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http://www.ncbi.nlm.nih.gov/pubmed/35511862 | 1. Stem Cells. 2022 Mar 3;40(1):2-13. doi: 10.1093/stmcls/sxab006.
Exploring Motor Neuron Diseases Using iPSC Platforms.
Johns AE(1), Maragakis NJ(1).
Author information:
(1)Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
The degeneration of motor neurons is a pathological hallmark of motor neuron
diseases (MNDs), but emerging evidence suggests that neuronal vulnerability
extends well beyond this cell subtype. The ability to assess motor function in
the clinic is limited to physical examination, electrophysiological measures,
and tissue-based or neuroimaging techniques which lack the resolution to
accurately assess neuronal dysfunction as the disease progresses. Spinal
muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), hereditary
spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS) are all MNDs
with devastating clinical outcomes that contribute significantly to disease
burden as patients are no longer able to carry out normal activities of daily
living. The critical need to accurately assess the cause and progression of
motor neuron dysfunction, especially in the early stages of those diseases, has
motivated the use of human iPSC-derived motor neurons (hiPSC-MN) to study the
neurobiological mechanisms underlying disease pathogenesis and to generate
platforms for therapeutic discovery and testing. As our understanding of MNDs
has grown, so too has our need to develop more complex in vitro models which
include hiPSC-MN co-cultured with relevant non-neuronal cells in 2D as well as
in 3D organoid and spheroid systems. These more complex hiPSC-derived culture
systems have led to the implementation of new technologies, including
microfluidics, multielectrode array, and machine learning which offer novel
insights into the functional correlates of these emerging model systems.
© The Author(s) 2022. Published by Oxford University Press. All rights reserved.
For permissions, please email: [email protected].
DOI: 10.1093/stmcls/sxab006
PMCID: PMC9199844
PMID: 35511862 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12710507 | 1. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Dec;3(4):186-9. doi:
10.1080/146608202760839003.
Hereditary motor neuropathies and motor neuron diseases: which is which.
Hanemann CO(1), Ludolph AC.
Author information:
(1)Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm,
Germany.
When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the
clinical and neuropathological pattern of vulnerability as a guideline.
Similarly other motor neuron diseases such as the spinal muscular atrophies
(SMA) and the motor neuropathies (MN) were grouped following clinical criteria.
However, ever since the etiology of these diseases has started to be disclosed
by genetics, we have learnt that the limits of the syndromes are not as well
defined as our forefathers thought. A mutation leading to ALS can also be
associated with the clinical picture of spinal muscular atrophy; even more
unexpected is the overlap of the so-called motor neuropathies with the clinical
syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can
be caused by the same gene as that responsible for some cases of ALS. In this
review we summarise recent work showing that there is a considerable overlap
between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to
study of the variants of motor neuron disease and possibly to a
reclassification. This comprehensive review should help to improve understanding
of the pathogenesis of motor neuron degeneration and finally may aid the
research for urgently needed new treatment strategies, perhaps with validity for
the entire group of motor neuron diseases.
DOI: 10.1080/146608202760839003
PMID: 12710507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34204831 | 1. Pharmaceuticals (Basel). 2021 Jun 12;14(6):565. doi: 10.3390/ph14060565.
Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases.
Karpe Y(1), Chen Z(1)(2), Li XJ(1)(2).
Author information:
(1)Department of Biomedical Sciences, University of Illinois College of
Medicine, Rockford, IL 61107, USA.
(2)Department of Bioengineering, University of Illinois at Chicago, Chicago, IL
60607, USA.
Motor neurons are large projection neurons classified into upper and lower motor
neurons responsible for controlling the movement of muscles. Degeneration of
motor neurons results in progressive muscle weakness, which underlies several
debilitating neurological disorders including amyotrophic lateral sclerosis
(ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA).
With the development of induced pluripotent stem cell (iPSC) technology, human
iPSCs can be derived from patients and further differentiated into motor
neurons. Motor neuron disease models can also be generated by genetically
modifying human pluripotent stem cells. The efficiency of gene targeting in
human cells had been very low, but is greatly improved with recent gene editing
technologies such as zinc-finger nucleases (ZFN), transcription activator-like
effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem
cell-based models and gene editing tools provides unique paradigms to dissect
pathogenic mechanisms and to explore therapeutics for these devastating
diseases. Owing to the critical role of several genes in the etiology of motor
neuron diseases, targeted gene therapies have been developed, including
antisense oligonucleotides, viral-based gene delivery, and in situ gene editing.
