (C.L.); the Department of Clinical
Sciences Malmö, Lund University, and the Department of Emergency and Internal
Medicine, Skåne University Hospital - both in Malmö, Sweden (S.E., O.M.); and
the Department of Molecular and Functional Genomics, Geisinger Health System,
Danville (D.J.C., C.D.S., T.M.), and the Department of Genetics, Perelman School
of Medicine, University of Pennsylvania, Philadelphia (D.J.R.) - both in
Pennsylvania.
Comment in
Gastroenterology. 2023 Feb;164(2):304-305. doi:
10.1053/j.gastro.2022.09.045.
Liver Int. 2022 Dec;42(12):2594-2596. doi: 10.1111/liv.15460.
BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the
identification of rare protein-coding genetic variants associated with
protection from human diseases like liver cirrhosis, providing a strategy for
the discovery of new therapeutic targets.
METHODS: We performed a multistage exome sequencing and genetic association
analysis to identify genes in which rare protein-coding variants were associated
with liver phenotypes. We conducted in vitro experiments to further characterize
associations.
RESULTS: The multistage analysis involved 542,904 persons with available data on
liver aminotransferase levels, 24,944 patients with various types of liver
disease, and 490,636 controls without liver disease. We found that rare coding
variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased
aminotransferase levels and an increased risk of liver disease. We also found
that variants in CIDEB, which encodes a structural protein found in hepatic
lipid droplets, had a protective effect. The burden of rare predicted
loss-of-function variants plus missense variants in CIDEB (combined carrier
frequency, 0.7%) was associated with decreased alanine aminotransferase levels
(beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to
-0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds
ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding
variants in CIDEB were associated with a decreased risk of liver disease across
different underlying causes and different degrees of severity, including
cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70).
Among 3599 patients who had undergone bariatric surgery, rare coding variants in
CIDEB were associated with a decreased nonalcoholic fatty liver disease activity
score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores
range from 0 to 8, with higher scores indicating more severe disease]). In human
hepatoma cell lines challenged with oleate, CIDEB small interfering RNA
knockdown prevented the buildup of large lipid droplets.
CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection
from liver disease. (Funded by Regeneron Pharmaceuticals.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2117872
PMID: 35939579 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34605036 | 1. Med Res Rev. 2022 Mar;42(2):654-709. doi: 10.1002/med.21856. Epub 2021 Oct 4.
Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and
revisiting the clinical and preclinical pipeline.
Bhurta D(1)(2), Bharate SB(1)(2).
Author information:
(1)Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of
Integrative Medicine, Jammu, India.
(2)Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India.
Kinases have gained an important place in the list of vital therapeutic targets
because of their overwhelming clinical success in the last two decades. Among
various clinically validated kinases, the cyclin-dependent kinases (CDK) are one
of the extensively studied drug targets for clinical development. Food and Drug
Administration has approved three CDK inhibitors for therapeutic use, and at
least 27 inhibitors are under active clinical development. In the last decade,
research and development in this area took a rapid pace, and thus the analysis
of scaffold diversity is essential for future drug design. Available reviews
lack the systematic study and discussion on the scaffold diversity of CDK
inhibitors. Herein we have reviewed and critically analyzed the chemical
diversity present in the preclinical and clinical pipeline of CDK inhibitors.
Our analysis has shown that although several scaffolds represent CDK inhibitors,
only the amino-pyrimidine is a well-represented scaffold. The three-nitrogen
framework of amino-pyrimidine is a fundamental hinge-binding unit. Further, we
have discussed the selectivity aspects among CDKs, the clinical trial
dose-limiting toxicities, and highlighted the most advanced clinical candidates.
We also discuss the changing paradigm towards selective inhibitors and an
overview of ATP-binding pockets of all druggable CDKs. We carefully analyzed the
clinical pipeline to unravel the candidates that are currently under active
clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there
are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.
© 2021 Wiley Periodicals LLC.
DOI: 10.1002/med.21856
PMID: 34605036 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35628286 | 1. Int J Mol Sci. 2022 May 13;23(10):5476. doi: 10.3390/ijms23105476.
Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.
Noblejas-López MDM(1)(2), Gandullo-Sánchez L(3), Galán-Moya EM(1)(2)(4),
López-Rosa R(1)(2), Tébar-García D(1)(2), Nieto-Jiménez C(5), Gómez-Juárez M(1),
Burgos M(1)(2)(6), Pandiella A(3), Ocaña A(1)(2)(5).
Author information:
(1)Translational Research Unit, Albacete University Hospital, 02008 Albacete,
Spain.
(2)Centro Regional de Investigaciones Biomédicas (CRIB), Castilla-La Mancha
University (UCLM), 02008 Albacete, Spain.
(3)Instituto de Biología Molecular y Celular del Cáncer, CSIC, IBSAL and
CIBERONC, 37007 Salamanca, Spain.
(4)Faculty of Nursing, Castilla-La Mancha University (UCLM), 02008 Albacete,
Spain.
(5)Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico
San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC) and CIBERONC,
28040 Madrid, Spain.
(6)Department of Nutrition, Food Science and Physiology, School of Pharmacy and
Nutrition, University of Navarra, 31008 Pamplona, Spain.
Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the
cell cycle and transcriptional regulation. In this article, we explore the
antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound
against CDK9. Breast cancer cell lines from different subtypes were used.
Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression
of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI =
1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+
expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC,
THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474
cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and
BT549 cells. The three cell lines with HER2 overexpression and no presence of
ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to
ER-positive and dual ER/HER2-positive cell lines. BT474-derived
trastuzumab-resistant cell lines displayed a particular sensitivity to
THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease
in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant
increase in apoptosis. Experiments in animals demonstrated an inverse
therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic
range. The identified toxicity was mainly due to an on-target off-tumor effect
of the compound in the gastrointestinal epithelium. In summary, the potent and
efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the
possibility of using this type of compound in breast cancer only if specifically
delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant
tumors.
DOI: 10.3390/ijms23105476
PMCID: PMC9146359
PMID: 35628286 [Indexed for MEDLINE]
Conflict of interest statement: A.O. is currently an employee of Symphogen,
Copengahen, Denmark. |
http://www.ncbi.nlm.nih.gov/pubmed/31603123 | 1. J Cancer Res Ther. 2019 Jul-Sep;15(5):1131-1140. doi: 10.4103/jcrt.JCRT_47_18.
Ligand- and structure-based pharmacophore modeling, docking study reveals
2-[[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3-b] pyridin-6-yl] amino]
ethanol as a potential anticancer agent of CDK9/cyclin T1 kinase.
Hussain A(1), Verma CK(1).
Author information:
(1)Department of Bioinformatics, MANIT, Bhopal, Madhya Pradesh, India.
OBJECTIVE: CDK9/Cyclin T1 kinase is a protein kinase, indirectly involved in the
cell cycle progression in the form of transcription elongation, CDK9 specific
inhibitors may be a potential alternative treatment not only for cancer but also
other life-threatening diseases.
MATERIALS AND METHODS: Ligand-based and structure-based pharmacophore model was
developed for discovering of the new anticancer agents. These models used as
three-dimensional query for virtual screening against the chemical structure
databases such as Maybridge HitFinder, MDPI, and ZINC. Subsequently, the
potential hit compound was filtered by the ADMET and docking score.
RESULTS: After applying all filtration, 11 hits were found as potential hits
based on good docking scores as well as good ADMET properties. Compound
2-[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3-b] pyridin-6-yl] amino]
ethanol was found to be most potent among all the potential hits. These hits
could be used as an anticancer agent in near future.
CONCLUSIONS: So many advances in the treatment of death leading diseases have
been made over the past few decades, However, looking for the development in
this research ligand-based and structure-based pharmacophore modeling was done,
hit1 2-[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3 b] pyridin-6 yl]
amino] ethanol was found to be more potent and selective. It is understandable
that these hits could be as selective and potent anticancer agents of
cyclin-dependent kinase complex.
DOI: 10.4103/jcrt.JCRT_47_18
PMID: 31603123 [Indexed for MEDLINE]
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/12432243 | 1. Cancer Biol Ther. 2002 Jul-Aug;1(4):342-7.
CDK9: from basal transcription to cancer and AIDS.
De Falco G(1), Giordano A.
Author information:
(1)Istituto di Anatomia ed Istologia Patologica, Università degli Studi di
Siena, Italy.
Cdk9 is a member of the Cdc2-like family of kinases. Its cyclin partners are
members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The
Cdk9/cyclin T complexes appear to be involved in regulating several
physiological processes. Cdk9/cyclin T1 belongs to the P-TEFb complex, and is
responsible for the phosphorylation of the carboxyl-terminal domain (CTD) of the
RNA Polymerase II, thus promoting general elongation. Cdk9 has also been
described as the kinase of the TAK complex, which is homologous to the P-TEFb
complex and involved in HIV replication. Cdk9 also appears to be involved in the
differentiation program of several cell types, such as muscle cells, monocytes
and neurons, suggesting that it may have a function in controlling specific
differentiative pathways. In addition, Cdk9 seems to have an anti-apoptotic
function in monocytes, that may be related to its control over differentiation
of monocytes. This data suggests the involvement of Cdk9 in several
physiological processes in the cell, the deregulation of which may be related to
the genesis of transforming events, that may in turn lead to the onset of
cancer. In addition, since the complex Cdk9/cyclin T1 is able to bind to the
HIV-1 product Tat, the study of the functions of Cdk9/cyclin T may be of
interest in understanding the basal mechanisms that regulate HIV replication.
PMID: 12432243 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20150322 | 1. Brain. 2010 Apr;133(Pt 4):957-72. doi: 10.1093/brain/awq002. Epub 2010 Feb 11.
RNA-targeted splice-correction therapy for neuromuscular disease.
Wood MJ(1), Gait MJ, Yin H.
Author information:
(1)Department of Physiology, Anatomy and Genetics, University of Oxford, South
Parks Road, Oxford OX1 3QX, UK. matthew.wood@dpag.ox.ac.uk
Splice-modulation therapy, whereby molecular manipulation of premessenger RNA
splicing is engineered to yield genetic correction, is a promising novel therapy
for genetic diseases of muscle and nerve-the prototypical example being Duchenne
muscular dystrophy. Duchenne muscular dystrophy is the most common childhood
genetic disease, affecting one in 3500 newborn boys, causing progressive muscle
weakness, heart and respiratory failure and premature death. No cure exists for
this disease and a number of promising new molecular therapies are being
intensively studied. Duchenne muscular dystrophy arises due to mutations that
disrupt the open-reading-frame in the DMD gene leading to the absence of the
essential muscle protein dystrophin. Of all novel molecular interventions
currently being investigated for Duchenne muscular dystrophy, perhaps the most
promising method aiming to restore dystrophin expression to diseased cells is
known as 'exon skipping' or splice-modulation, whereby antisense
oligonucleotides eliminate the deleterious effects of DMD mutations by
modulating dystrophin pre-messenger RNA splicing, such that functional
dystrophin protein is produced. Recently this method was shown to be promising
and safe in clinical trials both in The Netherlands and the UK. These trials
studied direct antisense oligonucleotide injections into single peripheral lower
limb muscles, whereas a viable therapy will need antisense oligonucleotides to
be delivered systemically to all muscles, most critically to the heart, and
ultimately to all other affected tissues including brain. There has also been
considerable progress in understanding how such splice-correction methods could
be applied to the treatment of related neuromuscular diseases, including spinal
muscular atrophy and myotonic dystrophy, where defects of splicing or
alternative splicing are closely related to the disease mechanism.
DOI: 10.1093/brain/awq002
PMID: 20150322 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9766517 | 1. J Cell Physiol. 1998 Nov;177(2):206-13. doi:
10.1002/(SICI)1097-4652(199811)177:2<206::AID-JCP2>3.0.CO;2-R.
Cloning of murine CDK9/PITALRE and its tissue-specific expression in
development.
Bagella L(1), MacLachlan TK, Buono RJ, Pisano MM, Giordano A, De Luca A.
Author information:
(1)Department of Pathology, Anatomy and Cell Biology, Sbarro Institute for
Cancer Research and Molecular Medicine, Jefferson Medical College, Thomas
Jefferson University, Philadelphia, Pennsylvania 19107, USA.
The cdc2-family of serine/threonine kinases and their binding partners recently
were implicated in developmental roles. We previously cloned a cdc2-related
kinase, cdk9/PITALRE, that is able to phosphorylate the retinoblastoma protein
in vitro. We describe here the cloning and the characterization of the mouse
homolog of cdk9/PITALRE. The murine cDNA is 98% identical with humans and is
expressed at high levels in brain and kidney tissues. The kinase activity and
protein expression of cdk9/PITALRE were highest in terminally differentiated
tissues such as the muscle and brain. In situ immunohistology and
immunofluorescence detected cdk9/PITALRE protein not only within terminally
differentiated cells such as muscle and neuronal cells, but also in
proliferating cells. C2C12 and P19 cells induced to differentiate along muscle
and neural lineages peaked in cdk9/PITALRE kinase activity at the end of
differentiation. These results suggest that, among other roles, cdk9/PITALRE
plays a role not unlike cdk5 in the differentiation of certain cell types.
DOI: 10.1002/(SICI)1097-4652(199811)177:2<206::AID-JCP2>3.0.CO;2-R
PMID: 9766517 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27833949 | 1. Mol Biosyst. 2017 Jan 31;13(2):246-276. doi: 10.1039/c6mb00387g.
The emerging picture of CDK9/P-TEFb: more than 20 years of advances since
PITALRE.
Paparidis NF(1), Durvale MC(2), Canduri F(1).
Author information:
(1)Department of Chemistry and Molecular Physics, Institute of Chemistry of Sao
Carlos, Sao Paulo University, Av. Trabalhador Sãocarlense, 400, Zip Code 780,
13560-970, São Carlos-SP, Brazil. fcanduri@iqsc.usp.br.
(2)Department of Biochemistry, Institute of Chemistry, Sao Paulo University, Av.
Prof. Lineu Prestes, 748, 05508-000, Butantã - São Paulo - SP, Brazil.
CDK9 is a prominent member of the transcriptional CDKs subfamily, a group of
kinases whose function is to control the primary steps of mRNA synthesis and
processing by eukaryotic RNA polymerase II. As a cyclin-dependent kinase, CDK9
activation in vivo depends upon its association with T-type cyclins to assemble
the positive transcription elongation factor (P-TEFb). Although CDK9/P-TEFb
phosphorylates the C-terminal domain of RNAP II in the same positions targeted
by CDK7 (TFIIH) and CDK8 (Mediator), the former does not participate in the
transcription initiation, but rather plays a unique role by driving the
polymerase to productive elongation. In addition to RNAP II CTD, the negative
transcription elongation factors DSIF and NELF also represent major CDK9
substrates, whose phosphorylation is required to overcome the proximal pause of
the polymerase. CDK9 is recruited to specific genes through proteins that
interact with both P-TEFb and distinct elements in DNA, RNA or chromatin, where
it modulates the activity of individual RNAP II transcription complexes. The
regulation of CDK9 function is an intricate network that includes
post-translational modifications (phosphorylation/dephosphorylation and
acetylation/deacetylation of key residues) as well as the association of P-TEFb
with various proteins that can stimulate or inhibit its kinase activity. Several
cases of CDK9 deregulation have been linked to important human diseases,
including various types of cancer and also AIDS (due to its essential role in
HIV replication). Not only HIV, but also many other human viruses have been
shown to depend strongly on CDK9 activity to be transcribed within host cells.
This review summarizes the main advances made on CDK9/P-TEFb field in more than
20 years, introducing the structural, functional and genetic aspects that have
been elucidated ever since.
DOI: 10.1039/c6mb00387g
PMID: 27833949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36454480 | 1. Cell Mol Life Sci. 2022 Dec 1;79(12):613. doi: 10.1007/s00018-022-04624-4.
RBM24 controls cardiac QT interval through CaMKIIδ splicing.
Liu J(#)(1)(2)(3), Wang K(#)(1), Liu X(4), Pan L(1), Zhou W(1), Huang J(1), Liu
H(1)(2), Su Z(1)(2), Xu XQ(5)(6).
Author information:
(1)The Institute of Stem Cell and Regenerative Medicine, School of Medicine,
Xiamen University, Xiamen, 361100, Fujian, People's Republic of China.
(2)Department of Gynecology, Women and Children's Hospital, School of Medicine,
Xiamen University, Xiamen, Fujian, 361100, People's Republic of China.
(3)Shenzhen Research Institute of Xiamen University, Shenzhen, 518000,
Guangdong, People's Republic of China.
(4)School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People's
Republic of China.
(5)The Institute of Stem Cell and Regenerative Medicine, School of Medicine,
Xiamen University, Xiamen, 361100, Fujian, People's Republic of China.
xuxq@xmu.edu.cn.
(6)Department of Gynecology, Women and Children's Hospital, School of Medicine,
Xiamen University, Xiamen, Fujian, 361100, People's Republic of China.
xuxq@xmu.edu.cn.
(#)Contributed equally
Calcium/calmodulin-dependent kinase II delta (CaMKIIδ) is the predominant
cardiac isoform and it is alternatively spliced to generate multiple variants.
Variable variants allow for distinct localization and potentially different
functions in the heart. Dysregulation of CaMKIIδ splicing has been demonstrated
to be involved in the pathogenesis of heart diseases, such as cardiac
hypertrophy, arrhythmia, and diastolic dysfunction. However, the mechanisms that
regulate CaMKIIδ are incompletely understood. Here, we show that RNA binding
motif protein 24 (RBM24) is a key splicing regulator of CaMKIIδ. RBM24 ablation
leads to the aberrant shift of CaMKIIδ towards the δ-C isoform, which is known
to activate the L-type Ca current. In line with this, we found marked alteration
in Ca2+ handling followed by prolongation of the ventricular cardiac action
potential and QT interval in RBM24 knockout mice, and these changes could be
attenuated by treatment with an inhibitor of CaMKIIδ. Importantly, knockdown of
RBM24 in human embryonic stem cell-derived cardiomyocytes showed similar
electrophysiological abnormalities, suggesting the important role of RBM24 in
the human heart. Thus, our data suggest that RBM24 is a critical regulator of
CaMKIIδ to control the cardiac QT interval, highlighting the key role of
splicing regulation in cardiac rhythm.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s00018-022-04624-4
PMID: 36454480 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35501714 | 1. BMC Neurol. 2022 May 2;22(1):162. doi: 10.1186/s12883-022-02687-1.
Characteristics of disease progression and genetic correlation in ambulatory
Iranian boys with Duchenne muscular dystrophy.
Zamani G(#)(1), Hosseinpour S(#)(2), Ashrafi MR(1), Mohammadi M(1), Badv RS(1),
Tavasoli AR(1), Akbari MG(3), Bereshneh AH(4), Malamiri RA(5), Heidari M(6).
Author information:
(1)Pediatrics Center of Excellence, Department of Pediatric Neurology,
Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
(2)Department of Pediatric Neurology, Vali-e-Asr Hospital, Imam Khomeini
Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
(3)Physical Medicine and Rehabilitation Department, Children's Medical Center ,
Tehran University of Medical Sciences, Tehran, Iran.
(4)Prenatal Diagnosis and Genetic Research Center, Dastgheib Hospital, Shiraz
University of Medical Sciences, Shiraz, Iran. alihoseinimg@gmail.com.
(5)Department of Pediatric Neurology, Golestan Medical, Educational, and
Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
(6)Pediatrics Center of Excellence, Department of Pediatric Neurology,
Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
m-heidari@sina.tums.ac.ir.
(#)Contributed equally
BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular
dystrophy in the pediatric population. The manifestations of this disease
include progressive muscle weakness, gait dysfunction, and motor impairment,
leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is
the standard diagnostic tool for DMD. This study aimed to investigate disease
progression and genetic patterns in Iranian ambulant boys and to find the
correlation between genotypes and motor function phenotypes.
METHODS: This study was performed on 152 DMD patients. Clinical history,
including the disease phenotype, steroid therapy, and the North Star Ambulatory
Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses
were confirmed by multiplex ligation-dependent probe amplification and
next-generation sequencing tests.
RESULTS: A total of 152 Iranian DMD patients were examined in this study. The
mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at
diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years.
Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA
score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual
changes in the NSAA score were determined for all cases, based on the mutation
type and exon site. Deletion mutation was found in 79.1% of cases, duplication
in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon
deletion was exon 44 (5.3%), and the most common multiexon deletions were
attributed to exons 45-50 and exons 45-52 (4.6%). The results did not indicate
any correlation between the mutation type and age at the time of disease onset,
loss of ambulation age, and wheelchair dependence; however, a significant
association was found between contracture and mutation type. The results showed
a significant difference in the NSAA score between the deletion and nonsense
groups at the age of 3 years (P = 0.04). No significant correlation was found
between the phenotype and exon site. Overall, 91.1% of the study population had
a history of corticosteroid use, and 54.1% showed compliance with rehabilitation
therapy.
CONCLUSION: This study demonstrated the phenotypes and mutational features of
Iranian DMD boys and provided information regarding the natural motor history of
the disease, disease progression, diagnosis, and status of DMD management in
Iran. The present findings can promote the development of clinical trials and
future advanced molecular therapies in Iran.
© 2022. The Author(s).
DOI: 10.1186/s12883-022-02687-1
PMCID: PMC9059913
PMID: 35501714 [Indexed for MEDLINE]
Conflict of interest statement: We declare no financial conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35626905 | 1. Children (Basel). 2022 May 16;9(5):728. doi: 10.3390/children9050728.
Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring
the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular
Dystrophy.
Emery N(1), Strachan K(1), Kulshrestha R(1), Kuiper JH(1)(2), Willis T(1).
Author information:
(1)Neuromuscular Service, TORCH Building, Robert Jones and Agnes Hunt
Orthopaedic Hopsital, Shropshire SY10 7AG, UK.
(2)School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5
5BG, UK.
OBJECTIVE: The North Star Ambulatory Assessment (NSAA) is a validated 17-item
functional rating scale and widely used to assess motor function in boys with
Duchenne muscular dystrophy (DMD). The SARS-CoV-2 pandemic and subsequent
Government 'lockdown' resulted in no face-to-face clinic visits hence the motor
abilities were not monitored. The aim was to investigate whether the NSAA was
feasible and reliable by video assessment.
METHOD: Ten ambulant DMD boys were selected from the electronic hospital
records. Two physiotherapists scored the boys' NSAA independently and the
intraclass correlation coefficient was used to assess agreement. The video
scores were compared to two previous NSAA in-clinic scores.
RESULTS: Mean scores (SD) for clinic visit one were 22.6 (4.19) and clinic visit
two 21.8 (5.3). The two physiotherapists video mean scores were 20.6 (5.66) for
physiotherapist 1 and 20.6 (6.53) for physiotherapist 2. The intraclass
correlation coefficient was 0.98 (95% CI 0.93-1.00) for the total NSAA and 1.00
(95% CI 1.00 to 1.00) for the rise time. The mean decline in score from clinic
visit one (-12 months) to video assessment was 2.0 (2.8SD).
CONCLUSION: The results from the study suggest that video NSAA is partially
feasible and reliable.
DOI: 10.3390/children9050728
PMCID: PMC9139300
PMID: 35626905
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34146121 | 1. Cell Mol Life Sci. 2021 Jul;78(14):5543-5567. doi: 10.1007/s00018-021-03878-8.
Epub 2021 Jun 19.
CDK9 keeps RNA polymerase II on track.
Egloff S(1).
Author information:
(1)Molecular, Cellular and Developmental Biology Department (MCD), Centre de
Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062, Toulouse,
France. sylvain.egloff@univ-tlse3.fr.
Cyclin-dependent kinase 9 (CDK9), the kinase component of positive transcription
elongation factor b (P-TEFb), is essential for transcription of most
protein-coding genes by RNA polymerase II (RNAPII). By releasing
promoter-proximally paused RNAPII into gene bodies, CDK9 controls the entry of
RNAPII into productive elongation and is, therefore, critical for efficient
synthesis of full-length messenger (m)RNAs. In recent years, new players
involved in P-TEFb-dependent processes have been identified and an important
function of CDK9 in coordinating elongation with transcription initiation and
termination has been unveiled. As the regulatory functions of CDK9 in gene
expression continue to expand, a number of human pathologies, including cancers,
have been associated with aberrant CDK9 activity, underscoring the need to
properly regulate CDK9. Here, I provide an overview of CDK9 function and
regulation, with an emphasis on CDK9 dysregulation in human diseases.
DOI: 10.1007/s00018-021-03878-8
PMCID: PMC8257543
PMID: 34146121 [Indexed for MEDLINE]
Conflict of interest statement: The author declares no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34062779 | 1. Cancers (Basel). 2021 May 1;13(9):2181. doi: 10.3390/cancers13092181.
Targeting CDK9 for Anti-Cancer Therapeutics.
Mandal R(1), Becker S(1), Strebhardt K(1)(2).
Author information:
(1)Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University,
Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
(2)German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription
regulatory members of the CDK family. In conjunction with its main cyclin
partner-Cyclin T1, it forms the Positive Transcription Elongation Factor b
(P-TEFb) whose primary function in eukaryotic cells is to mediate the positive
transcription elongation of nascent mRNA strands, by phosphorylating the S2
residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA
Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously
phosphorylates and inactivates a number of negative transcription regulators
like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing
Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced
activity of CDK9 is observed in multiple cancer types, which is universally
associated with significantly shortened Overall Survival (OS) of the patients.
In these cancer types, CDK9 regulates a plethora of cellular functions including
proliferation, survival, cell cycle regulation, DNA damage repair and
metastasis. Due to the extremely critical role of CDK9 in cancer cells,
inhibiting its functions has been the subject of intense research, resulting the
development of multiple, increasingly specific small-molecule inhibitors, some
of which are presently in clinical trials. The search for newer generation CDK9
inhibitors with higher specificity and lower potential toxicities and suitable
combination therapies continues. In fact, the Phase I clinical trials of the
latest, highly specific CDK9 inhibitor BAY1251152, against different solid
tumors have shown good anti-tumor and on-target activities and pharmacokinetics,
combined with manageable safety profile while the phase I and II clinical trials
of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance
the effectiveness and target diversity and reduce potential drug-resistance, the
future of CDK9 inhibition would likely involve combining CDK9 inhibitors with
inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.
DOI: 10.3390/cancers13092181
PMCID: PMC8124690
PMID: 34062779
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35862363 | 1. Dev Med Child Neurol. 2022 Dec;64(12):1453-1461. doi: 10.1111/dmcn.15345. Epub
2022 Jul 21.
Quality of instruments assessing activity and participation of people with
muscular dystrophy: A systematic review of participant-reported outcome
measures.
Andrade KKS(1), Soares LA(1), Macedo CC(1), Bispo NR(1), Sousa Junior RR(2),
Oliveira VC(1), Leite HR(1)(2), Gaiad TP(1).
Author information:
(1)Department of Physical Therapy, Faculty of Health Sciences, Universidade
Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, Minas Gerais, Brazil.
(2)School of Physical Education, Physiotherapy and Occupational Therapy,
Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
AIM: To identify the standardized assessment scales for people with muscular
dystrophy and investigate the quality/level of evidence of their measurement
properties.
METHOD: A systematic review of patient-reported outcome measures was conducted
on the MEDLINE, Embase, AMED, DiTA, and PsycINFO databases in August 2020. We
included psychometric studies that investigated the validity, reliability, and
responsiveness of instruments assessing activity and participation for muscular
dystrophy of any type (Duchenne, Becker, limb-girdle, facioscapulohumeral,
congenital, and myotonic) or age. Two independent reviewers selected the
studies, extracted data, and evaluated the instruments' quality and level of
evidence following the COnsensus-based Standards for the selection of health
status Measurement INstruments (COSMIN) checklist. The study followed the
Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020
guidelines.
RESULTS: The searches identified 6675 references; a total of 46 studies with 28
condition-specific or general instruments were included. The measurement
properties of most instruments had sufficient (68.8%) or indeterminate (25.7%)
results according to COSMIN. The quality of evidence of the measurement
properties was moderate (23.8%) or low (22.6%) according to the Grading of
Recommendations Assessment, Development, and Evaluation (GRADE).
INTERPRETATION: There is a lack of high-quality instruments whose psychometric
properties are adequately measured. The highest quality instrument is the
Muscular Dystrophy Functional Rating Scale. The Motor Function Measure (general
instrument), Duchenne Muscular Dystrophy Upper-limb Patient-reported Outcome
Measure, North Star Ambulatory Assessment, and Myotonic Dystrophy Type 1
Activity and Participation Scale for Clinical Use (specific) are also
recommended.
WHAT THIS PAPER ADDS: There are 28 available instruments for activity and
participation of people with muscular dystrophy. The evidence quality is
moderate or low because of imprecision and indirectness. The Muscular Dystrophy
Functional Rating Scale is the highest quality instrument. The Motor Function
Measure is the second most recommended instrument. The Duchenne Muscular
Dystrophy Upper-limb Patient-reported Outcome Measure, North Star Ambulatory
Assessment, and Myotonic Dystrophy Type 1 Activity and Participation Scale for
Clinical Use are also recommended.
© 2022 Mac Keith Press.
DOI: 10.1111/dmcn.15345
PMID: 35862363 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21200140 | 1. Cell Cycle. 2011 Jan 1;10(1):28-32. doi: 10.4161/cc.10.1.14364. Epub 2011 Jan
1.
A role for CDK9-cyclin K in maintaining genome integrity.
Yu DS(1), Cortez D.
Author information:
(1)Department of Radiation Oncology, Emory University School of Medicine,
Atlanta, GA, USA. dsyu@emory.edu
Cyclin-dependent kinase 9 (CDK9), with its cyclin T regulatory subunit, is a
component of the positive transcription elongation factor b (P-TEFb) complex,
which stimulates transcription elongation and also functions in
co-transcriptional histone modification, mRNA processing, and mRNA export. CDK9
also binds to cyclin K but the function of this CDK9-cyclin K complex is less
clear. We and others have recently shown that CDK9 functions directly in
maintaining genome integrity. This activity is restricted to CDK9-cyclin K.
Depletion of CDK9 or its cyclin K but not cyclin T regulatory subunit impairs
cell cycle recovery in response to replication stress and induces spontaneous
DNA damage in replicating cells. CDK9-cyclin K also interacts with ATR and other
DNA damage response and DNA repair proteins. CDK9 accumulates on chromatin and
limits the amount of single-stranded DNA in response to replication stress.
Collectively, these data are consistent with a model in which CDK9 responds to
replication stress by localizing to chromatin to reduce the breakdown of stalled
replication forks and promote recovery from replication arrest. The direct role
of CDK9-cyclin K in pathways that maintain genome integrity in response to
replication stress appear to be evolutionarily conserved.
DOI: 10.4161/cc.10.1.14364
PMCID: PMC3048070
PMID: 21200140 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35618576 | 1. Neuromuscul Disord. 2022 Jun;32(6):460-467. doi: 10.1016/j.nmd.2022.02.012.
Epub 2022 Feb 26.
Functional outcome measures in young, steroid-naïve boys with Duchenne muscular
dystrophy.
Mayhew AG(1), Moat D(2), McDermott MP(3), Eagle M(4), Griggs RC(5), King WM(6),
James MK(2), Muni-Lofra R(2), Shillington A(7), Gregson S(7), Pallant L(8),
Skura C(9), Staudt LA(9), Eichinger K(5), McMurchie H(10), Rabb R(10), Di Marco
M(11), Brown S(11), Zanin R(12), Arnoldi MT(12), McIntyre M(13), Wilson A(13),
Alfano LN(14), Lowes LP(14), Blomgren C(15), Milev E(16), Iodice M(16),
Pasternak A(17), Chiu A(18), Lehnert I(19), Claus N(19), Dieruf KA(20), Rolle
E(21), Nicorici A(22), Andres B(23), Hobbiebrunken E(24), Roetmann G(24), Kern
V(25), Civitello M(26), Vogt S(27), Hayes MJ(28), Scholtes C(29), Lacroix C(30),
Gunn T(31), Warner S(31), Newman J(32), Barp A(33), Kundrat K(34), Kovelman
S(34), Powers PJ(35), Guglieri M(2); Muscle Study Group and TREAT-NMD.
Author information:
(1)John Walton Muscular Dystrophy Research Centre, Translational and Clinical
Research Institute, Newcastle University, International Centre for Life, Central
Parkway, Newcastle Upon Tyne, NE1 3BZ, United Kingdom. Electronic address:
anna.mayhew@ncl.ac.uk.
(2)John Walton Muscular Dystrophy Research Centre, Translational and Clinical
Research Institute, Newcastle University, International Centre for Life, Central
Parkway, Newcastle Upon Tyne, NE1 3BZ, United Kingdom.
(3)Department of Neurology, University of Rochester Medical Center, Rochester,
NY, United States; Department of Biostatistics and Computational Biology,
University of Rochester Medical Center, Rochester, NY, United States.
(4)John Walton Muscular Dystrophy Research Centre, Translational and Clinical
Research Institute, Newcastle University, International Centre for Life, Central
Parkway, Newcastle Upon Tyne, NE1 3BZ, United Kingdom; ATOM International
Limited, Gateshead, United Kingdom.
(5)Department of Neurology, University of Rochester Medical Center, Rochester,
NY, United States.
(6)Department of Neurology, Neuromuscular Disease Center, The Ohio State
University, OH, United States. Electronic address: wking8@columbus.rr.com.
(7)Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
(8)Leeds General Infirmary, Leeds Children's Hospital, United Kingdom.
(9)Neurology Department, David Geffen School of Medicine at UCLA, Los Angeles,
California, United States.
(10)Heartlands Hospital, University Hospitals Birmingham, Birmingham, United
Kingdom.
(11)Royal Hospital for Children, Glasgow, United Kingdom.
(12)IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
(13)Department of Pediatrics, University of Utah School of Medicine, Salt Lake
City, UT, United States.
(14)The Abigail Wexner Research Institute at Nationwide Children's Hospital,
Columbus, OH, United States; Department of Pediatrics, The Ohio State
University, Columbus, OH, United States.
(15)Department of Rehabilitation Services, Ann and Robert H Lurie Children's
Hospital of Chicago, IL, United States.
(16)Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child
Health, London, United Kingdom.
(17)Department of Physical and Occupational Therapy Services, Boston Children's
Hospital, Boston, MA, United States.
(18)Neuroscience Program, Alberta Children's Hospital, Calgary, Canada.
(19)Department of Neuropediatrics, Medical Faculty Carl Gustav Carus, Technical
University Dresden, Germany.
(20)University of New Mexico, Albuquerque, NM, United States.
(21)Neuromuscular Unit, Department of Neurosciences, University of Torino,
Italy.
(22)Neuromuscular Research Lab in the Department of PM&R at UC Davis Health,
Sacramento, CA, United States.
(23)University Hospital Essen, Germany.
(24)Department of Pediatrics and Adolescent Medicine, Division of Pediatric
Neurology, University Medical Center Göttingen, Germany.
(25)Penn State Health Hershey Medical Center, Hershey, PA, United States.
(26)Nemours Children's Hospital, Orlando, FL, United States; St Jude Children's
Research Hospital, Memphis, TN, United States.
(27)Department of Neurosciences, University Children Hospital of Freiburg,
Germany.
(28)Department of Neurology, University of Kansas Medical Center, Kansas, United
States.
(29)London Health Science Centre, London ON, Canada.
(30)Children's Hospital of Eastern Ontario Research Institute, University of
Ottawa, Ottawa, ON, Canada.
(31)Royal Manchester Children's Hospital, Manchester, United Kingdom.
(32)UNC Health Care - Rehabilitation Services, University of North Carolina at
Chapel Hill, Chapel Hill, NC, United States.
(33)Department of Neurosciences, University of Padova, Padua, Italy.
(34)Children's National Hospital, Washington, DC, United States.
(35)Vanderbilt University Medical Center, Phi Beta Phi Rehabilitation Institute,
Nashville, TN, United States.
The purpose of this study was to quantitate motor performance in 196 genetically
confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate
the test-retest reliability of measures of motor performance in young DMD boys,
and to assess correlations among the different functional outcomes including
timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a
comparative effectiveness study of different steroid regimens in DMD. Eligible
boys had to be able to rise from the floor independently and to perform
pulmonary function testing consistently. The boys were evaluated with
standardized assessments at the screening and baseline visits at 32 sites in 5
countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from
floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory
Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9
years (range 4.1-8.1 years). Test-retest reliability was high for functional
assessments, regardless of time lag between assessments (up to 90 days) and for
the majority of age groups. Correlations were strong among the functional
measures and timed tests, less so with FVC. Physiotherapy measures are reliable
in a young, steroid-naïve population and rise from floor velocity appears to be
a sensitive measure of strength in this population.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2022.02.012
PMID: 35618576 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interests Anna G.
Mayhew has participated in SAB meetings for Roche, Regenxbio, Summit, PTC and
Biogen and performs Consultancy work (training physiotherapists for trial in
DMD) for Roche, Pfizer, PTC, Summit, Sarepta, Lysogene, Italfarmaco, Amicus,
Biogen and Avexis. Dionne Moat provides consultancy services for the following
companies: ATOM International (covers consultancy services provided to Amicus
Therapeutics Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen,
Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics
Ltd, Reveragen, Sarepta Therapeutics), outside the submitted work. Michael
McDermott has been supported by a research grant from PTC Therapeutics, has
received compensation for consulting from Fulcrum Therapeutics, Inc., and
NeuroDerm, Ltd., and has served on Data and Safety Monitoring Boards (DSMBs) for
AstraZeneca, Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex,
Inc., Cynapsus Therapeutics, Neurocrine Biosciences, Inc., Voyager Therapeutics,
Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS
Pharma, Inc. Michelle Eagle is Managing Director at ATOM International Limited
and is contracted with the following companies through ATOM: Amicus, Biomarin,
Capricor, Catabasis, Denali, Dyne, Edgewise, Faraday, Fibrogen, Genethon,
Italfarmaco, Lysogen, Modis, NSPharma, PTC, Sarepta, Solid, Referagen. Robert
Griggs receives research support from the NIH, the Muscular Dystrophy
Association, the Parent Project for Muscular Dystrophy, and from Sarepta
Biopharma, PTC Therapeutics and Santhera Pharmaceuticals. He serves as a
Consultant for Strongbridge and Stealth Pharmaceuticals. He is Chair of a DSMB
for Solid Pharmaceuticals. He receives monies for editorial work from Elsevier
as an Editor of Cecil Essentials and Cecil Textbook of Medicine. He serves as
Chair of the Research Advisory Committee and is a Board Member of the American
Brain Foundation. He is on the Executive Committee of the Muscle Study Group,
which receives support for its activities from Pharmaceutical companies.
Meredith K. James provides consultancy services for the following companies:
ATOM International (covers consultancy services provided to Amicus Therapeutics
Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon,
Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd,
Reveragen, Sarepta Therapeutics), outside the submitted work. MKJ has received
payment for participation on advisory boards for F. Hoffman La Roche AG, PTC
Therapeutics and fee support for PhD studies from the Jain Foundation, outside
the submitted work. Robert Muni-Lofra has participated in the advisory board for
Biogen and Roche and performs consultancy work (training physiotherapists for
trial in DMD and SMA) for Roche, Pfizer, PTC, Summit, Sarepta, Italfarmaco,
Amicus, Biogen and Avexis. Lindsey Pallant has performed consultancy work
(workshops and training physiotherapists in trials for DMD) for PTC and Sarepta.
Katy Eichinger has received personal compensation for serving on advisory boards
and/or as a consultant for Ionis, Biogen, Acceleron, Fulcrum, Avidity, PTC and
the Myotonic Dystrophy Foundation. Dr. Eichinger has received personal
compensation for serving as a speaker from Cure SMA, FSH Society, and Ology. She
has received research/grant support from the CMTA. Heather McMurchie has
received financial support from PTC and Biogen to access and provide training.
Marina DiMarco attended a World Muscle Society conference sponsored by PTC
Therapeutics and is a Consultant Physiotherapist presenting at PTC workshops.
Lindsay N. Alfano provides consultancy services through ATOM International, Ltd
for the following companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon,
Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics); reports royalties and other
support from Sarepta Therapeutics; royalties for licensed technologies; other
support from Novartis Gene Therapies; advisory board for Biogen. Linda P. Lowes
provides consultancy services through ATOM International, Ltd for the following
companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon, Italfarmaco, NS
Pharma, Pfizer, PTC Therapeutics); reports royalties and other support from
Sarepta Therapeutics; royalties for licensed technologies; other support from
Novartis Gene Therapies; advisory board for Biogen. Amy Pasternak has
participated in advisory boards for Roche, Biogen, Avexis, Scholar Rock and
Audentes. Victoria Kern has received an honorarium from the MDA USA for a
presentation. Cheryl Scholtes has sat on advisor panels for Biogen Canada and
Roche Canada, and has been provided education on behalf of Biogen Canada and
Roche Canada. Catherine Lacroix has acted as a consultant and advisory board
participant to Biogen. Katherine Kundrat has participated in an advisory board
for Biogen. Michela Guglieri is the study chair for a ReveraGen study. MG has
research collaborations with ReveraGen and Sarepta. MG is (has been over the
past 5 years) PI for clinical trials sponsored by Pfizer, Italfarmaco, Santhera,
ReveraGen, Dynacure, Roche, PTC, Summit. MG has been participating in advisory
boards for Pfizer, NS Pharma, Dyne (consultancies through Newcastle University).
MG has performed consultancy work (speaker) for Sarepta. Declarations of
interest: none for remaining authors |
http://www.ncbi.nlm.nih.gov/pubmed/11532614 | 1. Front Biosci. 2001 Sep 1;6:D1073-82. doi: 10.2741/simone.
New insight in cdk9 function: from Tat to MyoD.
Simone C(1), Giordano A.
Author information:
(1)Dept. of Pathology, Anatomy and Cell Biology, Thomas Jefferson University,
Philadelphia, PA 19107, USA.
Cdk9 is a serine-threonine cdc2-related kinase and its activity is not cell
cycle-regulated. Cdk9 function depends on its kinase activity and also on its
regulatory units: the T-family cyclins and cyclin K. Recently, several studies
confirmed the role of cdk9 in different cellular processes such as signal
transduction, basal transcription, HIV-Tat- and MyoD-mediated transcription and
differentiation. All the referred data strongly support the concept of a
multifunctional protein kinase with specific cytoplasmic and nuclear functions.
DOI: 10.2741/simone
PMID: 11532614 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35998119 | 1. PLoS One. 2022 Aug 23;17(8):e0272858. doi: 10.1371/journal.pone.0272858.
eCollection 2022.
Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in
Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial.
Muntoni F(1), Guglieri M(2), Mah JK(3), Wagner KR(4), Brandsema JF(5),
Butterfield RJ(6), McDonald CM(7), Mayhew AG(8), Palmer JP(9), Marraffino S(9),
Charnas L(9), Mercuri E(10).
Author information:
(1)NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond
Street Institute of Child Health, University College London, & Great Ormond
Street Hospital Trust, London, United Kingdom.
(2)The John Walton Muscular Dystrophy Research Centre, Newcastle University and
Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
(3)Cumming School of Medicine, University of Calgary, Alberta Children's
Hospital, Calgary, Alberta, Canada.
(4)Center for Genetic Muscle Disorders, and Departments of Neurology and
Neuroscience, Kennedy Krieger Institute, Johns Hopkins School of Medicine,
Baltimore, Maryland, United States of America.
(5)Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania, United States of America.
(6)University of Utah School of Medicine, Salt Lake City, Utah, United States of
America.
(7)Lawson Health Research Institute, Children's Hospital, London, Ontario,
Canada.
(8)Institute of Genetic Medicine, Newcastle University, Newcastle, United
Kingdom.
(9)Pfizer Inc, Cambridge, Massachusetts, United States of America.
(10)Paediatric Neurology, Catholic University, and Centro Clinico Nemo,
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
INTRODUCTION: The North Star Ambulatory Assessment (NSAA) tool is a key
instrument for measuring clinical outcomes in patients with Duchenne muscular
dystrophy (DMD). To gain a better understanding of the longitudinal utility of
the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD
treated with domagrozumab or placebo.
METHODS: The NSAA exploratory analyses included assessment of individual skills
gained/lost, total skills gained/lost, cumulative loss of function, and the
impact of transient loss of function due to a temporary disability on NSAA total
score (temporary zero score).
RESULTS: There was no significant difference in the total number of NSAA skills
gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p =
0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However,
domagrozumab-treated patients were less likely to lose the ability to perform a
NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65-0.98, p =
0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores
were changed to "not obtainable" (8 values from 7 patients),
domagrozumab-treated patients scored higher on the NSAA total score versus
placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1-3.9, p =
0.0359).
CONCLUSIONS: These exploratory analyses reveal additional approaches to
interpreting the NSAA data beyond just change in NSAA total score. These
observations also highlight the importance of reporting items as "not
obtainable" for a patient with a temporary/transient physical disability that
impacts their ability to perform the NSAA test.
CLINICALTRIALS.GOV IDENTIFIER: NCT02310763.
DOI: 10.1371/journal.pone.0272858
PMCID: PMC9397979
PMID: 35998119 [Indexed for MEDLINE]
Conflict of interest statement: F Muntoni has received support from, and/or has
served as a paid consultant for, Avexis, Biogen, Dyne Therapeutics, Roche,
Novartis, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Santhera, the National
Institute of Health Research Biomedical Research Centre at Great Ormond Street
Hospital for Children NHS Foundation Trust, and University College London. M
Guglieri has received support from, and/or has served as a paid consultant for,
PTC Therapeutic, Capricorn, Marathon Pharmaceutical, Pfizer, ReveraGen,
Italfarmaco SpA, WAVE Life Sciences, Santhera, Roche, Sarepta and Dynacure; and
grant funding from H2020 and NIH. J Mah has received support from Pfizer,
Sarepta Therapeutics, Bristol-Myers Squibb, Roche, NS Pharma, ReveraGen
Biopharma, Catabasis, Italfarmaco SpA, and PTC Pharmaceuticals. K Wagner has
received support from, and/or has served as a paid consultant for, Dynacure, PTC
Therapeutics, Roche, Asklepios Biopharmaceutical Inc, Pfizer, Sarepta
Therapeutics, Catabasis, and Vita Therapeutics. K Wagner is currently an
employee of F. Hoffmann-La Roche Ag. JF Brandsema has received support from,
and/or has served as a paid consultant for, Alexion, Audentes, AveXis, Biogen,
Genentech, PTC Therapeutics, Sarepta, WAVE Life Sciences, CSL Behring,
Cytokinetics, Fibrogen, Pfizer, and Summit. RJ Butterfield has received support
from, and/or has served as a paid consultant for, Avexis, Caspricor Therapudics,
Catabasis, PTC Therapeutics, Sarepta Therapeutics, Pfizer, Biogen, Avexis, and
Acceleron. CM McDonald has received support from, and/or has served as a paid
consultant for, PTC Therapeutics, Santhera Pharmaceuticals, Catabasis
Pharmaceuticals Inc, Sarepta Therapeutics, Prosensa, Biomarin Pharmaceutical,
Pfizer, Eli Lilly, Halo Therapeutics, Marathon Pharmaceuticals, Bristol-Myers
Squibb, Novartis, Italfarmaco, Astellas / Mitobridge, Epirium Bio (formerly
Cardero Therapeutics), Edgewise Therapeutics, Avidity Biosciences, Entrada
Therapeutics. AG Mayhew has received support from, and/or has served as a paid
consultant for, PTC Therapeutics, Biogen, BMS, Roche, Sarepta, Santhera,
Italfarmaco, Catabasis, Mallinckrodt, Pfizer, Summit, Wave Biogen, and Avexis. J
Palmer, L Charnas, and S Marraffino are employees of and own stock in Pfizer. EM
Mercuri has worked as a PI and on advisory boards for Pfizer, PTC Therapeutics,
Roche, Sarepta Therapeutics, Santhera, and NS. This does not alter our adherence
to PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/35385138 | 1. Dev Med Child Neurol. 2022 Aug;64(8):979-988. doi: 10.1111/dmcn.15176. Epub
2022 Feb 14.
Peak functional ability and age at loss of ambulation in Duchenne muscular
dystrophy.
Zambon AA(1)(2), Ayyar Gupta V(1), Ridout D(3)(4), Manzur AY(1)(4), Baranello
G(1), Trucco F(1)(5), Muntoni F(1)(4); UK Northstar Clinical Network.
Collaborators: Tirupath S, Douglas M, McFetridge J, Parasuraman D, Alhaswani Z,
McMurchie H, Rabb R, Majumdar A, Vijayakumar K, Amin S, Mason F, Frimpong-Ansah
C, Gibbon F, Parson B, Naismith K, Burslem J, Baxter A, Eadie C, Horrocks I, Di
Marco M, Childs AM, Pallant L, Spinty S, Shillington A, Gregson S, Cheshman L,
Wraige E, Gowda V, Jungbluth H, Sheehan J, Hughes I, Warner S, Straub V,
Guglieri M, Mayhew A, Chow G, Williamson S, Willis T, Kulshrestha R, Emery N,
Ramdas S, Ramjattan H, de Goede C, Selley A, Ong M, White K, Illingworth M,
Geary M, Palmer J, White C, Greenfield K, Hewawitharana G, Julien Y, Stephens E,
Tewnion J, Ambegaonkar G, Krishnakumar D, Taylor J, Ward C, Willis T, Wright E,
Rylance C.
Author information:
(1)Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child
Health & Great Ormond Street Hospital, London, UK.
(2)Neuromuscular Repair Unit, Institute of Experimental Neurology (InSpe),
Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
(3)Population, Policy and Practice Research and Teaching Department, UCL Great
Ormond Street Institute of Child Health, London, UK.
(4)NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.
(5)Children's Sleep Medicine, Evelina Children Hospital - Paediatric Respiratory
Department Royal Brompton Hospital, Guy's and St Thomas' Trust, London, UK.
AIM: To correlate the North Star Ambulatory Assessment (NSAA) and timed rise
from floor (TRF) recorded at age of expected peak with age at loss of ambulation
(LOA) in Duchenne muscular dystrophy (DMD).
METHOD: Male children with DMD enrolled in the UK North Start Network database
were included according to the following criteria: follow-up longer than 3
years, one NSAA record between 6 years and 7 years 6 months (baseline), at least
one visit when older than 8 years. Data about corticosteroid treatment, LOA,
genotype, NSAA, and TRF were analysed. Age at LOA among the different groups
based on NSAA and TRF was determined by log-rank tests. Cox proportional hazard
models were used for multivariable analysis.
RESULTS: A total of 293 patients from 13 different centres were included. Mean
(SD) age at first and last visit was 5 years 6 months (1 year 2 months) and 12
years 8 months (2 years 11 months) (median follow-up 7 years 4 months). Higher
NSAA and lower TRF at baseline were associated with older age at LOA (p<0.001).
Patients scoring NSAA 32 to 34 had a probability of 0.61 of being ambulant when
older than 13 years compared with 0.34 for those scoring 26 to 31. In
multivariable analysis, NSAA, TRF, and corticosteroid daily regimen (vs
intermittent) were all independently associated with outcome (p=0.01).
INTERPRETATION: Higher functional abilities at peak are associated with older
age at LOA in DMD. This information is important for counselling families. These
baseline measures should also be considered when designing clinical trials.
© 2022 The Authors. Developmental Medicine & Child Neurology published by John
Wiley & Sons Ltd on behalf of Mac Keith Press.
DOI: 10.1111/dmcn.15176
PMCID: PMC9303180
PMID: 35385138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28648683 | 1. Neuromuscul Disord. 2017 Aug;27(8):723-729. doi: 10.1016/j.nmd.2017.05.013.
Epub 2017 May 26.
Reliability and validity analyses of the North Star Ambulatory Assessment in
Brazilian Portuguese.
Okama LO(1), Zampieri LM(1), Ramos CL(1), Toledo FO(1), Alves CRJ(2),
Mattiello-Sverzut AC(2), Mayhew A(3), Sobreira CFR(4).
Author information:
(1)Department of Neurosciences, Ribeirão Preto Medical School, University of São
Paulo, São Paulo, Brazil.
(2)Department of Biomechanics, Medicine and Rehabilitation of the Locomotor
Apparatus, Ribeirão Preto Medical School, University of São Paulo, São Paulo,
Brazil.
(3)John Walton Muscular Dystrophy Research Centre, Institute of Genetic
Medicine, International Centre for Life, Newcastle Upon Tyne, United Kingdom.
(4)Department of Neurosciences, Ribeirão Preto Medical School, University of São
Paulo, São Paulo, Brazil. Electronic address: csobreira@fmrp.usp.br.
The North Star Ambulatory Assessment measures motor performance in ambulatory
boys with Duchenne muscular dystrophy, a hereditary and degenerative muscle
disorder. To use the North Star Ambulatory Assessment in Brazilian boys, we
performed the cross-cultural adaptation to the Portuguese language spoken in
Brazil and evaluated the reliability and validity of the instrument.
Cross-cultural adaptation included: independent translations, synthesis,
committee review, pre-testing in 12 boys, back-translation and comparison with
the original instrument. Thirty-five boys with Duchenne muscular dystrophy and
38 healthy age-matched controls were recruited for further analyses. Reliability
was assessed by internal consistency and reproducibility. Validity studies
included face, content, construct and known-groups analyses. Cross-cultural
adaptation resulted in an adequate instrument. Reliability studies demonstrated
high internal consistency (Cronbach's alpha = 0.935) and adequate intra and
inter-rater reproducibility (intraclass correlation coefficient = 0.988 and
0.962). Validation analyses indicated satisfactory content, face and convergent
construct validities, with positive correlations with the Motor Function Measure
total score (r = 0.863) and the 6-minute walk test (r = 0.433). The known group
validity was demonstrated by higher scores in younger boys with Duchenne
muscular dystrophy (p = 0.005). North Star Ambulatory Assessment in Brazilian
Portuguese is a reliable and valid instrument to measure functional capacity in
boys with Duchenne muscular dystrophy.
Copyright © 2017 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2017.05.013
PMID: 28648683 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31479456 | 1. PLoS One. 2019 Sep 3;14(9):e0221097. doi: 10.1371/journal.pone.0221097.
eCollection 2019.
Categorising trajectories and individual item changes of the North Star
Ambulatory Assessment in patients with Duchenne muscular dystrophy.
Muntoni F(1)(2), Domingos J(1), Manzur AY(1), Mayhew A(3), Guglieri M(3); UK
NorthStar Network; Sajeev G(4)(5), Signorovitch J(4)(5), Ward SJ(4).
Author information:
(1)Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child
Health & Great Ormond Street Hospital, London, United Kingdom.
(2)National Institute for Health Research Great Ormond Street Hospital
Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health,
London, United Kingdom.
(3)John Walton Muscular Dystrophy Research Centre, Newcastle University,
Newcastle, United Kingdom.
(4)Collaborative Trajectory Analysis Project, Cambridge, Massachusetts, United
States of America.
(5)Analysis Group Inc., Boston, Massachusetts, United States of America.
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well
recognised and complicates interpretation of clinical studies. We hypothesised
that boys with DMD could be clustered into groups sharing similar trajectories
of ambulatory function over time, as measured by the North Star Ambulatory
Assessment (NSAA) total score. We also explored associations with other
variables such as age, functional abilities, and genotype. Using the NorthStar
Clinical Network database, 395 patients with >1 NSAA assessment were identified.
We utilised latent class trajectory analysis of longitudinal NSAA scores, which
produced evidence for at least four clusters of boys sharing similar
trajectories versus age in decreasing order of clinical severity: 25% of the
boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2
(NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4
(NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters
(4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment,
a significant (p<0.05) association was observed between earlier declining
clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre
walk/run times, and younger age of steroid initiation. In order to assess the
probability of observing complete loss of function for individual NSAA items, we
examined the proportion of patients who shifted from a score of 1 or 2 at
baseline to a score of 0. We also assessed the probability of gain of function
using the inverse assessment and stratified the probability of deterioration,
improvement-or static behavior-by age ranges and using baseline functional
status. Using this tool, our study provides a comprehensive assessment of the
NSAA in a large population of patients with DMD and, for the first time,
describes discrete clusters of disease progression; this will be invaluable for
future DMD clinical trial design and interpretation of findings.
DOI: 10.1371/journal.pone.0221097
PMCID: PMC6719875
PMID: 31479456 [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: G.S. and J.S. are
employees of Analysis Group Inc., which has received research funding from the
study sponsors via the Collaborative Trajectory Analysis Project. S.J.W. is an
independent consultant who has received funding from the study sponsors via
cTAP, and has also received funds from patient foundations (CureDuchenne, Parent
Project Muscular Dystrophy) to establish the Collaborative Trajectory Analysis
Project This does not alter our adherence to PLOS ONE policies on sharing data
and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/25454732 | 1. Neuromuscul Disord. 2015 Jan;25(1):14-8. doi: 10.1016/j.nmd.2014.09.015. Epub
2014 Oct 6.
Suitability of North Star Ambulatory Assessment in young boys with Duchenne
muscular dystrophy.
De Sanctis R(1), Pane M(1), Sivo S(1), Ricotti V(2), Baranello G(3), Frosini
S(4), Mazzone E(1), Bianco F(1), Fanelli L(1), Main M(2), Corlatti A(3), D'Amico
A(5), Colia G(5), Scalise R(1), Palermo C(1), Alfonsi C(1), Tritto G(1), Romeo
DM(1), Graziano A(1), Battini R(4), Morandi L(3), Bertini E(5), Muntoni F(2),
Mercuri E(6).