This review summarizes recent advancements in these areas and discusses future
challenges toward the development of transformative medicines for motor neuron
diseases.
DOI: 10.3390/ph14060565
PMCID: PMC8231537
PMID: 34204831
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23255347 | 1. EMBO Mol Med. 2013 Feb;5(2):221-34. doi: 10.1002/emmm.201202303. Epub 2013 Jan
25.
Spliceosome integrity is defective in the motor neuron diseases ALS and SMA.
Tsuiji H(1), Iguchi Y, Furuya A, Kataoka A, Hatsuta H, Atsuta N, Tanaka F,
Hashizume Y, Akatsu H, Murayama S, Sobue G, Yamanaka K.
Author information:
(1)Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako,
Saitama, Japan. [email protected]
Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal
muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism,
TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared
defective mechanism in RNA metabolism common to these two diseases remains
unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through
an association with SMN, and that all three proteins function in spliceosome
maintenance. We also show that in ALS, Gems are lost, U snRNA levels are
up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in
motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology.
This aberrant accumulation of U snRNAs in ALS motor neurons is in direct
contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while
both have defects in the spliceosome. These findings indicate that a profound
loss of spliceosome integrity is a critical mechanism common to
neurodegeneration in ALS and SMA, and may explain cell-type specific
vulnerability of motor neurons.
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of
EMBO.
DOI: 10.1002/emmm.201202303
PMCID: PMC3569639
PMID: 23255347 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31031583 | 1. Front Neurosci. 2019 Apr 12;13:331. doi: 10.3389/fnins.2019.00331. eCollection
2019.
Dissecting Motor Neuron Disease With Drosophila melanogaster.
Walters R(1), Manion J(1), Neely GG(1).
Author information:
(1)Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre,
School of Life and Environmental Sciences, The University of Sydney, Sydney,
NSW, Australia.
Motor Neuron Disease (MND) typically affects patients during the later stages of
life, and thus, MND is having an increasingly devastating impact on diagnosed
individuals, their families and society. The umbrella term MND refers to
diseases which cause the progressive loss of upper and/or lower motor neurons
and a subsequent decrease in motor ability such as amyotrophic lateral sclerosis
(ALS) and spinal muscular atrophy (SMA). The study of these diseases is complex
and has recently involved the use of genome-wide association studies (GWAS).
However, in the case of MND, it has been difficult to identify the complex
genetics involved in subtypes, and functional investigation of new candidate
disease genes is warranted. Drosophila is a powerful model for addressing these
complex diseases. The UAS/Gal4/Gal80 system allows for the upregulation of
Drosophila genes, the "knockdown" of genes and the ectopic expression of human
genes or mutations in a tissue-specific manner; often resulting in Drosophila
models which exhibit typical MND disease pathologies. These can then be further
interrogated to identify disease-modifying genes or mutations and disease
pathways. This review will discuss two common MNDs and the current Drosophila
models which are being used to research their genetic basis and the different
pathologies of MND.
DOI: 10.3389/fnins.2019.00331
PMCID: PMC6473072
PMID: 31031583 |
http://www.ncbi.nlm.nih.gov/pubmed/14753656 | 1. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Dec;4(4):225-31. doi:
10.1080/14660820310011287.
The genetics of motor neuron diseases.
Figlewicz DA(1), Orrell RW.
Author information:
(1)Department of Neurology, University of Michigan, Ann Arbor, MI 48109-0588,
USA
Motor neuron diseases may be divided into three categories: those with lower
motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular
atrophy (SBMA or Kennedy's disease); those with upper motor neuron
involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and
those with combined upper and lower motor neuron involvement--amyotrophic
lateral sclerosis (ALS). Other familial motor neuron disorders include
hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome
of Guam. The contribution of genetics to the etiopathogenesis of motor neuron
considerably, accounting for a high percentage of spinal muscular atrophies, but
only a small fraction of cases of ALS. The mode of inheritance also varies, with
examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked
kindreds. (Tables 1 and 2).
DOI: 10.1080/14660820310011287
PMID: 14753656 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15372378 | 1. Am J Hum Genet. 2004 Nov;75(5):822-31. doi: 10.1086/425287. Epub 2004 Sep 15.
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal
muscular atrophy and amyotrophic lateral sclerosis.
Nishimura AL(1), Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio
D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M.
Author information:
(1)Human Genome Research Center, Department of Biology, Biosciences Institute,
São Paulo University, São Paulo, Brazil.
Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with
involvement of upper and/or lower motor neurons, such as amyotrophic lateral
sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and
primary lateral sclerosis. Recently, we have mapped a new locus for an atypical
form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a
large white Brazilian family. Here, we report the finding of a novel missense
mutation in the vesicle-associated membrane protein/synaptobrevin-associated
membrane protein B (VAPB) gene in patients from this family. Subsequently, the
same mutation was identified in patients from six additional kindreds but with
different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS
with rapid progression. Although it was not possible to link all these families,
haplotype analysis suggests a founder effect. Members of the vesicle-associated
proteins are intracellular membrane proteins that can associate with
microtubules and that have been shown to have a function in membrane transport.
These data suggest that clinically variable MNDs may be caused by a dysfunction
in intracellular membrane trafficking.
DOI: 10.1086/425287
PMCID: PMC1182111
PMID: 15372378 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35294812 | 1. N Engl J Med. 2022 Mar 17;386(11):1026-1033. doi: 10.1056/NEJMoa2109329.
Inhibition of Prekallikrein for Hereditary Angioedema.
Fijen LM(1), Riedl MA(1), Bordone L(1), Bernstein JA(1), Raasch J(1), Tachdjian
R(1), Craig T(1), Lumry WR(1), Manning ME(1), Alexander VJ(1), Newman KB(1),
Revenko A(1), Baker BF(1), Nanavati C(1), MacLeod AR(1), Schneider E(1), Cohn
DM(1).
Author information:
(1)From the Department of Vascular Medicine, Amsterdam Cardiovascular Sciences,
Amsterdam UMC, University of Amsterdam, Amsterdam (L.M.F., D.M.C.); the Division
of Rheumatology, Allergy, and Immunology, University of California, San Diego,
La Jolla (M.A.R.), Ionis Pharmaceuticals, Carlsbad (L.B., V.J.A., K.B.N., A.R.,
B.F.B., C.N., A.R.M., E.S.), and the Division of Allergy, Immunology, and
Rheumatology, University of California, Los Angeles, Los Angeles (R.T.) - all in
California; the Department of Internal Medicine, Division of Immunology-Allergy
Section and the Bernstein Clinical Research Center, University of Cincinnati
College of Medicine, Cincinnati (J.A.B.); the Midwest Immunology Clinic,
Plymouth, MN (J.R.); the Department of Medicine and Pediatrics, Penn State
Health Allergy, Asthma, and Immunology, Hershey, PA (T.C.); Asthma and Allergy
Research Associates, Dallas (W.R.L.); and Medical Research of Arizona,
Scottsdale (M.E.M.).
Comment in
N Engl J Med. 2022 Mar 17;386(11):1083-1085. doi: 10.1056/NEJMe2201729.
BACKGROUND: Hereditary angioedema is characterized by recurrent and
unpredictable swellings that are disabling and potentially fatal. Selective
inhibition of plasma prekallikrein production by antisense oligonucleotide
treatment (donidalorsen) may reduce the frequency of attacks and the burden of
disease.
METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients
with hereditary angioedema with C1 inhibitor deficiency to receive four
subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose
administered every 4 weeks. The primary end point was the time-normalized number
of investigator-confirmed angioedema attacks per month (attack rate) between
week 1 (baseline) and week 17. Secondary end points included quality of life, as
measured with the Angioedema Quality of Life Questionnaire (scores range from 0
to 100, with higher scores indicating worse quality of life), and safety.
RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned
to receive donidalorsen and 6 to receive placebo. The mean monthly rate of
investigator-confirmed angioedema attacks was 0.23 (95% confidence interval
[CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58
to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to
-76; P<0.001). The mean change from baseline to week 17 in the Angioedema
Quality of Life Questionnaire score was -26.8 points in the donidalorsen group
and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI,
-32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among
patients receiving donidalorsen and 83% among those receiving placebo.
CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment
resulted in a significantly lower rate of angioedema attacks than placebo in
this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2
ClinicalTrials.gov number, NCT04030598.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2109329
PMID: 35294812 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16036421 | 1. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Mar;6(1):8-16. doi:
10.1080/14660820410021267.
Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral
sclerosis: discrete entities or spectrum?
Strong MJ(1), Gordon PH.