Author information:
(1)Department of Paediatric Neurology, Catholic University, Rome, Italy.
(2)Dubowitz Neuromuscular Centre, Institute of Child Health, University College,
London, United Kingdom.
(3)Developmental Neurology Unit, C. Besta Neurological Institute IRCCS, Milan,
Italy.
(4)Department of Developmental Neuroscience, IRCSS Stella Maris, Pisa, Italy.
(5)Unit of Neuromuscular and Neurodegenerative diseases, Department of
Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.
(6)Department of Paediatric Neurology, Catholic University, Rome, Italy.
Electronic address: eumercuri@gmail.com.
The aim of this study was to establish the suitability of the North Star
Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We
studied 147 typically developing and 144 boys affected by Duchenne muscular
dystrophy between the ages of 3 and 5 years. More than 85% of the typically
developing boys by the age of 4 years had full scores on all the items with
total scores ≥33/34. Before the age of 4 years more than 15% of the typically
developing boys did not achieve full scores on all the items. Some items, such
as standing on one leg, showed significant improvement with age. In contrast,
other activities were rarely achieved even in the older boys. Even if there was
a progressive increase in scores with age, both total and individual item scores
in Duchenne were still far from those obtained in the typically developing
children of the same age. Our findings suggest that the North Star Ambulatory
Assessment can be reliably used at least from the age of 4 years. Longitudinal
natural history data studies are needed to assess possible changes over time and
the possible effect of early steroids.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2014.09.015
PMID: 25454732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21410696 | 1. Dev Med Child Neurol. 2011 Jun;53(6):535-42. doi:
10.1111/j.1469-8749.2011.03939.x. Epub 2011 Mar 17.
Moving towards meaningful measurement: Rasch analysis of the North Star
Ambulatory Assessment in Duchenne muscular dystrophy.
Mayhew A(1), Cano S, Scott E, Eagle M, Bushby K, Muntoni F; North Star Clinical
Network for Paediatric Neuromuscular Disease.
Collaborators: Manzur AY, Muntoni F, Robb S, Main M, Kemp J, Ricotti V, Scott E,
Bushby K, Straub V, Sarkozy A, Strehle E, Venkateswaran R, Eagle E, Mayhew A,
Roper H, McMurchie H, Grace A, Spinty S, Peachey G, Shillington S, Quinlivan R,
Groves L, Wraige E, Jungbluth H, Sheehan J, Spahr R, Hughes I, Bateman E,
Cammiss C, Childs AM, Pallant L, Psyden K, Baxter P, Naismith K, Keddie A,
Horrocks I, McWilliam R, Di Marco M, Hartley L, Sheen B, Fenton-May J, Jardine
P, Majumdar A, Jenkins L, Chow G, Miah A, de Goede C, Thomas N, Geary M, Keslake
K, White C, Greenfield K, MacAuley S, Baxter A, Yirrell Y, Longman C.
Author information:
(1)Institute of Human Genetics, International Centre for Life, Newcastle
University, Newcastle upon Tyne, UK. anna.mayhew@ncl.ac.uk
AIM: Reliable measurement of disease progression and the effect of therapeutic
interventions in Duchenne muscular dystrophy (DMD) require clinically meaningful
and scientifically sound rating scales. Therefore, we need robust evidence to
support such tools. The North Star Ambulatory Assessment (NSAA) is a promising,
clinician-rated scale with potential uses spanning clinical practice and
clinical trials. In this study, we used Rasch analysis to test its suitability
in these roles as a measurement instrument.
METHOD: NSAA data from 191 ambulant boys (mean age at assessment 7 y 8 mo, SD 2
y 4 mo; range 3 y 6 mo-15 y 5 mo) with a confirmed diagnosis of DMD were
examined for psychometric properties including clinical meaning, targeting,
response categories, model fit, reliability, dependency, stability, and raw to
interval-level measurement. All analyses were performed using the Rasch
Unidimensional Measurement Model.
RESULTS: Overall, Rasch analysis supported the NSAA as being a reliable (high
Person Separation Index of 0.91) and valid (good targeting, little misfit, no
reversed thresholds) measure of ambulatory function in DMD. One item displayed
misfit (lifts head, fit residual 6.9) and there was evidence for some local
dependency (stand on right/left leg, climb and descend box step right/left leg,
and hop on right/left leg, residual correlations >0.40), which we provide
potential solutions for in future use of the NSAA. Importantly, our findings
supported good clinical validity in that the hierarchy of items within the scale
produced by the analyses was supported by clinical opinion, thus increasing the
clinical interpretability of scale scores.
INTERPRETATION: In general, Rasch analysis supported the NSAA as a
psychometrically robust scale for use in DMD clinical research and trials. This
study also demonstrates how Rasch analysis is a useful instrument to detect and
understand the key measurement issues of rating scales.
© The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.
DOI: 10.1111/j.1469-8749.2011.03939.x
PMID: 21410696 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31629611 | 1. Neuromuscul Disord. 2019 Nov;29(11):857-862. doi: 10.1016/j.nmd.2019.09.010.
Epub 2019 Sep 26.
Longitudinal natural history in young boys with Duchenne muscular dystrophy.
Coratti G(1), Brogna C(1), Norcia G(2), Ricotti V(3), Abbott L(3), D'Amico A(4),
Berardinelli A(5), Vita GL(6), Lucibello S(1), Messina S(6), Sansone V(7),
Albamonte E(7), Colia G(4), Salmin F(7), Gardani A(5), Manzur A(3), Main M(3),
Baranello G(8), Arnoldi MT(9), Parsons J(10), Carry T(10), Connolly AM(11),
Bertini E(4), Muntoni F(12), Pane M(2), Mercuri E(13).
Author information:
(1)Paediatric Neurology, Catholic University, Rome, Italy; Centro Clinico Nemo,
Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli
IRCCS, Rome, Italy.
(2)Centro Clinico Nemo, Policlinico Gemelli, Fondazione Policlinico
Universitario Agostino Gemelli IRCCS, Rome, Italy.
(3)Dubowitz Neuromuscular Centre University College London, London, United
Kingdom.
(4)Unit of Neuromuscular and Neurodegenerative Disorders, Department of
Neurosciences, Bambino Gesù Children's Research Hospital IRCCS, Rome, Italy.
(5)Child and Adolescent Unit, IRCCS Mondino Foundation, Pavia, Italy.
(6)Department of Clinical and Experimental Medicine, University of Messina and
Nemo Sud Clinical Centre, Messina, Italy.
(7)The NEMO Center in Milan, Neurorehabilitation Unit, University of Milan, ASST
Niguarda Hospital, Milan, Italy.
(8)Dubowitz Neuromuscular Centre University College London, London, United
Kingdom; UO Neurologia dello Sviluppo, Fondazione IRCCS Istituto Neurologico
Carlo Besta, Milan, Italy; NIHR Great Ormond Street Hospital Biomedical Research
Centre, London, United Kingdom.
(9)UO Neurologia dello Sviluppo, Fondazione IRCCS Istituto Neurologico Carlo
Besta, Milan, Italy.
(10)Department of Pediatrics and Neurology, University of Colorado, Denver, CO,
United States.
(11)Nationwide Children's Hospital, Ohio State University, Columbus, Ohio,
United States.
(12)Dubowitz Neuromuscular Centre University College London, London, United
Kingdom; NIHR Great Ormond Street Hospital Biomedical Research Centre, London,
United Kingdom.
(13)Paediatric Neurology, Catholic University, Rome, Italy; Centro Clinico Nemo,
Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli
IRCCS, Rome, Italy. Electronic address: eugeniomaria.mercuri@unicatt.it.
The aim of this prospective multicentric study was to document disease
progression in young boys affected by Duchenne muscular dystrophy (DMD) between
age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale.
One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean:
4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our
results showed North Star Ambulatory Assessment scores progressively increased
with age. The largest increase was observed between age 3 and 4 years but
further increase was steadily observed until age of 6 years. Using a multiple
linear regression analysis, we found that both the use of corticosteroids and
the site of mutation significantly contributed to the North Star Ambulatory
Assessment changes (p < 0.001). At each age point, boys on corticosteroid
treatment had higher scores than corticosteroid naïve ones (p < 0.001).
Similarly, patients with mutations downstream exon 44, had lower baseline scores
and lower magnitude of changes compared to those with mutations located at the
5' end of the gene (p < 0,001). Very few boys achieved the age appropriate
maximum score. These results provide useful information for the assessment and
counselling of young DMD boys and for the design of clinical trials in this age
group.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2019.09.010
PMID: 31629611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35302767 | 1. J Med Chem. 2022 Apr 14;65(7):5300-5316. doi: 10.1021/acs.jmedchem.1c01170.
Epub 2022 Mar 18.
Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and
PRN1008 (Rilzabrutinib).
Owens TD(1), Brameld KA(1), Verner EJ(1), Ton T(1), Li X(1), Zhu J(1),
Masjedizadeh MR(1), Bradshaw JM(1), Hill RJ(1), Tam D(1), Bisconte A(1), Kim
EO(1), Francesco M(1), Xing Y(1), Shu J(1), Karr D(1), LaStant J(1), Finkle
D(1), Loewenstein N(1), Haberstock-Debic H(1), Taylor MJ(1), Nunn P(1), Langrish
CL(1), Goldstein DM(1).
Author information:
(1)Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco,
California 94080, United States.
Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in
immune pathways as an essential intracellular signaling element, participating
in both adaptive and immune responses. Currently approved BTK inhibitors are
irreversible covalent inhibitors and limited to oncology indications. Herein, we
describe the design of covalent reversible BTK inhibitors and the discoveries of
PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited
potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis
models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has
completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for
pemphigus vulgaris and immune thrombocytopenia.
DOI: 10.1021/acs.jmedchem.1c01170
PMID: 35302767 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35301810 | 1. Clin Transl Sci. 2022 Jun;15(6):1507-1518. doi: 10.1111/cts.13271. Epub 2022
Apr 3.
A thorough QTc study to evaluate the effects of oral rilzabrutinib administered
alone and with ritonavir in healthy subjects.
Ucpinar S(1), Darpo B(2), Neale A(1), Nunn P(1), Shu J(1), Chu KA(1), Kavanagh
M(1), Xue H(2), Phiasivongsa P(1), Thomas D(1), Smith PF(3).
Author information:
(1)Principia Biopharma Inc., A Sanofi Company, South San Francisco, California,
USA.
(2)ERT, Philadelphia, Pennsylvania, USA.
(3)Certara, Princeton, New Jersey, USA.
This study aimed to define the clinically relevant supratherapeutic dose of
rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate
potential effects of therapeutic and supratherapeutic exposures on cardiac
repolarization in healthy subjects. This was a two-part phase I study
(anzctr.org.au ACTRN12618001036202). Part A was a randomized, open-label,
three-period, single-dose crossover study (n = 12) with rilzabrutinib
100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized,
double-blind, placebo-controlled, four-way, single-dose crossover study (n = 39)
with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin
(positive control). Primary objectives: part A - pharmacokinetics (PK) of
rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B - effect
of rilzabrutinib therapeutic and supratherapeutic concentration on
electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded
before and post-dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17-fold
area under the concentration-time curve (AUC0-∞ ) and 7-fold maximum plasma
concentration (Cmax ) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg
was discontinued due to mild-to-moderate gastrointestinal intolerance. In Part
B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC0-∞ from 454
to 3800 ng h/mL and Cmax from 144 to 712 ng/mL. The concentration-QTc
relationship was slightly negative, shallow (-0.01 ms/ng/mL [90% CI -0.016 to
-0.001]), and an effect >10 ms on QTcF could be excluded within the observed
range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other
studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic
doses, had no clinically relevant effects on ECG parameters, including the QTc
interval.
© 2022 The Authors. Clinical and Translational Science published by Wiley
Periodicals LLC on behalf of American Society for Clinical Pharmacology and
Therapeutics.
DOI: 10.1111/cts.13271
PMCID: PMC9199881
PMID: 35301810 [Indexed for MEDLINE]
Conflict of interest statement: S.U., A.N., P.N., J.S., K.A.C., M.K., and P.P
are or were former employees of and received stock ownership from Principia
Biopharma Inc., a Sanofi company at the time of the study. B.D. reports stock or
other ownership with ERT and consulting/advisory role as his main employment
(excluding Principia Biopharma Inc., a Sanofi company). H.X. is an employee of
ERT. D.T. was a former employee of and received stock ownership from Principia
Biopharma Inc., a Sanofi company at the time of the study, and reports pending
patent regarding rilzabrutinib. P.F.S. reports employment with Certara and
received consulting fees from Principia Biopharma Inc, a Sanofi company. |
http://www.ncbi.nlm.nih.gov/pubmed/20634072 | 1. Neuromuscul Disord. 2010 Nov;20(11):712-6. doi: 10.1016/j.nmd.2010.06.014.
Epub 2010 Jul 14.
North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant
boys with Duchenne muscular dystrophy.
Mazzone E(1), Martinelli D, Berardinelli A, Messina S, D'Amico A, Vasco G, Main
M, Doglio L, Politano L, Cavallaro F, Frosini S, Bello L, Carlesi A, Bonetti AM,
Zucchini E, De Sanctis R, Scutifero M, Bianco F, Rossi F, Motta MC, Sacco A,
Donati MA, Mongini T, Pini A, Battini R, Pegoraro E, Pane M, Pasquini E, Bruno
C, Vita G, de Waure C, Bertini E, Mercuri E.
Author information:
(1)Department of Paediatric Neurology, Catholic University, Rome, Italy.
The North Star Ambulatory Assessment is a functional scale specifically designed
for ambulant boys affected by Duchenne muscular dystrophy (DMD). Recently the
6-minute walk test has also been used as an outcome measure in trials in DMD.
The aim of our study was to assess a large cohort of ambulant boys affected by
DMD using both North Star Assessment and 6-minute walk test. More specifically,
we wished to establish the spectrum of findings for each measure and their
correlation. This is a prospective multicentric study involving 10 centers. The
cohort included 112 ambulant DMD boys of age ranging between 4.10 and 17 years
(mean 8.18±2.3 DS). Ninety-one of the 112 were on steroids: 37/91 on
intermittent and 54/91 on daily regimen. The scores on the North Star assessment
ranged from 6/34 to 34/34. The distance on the 6-minute walk test ranged from
127 to 560.6 m. The time to walk 10 m was between 3 and 15 s. The time to rise
from the floor ranged from 1 to 27.5 s. Some patients were unable to rise from
the floor. As expected the results changed with age and were overall better in
children treated with daily steroids. The North Star assessment had a moderate
to good correlation with 6-minute walk test and with timed rising from floor but
less with 10 m timed walk/run test. The 6-minute walk test in contrast had
better correlation with 10 m timed walk/run test than with timed rising from
floor. These findings suggest that a combination of these outcome measures can
be effectively used in ambulant DMD boys and will provide information on
different aspects of motor function, that may not be captured using a single
measure.
Copyright © 2010. Published by Elsevier B.V.
DOI: 10.1016/j.nmd.2010.06.014
PMID: 20634072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36182620 | 1. Transfus Med Rev. 2022 Oct;36(4):175-180. doi: 10.1016/j.tmrv.2022.08.001.
Epub 2022 Sep 6.
New Therapies for the Treatment of Warm Autoimmune Hemolytic Anemia.
Fattizzo B(1), Barcellini W(2).
Author information:
(1)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy;
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Electronic address: bruno.fattizzo@unimi.it.
(2)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Electronic address: wilma.barcellini@policlinico.mi.it.
In this review article we provide a critical insight into recent reports
evaluating innovative therapies for warm type autoimmune hemolytic anemia
(wAIHA). Among published articles, we selected two reports on the use of the
proteasome inhibitor bortezomib in association with dexamethasone or rituximab,
one study on the spleen tyrosine kinase inhibitor fostamatinib, and a
retrospective study on recombinant erythropoietin (rEPO). Among recent
scientific communications, we discussed a report on the phosphoinositide
3-kinase delta inhibitor (PI3Kδi) parsaclisib. All studies highlighted a good
efficacy although to be confirmed in larger trials and with limitations due to
the heterogeneity of wAIHA patients enrolled, the small number of subjects, the
concomitant medications allowed, and the short follow-up. Ongoing trials include
new B-cell/plasma-cell targeting agents such as the Bruton tyrosine kinase
inhibitors ibrutinib and rilzabrutinib, and the anti-CD38 MoAbs daratumumab and
its analogue isatuximab. Further drugs in clinical trials target the complement
cascade in wAIHA with complement activation, such as the C3 inhibitor
pegcetacoplan and the C1q inhibitor ANX005. Finally, an interesting and
non-immuno-toxic strategy is to remove the pathogenic autoantibodies via
blocking the neonatal Fc receptor, by intravenous nipocalimab and subcutaneous
RVT-1401. Such novel agents targeting the several immunopathological mechanisms
acting in wAIHA and their possible combination, will increase the therapeutic
armamentarium and possibly fill the gap of wAIHA relapsed after/refractory to
rituximab. Moreover, these new target therapies may represent a tool for the
unmet need of very acute cases.
Copyright © 2022. Published by Elsevier Inc.
DOI: 10.1016/j.tmrv.2022.08.001
PMID: 36182620 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement BF received
consultancy for Amgen, Alexion, Annexon, Apellis, Momenta, Novartis, Sobi. WB
received consultancy for Agios, Alexion, Annexon, Sanofi, Novartis, Sobi. |
http://www.ncbi.nlm.nih.gov/pubmed/35562130 | 1. Indian J Pathol Microbiol. 2022 May;65(Supplement):S14-S23. doi:
10.4103/ijpm.ijpm_34_22.
A review of adult-type diffuse gliomas in the WHO CNS5 classification with
special reference to Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant
and 1p/19q codeleted.
Santosh V(1), Rao S(1).
Author information:
(1)Department of Neuropathology, National Institute of Mental Health and
Neurosciences, Bengaluru, Karnataka, India.
The fifth edition of the World Health Organization (WHO) Classification of
Tumors of the Central Nervous System (WHO CNS5) features several changes in the
classification, diagnostic criteria, nomenclature, and grading of diffuse
gliomas. Adult-type diffuse gliomas are genetically defined and include
astrocytoma, isocitrate dehydrogenase (IDH)-mutant, oligodendroglioma,
IDH-mutant and 1p/19q codeleted, and glioblastoma, IDH-wildtype. This review
briefly discusses two tumor types: astrocytoma, IDH-mutant, and
oligodendroglioma, IDH-mutant and 1p/19q codeleted, with emphasis on relevant
changes in their classification and defining molecular genetic alterations. A
simplified approach to the diagnosis of these tumors is provided.
DOI: 10.4103/ijpm.ijpm_34_22
PMID: 35562130 [Indexed for MEDLINE]
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/35587830 | 1. Eur Radiol. 2022 Nov;32(11):7780-7788. doi: 10.1007/s00330-022-08850-z. Epub
2022 May 19.
Diffuse glioma, not otherwise specified: imaging-based risk stratification
achieves histomolecular-level prognostication.
Jang EB(1), Kim HS(2), Park JE(1), Park SY(3), Nam YK(4), Nam SJ(5), Kim YH(6),
Kim JH(6).
Author information:
(1)Department of Radiology and Research Institute of Radiology, University of
Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu,
Seoul, 05505, Republic of Korea.
(2)Department of Radiology and Research Institute of Radiology, University of
Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu,
Seoul, 05505, Republic of Korea. radhskim@gmail.com.
(3)Department of Statistics and Data Science, Korea National Open University,
Seoul, Republic of Korea.
(4)Department of Radiology, Shinchon Yonsei Hospital, Seoul, Republic of Korea.
(5)Department of Pathology, University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Republic of Korea.
(6)Department of Neurosurgery, University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Republic of Korea.
Comment in
Eur Radiol. 2022 Nov;32(11):7778-7779. doi: 10.1007/s00330-022-09098-3.
OBJECTIVES: To determine whether imaging-based risk stratification enables
prognostication in diffuse glioma, NOS (not otherwise specified).
METHODS: Data from 220 patients classified as diffuse glioma, NOS, between
January 2011 and December 2020 were retrospectively included. Two
neuroradiologists analyzed pre-surgical CT and MRI to assign gliomas to the
three imaging-based risk types considering well-known imaging phenotypes (e.g.,
T2/FLAIR mismatch). According to the 2021 World Health Organization
classification, the three risk types included (1) low-risk, expecting
oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, and 1p/19q-codeleted;
(2) intermediate-risk, expecting astrocytoma, IDH-mutant; and (3) high-risk,
expecting glioblastoma, IDH-wildtype. Progression-free survival (PFS) and
overall survival (OS) were estimated for each risk type. Time-dependent receiver
operating characteristic analysis using 10-fold cross-validation with 100-fold
bootstrapping was used to compare the performance of an imaging-based survival
model with that of a historical molecular-based survival model published in
2015, created using The Cancer Genome Archive data.
RESULTS: Prognostication according to the three imaging-based risk types was
achieved for both PFS and OS (log-rank test, p < 0.001). The imaging-based
survival model showed high prognostic value, with areas under the curves (AUCs)
of 0.772 and 0.650 for 1-year PFS and OS, respectively, similar to the
historical molecular-based survival model (AUC = 0.74 for PFS and 0.87 for OS).
The imaging-based survival model achieved high long-term performance in both
3-year PFS (AUC = 0.806) and 5-year OS (AUC = 0.812).
CONCLUSION: Imaging-based risk stratification achieved histomolecular-level
prognostication in diffuse glioma, NOS, and could aid in guiding patient
referral for insufficient or unsuccessful molecular diagnosis.
KEY POINTS: • Three imaging-based risk types enable distinct prognostication in
diffuse glioma, NOS (not otherwise specified). • The imaging-based survival
model achieved similar prognostic performance as a historical molecular-based
survival model. • For long-term prognostication of 3 and 5 years, the
imaging-based survival model showed high performance.
© 2022. The Author(s), under exclusive licence to European Society of Radiology.
DOI: 10.1007/s00330-022-08850-z
PMID: 35587830 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31175262 | 1. Pract Neurol. 2019 Oct;19(5):412-416. doi: 10.1136/practneurol-2018-002116.
Epub 2019 Jun 6.
Clinical importance of molecular markers of adult diffuse glioma.
Molinari E(1), Curran OE(2), Grant R(3).
Author information:
(1)Department of Neurology, Queen Elizabeth University Hospital, Glasgow, UK.
(2)Neuropathology Unit, Department of Pathology, Western General Hospital,
Edinburgh, UK.
(3)Department of Neurology and Neurosurgery, Western General Hospital,
Edinburgh, UK robin.grant@nhslothian.scot.nhs.uk.
In 2016, the WHO incorporated molecular markers, in addition to histology, into
the diagnostic classification of central nervous system (CNS) tumours. This
improves diagnostic accuracy and prognostication: oligo-astrocytoma no longer
exists as a clinical entity; isocitrate dehydrogenase (IDH) mutant and 1p/19q
co-deleted oligodendroglioma is a smaller category with better prognosis; IDH
wild-type 'low-grade' glioma has a much poorer prognosis; and glioblastoma is
divided into IDH mutant (with an better prognosis than pre-2016 glioblastoma)
and IDH wild type (with a poorer prognosis). Previous advice based on phenotype
alone will change with respect to median survival, best management plan and
response to treatment. There are implications for routine neuropathology
reporting and future trial design. Cases that are difficult to classify may need
more advanced molecular genetic classification through DNA methylation-based
classification of CNS tumours (Heidelberg Classifier). We discuss the practical
implications.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and
permissions. Published by BMJ.
DOI: 10.1136/practneurol-2018-002116
PMID: 31175262 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/36006639 | 1. JAMA Oncol. 2022 Oct 1;8(10):1493-1501. doi: 10.1001/jamaoncol.2022.2844.
World Health Organization 2021 Classification of Central Nervous System Tumors
and Implications for Therapy for Adult-Type Gliomas: A Review.
Berger TR(1)(2), Wen PY(1)(2)(3), Lang-Orsini M(4), Chukwueke UN(1)(2)(3).
Author information:
(1)Division of Neuro-Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts.
(2)Harvard Medical School, Boston, Massachusetts.
(3)Division of Neuro-Oncology, Department of Neurology, Brigham and Women's
Hospital, Boston, Massachusetts.
(4)Division of Neuropathology, Department of Pathology, Massachusetts General
Hospital, Boston.
IMPORTANCE: Previous histologic classifications of brain tumors have been
limited by discrepancies in diagnoses reported by neuropathologists and
variability in outcomes and response to therapies. Such diagnostic discrepancies
have impaired clinicians' ability to select the most appropriate therapies for
patients and have allowed heterogeneous populations of patients to be enrolled
in clinical trials, hindering the development of more effective therapies. In
adult-type diffuse gliomas, histologic classification has a particularly
important effect on clinical care.
OBSERVATIONS: In 2021, the World Health Organization published the fifth edition
of the Classification of Tumors of the Central Nervous System. This
classification incorporates advances in understanding the molecular pathogenesis
of brain tumors with histopathology in order to group tumors into more
biologically and molecularly defined entities. As such, tumor classification is
significantly improved through better characterized natural histories. These
changes have particularly important implications for gliomas. For the first
time, adult- and pediatric-type gliomas are classified separately on the basis
of differences in molecular pathogenesis and prognosis. Furthermore, the
previous broad category of adult-type diffuse gliomas has been consolidated into
3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma,
IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major
changes are driven by IDH mutation status and include the restriction of the
diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification
of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH
mutated, grade 4; and the requirement for the presence of IDH mutations to
classify tumors as astrocytomas or oligodendrogliomas.
CONCLUSIONS AND RELEVANCE: The 2021 World Health Organization central nervous
system tumor classification is a major advance toward improving the diagnosis of
brain tumors. It will provide clinicians with more accurate guidance on
prognosis and optimal therapy for patients and ensure that more homogenous
patient populations are enrolled in clinical trials, potentially facilitating
the development of more effective therapies.
DOI: 10.1001/jamaoncol.2022.2844
PMID: 36006639 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35876874 | 1. Neuroradiology. 2023 Jan;65(1):41-54. doi: 10.1007/s00234-022-03015-7. Epub
2022 Jul 25.
Imaging-based stratification of adult gliomas prognosticates survival and
correlates with the 2021 WHO classification.
Kamble AN(1)(2), Agrawal NK(3)(4), Koundal S(5), Bhargava S(6), Kamble AN(7),
Joyner DA(8), Kalelioglu T(8), Patel SH(8), Jain R(9)(10).
Author information:
(1)University Hospitals Coventry & Warwickshire, Coventry, UK.
drakshaykumarkamble@gmail.com.
(2)Deep Learning Institute of Radiological Sciences (DeLoRIS), Mumbai, India.
drakshaykumarkamble@gmail.com.
(3)Deep Learning Institute of Radiological Sciences (DeLoRIS), Mumbai, India.
(4)Max Super-Specialty Hospital, Mohali, India.
(5)Department of Radiology, Institute of Nuclear Medicine & Allied Sciences
(INMAS), New Delhi, India.
(6)Sir Ganga Ram Hospital, Delhi, India.
(7)Saraswati College of Engineering, Mumbai, India.
(8)Department of Radiology, University of Virginia Health System,
Charlottesville, VA, USA.
(9)Department of Radiology, New York University Grossman School of Medicine, New
York, NY, USA.
(10)Department of Neurosurgery, New York University Grossman School of Medicine,
New York, NY, USA.
BACKGROUND: Because of the lack of global accessibility, delay, and
cost-effectiveness of genetic testing, there is a clinical need for an
imaging-based stratification of gliomas that can prognosticate survival and
correlate with the 2021-WHO classification.
METHODS: In this retrospective study, adult primary glioma patients with
pre-surgery/pre-treatment MRI brain images having T2, FLAIR, T1, T1
post-contrast, DWI sequences, and survival information were included in TCIA
training-dataset (n = 275) and independent validation-dataset (n = 200). A
flowchart for imaging-based stratification of adult gliomas(IBGS) was created in
consensus by three authors to encompass all adult glioma types. Diagnostic
features used were T2-FLAIR mismatch sign, central necrosis with peripheral
enhancement, diffusion restriction, and continuous cortex sign. Roman numerals
(I, II, and III) denote IBGS types. Two independent teams of three and two
radiologists, blinded to genetic, histology, and survival information, manually
read MRI into three types based on the flowchart. Overall survival-analysis was
done using age-adjusted Cox-regression analysis, which provided both
hazard-ratio (HR) and area-under-curve (AUC) for each stratification system(IBGS
and 2021-WHO). The sensitivity and specificity of each IBSG type were analyzed
with cross-table to identify the corresponding 2021-WHO genotype.