Author information:
(1)Department of Clinical Neurological Sciences, the University of Western
Ontario, the Cell Biology Research Group, Roberts Research Institute, London,
Ontario, Canada. [email protected]
Among the motor neuron diseases, three share the clinical features of prominent
upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral
sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic
testing can assist in the identification of several variants of the latter, in
the remaining cases, including those in which spasticity may be associated with
amyotrophy, clinical differentiation of the three disorders may prove difficult.
In this paper we review the evidence that these are distinct disorders and
conclude that, for ALS and PLS particularly, there may be justification in
considering them as single points along a continuum of multisystem disorders
with conspicuous motor neuron involvement. Only through the development and
application of exacting clinical diagnostic criteria to epidemiological studies,
along with greater numbers of post-mortem examinations, however, will these
questions be answered fully.
DOI: 10.1080/14660820410021267
PMID: 16036421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36172291 | 1. Front Allergy. 2022 Sep 12;3:952233. doi: 10.3389/falgy.2022.952233.
eCollection 2022.
Treatment of hereditary angioedema-single or multiple pathways to the rescue.
Valerieva A(1), Longhurst HJ(2).
Author information:
(1)Department of Allergology, Medical University of Sofia, Sofia, Bulgaria.
(2)Department of Immunology, Auckland District Health Board, and Department of
Medicine, University of Auckland, Auckland, New Zealand.
Hereditary angioedema (HAE) is a rare disease caused by mutations in the
SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor
(C1-INH) and affects multiple proteases involved in the complement,
contact-system, coagulation, and fibrinolytic pathways. Current options for the
treatment and prevention of HAE attacks include treating all affected pathways
via direct C1-INH replacement therapy; or specifically targeting components of
the contact activation system, in particular by blocking the bradykinin B2
receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin
generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and
recombinant human C1-INH have demonstrated efficacy and safety for treatment of
HAE attacks, although time to onset of symptom relief varied among trials,
specific agents, and dosing regimens. Data from retrospective and observational
analyses support that short-term prophylaxis with intravenous C1-INH products
can help prevent HAE attacks in patients undergoing medical or dental
procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH
significantly decreased the HAE attack rate vs. placebo, although breakthrough
attacks were observed. Pathway-specific therapies for the management of HAE
include the B2R antagonist icatibant and plasma kallikrein inhibitors
ecallantide, lanadelumab, and berotralstat. Icatibant, administered for
treatment of angioedema attacks, reduced B2R-mediated vascular permeability and,
compared with placebo, reduced the time to initial symptom improvement. Plasma
kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein
to prevent cleavage of high molecular weight kininogen and subsequent bradykinin
generation. Ecallantide was shown to be efficacious for HAE attacks and is
licensed for this indication in the United States, but the labeling recommends
that only health care providers administer treatment because of the risk of
anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein
inhibitors lanadelumab and berotralstat are recommended as first-line options
for long-term prophylaxis and have demonstrated marked reductions in HAE attack
rates. Investigational therapies, including the activated factor XII inhibitor
garadacimab and an antisense oligonucleotide targeting plasma prekallikrein
messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given
the requirement of lifelong management for HAE, further research is needed to
determine how best to individualize optimal treatments for each patient.
© 2022 Valerieva and Longhurst.
DOI: 10.3389/falgy.2022.952233
PMCID: PMC9510393
PMID: 36172291
Conflict of interest statement: AV has received consultancy/speaker
honoraria/meeting sponsorship from, or collaborated in research with, Pharming
Group NV, Takeda/Shire, Sobi, CSL Behring, and Pharvaris. HJL has consulted for,
acted as speaker for, or collaborated in research with the following: Adverum,
BioCryst, CSL Behring, GSK, Intellia, Ionis, KalVista, Pharming, Pharvaris, and
Takeda. |
http://www.ncbi.nlm.nih.gov/pubmed/33374658 | 1. Brain Sci. 2020 Dec 23;11(1):8. doi: 10.3390/brainsci11010008.
Cognitive Performance of Patients with Adult 5q-Spinal Muscular Atrophy and with
Amyotrophic Lateral Sclerosis.
Osmanovic A(1), Wieselmann G(1), Mix L(2), Siegler HA(1), Kumpe M(1), Ranxha
G(1), Wurster CD(3), Steinke A(1), Ludolph AC(2)(4), Kopp B(1), Lulé D(2), Petri
S(1), Schreiber-Katz O(1).