RESULTS: Imaging-based stratification was statistically significant in
predicting survival in both datasets with good inter-observer agreement
(age-adjusted Cox-regression, AUC > 0.5, k > 0.6, p < 0.001). IBGS type-I,
type-II, and type-III gliomas had good specificity in identifying IDHmut
1p19q-codel oligodendroglioma (training - 97%, validation - 85%); IDHmut 1p19q
non-codel astrocytoma (training - 80%, validation - 85.9%); and IDHwt
glioblastoma (training - 76.5%, validation- 87.3%) respectively
(p-value < 0.01).
CONCLUSIONS: Imaging-based stratification of adult diffuse gliomas predicted
patient survival and correlated well with 2021-WHO glioma classification.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,
part of Springer Nature.
DOI: 10.1007/s00234-022-03015-7
PMID: 35876874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36299937 | 1. Cureus. 2022 Sep 22;14(9):e29457. doi: 10.7759/cureus.29457. eCollection 2022
Sep.
T2-Fluid-Attenuated Inversion Recovery (FLAIR) Mismatch as a Novel Specific MRI
Marker for Adult Low-Grade Glioma (LGG): A Case Report.
Slaghour RM(1), Almarshedi RA(2), Alzahrani AM(3), Albadr F(4).
Author information:
(1)Medicine, King Abdulaziz University Faculty of Medicine, Jeddah, SAU.
(2)Medicine, University of Hail College of Medicine, Hail, SAU.
(3)Medicine, King Saud Medical City, King Saud University, Riyadh, SAU.
(4)Radiology and Medical Imaging/Neuroradiology, King Saud Medical City, King
Saud University, Riyadh, SAU.
Astrocytic tumors are primary central nervous system tumors. They are the most
common tumors arising from glial cells. In the new WHO classification 2021,
adult-type diffuse astrocytic gliomas subdivide into isocitrate dehydrogenase
(IDH)-mutant astrocytoma, IDH-mutant and 1p/19q-codeleted oligodendroglioma, and
IDH-wildtype glioblastoma. The T2-fluid-attenuated inversion recovery (FLAIR)
mismatch sign describes the MRI appearance of IDH-mutant astrocytoma, it is
considered a highly specific radiogenomic signature for diffuse astrocytoma, as
opposed to other lower-grade. MRI is the first and most accurate diagnostic tool
for low-grade gliomas (LGGs). It is particularly helpful in distinguishing a
diffuse astrocytoma from an oligodendroglioma that will not demonstrate T2-FLAIR
mismatch. The tumor displays a hyperintense signal on T2-weighted images and a
hypointense signal on T2-weighted FLAIR images, which distinguishes it from
other types of diffuse gliomas. We report a case of a 29-year-old female patient
who was diagnosed with IDH-mutant 1p/19q-non-codeleted diffuse astrocytoma based
on MRI T-2 FLAIR mismatch sign, which is confirmed by the molecular analysis in
the pathology lab. Our aim of this report is to confirm the power of the MRI
findings in the diagnosis of glioma genotypes and to assess neurosurgeons in the
preoperative surgical planning.
Copyright © 2022, Slaghour et al.
DOI: 10.7759/cureus.29457
PMCID: PMC9587756
PMID: 36299937
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21889777 | 1. Rev Neurol (Paris). 2011 Oct;167(10):683-90. doi:
10.1016/j.neurol.2011.07.006. Epub 2011 Sep 1.
Histomolecular classification of adult diffuse gliomas: the diagnostic value of
immunohistochemical markers.
Figarella-Branger D(1), Maues de Paula A, Colin C, Bouvier C.
Author information:
(1)Service d'anatomie pathologique et de neuropathologie, hôpital de la Timone,
Assistance publique-Hôpitaux de Marseille, rue Saint-Pierre, Marseille cedex 05,
France. dominique.figarella-branger@univmed.fr
Adult gliomas are most often infiltrative. The World Health Organization (WHO)
has classed them into three major groups according to the presomptive cell of
origin: astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Depending on
the presence or absence of a small number of signs of anaplasia (mitosis,
nuclear atypia, cell density, microvascular proliferation and necrosis) the WHO
distinguishes grade II (LGG), III (anaplastic), and IV (glioblastomas, GBM).
Mutation in the isocitrate deshydrogenase I and II (IDH1 and 2) genes
distinguishes grade II, III and secondary GBM from primary GBM. Moreover two
additional genetic alterations are recorded in grade II and III gliomas: TP53
mutations that characterize astrocytomas and 1p19q codeletion (as the result of
t(1;19)(q10;p10) translocation) recorded in oligodendrogliomas. Mixed gliomas,
the most non-reproducible category, share with astrocytomas and
oligodendrogliomas the same genetic alterations. Interestingly TP53 mutation
(p53+) and 1p19q codeletion (1p19q+) are mutually exclusive and involve IDH
mutated (IDH+) glial precursor cells. According to IDH, TP53, and 1p19q status,
four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-,
IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst
prognosis. Interestingly, p53 expression and internexin alpha (INA) expression
can replace to some extent TP53 mutation and 1p19 codeletion, respectively.
Moreover the antibody directed against the IDH1R132H isoform is highly specific.
Because this mutation is the most frequent it is sufficient to assess IDH status
in more than 80% of grade II and III gliomas. Taken together these three
immunohistochemical markers are contribute greatly to the classification of
gliomas and should be tested routinely as diagnostic markers. Finally, although
GBM are genetically heterogeneous, the vast majority display EGFR amplification,
often associated with EGFR expression, which can be helpful for diagnosis in
certain cases.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.neurol.2011.07.006
PMID: 21889777 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34729052 | 1. J Carcinog. 2021 Oct 11;20:20. doi: 10.4103/jcar.jcar_17_21. eCollection 2021.
Molecular classification and stratification of adult diffuse gliomas: A tertiary
care center study.
Anand N(1), Husain N(1), Varshney R(1), Malhotra KP(1), Kaif M(2).
Author information:
(1)Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences,
Lucknow, Uttar Pradesh, India.
(2)Department of Neurosurgery, Dr. Ram Manohar Lohia Institute of Medical
Sciences, Lucknow, Uttar Pradesh, India.
BACKGROUND: Diffuse gliomas in the adult population are the most common primary
central nervous system (CNS) tumors. The World Health Organization incorporated
isocitrate dehydrogenase (IDH) mutations and 1p/19q co-deletion with
histopathological features into an "integrated diagnosis" in the revised
classification of tumors of CNS. These molecular subgroups of diffuse gliomas
are found to stratify patients into prognostically distinct groups better than
the histological classification. The objectives of the current study were to
assess the frequency of IDH mutation, ATRX expression loss, p53 overexpression,
and 1p/19q co-deletion detection in adult diffuse gliomas (Grade II, III, and
IV) and to correlate them with clinicopathological and histopathological
features.
MATERIALS AND METHODS: The current study was a tertiary care hospital-based
retrospective case series of 112 cases of adult diffuse gliomas.
Immunohistochemistry (IHC)-based molecular detection was performed for IDH-1,
ATRX, and p53 and fluorescent in situ hybridization (FISH) was performed for
1p/19q co-deletion detection.
RESULTS: IDH-1 mutation was present in 30.4% (n = 34/112) cases, ATRX expression
was lost in 18% (n = 19/104) cases, p53 was mutated in 39.3% (n = 42/107) cases
and 1p19q was co-deleted in 25% (n = 4/16) cases. In the IDH1 mutant cases, with
retained ATRX, FISH for 1p/19q co-deletion was performed and was co-deleted in
four cases.
CONCLUSION: The results of the present study indicate that IHC including IDH1/2,
ATRX, and p53 is useful for the molecular classification of diffuse gliomas,
which could be useful for the evaluation of prognosis, especially Grade III and
II. Although the immunohistochemical approach does not replace genetic testing
completely, it is a practical and powerful means of assessing molecular genetic
changes. IDH mutations are the established markers of better prognosis in
diffuse gliomas.
Copyright: © 2021 Journal of Carcinogenesis.
DOI: 10.4103/jcar.jcar_17_21
PMCID: PMC8531577
PMID: 34729052
Conflict of interest statement: There are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32640746 | 1. Cancers (Basel). 2020 Jul 6;12(7):1817. doi: 10.3390/cancers12071817.
Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in
Adult Diffuse Gliomas.
Mirchia K(1), Richardson TE(1).
Author information:
(1)Department of Pathology, State University of New York, Upstate Medical
University, Syracuse, NY 13210, USA.
Diffuse gliomas are among the most common adult central nervous system tumors
with an annual incidence of more than 16,000 cases in the United States. Until
very recently, the diagnosis of these tumors was based solely on morphologic
features, however, with the publication of the WHO Classification of Tumours of
the Central Nervous System, revised 4th edition in 2016, certain molecular
features are now included in the official diagnostic and grading system. One of
the most significant of these changes has been the division of adult
astrocytomas into IDH-wildtype and IDH-mutant categories in addition to
histologic grade as part of the main-line diagnosis, although a great deal of
heterogeneity in the clinical outcome still remains to be explained within these
categories. Since then, numerous groups have been working to identify additional
biomarkers and prognostic factors in diffuse gliomas to help further stratify
these tumors in hopes of producing a more complete grading system, as well as
understanding the underlying biology that results in differing outcomes. The
field of neuro-oncology is currently in the midst of a "molecular revolution" in
which increasing emphasis is being placed on genetic and epigenetic features
driving current diagnostic, prognostic, and predictive considerations. In this
review, we focus on recent advances in adult diffuse glioma biomarkers and
prognostic factors and summarize the state of the field.
DOI: 10.3390/cancers12071817
PMCID: PMC7408495
PMID: 32640746
Conflict of interest statement: The authors have no conflict of interest to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/25744348 | 1. Neurol Med Chir (Tokyo). 2015;55(1):28-37. doi: 10.2176/nmc.ra.2014-0229. Epub
2014 Dec 20.
Pathology and genetics of diffuse gliomas in adults.
Komori T(1).
Author information:
(1)Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo
Metropolitan Neurological Hospital.
Republished in
Neurol Med Chir (Tokyo). 2015;55 Suppl 1:28-37.
The current World Health Organization (WHO) classification of tumors of the
central nervous system (CNS) is essentially a lineage-oriented classification
based on a presumable developmental tree of CNS. A four-tiered WHO grading
scheme has been successfully applied to a spectrum of diffusely infiltrative
astrocytomas, but it is not fully applicable to other gliomas, including
oligodendrogliomas and ependymomas. Recent genetic studies have revealed that
the major categories of gliomas, such as circumscribe astrocytomas, infiltrating
astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major
genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations,
TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion.
These genetic alterations are clinically significant in terms of the response to
treatment(s) and/or the prognosis. It is, thus, rational that future
classification of gliomas should be based on genotypes, rather than phenotypes,
although the genetic features of each tumor are not sufficiently understood at
present to draw a complete map of the gliomas, and genetic testing is not yet
available worldwide, particularly in Asian and African countries. This review
summarizes the current concepts of the WHO classification, as well as the
current understanding of the major genetic alterations in glioma and the
potential use of these alterations as diagnostic criteria.
DOI: 10.2176/nmc.ra.2014-0229
PMCID: PMC4533400
PMID: 25744348 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest Disclosure The author has
no conflict of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/25641008 | 1. Eur J Radiol. 2015 Apr;84(4):709-20. doi: 10.1016/j.ejrad.2014.12.025. Epub
2015 Jan 7.
Imaging of adult brainstem gliomas.
Purohit B(1), Kamli AA(2), Kollias SS(2).
Author information:
(1)Institute for Neuroradiology, University Hospital of Zurich,
Frauenklinikstrasse 10, 8091 Zurich, Switzerland. Electronic address:
purohitbela@yahoo.co.in.
(2)Institute for Neuroradiology, University Hospital of Zurich,
Frauenklinikstrasse 10, 8091 Zurich, Switzerland.
Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all
intracranial neoplasms. They are often phenotypically low-grade as compared to
their more common paediatric counterparts. Since brainstem biopsies are rarely
performed, these tumours are commonly classified according to their MR imaging
characteristics into 4 subgroups: (a) diffuse intrinsic low-grade gliomas, (b)
enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic
gliomas/other subtypes. The prognosis and treatment is variable for the
different types and is almost similar to adult supratentorial gliomas.
Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of
diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to
the exophytic subtypes. Review of previous literature shows that the detailed
imaging of adult BSGs has not received significant attention. This review
illustrates in detail the imaging features of adult BSGs using conventional and
advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor
imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as
well as 18F-fluoro-ethyl-tyrosine positron emission tomography (18F-FET/PET). We
have discussed the pertinent differences between childhood and adult BSGs,
imaging mimics, prognostic factors and briefly reviewed the treatment options of
these tumours.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ejrad.2014.12.025
PMID: 25641008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28339700 | 1. Neuro Oncol. 2017 May 1;19(5):614-624. doi: 10.1093/neuonc/now277.
A clinical perspective on the 2016 WHO brain tumor classification and routine
molecular diagnostics.
van den Bent MJ(1), Weller M(2), Wen PY(3), Kros JM(4), Aldape K(5), Chang S(6).
Author information:
(1)Department of Neurology and Brain Tumor Center, Erasmus MC Cancer Institute,
Rotterdam, the Netherlands
(2)Department of Neurology and Brain Tumor Center, University Hospital and
University of Zurich, Zurich, Switzerland
(3)Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts
(4)Department of Pathology, Erasmus MC, Rotterdam, the Netherlands
(5)Department of Pathology, Princess Margaret Hospital, Toronto, Canada
(6)Division of Neuro-Oncology, Department of Neurological Surgery, University of
California San Francisco,San Francisco, California
Comment in
Neuro Oncol. 2017 May 1;19(5):609-610. doi: 10.1093/neuonc/nox003.
The 2007 World Health Organization (WHO) classification of brain tumors did not
use molecular abnormalities as diagnostic criteria. Studies have shown that
genotyping allows a better prognostic classification of diffuse glioma with
improved treatment selection. This has resulted in a major revision of the WHO
classification, which is now for adult diffuse glioma centered around isocitrate
dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is
reviewed with a focus on adult brain tumors, and includes a recommendation of
genes of which routine testing is clinically useful. Apart from assessment of
IDH mutational status including sequencing of R132H-immunohistochemistry
negative cases and testing for 1p/19q, several other markers can be considered
for routine testing, including assessment of copy number alterations of
chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For
"glioblastoma, IDH mutated" the term "astrocytoma grade IV" could be considered.
It should be considered to treat IDH wild-type grades II and III diffuse glioma
with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments
must be more quickly translated into further revised diagnostic categories.
Quality control and rapid integration of molecular findings into the final
diagnosis and the communication of the final diagnosis to clinicians require
systematic attention.
© The Author(s) 2017. Published by Oxford University Press on behalf of the
Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/neuonc/now277
PMCID: PMC5464438
PMID: 28339700 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30148717 | 1. Curr Opin Oncol. 2018 Nov;30(6):375-382. doi: 10.1097/CCO.0000000000000482.
Molecular classification of adult gliomas: recent advances and future
perspectives.
Barritault M(1)(2)(3), Meyronet D(4)(2)(3), Ducray F(5)(2)(3).
Author information:
(1)Service de Biologie Moléculaire.
(2)Université Claude Bernard Lyon 1.
(3)Department of Cancer Cell Plasticity, Cancer Research Centre of Lyon, INSERM
U1052, CNRS UMR5286, Lyon, France.
(4)Service de Neuropathologie.
(5)Service de Neuro-Oncologie, Hospices Civils de Lyon, Groupe Hospitalier Est,
Lyon, Cedex.
PURPOSE OF REVIEW: This review summarizes recent advances in the molecular
classification of adult gliomas.
RECENT FINDINGS: According to the 2016 WHO classification, five main molecular
subgroups of adult diffuse gliomas can be distinguished based on the 1p/19q
codeletion, isocitrate dehydrogenase (IDH), and histone H3.3 mutation status. In
the future, this classification may be further refined based on the integration
of additional biomarkers, in particular CDKN2A/B homozygous deletion in
IDH-mutant astrocytomas, TERT promoter mutations, EGFR amplification, chromosome
7 gain and chromosome 10 loss in IDH-wildtype astrocytomas, and FGFR1 mutations
in midline gliomas. Histone H3.3 G34R/V defines a distinct subgroup of
hemispheric IDH-wildtype high-grade gliomas occurring in young patients and FGFR
gene fusions characterize a subgroup of IDH-wildtype glioblastomas that could
benefit from specific treatment approaches. RNA sequencing may identify
targetable gene fusions in circumscribed gliomas lacking classical BRAF
alterations. In chordoid gliomas, recurrent PRKCA mutations could serve as a new
diagnostic marker. Among comprehensive molecular analysis methods, DNA
methylation profiling appears as a particularly powerful approach to identify
new molecular subgroups of gliomas and to classify difficult cases.
SUMMARY: The classification of adult gliomas may be improved by the integration
of additional biomarkers and/or by comprehensive molecular analysis, in
particular DNA methylation profiling. The most relevant approach, however,
remains to be established.
DOI: 10.1097/CCO.0000000000000482
PMID: 30148717 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34788571 | 1. Nucleic Acid Ther. 2022 Feb;32(1):29-39. doi: 10.1089/nat.2021.0043. Epub 2021
Nov 17.
Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with
Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human,
Multicenter, Two-Part, Open-Label, Phase 1/2 Trial.
Servais L(1)(2)(3), Mercuri E(4)(5), Straub V(6), Guglieri M(6), Seferian AM(1),
Scoto M(7)(8), Leone D(5), Koenig E(9), Khan N(9), Dugar A(9), Wang X(9), Han
B(9), Wang D(9), Muntoni F(7)(8); SKIP-NMD Study Group.
Collaborators: Brusa C, Antonaci L, Brogna C, Merli L, Monforte M, Norcia G,
Pane M, Ferrantini G, Dickson G, Morgan J, Sardone V, Akana C, Charleston JS,
Desjardins CA, El-Husayni SH, Frank DE, Schnell FJ.
Author information:
(1)I-Motion Institute, Hôpital Armand Trousseau, Paris, France.
(2)Division of Child Neurology, Centre de Références des Maladies
Neuromusculaires, Department of Pediatrics, University Hospital Liège &
University of Liège, Liège, Belgium.
(3)MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, United
Kingdom.
(4)Pediatric Neurology Unit, Università Cattolica del Sacro Cuore Roma, Rome,
Italy.
(5)Nemo Clinical Centre, Fondazione Policlinico Universitario A Gemelli IRCCS,
Rome, Italy.
(6)John Walton Muscular Dystrophy Research Centre, Newcastle University and
Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
(7)Dubowitz Neuromuscular Centre, University College London, Great Ormond Street
Institute of Child Health, London, United Kingdom.
(8)National Institute for Health Research Great Ormond Street Hospital
Biomedical Research Centre, London, United Kingdom.
(9)Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical
safety and efficacy of long-term golodirsen treatment among ambulatory patients
with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a
12-week, randomized, double-blind, placebo-controlled, dose-titration study
followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation
of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary
endpoints were dystrophin protein expression and 6-minute walk test (6MWT);
secondary endpoints were percent predicted forced vital capacity (FVC%p) and
safety. Post hoc ambulation analyses used mutation-matched external natural
history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4)
plus 13 additional patients entered Part 2; 23 completed the study. Adverse
events were generally mild, nonserious, and unrelated to golodirsen, with no
safety-related discontinuations or deaths. Golodirsen increased dystrophin
protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3
years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients
versus -181.4 m for external controls (P = 0.067), and loss of ambulation
occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in
golodirsen-treated patients, comparing favorably with literature-reported rates.
This study provides evidence for golodirsen biologic activity and long-term
safety in a declining DMD population and suggests functional benefit versus
external controls. Clinical Trial Registration number: NCT02310906.
DOI: 10.1089/nat.2021.0043
PMCID: PMC8817703
PMID: 34788571 [Indexed for MEDLINE]
Conflict of interest statement: L.S. has served on advisory boards for Sarepta
Therapeutics, Inc.; E.M. has received consultant fees from Sarepta Therapeutics,
Inc.; V.S. has received speaker honoraria from Sanofi Genzyme, is or has
recently been on advisory boards for Audentes Therapeutics, Biogen, Exonics
Therapeutics/Vertex, Novartis, Roche, Sarepta Therapeutics, Inc., and Wave
Therapeutics, and has research collaborations with Sanofi Genzyme and
Ultragenyx; M.G. has received speaker honoraria from Sarepta Therapeutics, Inc.,
is on advisory boards for Pfizer, has research collaboration with Sarepta
Therapeutics, Inc., and is the Chair of the VBP15-004 study but does not have
any financial interest with ReveraGen; A.M.S., M.S., and D.L. have nothing to
disclose; E.K., N.K., A.D., X.W., B.H., and D.W. are or have been employees of
Sarepta Therapeutics, Inc.; F.M. has received consultant fees and speaker
honoraria from Sarepta Therapeutics, Inc., and is supported by the NIHR Great
Ormond Street Hospital Biomedical Research Centre. |
http://www.ncbi.nlm.nih.gov/pubmed/33833444 | 1. Nat Rev Drug Discov. 2021 Jun;20(6):476-488. doi: 10.1038/s41573-021-00175-8.
Epub 2021 Apr 8.
Industrializing engineered autologous T cells as medicines for solid tumours.
Britten CM(1)(2), Shalabi A(3), Hoos A(4).
Author information:
(1)Oncology R&D, GlaxoSmithKline, Stevenage, UK.
(2)Immatics Biotechnologies, Munich, Germany.
(3)Oncology R&D, GlaxoSmithKline, Philadelphia, PA, USA.
(4)Oncology R&D, GlaxoSmithKline, Philadelphia, PA, USA. axel.x.hoos@gsk.com.
Cell therapy is one of the fastest growing areas in the pharmaceutical industry,
with considerable therapeutic potential. However, substantial challenges
regarding the utility of these therapies will need to be addressed before they
can become mainstream medicines with applicability similar to that of small
molecules or monoclonal antibodies. Engineered T cells have achieved success in
the treatment of blood cancers, with four chimeric antigen receptor (CAR)-T cell
therapies now approved for the treatment of B cell malignancies based on their
unprecedented efficacy in clinical trials. However, similar results have not yet
been achieved in the treatment of the much larger patient population with solid
tumours. For cell therapies to become mainstream medicines, they may need to
offer transformational clinical effects for patients and be applicable in
disease settings that remain unaddressed by simpler approaches. This Perspective
provides an industry perspective on the progress achieved by engineered T cell
therapies to date and the opportunities and current barriers for accessing
broader patient populations, and discusses the solutions and new development
strategies required to fully industrialize the therapeutic potential of
engineered T cells as medicines.
DOI: 10.1038/s41573-021-00175-8
PMID: 33833444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36401026 | 1. Methods Mol Biol. 2023;2587:107-124. doi: 10.1007/978-1-0716-2772-3_6.
Restoring Dystrophin Expression by Skipping Exons 6 and 8 in Neonatal Dystrophic
Dogs.
Shah MNA(1), Yokota T(2)(3).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada. toshifumi.yokota@ualberta.ca.
(3)Muscular Dystrophy Canada Research Chair, Edmonton, AB, Canada.
toshifumi.yokota@ualberta.ca.
Duchenne muscular dystrophy (DMD) is caused by the mutations in the DMD gene
resulting in no dystrophin production. Skipping DMD exons using
phosphorodiamidate morpholino oligomers (PMOs) is an emerging treatment strategy
that can restore the reading frame of the mutated gene and produce truncated but
functional dystrophin protein. To date, four PMOs, including eteplirsen,
casimersen, viltolarsen, and golodirsen, have been conditionally approved by the
FDA for the treatment of DMD. Since degeneration of muscle fibers and
irreversible fibrosis occur from childhood, the earlier treatment is preferred.
The canine X-linked muscular dystrophy in Japan (CXMDj), a dog model of DMD,
produces no dystrophin and exhibits a severe phenotype similar to human patients
from early childhood. As such, CXMDj, which harbors a splice site mutation in
intron 6, is a useful model for examining the long-term effects of early PMO
treatment. In this chapter, we describe the systemic delivery of a cocktail of
four PMOs that can successfully induce multiple exon skipping (exons 6-9) in
neonatal dystrophic dogs. We also describe the procedures to evaluate the
efficacy and toxicity, including clinical grading of dystrophic dogs,
ELISA-based quantification of PMOs, histology, RT-PCR, and western blotting.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_6
PMID: 36401026 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32026421 | 1. Drugs. 2020 Feb;80(3):329-333. doi: 10.1007/s40265-020-01267-2.
Golodirsen: First Approval.
Heo YA(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. dru@adis.com.
Golodirsen (Vyondys 53™), an antisense oligonucleotide of the phophorodiamidate
morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been
developed by Sarepta Therapeutics for the treatment of Duchenne muscular
dystrophy (DMD). In December 2019, intravenous golodirsen received its first
global approval in the USA for the treatment of DMD in patients with a confirmed
mutation of the DMD gene that is amenable to exon 53 skipping, based on positive
results from a phase I/II clinical trial. Golodirsen is in phase III clinical
development for the treatment of DMD worldwide. This article summarizes the
milestones in the development of golodirsen leading to this first approval for
DMD.
DOI: 10.1007/s40265-020-01267-2
PMID: 32026421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33025945 | 1. Drugs Today (Barc). 2020 Aug;56(8):491-504. doi:
10.1358/dot.2020.56.8.3159186.
Golodirsen for Duchenne muscular dystrophy.
Anwar S(1), Yokota T(2).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Alberta, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Alberta, Canada; The Friends of Garrett Cumming Research
and Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair,
Edmonton, Alberta, Canada. toshifum@ualberta.ca.
Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder
characterized by progressive wasting and weakening of muscles in boys.
Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to
this disease. The majority of mutations in this gene result in the exclusion of
one or more exons from the transcript, eventually causing the remaining exons
not to fit together correctly (i.e., out-of-frame mutations). Antisense
oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can
induce therapeutic exon skipping during pre-mRNA processing to restore the
reading frame of the primary transcript of DMD. As a result, truncated but
partially functional dystrophin is produced, potentially slowing down the
disease progression. Golodirsen is a provisionally approved PMO-based drug for
approx. 8% of all DMD patients amenable to exon 53 skipping. This article
summarizes golodirsen's pharmacology, efficacy and safety information. It also
discusses some controversies that golodirsen met after the approval.
Copyright 2020 Clarivate Analytics.
DOI: 10.1358/dot.2020.56.8.3159186
PMID: 33025945 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16700618 | 1. Technol Cancer Res Treat. 2006 Jun;5(3):215-29. doi:
10.1177/153303460600500305.
Molecular diagnostics as a tool to personalize treatment in adult glioma
patients.
Jeuken JW(1), van der Maazen RW, Wesseling P.
Author information:
(1)Department of Pathology, Nijmegen Centre for Molecular Life Sciences (NCMLS),
Radboud University Nijmegen, Medical Centre, Nijmegen, The Netherlands.
j.jeuken@pathol.umcn.nl
Gliomas, the most frequent primary brain tumors in humans, form a heterogeneous
group, encompassing many different histological types and malignancy grades.
Within this group, the diffuse infiltrative gliomas are by far the most common
in adults. The major representatives in this subgroup are the diffuse
astrocytic, oligodendroglial, and mixed oligo-astrocytic tumors. Especially in
these diffuse gliomas, the role of molecular diagnostics is rapidly increasing.
After summarizing the most relevant genetic aberrations and pathways in these
tumors detected up till now, this review will discuss the clinical relevance of
this information. Several molecular markers have been identified in diffuse
gliomas that carry diagnostic and prognostic information. In addition, some of
these and other markers predict the response of these gliomas to particular
(chemo)therapeutic approaches. The techniques used to obtain this molecular
information, as well as the advantages and disadvantages of the different
techniques will be discussed. Finally, future perspectives will be presented
with regard to the contribution of molecular diagnostics to tailor-made therapy
in glioma patients.
DOI: 10.1177/153303460600500305
PMID: 16700618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35330989 | 1. J Inflamm Res. 2022 Mar 18;15:1935-1941. doi: 10.2147/JIR.S356316. eCollection
2022.
Application of Baricitinib in Dermatology.
Zhang J(1), Qi F(1), Dong J(1), Tan Y(1), Gao L(2), Liu F(1).
Author information:
(1)Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical
University, Beijing, 100020, People's Republic of China.
(2)China CDC Key Laboratory of Radiological Protection and Nuclear Emergency,
National Institute for Radiological Protection, Chinese Centre for Disease
Control and Prevention, Beijing, 100088, People's Republic of China.
There are four JAK subtypes: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).