Author information:
(1)Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
(2)Department of Neurology, Neuropsychology, University of Ulm, 89081 Ulm,
Germany.
(3)Department of Neurology, University of Ulm, 89081 Ulm, Germany.
(4)Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 89081 Ulm,
Germany.
Motor neuron diseases, such as spinal muscular atrophy (SMA) and amyotrophic
lateral sclerosis (ALS), share several clinical similarities while differing
substantially in etiology, disease onset and progression. Cognitive dysfunction,
a clinically relevant non-motor feature in a substantial proportion of ALS
patients, has been less frequently investigated in SMA. In this prospective
multicenter cross-sectional study, cognitive function was assessed by the
Edinburgh Cognitive (and Behavioural) ALS Screen (ECAS) and a German vocabulary
test (Wortschatztest, WST) in 34 adult patients with SMA types 2-4 and in 34
patients with ALS. Demographic and clinical parameters were assessed to identify
factors that potentially influence cognitive function. While SMA and ALS
patients were comparable in the vocabulary test, on average, SMA patients
performed better than ALS patients in the cognitive domains of memory, language
and executive function. Better cognitive abilities in SMA patients seemed to be
related to the early onset, rather than the extent or the duration, of their
physical handicap. Future studies should focus on disease-specific cognitive
functions in SMA.
DOI: 10.3390/brainsci11010008
PMCID: PMC7822456
PMID: 33374658
Conflict of interest statement: A.O. received honoraria as a speaker/consultant
from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke
“(DGM e.V.), Biogen GmbH and Impulze GmBH. G.W. reports no conflicts of
interest. L.M. reports no conflicts of interest. H.A.S. reports no conflicts of
interest. M.K. and G.R. received travel cost compensations from Biogen GmbH.
C.D.W. received honoraria from Biogen as an Advisory board member and for
lectures and from Hoffmann-La Roche as a consultant and Advisory board member.
She also received travel expenses from Biogen. A.S. reports no conflicts of
interest. A.C.L. received honoraria as a speaker/consultant from Biogen GmbH,
Roche Pharma AG, Biogen Brasil Produtos Farmacêuticos Ltd.a., Biologicx. B.K.
reports no conflicts of interest. D.L. reports no conflict of interest. S.P.
received honoraria as speaker/consultant from Biogen GmbH, Roche, Novartis,
Teva, Cytokinetics Inc., Desitin, and grants from DGM e.V, Federal Ministry of
Education and Research, German Israeli Foundation for Scientific Research and
Development, EU Joint Programme for Neurodegenerative Disease Research. O.S.K.
received honoraria as a speaker/consultant and/or funding for travel expenses
from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke
(DGM e.V.), Novartis, Biogen GmbH, Biermann Verlag GmbH and the Jain Foundation.
She received research support from the German Neuromuscular Society “Deutsche
Gesellschaft fuer Muskelkranke (DGM e.V.), 2019–2020. |
http://www.ncbi.nlm.nih.gov/pubmed/33991255 | 1. Pediatr Nephrol. 2022 Feb;37(2):315-328. doi: 10.1007/s00467-021-05093-w. Epub
2021 May 15.
Role of therapeutic apheresis in the treatment of pediatric kidney diseases.
Shah S(1), Joseph C(2), Srivaths P(2).
Author information:
(1)Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
[email protected].
(2)Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Therapeutic apheresis utilizes apheresis procedures in the treatment of a
variety of conditions including kidney disease. Therapeutic plasma exchange
(TPE) is the most common modality employed with the rationale of rapid reduction
of a pathogenic substance distributed primarily in the intravascular
compartment; however other techniques which adsorb such pathogenic substances or
alter the immune profile have been utilized in diseases affecting native and
transplanted kidneys. This article discusses the modalities and technical
details of therapeutic apheresis and summarizes its role in individual diseases
affecting the kidney. Complications related to pediatric apheresis procedures
and specifically related to apheresis in kidney disease are also discussed.
Though therapeutic apheresis modalities are employed frequently in children with
kidney disease, most experiences are extrapolated from adult studies.
International and national registries need to be established to elucidate the
role of apheresis modalities in children with kidney disease.
© 2021. IPNA.
DOI: 10.1007/s00467-021-05093-w
PMID: 33991255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35551087 | 1. BMJ Open. 2022 May 12;12(5):e050112. doi: 10.1136/bmjopen-2021-050112.