Small molecule Janus tyrosine kinase (JAK) inhibitors can inhibit a variety of
pro-inflammatory cytokines. Baricitinib is the first generation of JAK1/2
inhibitor targeting the ATPase of JAK, which blocks the intracellular
transmission of cytokines through JAK-STATs. Thus far, it has been approved for
the treatment of rheumatoid arthritis (RA); however, an increasing number of
studies have suggested that baricitinib can be used to treat dermatological
diseases, such as atopic dermatitis (AD), psoriasis, vitiligo, and alopecia
areata. Baricitinib can be a new choice for the treatment of dermatological
diseases, which cannot be treated with conventional drugs. We reviewed the
application, efficacy, side effects, precautions, limitations and prospect of
baricitinib in atopic dermatitis, psoriasis, vitiligo and alopecia areata (AA)
in recent 5 years including clinical trials and case reports. Among them, the
application in the field of alopecia areata is the most encouraging, and we
reviewed the mechanism in detail.
© 2022 Zhang et al.
DOI: 10.2147/JIR.S356316
PMCID: PMC8939862
PMID: 35330989
Conflict of interest statement: The authors report no conflicts of interest in
this work. |
http://www.ncbi.nlm.nih.gov/pubmed/35334197 | 1. N Engl J Med. 2022 May 5;386(18):1687-1699. doi: 10.1056/NEJMoa2110343. Epub
2022 Mar 26.
Two Phase 3 Trials of Baricitinib for Alopecia Areata.
King B(1), Ohyama M(1), Kwon O(1), Zlotogorski A(1), Ko J(1), Mesinkovska NA(1),
Hordinsky M(1), Dutronc Y(1), Wu WS(1), McCollam J(1), Chiasserini C(1), Yu
G(1), Stanley S(1), Holzwarth K(1), DeLozier AM(1), Sinclair R(1); BRAVE-AA
Investigators.
Collaborators: Harada K, Ishii N, Ito T, Tateishi C, Choi GS, Huh CH, Jang YH,
Kang H, Kim B, Kim MB, Kwon O, Lee YW, Lee Y, Lew BL, Yun SK, Barragan Estudillo
Z, Herz M, Lopez Lozano H, Poletti Vazquez E, Rodriguez Acosta ED, Rodriguez
Castellanos M, Villanueva Quintero DG, Bergfeld W, Blauvelt A, Browning J,
Callender V, Cather J, Cohen D, Cohen S, Colavincenzo M, Davis S, Deck K, Ferris
L, Forman S, Gonzalez-Chavez J, Gottlieb S, Greenstein D, Greiling T, Hordinsky
M, Jarell A, Jenkin P, Johnson S, Kaffenberger J, King B, Ko J, Korman N,
Krueger G, Kwong P, Lain E, Wine Lee L, Lee P, Ling M, Madkan V, Maverakis E,
Mayo T, McFalda W, Mercurio M, Mesinkovska N, Miller J, Mostaghimi A, Nahm W,
Owen C, Roberts J, Schmieder G, Senna M, Smith S, Sofen H, Taylor S, Teller C,
Tosti A, Trovato A, Tyring S, Vendrell-Benito P, Wolfe J, Cappetta E, Castro V,
Cecilia MN, Galimberti ML, Luna P, Marini M, Parra V, Abdulla EAK, Foley P,
Gebauer K, Rubel D, Sidhu S, Sinclair R, Spelman L, Azulay-Abulafia L, Blessmann
Weber M, Chicralla da Rocha N, Gonzaga da Cunha M, Kakizaki P, Lazzarini R,
Magalhaes R, Romanelli Tiburcio Alves C, Yang Q, Zhang CL, Goldsmith T,
Lyakhovitsky A, Martinez H, Ramon M, Valdman-Grinshpoun Y, Ziv M, Zlotogorski A,
Kinoshita-Ise M, Komiyama E, Sato K, Shimomura Y, Ueki R, Choi JW, Kim DY, Lee
SH, Park BC, Park H, Huang YH, Lai PJ, Tsai TF, Yang CC, Boyce B, Poynot
Couvillion M, Dabiri G, Dhawan S, Filipof N, Fretzin S, Hamzavi F, Hake Harris
H, Hussain I, Kelly J, Kempers S, Kerdel F, Krell JM, Laquer V, LaTowsky B, Lee
M, Lockshin B, Lugo-Somolinos A, Martinez M, Mirmirani P, Moss J, Nasir A, Nixon
D, Nunez L, Osman L, Pariser D, Rich P, Rosmarin D, Schwartz J, Serrao R, Ston
M, Truett A, Zirwas M.
Author information:
(1)From the Yale School of Medicine, New Haven, CT (B.K.); the Department of
Dermatology, Kyorin University Faculty of Medicine, Tokyo (M.O.); the Seoul
National University College of Medicine, Seoul, South Korea (O.K.); the
Department of Dermatology, Hadassah Medical Center, Hebrew University of
Jerusalem, Faculty of Medicine, Jerusalem, Israel (A.Z.); Stanford University
School of Medicine, Stanford (J.K.), and the University of California Irvine,
Irvine (N.A.M.) - both in California; the Department of Dermatology, University
of Minnesota Medical School, Minneapolis (M.H.); Eli Lilly, Indianapolis (Y.D.,
W.-S.W., J.M., C.C., G.Y., S.S., K.H., A.M.D.); and Sinclair Dermatology,
Melbourne, VIC, Australia (R.S.).
Comment in
N Engl J Med. 2022 May 5;386(18):1751-1752. doi: 10.1056/NEJMe2203440.
Dermatol Ther. 2022 Dec;35(12):e15845. doi: 10.1111/dth.15845.
Br J Dermatol. 2023 Feb 10;188(2):163. doi: 10.1093/bjd/ljac080.
BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid
hair loss in the scalp, eyebrows, and eyelashes, for which treatments are
limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases
1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of
alopecia areata.
METHODS: We conducted two randomized, placebo-controlled, phase 3 trials
(BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a
Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair
loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a
3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at
a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less
at week 36.
RESULTS: We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the
BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or
less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib,
and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in
BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was
32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the
difference between 2-mg baricitinib and placebo was 16.6 percentage points (95%
CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the
corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1
percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo).
Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg
generally favored baricitinib over placebo. Acne, elevated levels of creatine
kinase, and increased levels of low- and high-density lipoprotein cholesterol
were more common with baricitinib than with placebo.
CONCLUSIONS: In two phase 3 trials involving patients with severe alopecia
areata, oral baricitinib was superior to placebo with respect to hair regrowth
at 36 weeks. Longer trials are required to assess the efficacy and safety of
baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte;
BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and
NCT03899259.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2110343
PMID: 35334197 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35774427 | 1. Chronic Dis Transl Med. 2022 Apr 18;8(2):134-144. doi: 10.1002/cdt3.23.
eCollection 2022 Jun.
Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa
injection for the treatment of renal anemia in Chinese hemodialysis patients: A
randomized, open-label, parallel-group, noninferiority phase III trial.
Liu B(1), Chen N(2), Zhao J(3), Yin A(4), Wu X(5), Xing C(6), Jiang G(7), Fu
J(8), Wang M(9), Wang R(10), Niu J(11), Fu P(12), Ni Z(13), Hou F(14), Zhao
J(15), Chen J(16), Chen Y(17), Shi W(18), Chen J(19), Li W(20), Xu G(21), Zhong
L(22), Liu W(23), Ding G(24), Kondo Y(25), Yue C(26), Mei C(27).
Author information:
(1)Department of Nephrology Zhongda Hospital Southeast University Nanjing
Jiangsu 210009 China.
(2)Department of Nephrology Ruijin Hospital Shanghai Jiaotong University School
of Medicine Shanghai 200025 China.
(3)Department of Nephrology Xinqiao Hospital of Army Medical University
Chongqing 400037 China.
(4)Department of Nephrology First Affiliated Hospital of Xi'an Jiaotong
University Xi'an Shaanxi 710061 China.
(5)Department of Nephrology Southwest Hospital of Army Medical University
Chongqing 400039 China.
(6)Department of Nephrology Jiangsu Provincial Hospital Nanjing Jiangsu 210036
China.
(7)Department of Nephrology Xinhua Hospital Affiliated to Shanghai Jiao Tong
University School of Medicine Shanghai 200092 China.
(8)Department of Nephrology Guangzhou First People's Hospital Guangzhou
Guangdong 510180 China.
(9)Department of Nephrology Peking University People's Hospital Beijing 100044
China.
(10)Department of Nephrology Shandong Provincial Hospital Jinan Shandong 250021
China.
(11)Department of Nephrology, Shanghai Fifth People's Hospital Fudan University
Shanghai 200240 China.
(12)Department of Nephrology, West China Hospital Sichuan University Chengdu
Sichuan 610041 China.
(13)Department of Nephrology Renji Hospital Shanghai Jiaotong University School
of Medicine Shanghai 200001 China.
(14)Department of Nephrology Nanfang Hospital Southern Medical University
Guangzhou Guangdong 510510 China.
(15)Department of Nephrology The Second Hospital of Dalian Medical University
Dalian Liaoning 116023 China.
(16)Department of Nephrology, Huashan Hospital Fudan University Shanghai 200040
China.
(17)Department of Nephrology Peking University First Hospital Beijing 100034
China.
(18)Department of Nephrology Guangdong Provincial People's Hospital Guangzhou
Guangdong 510080 China.
(19)Department of Nephrology, The First Affiliated Hospital Zhejiang University
School of Medicine Hangzhou Zhejiang 310003 China.
(20)Department of Nephrology China-Japan Friendship Hospital Beijing 100029
China.
(21)Department of Nephrology Tongji Hospital Tongji Medical College Huazhong
University of Science and Technology Wuhan Hubei 430030 China.
(22)Department of Nephrology The Second Affiliated Hospital of Chongqing Medical
University Chongqing 400010 China.
(23)Department of Nephrology, Beijing Friendship Hospital Capital Medical
University Beijing 100050 China.
(24)Department of Nephrology Renmin Hospital of Wuhan University Wuhan Hubei
430060 China.
(25)R&D Planning Department, R&D Division Kyowa Kirin Co., Ltd. Tokyo 520-5292
Japan.
(26)D&R Office, Kyowa Kirin China Pharmaceutical Co., Ltd. Shanghai 201203
China.
(27)Department of Nephrology Shanghai Changzheng Hospital Shanghai 200003 China.
BACKGROUND: This study was to explore the clinical efficacy and safety of
darbepoetin alfa injection replacing epoetin alfa injection (recombinant human
erythropoietin injection, rHuEPO) for the treatment of anemia associated with
chronic kidney failure in Chinese patients undergoing hemodialysis.
METHOD: This study was a multicenter, randomized, open-label, intergroup
parallel control phase III noninferiority trial from April 19, 2013 to September
9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group
underwent intravenous administration once per week or once every two weeks. The
members of the control drug epoetin alfa group underwent intravenous
administration two or three times per week. All subjects underwent epoetin alfa
administration during the 8-week baseline period. After that, subjects were
randomly assigned to the darbepoetin alfa group or epoetin alfa group. The
noninferiority in the changes of the average Hb concentrations from the baseline
to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was
tested between the two treatments. The time-dependent hemoglobin (Hb)
concentration and the maintenance rate of the target Hb concentration (the
proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were
also evaluated. Iron metabolism, including changes in the serum iron, total
iron-binding capacity, ferritin, transferrin saturation, and comparisons of the
dose adjustments between the two groups during the treatment period were
analyzed further. Adverse events (AEs) were also observed and compared, and the
safety was analyzed between the two treatment groups. The conversion rate
switching from epoetin alfa to darbepoetin alfa was also discussed. SAS®
software version 9.2 was used to perform all statistical analyses. Descriptive
statistics were used for all efficacy, safety, and demographic variable
analyses, including for the primary efficacy indicators.
RESULTS: Four hundred and sixty-six patients were enrolled in this study, and
ultimately 384 cases were analyzed for safety, including 267 cases in the
darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211
cases in the per-protocol set, including 152 cases in the darbepoetin alfa group
and 59 cases in the epoetin alfa group. The changes in the average Hb
concentrations from the baseline to the end of the evaluation period were -0.07
and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group
respectively. The difference between the two groups was 0.08 g/dl (95%
confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was
-0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were
10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during
the study period of Weeks 0-28, with the maintenance rates of the target Hb
concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group
and epoetin alfa group respectively. During the period of comparison between the
two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while
in the epoetin alfa group it was 56.41%. All of the adverse events and reactions
in the study were those commonly associated with hemodialysis.
CONCLUSION: The overall efficacy and safety of darbepoetin alfa for the
treatment of Chinese renal anemia patients undergoing hemodialysis are
consistent with those of epoetin alfa.
© 2022 The Authors. Chronic Diseases and Translational Medicine published by
John Wiley & Sons Ltd on behalf of Chinese Medical Association.
DOI: 10.1002/cdt3.23
PMCID: PMC9215713
PMID: 35774427
Conflict of interest statement: Kyowa Kirin Co., Ltd. (KKC) and Kyowa Kirin
China Pharmaceutical Co., Ltd (KKCN) participated in and approved the design and
conduct of the study. Professor Wenge Li is a member of Chronic Diseases and
Translational Medicine editorial board and is not involved in the peer review
process of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/21877597 | 1. Vnitr Lek. 2011 Jul-Aug;57(7-8):631-4.
[Anemia and chronic kidney failure].
[Article in Czech]
Stepánková S(1).
Author information:
(1)Centrum kardiovaskulární a transplantacní chirurgie Brno.
sona.stepankova@cktch.cz
Anaemia is a common manifestation ofa chronic kidney failure. It is caused by a
relative shortage oferythropoetine (EPO) and iron deficite with its metabolism
defect. The most important factor in the pathogenesis of iron metabolism defects
is hepcidin. Hepcidin maintains the iron homeostasis in the organism. The
therapy of renal anaemia is based on the iron substitution and erythropoiesis
stimulating agents (ESA) application. The most common reasons for the resistance
to ESA are (after iron deficiency) inflammation and malnutrition.
PMID: 21877597 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15467179 | 1. Perspect Biol Med. 2004 Autumn;47(4):575-89. doi: 10.1353/pbm.2004.0072.
The role of anemia in congestive heart failure and chronic kidney insufficiency:
the cardio renal anemia syndrome.
Silverberg DS(1), Wexler D, Iaina A.
Author information:
(1)Department of Nephrology, Tel Aviv Medical Center, Weizman 6, Israel.
donald@netvision.net.il
Anemia is a major problem in patients with chronic kidney insufficiency. The
development of recombinant human erythropoietin has enabled physicians to
correct this anemia. Although anemia has not been considered to be a common or
important contributor to congestive heart failure, anemia of any cause can lead
to cardiac damage and eventually congestive heart failure. Our joint
renal-cardiac heart failure team found that anemia was indeed very common in
congestive heart failure and was associated with severe, medication-resistant
cardiac failure. Correction of the anemia with erythropoietin and intravenous
iron led to a marked improvement in patients' functional status and their
cardiac function, and to a marked fall in the need for hospitalization and for
high-dose diuretics; renal function usually improved or at least stabilized.
Subsequent investigations by others have confirmed many of our observations. We
call this interrelationship between congestive heart failure, chronic kidney
insufficiency, and anemia the Cardio-Renal Anemia syndrome. Treatment of the
anemia in congestive heart failure may prove vital in preventing progression of
both the heart failure and the associated renal disease.
DOI: 10.1353/pbm.2004.0072
PMID: 15467179 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16623112 | 1. Przegl Lek. 2005;62 Suppl 2:19-21.
[Anemia in kidney diseases as a cardiovascular risk factor].
[Article in Polish]
Myśliwiec M(1), Zalewski G.
Author information:
(1)Klinika Nefrologii i Transplantologii z Ośrodkiem Dializ Akademii Medycznej w
Białymstoku. mysmich@poczta.onet.pl
Cardiovascular mortality is increased in chronic kidney diseases. Patients'
survival correlates with hemoglobin concentration. Anemia significantly affects
cardiovascular system, especially the heart. Heart failure, anemia and chronic
renal failure are mutually related. Recently, cardio-renal-anemia syndrome
(CRAS) was defined. Iron replacement and EPO treatment can break the
pathogenetic circle of events leading to heart failure. Increased hemoglobin
concentration can also induce a positive impact on renal function. Early
diagnosis and correction of anemia has a substantial role in prophylaxis of left
ventricular hypertrophy in patients with chronic renal insufficiency.
PMID: 16623112 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16442920 | 1. Am Heart J. 2006 Feb;151(2):492-500. doi: 10.1016/j.ahj.2005.03.055.
Kidney function and anemia as risk factors for coronary heart disease and
mortality: the Atherosclerosis Risk in Communities (ARIC) Study.
Astor BC(1), Coresh J, Heiss G, Pettitt D, Sarnak MJ.
Author information:
(1)Department of Epidemiology, The Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA. bastor@jhsph.edu
Comment in
Am Heart J. 2006 Aug;152(2):e21. doi: 10.1016/j.ahj.2006.04.031.
BACKGROUND: Kidney failure causes anemia and is associated with a very high risk
of coronary heart disease (CHD). Mildly to moderately decreased kidney function
is far more common and also is associated with an elevated prevalence of anemia
and CHD risk. Recent data suggest an even higher risk of CHD when both
conditions are present.
METHODS: We investigated the association of kidney dysfunction and anemia with
CHD events (fatal or nonfatal CHD or coronary revascularization procedures) and
CHD and all-cause mortality over 12 years of follow-up in 14971 adults aged 45
to 64 years in the ARIC Study. Glomerular filtration rate (GFR) was estimated
from calibrated serum creatinine using the MDRD Study equation (< 30 mL/min per
1.73 m2 excluded, n = 32). Anemia was defined as hemoglobin level < 13.5 g/dL in
men (648/6746, 9.6%) and < 12 g/dL in women (1049/8225, 12.8%).
RESULTS: The prevalence of anemia was progressively higher at lower estimated
GFR < 75 mL/min per 1.73 m2 (both P < .001) for both men and women. A total of
1635 (10.9%) participants had a CHD event, 360 (2.4%) died of CHD, and 1722
(11.5%) died of any cause during follow-up. After adjustment for known risk
factors, including diabetes, lipid levels, blood pressure, and use of
antihypertensive medication, decreased kidney function was associated with a
higher risk of recurrent CHD events and mortality from CHD and all causes. These
associations were significantly stronger among participants with anemia. The
adjusted relative hazards of all-cause mortality associated with moderately
decreased versus normal kidney function (GFR 30-59 vs > or = 90 mL/min per 1.73
m2) were 1.7 (95% CI 1.3-2.2) in the absence of anemia and 3.5 (95% CI 2.4-5.1)
in the presence of anemia (P interaction = .001).
CONCLUSIONS: The combination of moderately decreased kidney function and anemia
is associated with an increased risk of CHD events and mortality, emphasizing
the need to identify individuals with these conditions and evaluate
interventions to treat anemia and slow the progression of chronic kidney
disease.
DOI: 10.1016/j.ahj.2005.03.055
PMID: 16442920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17108343 | 1. N Engl J Med. 2006 Nov 16;355(20):2085-98. doi: 10.1056/NEJMoa065485.
Correction of anemia with epoetin alfa in chronic kidney disease.
Singh AK(1), Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR
Investigators.
Author information:
(1)Renal Division, Brigham and Women's Hospital and Harvard Medical School,
Boston, MA 02115, USA. asingh@partners.org
Comment in
N Engl J Med. 2006 Nov 16;355(20):2144-6. doi: 10.1056/NEJMe068233.
Nephrol Dial Transplant. 2007 Feb;22(2):309-12. doi: 10.1093/ndt/gfl824.
N Engl J Med. 2007 Mar 1;356(9):956; author reply 958-9. doi:
10.1056/NEJMc063535.
N Engl J Med. 2007 Mar 1;356(9):956-7; author reply 958-9.
N Engl J Med. 2007 Mar 1;356(9):957; author reply 958-9.
N Engl J Med. 2007 Mar 1;356(9):958; author reply 958-9.
N Engl J Med. 2007 Mar 1;356(9):957-8; author reply 958-9.
Nat Clin Pract Nephrol. 2007 May;3(5):244-5. doi: 10.1038/ncpneph0463.
Semin Dial. 2007 May-Jun;20(3):277-9. doi: 10.1111/j.1525-139X.2007.00290.x.
BACKGROUND: Anemia, a common complication of chronic kidney disease, usually
develops as a consequence of erythropoietin deficiency. Recombinant human
erythropoietin (epoetin alfa) is indicated for the correction of anemia
associated with this condition. However, the optimal level of hemoglobin
correction is not defined.
METHODS: In this open-label trial, we studied 1432 patients with chronic kidney
disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa
targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom
were assigned to receive a dose targeted to achieve a level of 11.3 g per
deciliter. The median study duration was 16 months. The primary end point was a
composite of death, myocardial infarction, hospitalization for congestive heart
failure (without renal replacement therapy), and stroke.
RESULTS: A total of 222 composite events occurred: 125 events in the
high-hemoglobin group, as compared with 97 events in the low-hemoglobin group
(hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were
65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25
myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%)
were hospitalized for congestive heart failure and myocardial infarction
combined, and one patient (0.5%) died after having a stroke. Improvements in the
quality of life were similar in the two groups. More patients in the
high-hemoglobin group had at least one serious adverse event.
CONCLUSIONS: The use of a target hemoglobin level of 13.5 g per deciliter (as
compared with 11.3 g per deciliter) was associated with increased risk and no
incremental improvement in the quality of life. (ClinicalTrials.gov number,
NCT00211120 [ClinicalTrials.gov].).
Copyright 2006 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa065485
PMID: 17108343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17437743 | 1. Am J Cardiol. 2007 Apr 15;99(8):1137-42. doi: 10.1016/j.amjcard.2006.11.055.
Epub 2007 Mar 7.
Anemia as a risk factor for kidney function decline in individuals with heart
failure.
Bansal N(1), Tighiouart H, Weiner D, Griffith J, Vlagopoulos P, Salem D, Levin
A, Sarnak MJ.
Author information:
(1)Division of Nephrology, Tufts-New England Medical Center, Boston,
Massachusetts, USA.
Chronic kidney disease (CKD), anemia, and declining kidney function are
recognized as risk factors for adverse outcomes in patients with heart failure.
This analysis was conducted to evaluate whether anemia is a risk factor for
kidney function decrease in patients with heart failure. Data from the Studies
of Left Ventricular Dysfunction (SOLVD), a randomized trial of enalapril versus
placebo in patients with ejection fractions <or=35%, were analyzed. After
randomization, creatinine measurements were taken at 2 weeks, 6 weeks, 4 months,
and every 4 months thereafter. The glomerular filtration rate (GFR) was
estimated using the Modification of Diet in Renal Disease Study (MDRD) equation,
and GFR slope was calculated. "Rapid decrease" was defined as a decrease in the
GFR of >or=6 ml/min/1.73 m(2)/year. Anemia was defined as baseline hematocrit
<36%. Multivariate logistic regression weighted by the number of GFR assessments
was used to test the relation between anemia and rapid decrease. We also
evaluated whether CKD (baseline GFR </=60 ml/min/1.73 m(2)) modified the
relation between anemia and rapid decrease. In the 6,360 subjects, the mean age
was 59 years, 31% had CKD, and 6% had anemia. Median follow-up was 2 years. In
multivariate analysis, anemia was associated with a 1.30 increased odds (95%
confidence interval 1.18 to 1.45) of rapid decrease in GFR. In subjects with
CKD, anemia was associated with a 1.71 increased odds (95% confidence interval
1.43 to 2.05) of rapid decrease, while in subjects without CKD, anemia was
associated with a 1.16 increased odds (95% confidence interval 1.03 to 1.31) of
rapid decrease (p for interaction <0.001). In conclusion, anemia is associated
with a rapid decrease in kidney function in patients with heart failure,
particularly in those with underlying CKD.
DOI: 10.1016/j.amjcard.2006.11.055
PMID: 17437743 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2010480 | 1. Hosp Pract (Off Ed). 1991 Apr 15;26(4):61-9. doi:
10.1080/21548331.1991.11704158.
Recombinant erythropoietin and chronic renal failure.
Lundin AP(1).
Author information:
(1)State University of New York, Brooklyn.
The hormone deficiency that underlies anemia in chronic kidney failure can now
be corrected. Along with the primary benefit of raising the hematocrit and
reversing anemia, dramatic secondary benefits can be achieved. Exercise
capacity, neuropsychiatric and sexual function, and overall quality of life are
enhanced. Guidelines for management are discussed.
DOI: 10.1080/21548331.1991.11704158
PMID: 2010480 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2357306 | 1. Crit Care Nurs Clin North Am. 1990 Mar;2(1):101-13.
Use of EPOGEN for treatment of anemia associated with chronic renal failure.
Erlich L.
The anemia of chronic renal failure is a major contributor to the symptoms that
limit the quality of life and preclude rehabilitation. The primary cause of the
anemia of chronic renal failure is an inability on the part of the impaired
kidney to produce adequate amounts of erythropoietin. This hormone stimulates
the bone marrow to produce red blood cells. EPOGEN (Epoietin alfa), a
glycoprotein produced through recombinant DNA technology, corrects this anemia.
Its contribution to the care of persons with chronic renal failure is explored.
PMID: 2357306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22680636 | 1. Curr Med Chem. 2012;19(21):3502-7. doi: 10.2174/092986712801323261.
Cardio-renal-anemia syndrome: a link between erythropoietin, dimethylarginine
and homocysteine.
Righetti M(1).
Author information:
(1)Nephrology & Dialysis Unit, Uboldo Hospital, Cernusco S/N (Milan), Italy.
righettim@hotmail.com
Cardio-renal-anemia syndrome is a combination of heart failure, kidney failure,
and anemia. Many advanced chronic kidney disease patients have both anemia and
chronic heart failure. They have often hyperhomocysteinemia, high
dimethylarginine values and low erythropoietin levels. Nephrologists treat
advanced chronic kidney disease patients with erythropoiesis stimulating agents
to improve anemia, renal and heart disease. Erythropoiesis stimulating agents,
though considered essential to improve anemia in chronic kidney disease
patients, have shown no significant protective effect on cardiovascular disease
when used in large clinical trials targeting normal hemoglobin levels. It is
possible that the high amounts of these drugs, given to reach normal hemoglobin
values, may have counterbalanced the positive effect on endothelium obtained
with low doses. Many studies have shown that erythropoietin improves endothelial
function in animals with high dimethylarginine levels, lowering asymmetric
dimethylarginine and increasing nitric oxide synthesis. Advanced chronic kidney
disease patients have also high homocysteine levels which further reduce
endothelial function by increasing asymmetric dimethylarginine.
Homocysteine-lowering vitamin B treatment has been associated to a significant
reduction of cardiovascular disease in advanced chronic kidney disease patients.
Low doses of epoetin and B vitamins may improve cardiovascular morbidity by
reducing asymmetric dimethylarginine and by increasing nitric oxide synthase
activity. This review analyses the interaction between erythropoietin,
dimethylarginine and homocysteine, and their role in cardio-renal-anemia
syndrome.
DOI: 10.2174/092986712801323261
PMID: 22680636 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9375826 | 1. Nephron. 1997;77(3):315-8. doi: 10.1159/000190294.
Relative contributions of body iron status and uremia severity to anemia in
patients with advanced chronic renal failure.
Ifudu O(1), Dawood M, Friedman EA.
Author information:
(1)Department of Medicine, State University of New York Health Science Center at
Brooklyn, 11203, USA.
Anemia in chronic renal failure is predominantly caused by diminished
erythropoietin synthesis by diseased kidneys. While iron deficiency is often
stated as a cause of anemia in chronic renal failure prior to end-stage renal
disease, its relative contribution is debated. It is speculated that rather than
frank 'iron deficiency', many patients with chronic renal failure may indeed
have impaired utilization of iron. We analyzed 139 consecutive patients with
chronic renal failure starting maintenance hemodialysis to determine the
relationship between hematocrit, measures of renal function (blood urea nitrogen
and serum creatinine concentration), and measures of iron availability (serum
transferrin saturation, serum iron level and serum ferritin). The 139 study
subjects (60 men, 79 women) comprised 116 blacks (83%), 15 hispanics (11%), and
8 whites (6%) of a mean age 56 +/- 15 years. Only 23 (17%) of 139 subjects had
positive hemoccult stool test for blood. Their mean hematocrit was 24 +/- 4.5%,
mean blood urea nitrogen concentration was 121 +/- 38, mean serum creatinine
concentration was 12.6 +/- 5.2 mg/dl, mean serum transferrin saturation was 22
+/- 14%, mean serum ferritin level was 235 +/- 194 U/l, mean serum iron level
was 55 +/- 40 U/l, and mean total iron binding capacity was 254 +/- 93%.
Multiple regression analysis with hematocrit as the outcome variable, and blood
urea nitrogen level, serum creatinine concentration, serum albumin
concentration, serum transferrin saturation, and serum ferritin level as the
independent variables, showed an inverse correlation between hematocrit and
serum creatinine concentration (p = 0.002). We conclude that in patients with
chronic renal failure starting uremia therapy, anemia does not correlate with
any of the commonly measured indices of body iron stores. We infer that impaired
utilization of iron may be a significant factor in the anemia of chronic renal
failure.
DOI: 10.1159/000190294
PMID: 9375826 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18670732 | 1. Clin Exp Nephrol. 2009 Apr;13(2):101-106. doi: 10.1007/s10157-008-0074-1. Epub
2008 Aug 1.
The correction of anemia in patients with the combination of chronic kidney
disease and congestive heart failure may prevent progression of both conditions.
Silverberg DS(1), Wexler D(2), Iaina A(3), Schwartz D(3).
Author information:
(1)Department of Nephrology, Tel Aviv Medical Center, Weizman 6, 64239, Tel
Aviv, Israel. donald@netvision.net.il.
(2)Department of Cardiology and Heart Failure Unit, Tel Aviv Medical Center,
Weizman 6, 64239, Tel Aviv, Israel.
(3)Department of Nephrology, Tel Aviv Medical Center, Weizman 6, 64239, Tel
Aviv, Israel.
It has recently been recognized that many patients with congestive heart failure
(CHF) are anemic. The anemia is very often associated with chronic kidney
disease (CKD). The more severe the anemia the more severe the CHF, with higher
mortality, morbidity, and hospitalization rate. The only way to prove that the
anemia is itself a causative factor in the progression of both the CKD and the
CHF is to correct it. In this paper we review the results of published papers
and some preliminary reports about correction of this anemia in CHF. These
studies frequently showed that erythropoietic stimulating agents (ESA) with oral
or IV iron often resulted in improvement in left ventricular systolic and
diastolic function, dilation, and hypertrophy, stabilization or improvement in
renal function, reduced hospitalizations, diuretic dose, mitral regurgitation,
pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic
peptide levels, and the inflammatory markers C reactive protein and Interleukin
6, and an improvement in New York Heart Association class, exercise capacity,
oxygen utilization during exercise, sleep apnea, caloric intake, depression, and
quality of life. The activity of endothelial progenitor cells was also
increased. Iron deficiency may also play an important role in the anemia,
because significant improvement of cardiac, renal, and functional status in
these anemic CKD-CHF has been seen after treatment with IV iron alone. Clearly
more work is needed to clarify the relationship between anemia, CKD and CHF.
DOI: 10.1007/s10157-008-0074-1
PMID: 18670732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12076240 | 1. Arch Intern Med. 2002 Jun 24;162(12):1401-8. doi:
10.1001/archinte.162.12.1401.
Association of kidney function with anemia: the Third National Health and
Nutrition Examination Survey (1988-1994).
Astor BC(1), Muntner P, Levin A, Eustace JA, Coresh J.
Author information:
(1)Department of Epidemiology, The Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD 21205, USA. bastor@jhsph.edu
BACKGROUND: Kidney failure is known to cause anemia, which is associated with a
higher risk of cardiac failure and mortality. The impact of milder decreases in
kidney function on hemoglobin levels and anemia in the US population, however,
is unknown.
METHODS: We analyzed a population-based sample of 15419 participants 20 years
and older in the Third National Health and Nutrition Examination Survey,
conducted from 1988 to 1994.
RESULTS: Lower kidney function was associated with a lower hemoglobin level and
a higher prevalence and severity of anemia below, but not above, an estimated
glomerular filtration rate (GFR) of 60 mL/min per 1.73 m(2). Adjusted to the age
of 60 years, the predicted median hemoglobin level among men (women) decreased
from 14.9 (13.5) g/dL at an estimated GFR of 60 mL/min per 1.73 m(2) to 13.8
(12.2) g/dL at an estimated GFR of 30 mL/min per 1.73 m(2) and to 12.0 (10.3)
g/dL at an estimated GFR of 15 mL/min per 1.73 m(2). The prevalence of anemia
(hemoglobin level <12 g/dL in men and <11 g/dL in women) increased from 1% (95%
confidence interval, 0.7%-2%) at an estimated GFR of 60 mL/min per 1.73 m(2) to
9% (95% confidence interval, 4%-19%) at an estimated GFR of 30 mL/min per 1.73
m(2) and to 33% (95% confidence interval, 11%-67%) at an estimated GFR of 15
mL/min per 1.73 m(2) among men and to 67% (95% confidence interval, 30%-90%) at
an estimated GFR of 15 mL/min per 1.73 m(2) among women. An estimated GFR of 15
to 60 mL/min per 1.73 m(2) was present in 4% of the entire population and in 17%
of the individuals with anemia.
CONCLUSION: Below an estimated GFR of 60 mL/min per 1.73 m(2), lower kidney
function is strongly associated with a higher prevalence of anemia among the US
adult population.
DOI: 10.1001/archinte.162.12.1401
PMID: 12076240 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22536082 | 1. Int J Nephrol Renovasc Dis. 2012;5:53-60. doi: 10.2147/IJNRD.S23447. Epub 2012
Mar 30.
Methoxy polyethylene glycol-epoetin beta for anemia with chronic kidney disease.
Ohashi N(1), Sakao Y, Yasuda H, Kato A, Fujigaki Y.
Author information:
(1)Internal Medicine 1, Hamamatsu University School of Medicine, Hamamatsu,
Shizuoka, Japan.
Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and
cardiovascular events. In patients with CKD, anemia is often caused by decreased
erythropoietin production relative to hemoglobin levels. As correction of anemia
is associated with improved cardiac and renal function and quality of life,
erythropoiesis-stimulating agents (ESAs) are standard therapy for anemia in CKD
patients. However, traditional ESAs such as epoetin or darbepoetin have short
half-lives and require frequent administration, dose changes, and close
monitoring of hemoglobin concentration to maintain target hemoglobin levels.
Methoxy polyethylene glycol-epoetin beta (MPG-EPO) is the only ESA that is
generated by chemical modification of glycosylated erythropoietin through the
integration of one specific, long, linear chain of polyethylene glycol. This ESA
induces continuous erythropoietin receptor activation and has a long half-life
(approximately 130 hours). Subcutaneous or intravenous administration of MPG-EPO
once every 2 weeks or monthly achieved a high hemoglobin response rate in
patients with anemia associated with CKD, regardless of whether the patient was
undergoing dialysis. According to data from an observational time and motion
study, MPG-EPO maintains hemoglobin levels when the same dose is administered,
however infrequently. This suggests that compared with the use of traditional
ESAs, administration of MPG-EPO reduces the overall time and cost associated
with the management of anemia in CKD patients undergoing dialysis. MPG-EPO is
generally well tolerated and most adverse events are of mild to moderate
severity. The most commonly reported adverse effects are hypertension,
nasopharyngitis, and diarrhea. Subcutaneous injection of MPG-EPO is
significantly less painful than subcutaneous injection of darbepoetin. In
conclusion, MPG-EPO is as effective and safe as traditional ESAs in managing
renal anemia, irrespective of whether the patient is undergoing dialysis.
DOI: 10.2147/IJNRD.S23447
PMCID: PMC3333806
PMID: 22536082 |
http://www.ncbi.nlm.nih.gov/pubmed/19833421 | 1. Blood Rev. 2010 Jan;24(1):39-47. doi: 10.1016/j.blre.2009.09.001. Epub 2009
Oct 14.
Anemia in renal disease: diagnosis and management.
Lankhorst CE(1), Wish JB.
Author information:
(1)Division of Nephrology, University Hospitals Case Medical Center, 11100
Euclid Ave, Cleveland, OH 44106, USA. christina.lankhorst@uhhospitals.org
Chronic kidney disease (CKD) is a widespread health problem in the world and
anemia is a common complication. Anemia conveys significant risk for
cardiovascular disease, faster progression of renal failure and decreased
quality of life. Patients with CKD can have anemia for many reasons, including
but not invariably their renal insufficiency. These patients require a thorough
evaluation to identify and correct causes of anemia other than erythropoietin
deficiency. The mainstay of treatment of anemia secondary to CKD has become
erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and
these agents need to be used judiciously. Iron deficiency often co-exists in
this population and must be evaluated and treated. Correction of iron deficiency
can improve anemia and reduce ESA requirements. Partial, but not complete,
correction of anemia is associated with improved outcomes in patients with CKD.
Copyright 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.blre.2009.09.001
PMID: 19833421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32899941 | 1. Cells. 2020 Sep 6;9(9):2039. doi: 10.3390/cells9092039.
Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease:
A Review.
Hamza E(1), Metzinger L(1), Metzinger-Le Meuth V(1)(2).
Author information:
(1)HEMATIM UR 4666, C.U.R.S, University of Picardie Jules Verne, CEDEX 1, 80025
Amiens, France.
(2)INSERM UMRS 1148, Laboratory for Vascular Translational Science (LVTS), UFR
SMBH, University of Paris Nord, 93000 Bobigny, France.
Chronic kidney disease (CKD) is a global health problem characterized by
progressive kidney failure due to uremic toxicity and the complications that
arise from it. Anemia consecutive to CKD is one of its most common complications
affecting nearly all patients with end-stage renal disease. Anemia is a
potential cause of cardiovascular disease, faster deterioration of renal failure
and mortality. Erythropoietin (produced by the kidney) and iron (provided from
recycled senescent red cells) deficiencies are the main reasons that contribute
to CKD-associated anemia. Indeed, accumulation of uremic toxins in blood impairs
erythropoietin synthesis, compromising the growth and differentiation of red
blood cells in the bone marrow, leading to a subsequent impairment of
erythropoiesis. In this review, we mainly focus on the most representative
uremic toxins and their effects on the molecular mechanisms underlying anemia of
CKD that have been studied so far. Understanding molecular mechanisms leading to
anemia due to uremic toxins could lead to the development of new treatments that
will specifically target the pathophysiologic processes of anemia consecutive to
CKD, such as the newly marketed erythropoiesis-stimulating agents.
DOI: 10.3390/cells9092039
PMCID: PMC7565991
PMID: 32899941 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29151105 | 1. Kidney Blood Press Res. 2017;42(4):749-760. doi: 10.1159/000484215. Epub 2017
Oct 23.
Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease.
Lang F(1)(2), Bissinger R(3), Abed M(1), Artunc F(4)(5)(6).
Author information:
(1)Department of Physiology I, University of Tübingen, Tübingen, Germany.
(2)Department of Molecular Medicine II, Medical Faculty, Heinrich Heine
University, Düsseldorf, Germany.
(3)Department of Internal Medicine III, University of Tübingen, Tübingen,
Germany.
(4)Department of Internal Medicine IV, Division of Endocrinology, Diabetology,
Vascular Disease, Nephrology and Clinical Chemistry, University Hospital
Tübingen, Tübingen, Germany.
(5)Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz
Center Munich at the University Tübingen, Tübingen, Germany.
(6)German Center for Diabetes Research (DZD) at the University Tübingen,
Tübingen, Germany.
End stage renal disease (ESRD) invariably leads to anemia which has been mainly
attributed to compromised release of erythropoietin from the defective kidneys
with subsequent impairment of erythropoiesis. However, erythropoietin
replacement only partially reverses anemia pointing to the involvement of
additional mechanisms. As shown more recently, anemia of ESRD is indeed in large
part a result of accelerated erythrocyte loss due to suicidal erythrocyte death
or eryptosis, characterized by cell shrinkage and cell membrane scrambling with
phosphatidylserine translocation to the cell surface. Phosphatidylserine
exposing erythrocytes are bound to and engulfed by macrophages and are thus
rapidly cleared from circulating blood. If the loss of erythrocytes cannot be
fully compensated by enhanced erythropoiesis, stimulation of eryptosis leads to
anemia. Eryptotic erythrocytes may further adhere to the vascular wall and thus
impair microcirculation. Stimulators of eryptosis include complement,
hyperosmotic shock, energy depletion, oxidative stress, and a wide variety of
xenobiotics. Signaling involved in the stimulation of eryptosis includes
increase of cytosolic Ca2+ activity, ceramide, caspases, calpain, p38 kinase,
protein kinase C, Janus-activated kinase 3, casein kinase 1α, and
cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase,
p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and
stress-activated kinase MSK1/2, and some illdefined tyrosine kinases. In ESRD
eryptosis is stimulated at least in part by a plasma component, as it is
triggered by exposure of erythrocytes from healthy individuals to plasma from
ESRD patients. Several eryptosis-stimulating uremic toxins have been identified,
such as vanadate, acrolein, methylglyoxal, indoxyl sulfate, indole-3-acetic acid
and phosphate. Attempts to fully reverse anemia in ESRD with excessive
stimulation of erythropoiesis enhances the number of circulating suicidal
erythrocytes and bears the risk of interference with micocirculation, At least
in theory, anemia in ESRD could preferably be treated with replacement of
erythropoietin and additional inhibition of eryptosis thus avoiding
eryptosis-induced impairment of microcirculation. A variety of eryptosis
inhibitors have been identified, their efficacy in ESRD remains, however, to be
shown.
© 2017 The Author(s). Published by S. Karger AG, Basel.
DOI: 10.1159/000484215
PMID: 29151105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20443766 | 1. Cardiovasc Hematol Agents Med Chem. 2010 Jul;8(3):164-72. doi:
10.2174/187152510791698398.
Erythropoiesis stimulating agents and anaemia of end-stage renal disease.
Schmid H(1), Schiffl H.
Author information:
(1)KfH Nierenzentrum Muenchen-Laim, Munich, Germany.
Chronic kidney disease (CKD) is a widespread health problem in the world and
anaemia of renal origin is a common problem. Anaemia associated with CKD covers
significant risk for faster progression of chronic renal failure, decreased
quality of life, and clinical manifestation of cardiovascular disease. The
mainstay of anaemia treatment secondary to end-stage renal disease (ESRD) has
become erythropoiesis stimulating agents (ESAs). More than 90 % of ESRD patients
maintained on dialysis respond to traditional recombinant human erythropoietin
(rHU EPO) or to EPO analogues, also called "biosimilars". Iron deficiency often
co-exists in dialysis patients and must be evaluated and treated to reduce ESA
requirements. Partial, but not complete correction of renal anaemia is
associated with improved outcomes in patients with CKD. The use of ESAs does
carry risks such as hypertension, pure red cell aplasia, or cancer, and these
agents need to be used judiciously.
DOI: 10.2174/187152510791698398
PMID: 20443766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26948278 | 1. Proteomics Clin Appl. 2016 Aug;10(8):778-90. doi: 10.1002/prca.201500127. Epub
2016 Mar 29.
Red blood cell abnormalities and the pathogenesis of anemia in end-stage renal
disease.
Georgatzakou HT(1), Antonelou MH(1), Papassideri IS(1), Kriebardis AG(2).
Author information:
(1)Department of Cell Biology and Biophysics, Faculty of Biology, National and
Kapodistrian University of Athens, Greece.
(2)Department of Medical Laboratories, Faculty of Health and Caring Professions,
Technological and Educational Institute of Athens, Greece.
Anemia is the most common hematologic complication in end-stage renal disease
(ESRD). It is ascribed to decreased erythropoietin production, shortened red
blood cell (RBC) lifespan, and inflammation. Uremic toxins severely affect RBC
lifespan; however, the implicated molecular pathways are poorly understood.
Moreover, current management of anemia in ESRD is controversial due to the
"anemia paradox" phenomenon, which underlines the need for a more individualized
approach to therapy. RBCs imprint the adverse effects of uremic, inflammatory,
and oxidative stresses in a context of structural and functional deterioration
that is associated with RBC removal signaling and morbidity risk. RBCs circulate
in hostile plasma by raising elegant homeostatic defenses. Variability in
primary defect, co-morbidity, and therapeutic approaches add complexity to the
pathophysiological background of the anemic ESRD patient. Several blood
components have been suggested as biomarkers of anemia-related morbidity and
mortality risk in ESRD. However, a holistic view of blood cell and plasma
modifications through integrated omics approaches and high-throughput studies
might assist the development of new diagnostic tests and therapies that will
target the underlying pathophysiologic processes of ESRD anemia.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/prca.201500127
PMID: 26948278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9241712 | 1. Semin Nephrol. 1997 Jul;17(4):257-69.
Anemia, hypertension, and myocardial dysfunction in end-stage renal disease.
Venkatesan J(1), Henrich WL.
Author information:
(1)Department of Medicine, Medical College of Ohio, Toledo 43699-0008, USA.
Cardiovascular disease remains the major cause of mortality in patients with end
stage renal disease (ESRD). The pathophysiology of cardiac dysfunction in ESRD
is complex and not fully understood. However, it appears that the two major
determinants of left ventricular (LV) hypertrophy and dysfunction are anemia and
hypertension, both of which are very common in ESRD patients. Early and
aggressive correction of anemia and hypertension may have a significant impact
on cardiac disease in ESRD patients. This article presents a discussion on the
management of anemia and hypertension, and the current information available on
the pathogenesis and management of LV dysfunction in ESRD.
PMID: 9241712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7034633 | 1. Ann Clin Lab Sci. 1981 Nov-Dec;11(6):484-7.
Anemia of chronic renal failure.
Sexauer CL, Matson JR.
Anemia is one of the most characteristic and visable manifestations of chronic
renal failure. Investigators in the past decade have provided a better
understanding of this anemia. The etiology of the anemia of chronic renal
failure has three facets: first is reduced erythropoietin production by damaged
kidneys; second is the presence of inhibitors to red blood cell (RBC) production
in uremic serum; and third is red blood cell hemolysis. Unfortunately,
transfusion therapy with its expense and risk of transmissable viral disease
remains the mainstay of management for symptomatic anemia. Other modalities
include dialysis, androgens, histidine supplementation, and erythropoietin
replacement.
PMID: 7034633 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31994917 | 1. Arch Physiol Biochem. 2022 Jun;128(3):703-707. doi:
10.1080/13813455.2020.1720742. Epub 2020 Jan 29.
Association between neutrophil gelatinase-associated lipocalin (NGAL) and iron
profile in chronic renal disease.
Aghsaeifard Z(1)(2), Alizadeh R(3), Bagheri N(4).
Author information:
(1)Department of Internal Medicine, School of Medicine, Sina Hospital Tehran
University of Medical Sciences, Tehran, Iran.
(2)Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
(3)Department of Anesthesiology and Intensive Care, AJA University of Medical
Sciences, Tehran, Iran.
(4)Department of Adult Nephrology, School of Medicine, Ayatollah Taleghani
Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
NGAL, also known as lipocalin 2, is a stress protein located on the cell surface
that is known for its involvement in iron transport. This study is aimed to
evaluate the correlation between the iron profile and NGAL concentration in
serum among chronic kidney disease patients under dialysis in order to find its
diagnostic value with regards to iron deficiency anaemia (IDA). 47 patients
under chronic haemodialysis in end-stage renal disease (ESRD) and 15 healthy
controls were evaluated to determine the correlation between serum NGAL
concentration and IDA characteristics. Our results recorded a significant
correlation between IDA (TSAT < 20%) and NGAL serum concentration with a
Spearman's coefficient of 0.314. Serum NGAL was also significantly related to
serum ferritin, TIBC, uric acid, creatinine and blood sugar whereas, an inverse
relationship with albumin, total cholesterol and LDL. Our study reports a
positive correlation between IDA and serum NGAL levels in CKD patients.
DOI: 10.1080/13813455.2020.1720742
PMID: 31994917 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26785833 | 1. Eur J Hum Genet. 2016 Aug;24(9):1255-61. doi: 10.1038/ejhg.2015.283. Epub 2016
Jan 20.
Online genetic counseling from the providers' perspective: counselors'
evaluations and a time and cost analysis.
Otten E(1), Birnie E(1), Ranchor AV(2), van Langen IM(1).
Author information:
(1)Department of Genetics, University of Groningen, University Medical Center
Groningen, Groningen, The Netherlands.
(2)Department of Health Psychology, University of Groningen, University Medical
Center Groningen, Groningen, The Netherlands.
Telemedicine applications are increasingly being introduced in patient care in
various disciplines, including clinical genetics, mainly to increase access to
care and to reduce time and costs for patients and professionals. Most
telegenetics reports describe applications in large geographical areas, showing
positive patients' and professionals' satisfaction. One economic analysis
published thus far reported lower costs than in-person care. We hypothesized
that telegenetics can also be beneficial from the professional's view in
relatively small geographical areas. We performed a pilot study in the Northern
Netherlands of 51 home-based online counseling sessions for cardiogenetic and
oncogenetic cascade screening, and urgent prenatal counseling. Previously, we
showed patient satisfaction, anxiety, and perceived control of online counseling
to be comparable to in-person counseling. This study focuses on expectations,
satisfaction, and practical evaluations of the involved counselors, and the
impact in terms of time and costs. Most counselors expected disadvantages of
online counseling for themselves and their patients, mainly concerning
insufficient non-verbal communication; few expected advantages for themselves.
Afterwards, counselors additionally raised the disadvantage of insufficient
verbal communication, and reported frequent technical problems. Their overall
mean telemedicine satisfaction itemscore was 3.38 before, and 2.95 afterwards,
being afterwards slightly below the minimum level we set for a satisfactory
result. We estimated reduced time and costs by online counseling with about 8%
and 10-12%, respectively. We showed online genetic counseling to be effective,
feasible and cost-efficient, but technical improvements are needed to increase
counselors' satisfaction.
DOI: 10.1038/ejhg.2015.283
PMCID: PMC4989197
PMID: 26785833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35723111 | 1. J Neuromuscul Dis. 2022;9(4):463-476. doi: 10.3233/JND-210776.
Comparing Deflazacort and Prednisone in Duchenne Muscular Dystrophy.
Biggar WD(1), Skalsky A(2), McDonald CM(3).
Author information:
(1)University of Toronto, 15583 22nd Side Road, Georgetown, Ontario, Canada.
(2)University of California San Diego, Rady Children's Hospital San Diego, MC,
San Diego, CA, USA.
(3)University of California Davis Health, Departments of Physical Medicine &
Rehabilitation and Pediatrics, Lawrence J. Ellison Ambulatory Care Center,
Sacramento, CA, USA.
Deflazacort and prednisone/prednisolone are the current standard of care for
patients with Duchenne muscular dystrophy (DMD) based on evidence that they
improve muscle strength, improve timed motor function, delay loss of ambulation,
improve pulmonary function, reduce the need for scoliosis surgery, delay onset
of cardiomyopathy, and increase survival. Both have been used off-label for many
years (choice dependent on patient preference, cost, and geographic location)
before FDA approval of deflazacort for DMD in 2017. In this review, we compare
deflazacort and prednisone/prednisolone in terms of their key pharmacological
features, relative efficacy, and safety profiles in patients with DMD.
Differentiating features include lipid solubility, pharmacokinetics, changes in
gene expression profiles, affinity for the mineralocorticoid receptor, and
impact on glucose metabolism. Evidence from randomized clinical trials,
prospective studies, meta-analyses, and post-hoc analyses suggests that patients
receiving deflazacort experience similar or slower rates of functional decline
compared with those receiving prednisone/prednisolone. Regarding side effects,
weight gain and behavior side effects appear to be greater with
prednisone/prednisolone than with deflazacort, whereas bone health, growth
parameters, and cataracts appear worse with deflazacort.
DOI: 10.3233/JND-210776
PMCID: PMC9398085
PMID: 35723111 [Indexed for MEDLINE]
Conflict of interest statement: W. Douglas Biggar, MD has served as a consultant
for PTC Therapeutics and Marathon. Andrew Skalsky, MD has no conflicts of
interest to report. Craig M. McDonald, MD has served as a consultant for
clinical trials for PTC Therapeutics, and outside the submitted work with
Astellas Pharma, Avidity Biosciences, Capricor Therapeutics, Catabasis
Pharmaceuticals, Edgewise Therapeutics, Entrada Therapeutics, Epirium Bio
(formerly Cardero Therapeutics), FibroGen, Italfarmaco, Pfizer, PTC
Therapeutics, Roche, Santhera Pharmaceuticals and Sarepta Therapeutics. He has
received research support for clinical trials from Capricor Therapeutics,
Catabasis Pharmaceuticals, Italfarmaco, Pfizer, PTC Therapeutics, Santhera
Pharmaceuticals and Sarepta Therapeutics. He serves on external advisory boards
related to Duchenne muscular dystrophy for PTC Therapeutics, Edgewise
Therapeutics, Eli Lilly, Sarepta Therapeutics, Santhera Pharmaceuticals, and
Capricor Therapeutics. The authors received no compensation for writing this
article. |
http://www.ncbi.nlm.nih.gov/pubmed/1822804 | 1. Neuromuscul Disord. 1991;1(4):261-6. doi: 10.1016/0960-8966(91)90099-e.
Steroids in Duchenne muscular dystrophy--deflazacort trial.
Mesa LE(1), Dubrovsky AL, Corderi J, Marco P, Flores D.
Author information:
(1)Sección de Enfermedades Neuromusculares, Hospital Frances, Buenos Aires,
Argentina.
We conducted a double blind controlled trial in 28 Duchenne muscular dystrophy
(DMD) patients with Deflazacort (DF), an oxazoline derivative of prednisolone
which reduces its side-effects. Myometric muscle strength measurements, Scott
Score and timed tests showed statistically significant improvement for the
treated group (P less than 0.05). Side-effects after 9 months of treatment
included mild cushingoid appearance in four patients (28%) and moderate in only
one (7%), increased appetite in seven (50%), increased body hair in four (28%),
irritability and hyperactivity in three (21%). Increased body weight was not
prominent and was controlled with dietary measures. No patient had to be
withdrawn from medication. More research and long-term follow-up are needed in
order to establish the mechanism of improvement and the consequences of
long-term steroid administration in DMD. In this regard DF appears as an
alternative to prednisone preserving its benefits but with fewer side-effects.
DOI: 10.1016/0960-8966(91)90099-e
PMID: 1822804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33104035 | 1. J Neuromuscul Dis. 2021;8(1):39-52. doi: 10.3233/JND-200556.
Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular
Dystrophy.
Quattrocelli M(1)(2), Zelikovich AS(1), Salamone IM(1), Fischer JA(1), McNally
EM(1).
Author information:
(1)Center for Genetic Medicine, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA.
(2)Molecular Cardiovascular Biology Division, Heart Institute, Cincinnati
Children's Hospital Medical Center, Cincinnati, OH, USA.
Glucocorticoid steroids are widely used as immunomodulatory agents in acute and
chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort
are recommended for treating Duchenne Muscular Dystrophy where their use
prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid
use in Duchenne Muscular Dystrophy is also associated with significant adverse
consequences including adrenal suppression, growth impairment, poor bone health
and metabolic syndrome. For other forms of muscular dystrophy like the limb
girdle dystrophies, glucocorticoids are not typically used. Here we review the
experimental evidence supporting multiple mechanisms of glucocorticoid action in
dystrophic muscle including their role in dampening inflammation and myofiber
injury. We also discuss alternative dosing strategies as well as novel steroid
agents that are in development and testing, with the goal to reduce adverse
consequences of prolonged glucocorticoid exposure while maximizing beneficial
outcomes.
DOI: 10.3233/JND-200556
PMCID: PMC7902991
PMID: 33104035 [Indexed for MEDLINE]
Conflict of interest statement: MQ and EMM are listed as co-inventors on a
patent application related to intermittent glucocorticoid use filed by
Northwestern University. |
http://www.ncbi.nlm.nih.gov/pubmed/35381069 | 1. JAMA. 2022 Apr 19;327(15):1456-1468. doi: 10.1001/jama.2022.4315.
Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys
With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.
Guglieri M(1), Bushby K(1), McDermott MP(2)(3), Hart KA(2), Tawil R(2), Martens
WB(2), Herr BE(2), McColl E(4), Speed C(4)(5), Wilkinson J(4), Kirschner
J(6)(7), King WM(8), Eagle M(1), Brown MW(2), Willis T(9), Griggs RC(2); FOR-DMD
Investigators of the Muscle Study Group; Straub V(1), van Ruiten H(1), Childs
AM(10), Ciafaloni E(2), Shieh PB(11), Spinty S(12), Maggi L(13), Baranello
G(13)(14), Butterfield RJ(15), Horrocks IA(16), Roper H(17), Alhaswani Z(17),
Flanigan KM(18), Kuntz NL(19), Manzur A(20), Darras BT(21), Kang PB(21)(22),
Morrison L(23), Krzesniak-Swinarska M(23), Mah JK(24), Mongini TE(25), Ricci
F(25), von der Hagen M(26), Finkel RS(27)(28), O'Reardon K(27), Wicklund
M(29)(30), Kumar A(29), McDonald CM(31), Han JJ(31), Joyce N(31), Henricson
EK(31), Schara-Schmidt U(32), Gangfuss A(32), Wilichowski E(33), Barohn RJ(34),
Statland JM(35), Campbell C(36), Vita G(37), Vita GL(38), Howard JF Jr(39),
Hughes I(40), McMillan HJ(41), Pegoraro E(42), Bello L(42), Burnette WB(43),
Thangarajh M(44), Chang T(45).