Rescuing Cancer Immunity by Plasma Exchange in Metastatic Melanoma (ReCIPE-M1):
protocol for a single-institution, open-label safety trial of plasma exchange to
clear sPD-L1 for immunotherapy.
Davidson TM(1), Foster N(2), Lucien F(3), Markovic S(4), Dong H(3), Winters
JL(5), Park SS(#)(6), Orme JJ(#)(7).
Author information:
(1)Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
(2)Department of Quantitative Health Sciences, Mayo Clinic, Rochester,
Minnesota, USA.
(3)Department of Urology, Mayo Clinic, Rochester, Minnesota, USA.
(4)Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
(5)Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester,
Minnesota, USA.
(6)Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
(7)Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
[email protected].
(#)Contributed equally
BACKGROUND: Patients with metastatic melanoma rely on PD-(L)1 immunotherapy, but
only one-third of patients experience treatment response and all initial
responders eventually develop resistance. Tumour-derived extracellular vesicles
expressing Programmed death ligand 1 (evPD-L1) and soluble Programmed death
ligand 1 (sPD-L1) in peripheral blood of patients with melanoma limit PD-(L)1
immunotherapy and correlate with poor survival. Therapeutic plasma exchange
(TPE) removes immunosuppressive evPD-L1 and sPD-L1. We hypothesise that TPE may
rescue and restore antimelanoma immunity.
METHODS: In this two-arm study, 60 patients with metastatic melanoma progressing
on checkpoint inhibition will be accrued. All patients will undergo radiotherapy
on days 1-5 (at least one measurable lesion will not be irradiated) and ongoing
checkpoint inhibition on day 8 and every 2-3 weeks per standard of care.
Patients with baseline sPD-L1 level of ≥1.7 ng/mL and adequate clinical capacity
will be enrolled in the TPE intervention arm and will undergo TPE on days 5-7,
in addition to standard of care radiotherapy and immunotherapy. Other patients
will remain in the standard of care arm.The primary endpoint of the study is to
evaluate safety. Secondary endpoints include kinetics of sPD-L1 and evPD-L1 and
clinical response by RECIST (Response Evaluation Criteria in Solid Tumors)
criteria. Study registered at ClinicalTrials.gov (NCT04581382).
ETHICS AND DISSEMINATION: This trial has been approved by the Mayo Clinic
Institutional Review Board. It will assess the safety and feasibility of TPE in
improving outcomes for PD-(L)1 inhibitor immunotherapy in melanoma. Data will be
maintained on a secure database with deidentified patient information. Data will
be shared on publication in a peer-reviewed journal without the aid of
professional writers. If successful, this trial will lay the ground for phase II
studies that will include cancer treated with PD-(L)1 inhibitors which may
benefit from TPE such as renal, bladder and lung cancers.
TRIAL REGISTRATION NUMBER: NCT04581382.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published
by BMJ.
DOI: 10.1136/bmjopen-2021-050112
PMCID: PMC9109028
PMID: 35551087 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35547461 | 1. Cureus. 2022 Apr 8;14(4):e23964. doi: 10.7759/cureus.23964. eCollection 2022
Apr.
Fulminant Hepatic Failure in Dengue Fever Without Plasma Leakage: A Case Report.
Arunpriyandan V(1), Sundaresan KT(2).
Author information:
(1)General Medicine, University Medical Unit, Teaching Hospital Batticaloa,
Batticaloa, LKA.
(2)Clinical Medicine, University Medical Unit, Teaching Hospital Batticaloa,
Batticaloa, LKA.
Dengue is an important arboviral disease in the tropics and subtropics. Although
mild to moderate elevation of liver transaminases is a common phenomenon, dengue
infection leading to hepatic failure is a rare complication in adults. We
present a case of dengue fever in a young adult, leading to the rare
complication of acute liver failure, without dengue shock syndrome. We tried
evidence-based management with therapeutic plasma exchange, which led to a
significant improvement in liver function.
Copyright © 2022, Arunpriyandan et al.
DOI: 10.7759/cureus.23964
PMCID: PMC9090125
PMID: 35547461
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/35551628 | 1. Crit Care. 2022 May 12;26(1):134. doi: 10.1186/s13054-022-04003-2.
Clinical and biochemical endpoints and predictors of response to plasma exchange
in septic shock: results from a randomized controlled trial.
Stahl K(#)(1), Wand P(#)(2), Seeliger B(3), Wendel-Garcia PD(4), Schmidt JJ(2),
Schmidt BMW(2), Sauer A(5), Lehmann F(5), Budde U(6), Busch M(1), Wiesner O(3),
Welte T(3), Haller H(2), Wedemeyer H(1), Putensen C(5), Hoeper MM(3), Bode
C(#)(5), David S(#)(7)(8).
Author information:
(1)Department of Gastroenterology, Hepatology and Endocrinology, Hannover
Medical School, Hannover, Germany.
(2)Department of Nephrology and Hypertension, Hannover Medical School, Hannover,
Germany.
(3)Department of Respiratory Medicine and German Centre of Lung Research (DZL),
Hannover Medical School, Hannover, Germany.
(4)Institute of Intensive Care Medicine, University Hospital Zurich, Zurich,
Switzerland.
(5)Department of Anesthesiology and Intensive Care Medicine, University Hospital
Bonn, Bonn, Germany.
(6)Medilys Laborgesellschaft mbH, Hamburg, Germany.
(7)Department of Nephrology and Hypertension, Hannover Medical School, Hannover,
Germany. [email protected].
(8)Institute of Intensive Care Medicine, University Hospital Zurich, Zurich,
Switzerland. [email protected].
(#)Contributed equally
BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but
individually variable hemodynamic improvement with therapeutic plasma exchange
(TPE) in patients with septic shock. Prediction of clinical efficacy in specific
sepsis treatments is fundamental for individualized sepsis therapy.
METHODS: In the original RCT, patients with septic shock of < 24 h duration and
norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC)
or SOC + one single TPE. Here, we report all clinical and biological endpoints
of this study. Multivariate mixed-effects modeling of NE reduction was performed
to investigate characteristics that could be associated with clinical response
to TPE.
RESULTS: A continuous effect of TPE on the reduction in NE doses over the
initial 24 h was observed (SOC group: estimated NE dose reduction of
0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004).
Similarly, under TPE, serum lactate levels, continuously decreased over the
initial 24 h in the TPE group, whereas lactate levels increased under SOC
(p = 0.001). A reduction in biomarkers and disease mediators (such as PCT
(p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along
with a repletion of exhausted protective factors (such as AT-III (p = 0.026),
Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but
not in the SOC group. In a multivariate mixed effects model, increasing baseline
lactate levels led to greater NE dose reduction effects with TPE as opposed to
SOC (p = 0.004).
CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious
mediators and repletion of consumed protective factors altogether leading to
preserved hemodynamic stabilization in refractory septic shock. We identified
that baseline lactate concentration as a potential response predictor might
guide future designing of large RCTs that will further evaluate TPE with regard
to hard endpoints. Trial registration Retrospectively registered 18th January
2020 at clinicaltrials.gov (Identifier: NCT04231994 ).
© 2022. The Author(s).
DOI: 10.1186/s13054-022-04003-2
PMCID: PMC9097091
PMID: 35551628 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35689538 | 1. J Clin Lab Anal. 2022 Jul;36(7):e24547. doi: 10.1002/jcla.24547. Epub 2022 Jun
11.
Prognostic value of dynamic cardiac biomarkers in patients with acquired
refractory thrombocytopenic purpura: A retrospective study in Chinese
population.
Xu Y(1)(2), Gu C(1), Wang R(1), Qi J(1), Wang J(3), Jiang T(2), Jiang M(4), Wu
D(1), You T(1), Fu J(1).
Author information:
(1)Hematological Intensive Care Unit，Department of Hematology, The First
Affiliated Hospital of Soochow University, Suzhou, China.
(2)Department of Cardiology, The First Affiliated Hospital of Soochow
University, Suzhou, China.
(3)Department of Intensive Care Medicine, The First Affiliated Hospital of
Soochow University, Suzhou, China.
(4)Department of Blood Transfusion, The First Affiliated Hospital of Soochow
University, Suzhou, China.
INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is becoming a curable
disease with the introduction of therapeutic plasma exchange (TPE). However,
cardiovascular complications remain essential causes of mortality in patients
with refractory TTP, while the association of cardiac biomarkers with the
prognosis of TTP warrants further investigation.
METHODS: Patients admitted to the First Affiliated Hospital of Soochow
University for refractory TTP from 2013 through 2020 were included in this
retrospective study. Clinical characteristics were collected from electronic
health records. Biomarker levels on admission and post TPE were recorded.