Author information:
(1)John Walton Muscular Dystrophy Research Centre, Newcastle University and
Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, England.
(2)Department of Neurology, University of Rochester Medical Center, Rochester,
New York.
(3)Department of Biostatistics and Computational Biology, University of
Rochester Medical Center, Rochester, New York.
(4)Newcastle University, Newcastle upon Tyne, England.
(5)NIHR Clinical Research Network North East and North Cumbria, Newcastle upon
Tyne, England.
(6)Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine,
University Hospital Freiburg, Freiburg, Germany.
(7)Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany.
(8)Ohio State University, Columbus.
(9)Robert Jones and Agnes Hunt Orthopaedic Hospital, NHS Foundation Trust,
Oswestry, England.
(10)Leeds General Infirmary, Leeds, England.
(11)David Geffen School of Medicine, University of California, Los Angeles.
(12)Alderhey Children's Hospital NHS Foundation Trust, Liverpool, England.
(13)Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
(14)Dubowitz Neuromuscular Centre, UCL NIHR GOSH Biomedical Research Centre, UCL
Great Ormond Street Institute of Child Health, London, England.
(15)Department of Pediatric Neurology, University of Utah, Salt Lake City.
(16)Glasgow Paediatric Neuromuscular Research Centre, Greater Glasgow and Clyde
NHS Yorkhill Hospital, Glasgow, Scotland.
(17)University Hospitals Birmingham NHS Foundation Trust, Birmingham, England.
(18)Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide
Children's Hospital, Columbus, Ohio.
(19)Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
(20)Great Ormond Street Hospital, London, England.
(21)Department of Neurology, Boston Children's Hospital and Harvard Medical
School, Boston, Massachusetts.
(22)Paul and Sheila Wellstone Muscular Dystrophy Center and Department of
Neurology, University of Minnesota Medical School, Minneapolis.
(23)Health Sciences Center, University of New Mexico, Albuquerque.
(24)Cumming School of Medicine, University of Calgary and Alberta Children's
Hospital Research Institute, Calgary, Canada.
(25)Neuromuscular Center, AOU Città della Salute e della Scienza, University of
Turin, Turin, Italy.
(26)Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus,
Technische Universität Dresden, Dresden, Germany.
(27)Nemours Children's Hospital, Orlando, Florida.
(28)Center for Experimental Neurotherapeutics, St Jude Children's Research
Hospital, Memphis, Tennessee.
(29)Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania.
(30)Department of Neurology, School of Medicine, University of Colorado, Aurora.
(31)Department of Physical Medicine and Rehabilitation and Department of
Pediatrics, University of California-Davis, Sacramento.
(32)Clinic for Pediatrics I, Pediatric Neurology, University Hospital Essen,
Essen, Germany.
(33)Department of Pediatrics and Adolescent Medicine, Division of Pediatric
Neurology, University Medical Center Göttingen, Göttingen, Germany.
(34)University of Missouri, Columbia.
(35)University of Kansas Medical Center, Kansas City.
(36)Departments of Pediatrics, Clinical Neurological Sciences, and Epidemiology,
University of Western Ontario, London, Canada.
(37)ERN Neuromuscular Unit, Department of Clinical and Experimental Medicine,
University of Messina, Messina, Italy.
(38)Unit of Neurology, IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
(39)School of Medicine, University of North Carolina, Chapel Hill.
(40)Royal Manchester Children's Hospital, Manchester, England.
(41)Children's Hospital of Eastern Ontario Research Institute, University of
Ottawa, Ottawa, Canada.
(42)ERN Neuromuscular Unit, Department of Neuroscience, University of Padova,
Padua, Italy.
(43)Vanderbilt University Medical Center, Nashville, Tennessee.
(44)Department of Neurology, Virginia Commonwealth University, Richmond.
(45)Children's National Hospital, George Washington University, Washington, DC.
IMPORTANCE: Corticosteroids improve strength and function in boys with Duchenne
muscular dystrophy. However, there is uncertainty regarding the optimum regimen
and dosage.
OBJECTIVE: To compare efficacy and adverse effects of the 3 most frequently
prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.
DESIGN, SETTING, AND PARTICIPANTS: Double-blind, parallel-group randomized
clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular
dystrophy who had not previously been treated with corticosteroids; enrollment
occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in
5 countries. The boys were assessed for 3 years (last participant visit on
October 16, 2019).
INTERVENTIONS: Participants were randomized to daily prednisone (0.75 mg/kg)
(n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone
(0.75 mg/kg for 10 days on and then 10 days off) (n = 66).
MAIN OUTCOMES AND MEASURES: The global primary outcome comprised 3 end points:
rise from the floor velocity (in rise/seconds), forced vital capacity (in
liters), and participant or parent global satisfaction with treatment measured
by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0
to 100), each averaged across all study visits after baseline. Pairwise group
comparisons used a Bonferroni-adjusted significance level of .017.
RESULTS: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]),
164 (84%) completed the trial. Both daily prednisone and daily deflazacort were
more effective than intermittent prednisone for the primary outcome (P < .001
for daily prednisone vs intermittent prednisone using a global test; P = .017
for daily deflazacort vs intermittent prednisone using a global test) and the
daily regimens did not differ significantly (P = .38 for daily prednisone vs
daily deflazacort using a global test). The between-group differences were
principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI,
0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003];
0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs
intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02
rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise
comparisons for forced vital capacity and TSQM global satisfaction subscale
score were not statistically significant. The most common adverse events were
abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily
deflazacort group, and 24 [36%] in the intermittent prednisone group), upper
respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively),
and vomiting (19 [29%], 17 [26%], and 15 [23%]).
CONCLUSIONS AND RELEVANCE: Among patients with Duchenne muscular dystrophy,
treatment with daily prednisone or daily deflazacort, compared with intermittent
prednisone alternating 10 days on and 10 days off, resulted in significant
improvement over 3 years in a composite outcome comprising measures of motor
function, pulmonary function, and satisfaction with treatment; there was no
significant difference between the 2 daily corticosteroid regimens. The findings
support the use of a daily corticosteroid regimen over the intermittent
prednisone regimen tested in this study as initial treatment for boys with
Duchenne muscular dystrophy.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01603407.
DOI: 10.1001/jama.2022.4315
PMCID: PMC8984930
PMID: 35381069 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: Dr Guglieri
reported receiving grants from Duchenne UK, the European Union’s Horizon 2020
program for the Vision-DMD study (in collaboration with ReveraGen BioPharma
Inc), and Sarepta Therapeutics; serving as a consultant to Dyne Therapeutics
Inc, Pfizer, and NS Pharma Inc; receiving personal fees from Sarepta
Therapeutics; and receiving nonfinancial support from Italfarmaco, Pfizer,
ReveraGen BioPharma Inc, and Santhera Pharmaceuticals. Dr McDermott reported
receiving grant support from PTC Therapeutics and receiving personal fees from
Fulcrum Therapeutics, NeuroDerm Ltd, AstraZeneca, Eli Lilly, Catabasis
Pharmaceuticals, Vaccinex Inc, Cynapsus Therapeutics, Neurocrine Biosciences,
Voyager Therapeutics, Prilenia Therapeutics, ReveraGen BioPharma Inc, and NS
Pharma Inc. Ms Hart reported receiving personal fees from Sarepta Therapeutics,
Santhera Pharmaceuticals, and PTC Therapeutics. Dr McColl reported receiving
grants from the National Institute for Health Research. Dr Kirschner reported
receiving personal fees from PTC Therapeutics, Pfizer, Roche, and Sarepta
Therapeutics. Dr Eagle reported receiving personal fees from ATOM International
Ltd. Dr Willis reported receiving personal fees from Newcastle University,
Novartis, Biogen Inc, Sarepta, Santhera, PTC Therapeutics, and Sanofi Genzyme.
Dr Straub reported receiving grants from Sarepta Therapeutics and Sanofi Genzyme
and serving as a consultant to Sarepta Therapeutics, Edgewise Therapeutics,
Sanofi Genzyme, Vertex Pharmaceuticals, Biogen Inc, Roche, Novartis Gene
Therapies, Astellas Gene Therapies, Wave Therapeutics, Kate Therapeutics Inc,
and Pfizer. Dr Childs reported receiving personal fees from PTC Therapeutics,
Sarepta Therapeutics, FibroGen Inc, the University of Basel, and ReveraGen
BioPharma Inc. Dr Ciafaloni reported receiving personal fees from Viela Bio,
AveXis Inc (now Novartis Gene Therapies), Biogen Inc, Medscape, Pfizer, PTC
Therapeutics, Sarepta Therapeutics, Ra Pharmaceuticals, Wave Therapeutics, and
Strongbridge Biopharma; receiving grants from the US Centers for Disease Control
and Prevention, Cure SMA, the Muscular Dystrophy Association, the National
Institutes of Health, Orphazyme, the Patient-Centered Outcomes Research
Institute, Parent Project Muscular Dystrophy, PTC Therapeutics, Santhera
Pharmaceuticals, Sarepta Therapeutics, and the US Food and Drug Administration;
receiving royalties from Oxford University Press; and receiving compensation
from MedLink for editorial duties. Dr Shieh reported receiving grants from
Catalyst Pharmaceuticals, Sarepta Therapeutics, PTC Therapeutics, Pfizer,
Sanofi, AveXis (now Novartis Gene Therapies), Biogen Inc, Santhera
Pharmaceuticals, Fulcrum Therapeutics Inc, Astellas Gene Therapies, Solid
Biosciences, ReveraGen BioPharma Inc, AMO Pharma, and Zogenix Inc and receiving
personal fees from Sarepta Therapeutics, Ra Pharmaceuticals, Argenx, PTC
Therapeutics, Pfizer, CSL Behring, Genentech, AveXis, Grifols, Alexion
Pharmaceuticals, and Biogen Inc. Mr Spinty reported receiving personal fees from
Roche, Sarepta Therapeutics, Pfizer, and Biogen Inc and receiving grants from
PTC Therapeutics. Dr Maggi reported receiving personal fees from Biogen Inc,
Sanofi-Genzyme, and Roche. Dr Baranello reported receiving personal fees from
PTC Therapeutics, Sarepta Therapeutics, ReveraGen BioPharma Inc, NS Pharma Inc,
Pfizer, and Roche. Dr Butterfield reported receiving personal fees from
AavantiBio, Scholar Rock Inc, AveXis (now Novartis Gene Therapies), Pfizer, PTC
Therapeutics, Biogen Inc, and Sarepta Therapeutics. Dr Roper reported reported
receiving personal fees from GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical
Inc, and Biogen Inc and receiving grants from Summit Therapeutics and Roche. Dr
Flanigan reported receiving grants and royalty payments from Astellas Gene
Therapies and receiving grants from Sarepta Therapeutics. Dr Kuntz reported
receiving personal fees from Sarepta Therapeutics, Astellas Gene Therapies,
Novartis, and Genentech. Dr Manzur reported receiving grants from Muscular
Dystrophy UK. Dr Darras reported receiving personal fees from Amicus Inc,
Audentes Therapeutics (now Astellas Gene Therapies), AveXis (now Novartis Gene
Therapies), Biogen Inc, Pfizer, Vertex, Roche, and Genentech; receiving research
support from the National Institute of Neurological Disorders and Stroke, the
Slaney Family Fund, the Spinal Muscular Atrophy Foundation, Cure SMA, and
Working on Walking Fund; receiving grants from Ionis Pharmaceuticals Inc, Biogen
Inc, AveXis, Sarepta Therapeutics, Novartis, PTC Therapeutics, Roche, Scholar
Rock Inc, and FibroGen Inc; and receiving royalties for books and online
publications from Elsevier and UpToDate Inc. Dr Kang reported receiving grants
from PTC Therapeutics. Dr Mah reported receiving grants from ReveraGen BioPharma
Inc, Pfizer, Italfarmaco, Sarepta Therapeutics, Catabasis Pharmaceuticals, NS
Pharma, and PTC Therapeutics. Dr Mongini reported receiving personal fees from
Sanofi Genzyme, Biogen Inc, Sarepta Therapeutics, Spark, Roche, and Novartis. Dr
Ricci reported receiving grants from the University of Rochester. Dr von der
Hagen reported receiving personal fees from PTC Therapeutics Germany GmbH and
Pfizer Pharma GmbH and receiving grants from Sarepta Therapeutics. Dr Finkel
reported receiving grants from ReveraGen BioPharma Inc, the Muscular Dystrophy
Association, the National Institutes of Health, Capricor Therapeutics, Catabasis
Pharmaceuticals, Eli Lilly, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta
Therapeutics, and Summit Therapeutics. Ms O’Reardon reported receiving grants
from Nemours Children’s Hospital. Dr Wicklund reported receiving personal fees
from Affinia Therapeutics, Amicus Therapeutics, Edgewise Therapeutics, ML Bio
Solutions, Sarepta Therapeutics, and Sanofi-Genzyme. Dr Kumar reported receiving
grants from PTC Therapeutics, Sarepta Therapeutics, AveXis (now Novartis Gene
Therapies), the Muscular Dystrophy Association, and FibroGen Inc and receiving
personal fees from Sarepta Therapeutics, Audentes Therapeutics, AveXis, Roche,
Genetech, PTC Therapeutics, Biogen Inc, and the American Academy of Pediatrics.
Dr McDonald reported receiving grants from Capricor Therapeutics, Catabasis
Pharmaceuticals, FibroGen Inc, Pfizer, PTC Therapeutics, ReveraGen BioPharma
Inc, Santhera Pharmaceuticals, the University of Rochester, and Sarepta
Therapeutics and receiving personal fees from PTC Therapeutics, Sarepta
Therapeutics, Astellas, Avidity Biosciences, BioMarin Pharmaceutical Inc,
Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Eli
Lilly, Entrada Therapeutics, Epirium Bio, FibroGen Inc, Hoffmann-La Roche,
Italfarmaco, Marathon Pharmaceuticals, Pfizer, PTC Therapeutics, Sarepta
Therapeutics, and Santhera Pharmaceuticals. Dr Henricson reported receiving
personal fees from PTC Therapeutics and Santhera Pharmaceuticals. Dr
Schara-Schmidt reported receiving personal fees from Sarepta Therapeutics,
Santhera Pharmaceuticals, Roche, PTC Therapeutics, and Pfizer. Dr Wilichowski
reported receiving grants from the University of Rochester. Dr Statland reported
receiving grants from the National Institutes of Health, the FSHD Society, the
FSHD Canada Foundation, and the Friends of FSH Research and receiving personal
fees from Fulcrum Therapeutics, Dyne Therapeutics Inc, Avidity Biosciences,
Mitsubishi Tanabe Pharma, ML Bio Solutions, and Amylyx Pharmaceuticals. Dr
Campbell reported receiving personal fees from Acceleron Pharma, AMO Pharma,
BioMarin Pharmaceutical Inc, Bristol Myers Squibb, Eli Lily, Biogen Inc, Pfizer,
Roche, PTC Therapeutics, Sarepta Therapeutics, Cytokinetics, Wave Therapeutics,
Catabasis Pharmaceuticals, Edgewise Therapeutics, and Solid Biosciences and
receiving grants from PTC Therapeutics, Genzyme, and Biogen Inc. Dr G. Vita
reported receiving grants from Sarepta Therapeutics, Santhera Pharmaceuticals,
Italfarmaco, and Wave Therapeutics. Dr G. L. Vita reported receiving grants from
Sarepta Therapeutics, Santhera Pharmaceuticals, Italfarmaco, and Wave
Therapeutics. Dr Howard reported receiving grants from Alexion Pharmaceuticals,
Ra Pharmaceuticals (now UCB), Argenx BVBA, and Millennium Pharmaceuticals Inc
and receiving personal fees from Alexion Pharmaceuticals, Argenx BVBA, Ra
Pharmaceuticals, Immunovant Inc, Regeneron Pharmaceuticals, Toleranzia, and
Viela Bio Inc (now Horizon Therapeutics). Dr Hughes reported receiving personal
fees from PTC Therapeutics, Novartis, Santhera Pharmaceuticals, Summit
Therapeutics, and Roche. Dr Pegoraro reported receiving personal fees from PTC
Therapeutics, Sarepta Therapeutics, Epirium Bio, Roche, Biogen Inc, UCB, and
Alexion Pharmaceuticals and receiving grants and nonfinancial support from
Santhera Pharmaceuticals. Dr Bello reported serving on boards for Edgewise
Therapeutics, PTC Therapeutics, and Sarepta Therapeutics; receiving grant
support from Santhera Pharmaceuticals; and receiving personal fees from PTC
Therapeutics and Epirium Bio. Dr Burnette reported serving on working groups or
boards for PTC Therapeutics, Sarepta Therapeutics, and SteroTherapeutics LLC. Dr
Thangarajh reported serving as a consultant to Sarepta Therapeutics. Dr Griggs
reported serving as a consultant to Strongbridge and Stealth Pharmaceuticals;
receiving personal fees from Solid Biosciences and Elsevier; serving as chair of
the research advisory committee and is a board member of the American Brain
Foundation; and serving on the executive committee of the Muscle Study Group,
which receives support for its activities from pharmaceutical companies. No
other disclosures were reported. |
http://www.ncbi.nlm.nih.gov/pubmed/19488064 | 1. Pharmacogenomics J. 2009 Dec;9(6):411-8. doi: 10.1038/tpj.2009.22. Epub 2009
Jun 2.
Corticosteroid effects on blood gene expression in Duchenne muscular dystrophy.
Lit L(1), Sharp FR, Apperson M, Liu DZ, Walker WL, Liao I, Xu H, Ander BP, Wong
B.
Author information:
(1)Department of Neurology, MIND Institute, University of California at Davis,
Sacramento, CA 95817, USA. llit@ucdavis.edu
Though Deflazacort and prednisone improve clinical endpoints in Duchenne
muscular dystrophy (DMD) patients, Deflazacort produces fewer side effects. As
mechanisms of improvement and side effect differences remain unknown, we
evaluated effects of corticosteroid administration on gene expression in blood
of DMD patients. Whole blood was obtained from 14 children and adolescents with
DMD treated with corticosteroids (DMD-STEROID) and 20 DMD children and
adolescents naïve to corticosteroids (DMD). The DMD-STEROID group was further
subdivided into Deflazacort and prednisone groups. Affymetrix U133 Plus 2.0
expression microarrays were used to evaluate mRNA expression. Expression of 524
probes changed with corticosteroids, including genes in iron trafficking and the
chondroitin sulfate biosynthesis pathway. Deflazacort compared with prednisone
yielded 508 regulated probes, including many involved in adipose metabolism.
These genes and pathways help explain mechanisms of efficacy and side effects of
corticosteroids, and could provide new treatment targets for DMD and other
neuromuscular disorders.
DOI: 10.1038/tpj.2009.22
PMID: 19488064 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35928819 | 1. Front Immunol. 2022 Jul 19;13:909008. doi: 10.3389/fimmu.2022.909008.
eCollection 2022.
Role of Bispecific Antibodies in Relapsed/Refractory Diffuse Large B-Cell
Lymphoma in the CART Era.
González Barca E(1).
Author information:
(1)Hematology Department, Catalan Institute of Oncology, University of
Barcelona, IDIBELL, Barcelona, Spain.
Diffuse large B-cell lymphoma is an aggressive and biologically heterogeneous
disease. R-CHOP is the standard first line therapy and cures more than 60% of
patients. Salvage high-dose chemotherapy with autologous stem cell transplant
remains the standard second-line treatment for relapsed or refractory patients,
and recently, three CD19 chimeric antigen receptor T cells (CART) cell products
have been approved beyond 2 prior lines of systemic therapy. Nevertheless, some
patients are not eligible for transplant or CARTs, or progress after these
treatments. In this context, IgG-like bispecific antibodies (BsAbs) have been
designed to treat B-cell lymphomas. They combine two different monospecific
antigen-binding regions that target CD20 on B cells and engage T cells via CD3
in a 1:1 or 2:1 CD20:CD3 antigen binding fragment (Fab) format. The results of
different phase 1 trials with BsAbs, including mosunetuzumab, glofitamab,
epcoritamab and odeonextamab, have been recently published. They are infused
intravenously or subcutaneously, and have a favorable toxicity profile, with
reduced cytokine release syndrome and neurological toxicity. Moreover, these
BsAbs have demonstrated very promising efficacy in B-cell lymphomas, including
in aggressive lymphomas. New trials are currently ongoing to confirm BsAbs
efficacy and tolerability, as well as to explore its efficacy in different lines
of therapy or in combination with other drugs.
Copyright © 2022 González Barca.
DOI: 10.3389/fimmu.2022.909008
PMCID: PMC9344863
PMID: 35928819 [Indexed for MEDLINE]
Conflict of interest statement: EG declares having received lecture fees and
advisory board fees from Janssen, Abbvie, Gilead, Kiowa, EUSAPharma, Incyte,
Lilly, Beigene, Novartis, Abbvie, Takeda, and Roche. |
http://www.ncbi.nlm.nih.gov/pubmed/35803286 | 1. Lancet Oncol. 2022 Aug;23(8):1055-1065. doi: 10.1016/S1470-2045(22)00335-7.
Epub 2022 Jul 5.
Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with
relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2
study.
Budde LE(1), Sehn LH(2), Matasar M(3), Schuster SJ(4), Assouline S(5), Giri
P(6), Kuruvilla J(7), Canales M(8), Dietrich S(9), Fay K(10), Ku M(11),
Nastoupil L(12), Cheah CY(13), Wei MC(14), Yin S(14), Li CC(14), Huang H(15),
Kwan A(14), Penuel E(14), Bartlett NL(16).
Author information:
(1)Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
National Medical Center, Duarte, CA, USA.
(2)Department of Medical Oncology, BC Cancer Centre for Lymphoid Cancer,
Vancouver, BC, Canada; Department of Medicine, The University of British
Columbia, Vancouver, BC, Canada.
(3)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,
USA.
(4)Lymphoma Translational Research, Abramson Cancer Center, University of
Pennsylvania, Philadelphia, PA, USA.
(5)Division of Hematology, Jewish General Hospital, Montreal, QC, Canada.
(6)Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia.
(7)Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre,
Toronto, ON, Canada.
(8)Servicio de Hematología, Hospital Universitario La Paz, Madrid, Spain.
(9)Department of Internal Medicine V: Hematology, Oncology and Rheumatology,
Heidelberg University, Heidelberg, Germany.
(10)Department of Haematology, Royal North Shore Hospital, Sydney, NSW,
Australia; Department of Haematology, St Vincent's Hospital, University of
Melbourne, Melbourne, VIC, Australia.
(11)Department of Haematology, St Vincent's Hospital, University of Melbourne,
Melbourne, VIC, Australia.
(12)Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, USA.
(13)Linear Clinical Research, Sir Charles Gairdner Hospital, Perth, WA,
Australia; Lymphoma Translational Research, Abramson Cancer Center, University
of Pennsylvania, Philadelphia, PA, USA; Department of Haematology, The
University of Western Australia, Perth, WA, Australia.
(14)Genentech, San Francisco, CA, USA.
(15)F Hoffmann-La Roche, Mississauga, ON, Canada.
(16)Division of Oncology, Siteman Cancer Center, Washington University School of
Medicine, St Louis, MO, USA. Electronic address: nbartlet@wustl.edu.
Comment in
Lancet Oncol. 2022 Aug;23(8):967-969. doi: 10.1016/S1470-2045(22)00385-0.
BACKGROUND: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal
antibody that redirects T cells to eliminate malignant B cells. In a phase 1
study, mosunetuzumab was well tolerated and active in patients with relapsed or
refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and
anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed
or refractory follicular lymphoma who had received two or more previous
therapies.
METHODS: We conducted a single-arm, multicentre, phase 2 study at 49 centres in
seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA).
All patients were aged 18 years or older with histologically confirmed
follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group
performance status of 0-1. Patients had disease that was relapsed or refractory
to two or more previous lines of treatment, including an anti-CD20 therapy and
an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles
with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg
on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards.
Patients with a complete response by investigator assessment using the
International Harmonisation Project criteria completed treatment after cycle 8,
whereas patients with a partial response or stable disease continued treatment
for up to 17 cycles. The primary endpoint was independent review
committee-assessed complete response rate (as best response) in all enrolled
patients; the primary efficacy analysis compared the observed IRC-assessed
complete response rate with a 14% historical control complete response rate in a
similar patient population receiving the pan class I PI3K inhibitor copanlisib.
Safety was assessed in all enrolled patients. This study is registered with
ClinicalTrials.gov, number NCT02500407, and is ongoing.
FINDINGS: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of
the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR
13·8-23·3). According to independent review committee assessment, a complete
response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed
complete response rate was significantly higher than the historical control
complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the
primary study endpoint. Cytokine release syndrome was the most common adverse
event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90)
and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade
3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of
90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and
anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90
patients. No treatment-related grade 5 (ie, fatal) adverse event occurred.
INTERPRETATION: Fixed-duration mosunetuzumab has a favourable safety profile and
induces high rates of complete remissions, allowing potential administration as
an outpatient regimen, in patients with relapsed or refractory follicular
lymphoma and two or more previous therapies.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00335-7
PMID: 35803286 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests LEB reports consulting
fees from Genentech, ADC Therapeutics, Merck, AstraZeneca, and Amgen; and
participation on a data safety monitoring board for Ziopharm Oncology. LHS
reports research grants from Roche/Genentech and Teva; consulting fees from
AbbVie, Acerta, Amgen, AstraZeneca, Celgene/Bristol-Myers Squibb (BMS),
Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz, and TG
therapeutics; and honoraria from AbbVie, Acerta, Amgen, AstraZeneca,
Celgene/BMS, Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz,
and TG therapeutics. MM reports research grants from AstraZeneca, Genentech,
Janssen, Roche, Bayer, IGM Biosciences, Pharmacyclics, and Seattle Genetics;
payment or honoraria from lectures, presentations, speaker's bureaus or
manuscript writing, or educational events from ADC Therapeutics, Bayer, Daiichi
Sankyo, MEI Pharma, Genentech, Seattle Genetics, Epizyme, IMV Therapeutics,
Janssen, Pharmacyclics, and Roche; payment from expert testimony from Bayer; and
owns stock or stock options in Merck. SJS reports grants or contracts from
Genentech, AbbVie, Acerta, AstraZeneca, Celgene/BMS/Juno, Incyte, Merck,
Novartis, TG Therapeutics, and Theredex; consulting fees from AstraZeneca,
BeiGene, Celgene/BMS/Juno, Genentech/Roche, Genmab, Incyte, Janssen, MorphoSys,
Mustang Biotech, Novartis, and Regeneron; payment or honoraria from lectures,
presentations, speaker's bureaus or manuscript writing, or educational events
for Incyte, Novartis, and Takeda; participation on a monitoring board or
advisory board for AstraZeneca, BeiGene, Celgene/BMS/Juno, Genentech/Roche,
Genmab, Incyte, Janssen, MorphoSys, Mustang Biotech, Novartis, and Regeneron; a
role in board, society, committee, or advocacy groups for Genentech, Legend
Biotech, Novartis, and Nordic Nanovector; and research support for Genentech and
Merck. SA reports research grants from AbbVie, Roche, Genentech, Takeda, Lilly,
and Merck; speaker's bureau from Pfizer; and is chair of the haematology group
(unpaid) of the Canadian Cancer Trials Group. JK reports research grants from
Roche, AstraZeneca, and Merck; consulting fees from AbbVie, Antengene, BMS,
Gilead, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics;
payment or honoraria from lectures, presentations, and educational events for
AbbVie, Amgen, AstraZeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck,
Novartis, Pfizer, Roche, and Seattle Genetics; participation in a data safety
monitoring board for Karyopharm; and participation as chair, scientific advisory
board, and director in the board of directors for Lymphoma Canada. MC reports
consulting fees from BeiGene, BMS, Incyte, Janssen, Kite, Kyowa, Miltenyi
Biotec, Novartis, Roche, and Takeda; payment from lectures, presentations,
speaker's bureaus or manuscript writing, or educational events from Amgen, Eusa
Pharma, Janssen, Kite, Kyowa, Roche, and Takeda; and meeting attendance or
travel support, or both, from Kite, Janssen, Roche, Sanofi, and Takeda. LN
reports grants from BMS, Caribou Biosciences, Epizyme, Gilead/Kite, Janssen, IGM
Biosciences, Takeda, and TG Therapeutics; payment or honoraria from lectures,
presentations, speaker's bureaus or manuscript writing, or educational events
from Genentech, Gilead/Kite, and Takeda; meeting attendance or travel, or both,
support from Genentech; and participation in data safety monitoring board or
advisory board for ADC Therapeutics, Bayer, Epizyme, BMS, MorphoSys, Novartis,
Genentech, Takeda, MEI, DeNovo, and TG Therapeutics. CYC reports payment or
honoraria from lectures, presentations, speaker's bureaus or manuscript writing,
or educational events for Janssen, AstraZeneca, Roche, and Beigene; and
participation in data safety monitoring board or advisory board for Roche,
Janssen, TG Therapeutics, AstraZeneca, Lilly, and Gilead. MCW reports meeting
attendance or travel support, or both, from Roche/Genentech; and stocks and
stock options in Roche. SY reports meeting attendance or travel support, or
both, for Genentech; patents planned, issued, or pending from Genentech; and
stocks and stock options in Genentech. C-CL reports stocks and stock options in
Roche; and patents planned, issued, or pending for Genentech. AK reports stocks
or stock options in Roche. EP reports stocks or stock options in Genentech. NLB
reports research funding from ADC Therapeutics, Affimed, Autolus, BMS, Celgene,
Forty Seven, Immune Design, Janssen, Kite Pharma, Merck, Millennium, Pfizer,
Pharmacyclics, Roche/Genentech, and Seattle Genetics. All other authors declare
no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35947358 | 1. Drugs. 2022 Jul;82(11):1229-1234. doi: 10.1007/s40265-022-01749-5.
Mosunetuzumab: First Approval.
Kang C(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. dru@adis.com.
Mosunetuzumab (Lunsumio®), an anti-CD20/CD3 T-cell engaging bispecific antibody,
is being developed by Roche for the treatment of relapsed or refractory
follicular lymphoma. Mosunetuzumab was recently conditionally approved in the EU
for the treatment of relapsed or refractory follicular lymphoma in adults who
have received at least two prior systemic therapies. This article summarizes the
milestones in the development of mosunetuzumab leading to this first approval
for relapsed or refractory follicular lymphoma.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01749-5
PMID: 35947358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35182296 | 1. Curr Treat Options Oncol. 2022 Feb;23(2):155-170. doi:
10.1007/s11864-021-00925-1. Epub 2022 Feb 19.
Bispecific Antibodies for Non-Hodgkin Lymphoma Treatment.
Bock AM(1), Nowakowski GS(1), Wang Y(2).
Author information:
(1)Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN,
55905, USA.
(2)Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN,
55905, USA. wang.yucai@mayo.edu.
While there have been numerous advances in the field of non-Hodgkin lymphoma
(NHL) over the last decade, relapsed and/or refractory (R/R) NHL remains a
challenge and an area with unmet needs. T-cell redirecting immunotherapeutic
approaches including chimeric antigen receptor (CAR) T-cells and bispecific
antibodies (BsAbs) have the potential to revolutionize NHL therapy. BsAbs target
CD3 on T-cells and CD19 or CD20 on malignant B-cells and have shown promises as
a novel immunotherapy for NHL. The development of CD19 × CD3 BsAbs such as
blinatumomab was met with significant challenges due to dose-limiting neurologic
side effects. However, several CD20 × CD3 BsAbs including odronextamab,
mosunetuzumab, glofitamab, and epcoritamab emerged recently. They have favorable
toxicity profiles, with reduced cytokine release syndrome and neurotoxicity. In
addition, all these BsAbs have demonstrated very promising efficacy in R/R NHL.
With expansion and registrational studies actively ongoing, approvals of these
agents for R/R NHL are anticipated in the near future. Some important questions
pertinent to future clinical development of BsAbs include when and how to best
utilize BsAbs in the management of R/R NHL, whether there is a role of BsAbs in
treatment-naïve NHL, and how to combine BsAbs with other therapies. For example,
whether BsAbs can be combined with cytotoxic chemotherapy effectively remains to
be seen. A plethora of clinical studies will be needed to help address these
questions, some of which are already ongoing. In addition, how do BsAbs compare
to CAR T-cell therapy and how to choose and sequence between BsAbs and CAR
T-cell therapy need to be addressed. While many of these critical questions
remain to be answered in clinical studies, we believe the future of BsAbs in the
NHL is very bright.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s11864-021-00925-1
PMID: 35182296 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20678798 | 1. Mol Immunol. 2010 Nov-Dec;48(1-3):14-25. doi: 10.1016/j.molimm.2010.07.009.
Epub 2010 Aug 1.
Mast cells: emerging sentinel innate immune cells with diverse role in immunity.
Kumar V(1), Sharma A.
Author information:
(1)Department of Microbiology, Panjab University, Chandigarh-160014, India. vij
tox@yahoo.com
Mast cells are phylogenetically old innate immune cells with less recognition in
normal function of immune system as no such disease has been observed in humans
due to their deficiency or inadequate function. Earlier mast cells were only
known for their important role in the type 1 allergic reactions (i.e.
anaphylaxis or some contact hypersensitivity reactions) due to release of
various biochemical mediators (i.e. cytokines, chemokines, lipid mediators,
proteases and biologic amines). Several studies indicated that they do not only
come in action upon binding of IgE to its corresponding receptors expressed by
them but also play an important role in host immunity. Recent development in
understanding the mast cell biology has established various important roles of
these cells in regulating both innate as well as adaptive immune response under
normal or pathophysiological conditions (i.e. acute or chronic bacterial or
parasitic infections, various autoimmune disease, pregnancy, etc.). Present
review is designed to accommodate up to date information regarding mast cell
development (i.e. factors governing mast cell development and their homing to
various compartments (i.e. skin, lungs, intestine, uterus, etc.) along with
their role in innate immunity, human pregnancy and future immunomodulatory
approach comprising of targeting mast cells.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.molimm.2010.07.009
PMID: 20678798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23855441 | 1. J Vet Emerg Crit Care (San Antonio). 2013 Jul-Aug;23(4):377-94. doi:
10.1111/vec.12066. Epub 2013 Jul 15.
Anaphylaxis in dogs and cats.
Shmuel DL(1), Cortes Y.
Author information:
(1)Oradell Animal Hospital, Emergency and Critical Care, 580 Winters Avenue,
Paramus, NJ 07652, USA. daniella.shmuel@gmail.com
Comment in
J Vet Emerg Crit Care (San Antonio). 2014 Mar-Apr;24(2):134; discussion 134.
doi: 10.1111/vec.12149.
OBJECTIVE: To review and summarize current information regarding the
pathophysiology and clinical manifestations associated with anaphylaxis in dogs
and cats. The etiology, diagnosis, treatment, and prognosis is discussed.
ETIOLOGY: Anaphylaxis is a systemic, type I hypersensitivity reaction that often
has fatal consequences. Many of the principal clinical manifestations involve
organs where mast cell concentrations are highest: the skin, the lungs, and the
gastrointestinal tract. Histamine and other deleterious inflammatory mediators
promote vascular permeability and smooth muscle contraction; they are readily
released from sensitized mast cells and basophils challenged with antigen.
Anaphylaxis may be triggered by a variety of antigens including insect and
reptile venom, a variety of drugs, vaccines, and food.
DIAGNOSIS: Anaphylaxis is a clinical diagnosis made from a collection of signs
and symptoms. It is most commonly based on pattern recognition. Differential
diagnoses include severe asthma, pheocromocytoma, and mastocytosis.
THERAPY: Epinephrine is considered the drug of choice for the treatment of
anaphylaxis. It acts primarily as a vasopressor in improving hemodynamic
recovery. Adjunctive treatments include fluid therapy, H1 and H2 antihistamines,
corticosteroids, and bronchodilators; however, these do not substitute for
epinephrine.
PROGNOSIS: Prognosis depends on the severity of the clinical signs. The clinical
signs will vary among species and route of exposure. The most severe clinical
reactions are associated when the antigen is administered parenterally.
© Veterinary Emergency and Critical Care Society 2013.
DOI: 10.1111/vec.12066
PMID: 23855441 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17128671 | 1. Lijec Vjesn. 2006 Sep-Oct;128(9-10):317-21.
[Anaphylactic reaction as a side-effect of administration of general anesthetics
and neuromuscular blocking agents].
[Article in Croatian]
Milavec D(1), Husedzinović I.
Author information:
(1)Klinika za anesteziologiju, reanimatologiju i intenzivno lijecenje, Klinicka
bolnica Dubrava, Zagreb.
The incidence of anaphylactic reactions during anesthesia is between 1:5000 and
1:25000 anesthetics. During the IgE-mediated anaphylactic reaction mast cells
release proteases such as tryptase, histamine and vasoactive mediators. The
release of mediators from the mast cells and basophils is responsible for the
immediate clinical manifestations of anaphylaxis. Anaphylactoid reactions can be
caused directly by a release of histamine and other mediators from mast cells
and basophils and they don't depend on interaction of IgE antibodies with
antigen. The most frequent agents that cause anaphylactic and anaphylactoid
reactions during anesthesia are neuromuscular blocking agents (among them the
highest percent refers to rocuronium and succinylcholine), some general
anesthetics, antibiotics, blood and blood products, opioids and latex. Increased
tryptase concentration in serum is a marker for systemic mast cell activation.
Skin tests (in vivo) are used for verification of specific hypersensitivity to
drugs in patients after anaphylactic reaction. In vitro tests prove the presence
of specific IgE antibodies for drugs. The plan for the treatment of anaphylactic
reactions must be established before the event. Airway maintenance, 100% oxygen
administration, intravascular volume expansion and epinephrine are essential to
treat the hypotension and hypoxia that result from vasodilatation, increased
capillary permeability and bronchospasm. As soon as the diagnosis has been made
the adrenalin should be given intravenously 1 to 3 ml of 1:10000 aqueous
solution (0.1 mg/ml) over 10 minutes. Prevention is possible with
methylprednisolone 125 mg i.v. 1 hour before administering of anesthetics and
neuromuscular blocking agents with or without antihistaminic
chlorpiramine-chloride 1 amp i.v. few minutes before anesthesia.
PMID: 17128671 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19082920 | 1. Arch Immunol Ther Exp (Warsz). 2008 Nov-Dec;56(6):385-99. doi:
10.1007/s00005-008-0041-2. Epub 2008 Dec 1.
Positive and negative regulatory mechanisms in high-affinity IgE
receptor-mediated mast cell activation.
Roth K(1), Chen WM, Lin TJ.
Author information:
(1)Department of Microbiology and Immunology, Dalhousie University, 5850
University Ave., Halifax, NS, Canada B3K6R8.
Mast cells are important effector cells in allergic inflammatory reactions. The
aggregation of the high-affinity IgE receptor (FcepsilonRI) on the surface of
mast cells initiates a complex cascade of signaling events that ultimately leads
to the release of various mediators involved in allergic inflammation and
anaphylactic reactions. The release of these mediators is tightly controlled by
signaling pathways that are propagated through the cell by specific
phosphorylation and dephosphorylation events. These events are controlled by
protein kinases and protein phosphatases which either positively or negatively
regulate the propagation of the signal through the cell. This review summarizes
the role of both positive and negative regulators of FcepsilonRI-induced mast
cell activation.
DOI: 10.1007/s00005-008-0041-2
PMID: 19082920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32276688 | 1. J Allergy Clin Immunol Pract. 2020 Apr;8(4):1196-1201. doi:
10.1016/j.jaip.2019.10.048.
Idiopathic Anaphylaxis: A Form of Mast Cell Activation Syndrome.
Giannetti MP(1), Akin C(2), Castells M(3).
Author information:
(1)Brigham and Women's Hospital, Division of Allergy and Clinical Immunology,
Boston, Mass; Harvard Medical School, Boston, Mass. Electronic address:
mgiannetti@bwh.harvard.edu.
(2)Division of Allergy and Immunology, University of Michigan, Ann Arbor, Mich.
(3)Brigham and Women's Hospital, Division of Allergy and Clinical Immunology,
Boston, Mass; Harvard Medical School, Boston, Mass.
Idiopathic anaphylaxis is a condition caused by paroxysmal episodes of
sudden-onset multiorgan involvement variably including laryngeal edema,
urticaria, bronchoconstriction, dyspnea, hypoxia, abdominal pain, nausea,
vomiting, diarrhea, and hypotension. Rarely, the episodes can lead to
cardiovascular collapse and death in the absence of a clear trigger, especially
in the presence of other cardiovascular comorbidities. Elevated mast cell
mediators such as tryptase and histamine have been reported during episodes, and
mast cells are considered the primary cells responsible for driving anaphylaxis
in humans. Basophils also secrete histamine and LTC4 when activated and
theoretically can contribute to symptoms. As our understanding of mast cell
disorders continue to grow, the classification for these disorders evolves. The
purpose of this article was 2-fold: to review the epidemiology, clinical
manifestations, and diagnosis of idiopathic anaphylaxis and to discuss the
classification of idiopathic anaphylaxis within the broader context of mast cell
activation disorders.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaip.2019.10.048
PMID: 32276688 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25841551 | 1. Immunol Allergy Clin North Am. 2015 May;35(2):277-85. doi:
10.1016/j.iac.2015.01.010.
Mast cell activation syndromes presenting as anaphylaxis.
Akin C(1).
Author information:
(1)Department of Medicine, Division of Rheumatology, Immunology and Allergy,
Mastocytosis Center, Brigham and Women's Hospital, Harvard Medical School, One
Jimmy Fund Way, Room 616D Boston, MA 02115, USA. Electronic address:
cakin@partners.org.
Anaphylaxis results from severe systemic mast cell activation. In addition to
IgE-mediated and physical triggers, it may occur with a clonal mast cell disease
and in an idiopathic fashion without clear provoking factors. Disorders of mast
cell activation are classified into primary (clonal), secondary, and idiopathic.
Mast cell activation syndrome (MCAS) is a multisystem disorder characterized by
objective documentation of elevated mast cell mediators during attacks and a
favorable response to antimediator therapy. It should be considered in the
differential diagnosis of patients presenting with recurrent anaphylaxis without
a clear cause. This article discusses the diagnosis of MCAS.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.iac.2015.01.010
PMID: 25841551 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28798744 | 1. Front Immunol. 2017 Jul 26;8:846. doi: 10.3389/fimmu.2017.00846. eCollection
2017.
The Mast Cell, Contact, and Coagulation System Connection in Anaphylaxis.
Guilarte M(1)(2), Sala-Cunill A(1)(2), Luengo O(1)(2), Labrador-Horrillo
M(1)(2), Cardona V(1)(2).
Author information:
(1)Allergy Section, Internal Medicine Department, Hospital Universitari Vall
d'Hebron, Barcelona, Spain.
(2)VHIR Institut de Recerca Vall d'Hebron, Barcelona, Spain.
Anaphylaxis is the most severe form of allergic reaction, resulting from the
effect of mediators and chemotactic substances released by activated cells. Mast
cells and basophils are considered key players in IgE-mediated human
anaphylaxis. Beyond IgE-mediated activation of mast cells/basophils, further
mechanisms are involved in the occurrence of anaphylaxis. New insights into the
potential relevance of pathways other than mast cell and basophil degranulation
have been unraveled, such as the activation of the contact and the coagulation
systems. Mast cell heparin released upon activation provides negatively charged
surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the
initiating serine protease in both the contact and the intrinsic coagulation
system, activates factor XI and prekallikrein, respectively. FXII-mediated
bradykinin (BK) formation has been proven in the human plasma of anaphylactic
patients as well as in experimental models of anaphylaxis. Moreover, the
severity of anaphylaxis is correlated with the increase in plasma heparin, BK
formation and the intensity of contact system activation. FXII also activates
plasminogen in the fibrinolysis system. Mast cell tryptase has been shown to
participate in fibrinolysis through plasmin activation and by facilitating the
degradation of fibrinogen. Some usual clinical manifestations in anaphylaxis,
such as angioedema or hypotension, or other less common, such as metrorrhagia,
may be explained by the direct effect of the activation of the coagulation and
contact system driven by mast cell mediators.
DOI: 10.3389/fimmu.2017.00846
PMCID: PMC5526842
PMID: 28798744 |
http://www.ncbi.nlm.nih.gov/pubmed/26857018 | 1. Curr Allergy Asthma Rep. 2016 Mar;16(3):20. doi: 10.1007/s11882-016-0598-5.
Mast Cells and Anaphylaxis.
Lieberman P(1)(2), Garvey LH(3).
Author information:
(1)Divisions of Allergy and Immunology, Departments of Medicine and Pediatrics,
University of Tennessee, Memphis, TN, USA. aac@allergymemphis.com.
(2), 7205 Wolf River Blvd., Suite 200, Germantown, TN, 38138-1777, USA.
aac@allergymemphis.com.
(3)Allergy Clinic UA-816, Department of Dermato-allergology, Copenhagen
University Hospital, Gentofte, Kildegårdsvej 28, DK-2900, Hellerup, Denmark.
lene.heise.garvey@regionh.dk.
For half a century, it has been known that the mast cell is the cell responsible
for the majority of anaphylactic events. Its mediators, taken as a whole, are
capable of producing all of the clinical manifestations of these events. With
the discovery of immunoglobulin E (IgE), it was originally felt that the vast
majority of anaphylactic episodes were due to antigen coupling with two
cell-bound IgE molecules. More recently it has been learned that many episodes
are produced by direct activation of mast cells, not involving antigen binding
to IgE, and that monomeric IgE under certain conditions can also cause
degranulation. Of note--in regard to antigen independent degranulation--are
recent reports that the human G-protein-coupled receptor, MRGPRX2, may be the
receptor for many drugs and cationic proteins capable of producing direct mast
cell degranulation and anaphylactic events.
DOI: 10.1007/s11882-016-0598-5
PMID: 26857018 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33832694 | 1. J Allergy Clin Immunol. 2021 Apr;147(4):1123-1131. doi:
10.1016/j.jaci.2021.02.012.
Non-IgE-mediated anaphylaxis.
Cianferoni A(1).
Author information:
(1)Perelman School of Medicine, University of Pennsylvania, Allergy and
Immunology Division, The Children's Hospital of Philadelphia, Philadelphia, Pa.
Electronic address: cianferonia@chop.edu.
Anaphylaxis is a rapidly evolving, acute, life-threatening reaction that occurs
rapidly on contact with a trigger. Anaphylaxis is classically defined as an
allergen-driven process that induces specific IgE and the activation of mast
cells and basophils through the cross-linking of IgE receptors. However, it is
clear that non-IgE-mediated pathways can induce symptoms indistinguishable from
those of classic anaphylaxis, and their activation could explain the severity of
IgE-mediated anaphylaxis. Indeed, mast cells and basophils can be activated by
antibodies against IgE or their receptors, by molecules such as anaphylatoxins,
or through G-coupled receptors. Some other allergens can induce antibodies of
class IgG that can activate neutrophils to produce a molecule similar to
histamine to induce anaphylaxis. Finally, some inflammatory mediators such as
bradykinin or prostaglandin can also modulate mast cell and basophil activation
as well as directly cause vasodilation and bronchoconstriction, resulting in
anaphylaxis-like reactions.
Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaci.2021.02.012
PMID: 33832694 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20519881 | 1. Chem Immunol Allergy. 2010;95:45-66. doi: 10.1159/000315937. Epub 2010 Jun 1.
Anaphylaxis: mechanisms of mast cell activation.
Kalesnikoff J, Galli SJ.
Anaphylaxis is a severe systemic allergic response that is rapid in onset and
potentially lethal, and that typically is induced by an otherwise innocuous
substance. In IgE-dependent and other examples of anaphylaxis, tissue mast cells
and circulating basophilic granulocytes (basophils) are thought to represent
major (if not the major) sources of the biologically active mediators that
contribute to the pathology and, in unfortunate individuals, fatal outcome, of
anaphylaxis. In this chapter, we will describe the mechanisms of mast cell (and
basophil) activation in anaphylaxis, with a focus on IgE-dependent activation,
which is thought to be responsible for most examples of antigen-induced
anaphylaxis in humans. We will also discuss the use of mouse models to
investigate the mechanisms that can contribute to anaphylaxis in that species in
vivo, and the relevance of such mouse studies to human anaphylaxis.
Copyright 2010 S. Karger AG, Basel.
DOI: 10.1159/000315937
PMID: 20519881 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31690393 | 1. Allergy Asthma Proc. 2019 Nov 1;40(6):453-456. doi: 10.2500/aap.2019.40.4270.
Anaphylaxis.
Watts MM, Marie Ditto A.
Anaphylaxis is a sudden onset, immediate reaction that implies a risk of death.
Think of a "rule of 2s" for anaphylaxis, which implies that reactions usually
begin within 2 minutes to 2 hours after injection, infusion, ingestion, contact,
or inhalation. Fatalities can be from asphyxiation from laryngeal or
oropharyngeal swelling, collapse from hypotensive shock, cardiac arrest, or
acute severe bronchoconstriction that causes respiratory failure and arrest.
When there is activation of mast cells and basophils in anaphylaxis, chemical
mediators are detectable. The preformed mediators from mast cells include
histamine, tryptase, carboxypeptidase A, and proteoglycans (heparin, chondroitin
sulfates). Newly synthesized mediators include prostaglandin D₂, leukotriene D₄,
and platelet activating factor. Crucial actions of the mediators include an
abrupt increase in vascular permeability, vascular smooth muscle relaxation, and
bronchial smooth muscle contraction. Anaphylaxis can be classified into
immunologic, nonimmunologic, or idiopathic based on the associated mechanism.
For example, immunologic causes of anaphylaxis are those mediated by
immunoglobulin E (IgE) antibodies acting through the FcεR I (foods, insect
venom, 32 β-lactam antibiotics), whereas non-IgE immunologic anaphylaxis is
mediated without the presence of anti-allergen IgE antibodies or via FcεRI
activation (radiographic contrast material). Nonimmunologic anaphylaxis involves
mast cell mediator release such as occurs with exercise or with cold temperature
exposure, or from medications such as opioids or vancomycin. Idiopathic
anaphylaxis involves mast cell activation (acutely elevated urine histamine or
serum tryptase) and activated lymphocytes. Because anaphylaxis is a medical
emergency, the drug of choice is epinephrine, not H1 antihistamines or H₂
receptor antagonists.
DOI: 10.2500/aap.2019.40.4270
PMID: 31690393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34292177 | 1. Curr Opin Allergy Clin Immunol. 2021 Oct 1;21(5):426-434. doi:
10.1097/ACI.0000000000000768.
Mast cell activation syndrome: is anaphylaxis part of the phenotype? A
systematic review.
Sabato V(1)(2), Michel M(3)(4)(5), Blank U(6), Ebo DG(1)(2), Vitte J(4)(5)(7).
Author information:
(1)University of Antwerp, Faculty of Medicine and Health Sciences, Department of
Immunology, Allergology, Rheumatology and the Infla-Med Centre of Excellence.
(2)AZ Jan Palfijn Gent, Department of Immunology and Allergology, Ghent,
Belgium.
(3)Laboratoire d'Immunologie, CHU de Nîmes, Nîmes.
(4)Aix-Marseille Univ, IRD, APHM, MEPHI.
(5)IHU Méditerranée Infection, Marseille.
(6)Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149,
CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France; Laboratoire
d'Excellence Inflamex, Paris, France.
(7)IDESP, INSERM UMR UA 11, Montpellier, France.
PURPOSE OF REVIEW: Mast cell activation syndrome (MCAS) and anaphylaxis are the
result of a spontaneous or triggered pathological degranulation of mast cells
(MCs) and might have as substrate normal or pathological MCs (increased burden,
aberrant MCs or both).
RECENT FINDINGS: This review summarizes the most recent evidence on
immunoglobulin E (IgE)-mediated and non IgE-mediated mechanisms underlying MC
activation and degranulation and highlights the importance of standardized
diagnostic criteria for MCAS. Application of these criteria implies that in most
cases the clinical presentation of MCAS meets the diagnostic criteria for
anaphylaxis.
SUMMARY: Integrating clinical parameters and diagnostic test recognition and
underlying clonal MC disease are of utmost importance for a patient-tailored
approach. Hereditary alpha-tryptasemia can be encountered in context of
anaphylaxis, MCAS and primary MC disorders.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/ACI.0000000000000768
PMID: 34292177 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25240785 | 1. J Allergy Clin Immunol. 2015 Apr;135(4):1031-1043.e6. doi:
10.1016/j.jaci.2014.07.057. Epub 2014 Sep 18.
Plasma contact system activation drives anaphylaxis in severe mast cell-mediated
allergic reactions.
Sala-Cunill A(1), Björkqvist J(2), Senter R(3), Guilarte M(4), Cardona V(4),
Labrador M(4), Nickel KF(5), Butler L(5), Luengo O(4), Kumar P(2), Labberton
L(2), Long A(6), Di Gennaro A(2), Kenne E(2), Jämsä A(2), Krieger T(6), Schlüter
H(6), Fuchs T(5), Flohr S(7), Hassiepen U(7), Cumin F(7), McCrae K(8), Maas
C(9), Stavrou E(10), Renné T(11).
Author information:
(1)Allergy Section, Internal Medicine Department, Hospital Universitari Vall
d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall
d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Clinical
Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet
and University Hospital, Stockholm, Sweden.
(2)Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska
Institutet and University Hospital, Stockholm, Sweden; Center for Molecular
Medicine, Karolinska Institutet, Stockholm, Sweden.
(3)Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska
Institutet and University Hospital, Stockholm, Sweden; Department of Medicine,
University of Padova, Padua, Italy.
(4)Allergy Section, Internal Medicine Department, Hospital Universitari Vall
d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall
d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
(5)Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska
Institutet and University Hospital, Stockholm, Sweden; Center for Molecular
Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical
Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany.
(6)Institute for Clinical Chemistry and Laboratory Medicine, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany.
(7)Novartis Institute for Biomedical Research, Novartis Campus, Basel,
Switzerland.
(8)Departments of Hematology and Medical Oncology and Cellular and Molecular
Medicine, Cleveland Clinic, Cleveland, Ohio.
(9)Department of Clinical Chemistry and Haematology, University Medical Center
Utrecht, Utrecht, The Netherlands.
(10)Department of Medicine, Hematology and Oncology Division, Case Western
Reserve University and University Hospitals Case Medical Center, Cleveland,
Ohio.
(11)Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska
Institutet and University Hospital, Stockholm, Sweden; Center for Molecular
Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical
Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany. Electronic address: thomas@renne.net.
BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome
resulting from the sudden release of mast cell-derived mediators into the
circulation.
OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the
factor XII-driven contact system, critically contributes to the pathogenesis of
anaphylaxis in both murine models and human subjects.
RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma
kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but
not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell
hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human
factor XII restored susceptibility for allergen/IgE-mediated hypotension.
Activated mast cells systemically released heparin, which provided a negatively
charged surface for factor XII autoactivation. Activated factor XII generates
plasma kallikrein, which proteolyzes kininogen, leading to the liberation of
bradykinin. We evaluated the contact system in patients with anaphylaxis. In all
10 plasma samples immunoblotting revealed activation of factor XII, plasma
kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal
conditions or in healthy control subjects. The severity of anaphylaxis was
associated with mast cell degranulation, increased plasma heparin levels, the
intensity of contact system activation, and bradykinin formation.
CONCLUSIONS: In summary, the data collectively show a role of the contact system
in patients with anaphylaxis and support the hypothesis that targeting
bradykinin generation and signaling provides a novel and alternative treatment
strategy for anaphylactic attacks.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaci.2014.07.057
PMID: 25240785 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31011586 | 1. J Immunol Res. 2019 Mar 18;2019:9542656. doi: 10.1155/2019/9542656.
eCollection 2019.
Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis.
Klein O(1), Sagi-Eisenberg R(1).
Author information:
(1)Department of Cell and Developmental Biology, Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv 69978, Israel.
Anaphylaxis is a notorious type 2 immune response which may result in a systemic
response and lead to death. A precondition for the unfolding of the anaphylactic
shock is the secretion of inflammatory mediators from mast cells in response to
an allergen, mostly through activation of the cells via the IgE-dependent
pathway. While mast cells are specialized secretory cells that can secrete
through a variety of exocytic modes, the most predominant mode exerted by the
mast cell during anaphylaxis is compound exocytosis-a specialized form of
regulated exocytosis where secretory granules fuse to one another. Here, we
review the modes of regulated exocytosis in the mast cell and focus on compound
exocytosis. We review historical landmarks in the research of compound
exocytosis in mast cells and the methods available for investigating compound
exocytosis. We also review the molecular mechanisms reported to underlie
compound exocytosis in mast cells and expand further with reviewing key findings
from other cell types. Finally, we discuss the possible reasons for the mast
cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence
in different mast cell models, and the open questions in the field which remain
to be answered.
DOI: 10.1155/2019/9542656
PMCID: PMC6442490
PMID: 31011586 [Indexed for MEDLINE] |