Logistic regression was adopted to identify risk factors for mortality.
RESULTS: A total of 78 patients with refractory TTP were included in this study.
Twenty-one patients died during hospitalization, with a mortality rate of 26.9%.
High-sensitivity cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic
peptide (NT-proBNP), and aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ratios (AAR) were increased in deceased patients compared
with the survival group. Multivariate analysis showed that AAR after TPE was
associated with overall mortality (OR: 4.45, 95% CI 1.09-18.19). The areas under
the receiver operator characteristic curve (AUC) of AAR, hs-cTnT, and NT-proBNP
for the association with mortality were 0.814, 0.840, and 0.829, respectively.
CONCLUSION: Higher post-TPE cardiac biomarker levels are associated with
increased in-hospital mortality in patients with refractory TTP.
© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley
Periodicals LLC.
DOI: 10.1002/jcla.24547
PMCID: PMC9280007
PMID: 35689538 [Indexed for MEDLINE]
Conflict of interest statement: All authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35585996 | 1. Int J Gen Med. 2022 May 12;15:4907-4916. doi: 10.2147/IJGM.S362151.
eCollection 2022.
Role of Therapeutic Plasmapheresis in SARS-CoV-2 Induced Cytokine Release
Syndrome: A Retrospective Cohort Study on COVID-19 Patients.
Jamil Z(1), Khan AA(2), Yousuf H(3), Khalid K(4), Abbasi SM(5), Waheed Y(4).
Author information:
(1)Department of Medicine, Foundation University Medical College, Foundation
University Islamabad, Islamabad, 44000, Pakistan.
(2)Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical
Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi
Arabia.
(3)Department of Medicine, Betsi Cadwaladr University Health Board, Wrexham,
North Wales, UK.
(4)Clinical and Biomedical Research Center, Foundation University Medical
College, Foundation University Islamabad, Islamabad, 44000, Pakistan.
(5)Department of Medicine, Fauji Foundation Hospital, Rawalpindi, 46000,
Pakistan.
BACKGROUND: Cytokine release syndrome (CRS) significantly contributes to the
pathophysiology and progression of COVID-19. It is speculated that therapeutic
plasma exchange (TPE) can dampen CRS via elimination of pathogenic cytokines.
OBJECTIVES: The study is intended to compare the outcomes of COVID-19 patients
with CRS treated with TPE and standard care (SC) to their counterparts receiving
SC alone.
METHODOLOGY: A retrospective cohort study of severe COVID-19 confirmed patients
presenting with CRS and admitted to the medical ICU was conducted between March
and August 2021. Using case-control (CC) matching 1:1, 162 patients were
selected and divided into two equal groups. The primary outcome was 28-day
in-hospital survival analysis in severe COVID-19 patients with CRS. However,
secondary outcomes included the effect of plasmapheresis on inflammatory
markers, the need for mechanical ventilation, the rate of extubation, and the
duration of survival.
RESULTS: After CC matching, the study cohort had a mean age of 55.41 (range
56.41±11.56 in TP+SC and 54.42±8.94 in SC alone; p=0.22). There were 25.95%
males and 74.05% females in both groups. The mean time from first day of illness
to hospitalization was 6.53±2.18 days. The majority of patients with CRS had
comorbid conditions (75.9%). Diabetes mellitus was the most common comorbidity
(40.1%), followed by hypertension (25.3%), and chronic kidney disease (21%).
Notable reduction in some inflammatory markers (D-dimers, LDH, CRP and serum
ferritin) (p<0.0001) was observed in the group that received TPE+SC. Moreover,
the patients in the plasmapheresis plus standard care group required relatively
less mechanical ventilation as compared to the group receiving SC alone (46.9%
vs 58.1%, respectively; p>0.05). The rate of extubation in the TP+SC group vs SC
alone was 60.5% vs 44.7%, respectively (p>0.05). Similarly, the mortality
percentages in both groups were 19.8% and 24.7%, respectively.
CONCLUSION: For this particular group of matched patients with COVID-19-induced
CRS, TPE+SC was linked with relatively better overall survival, early
extubation, and earlier discharge compared to SC alone. As these results were
not statistically significant, multi-centered randomized control trials are
needed to further elaborate the role of therapeutic plasmapheresis in COVID-19
induced CRS.
© 2022 Jamil et al.
DOI: 10.2147/IJGM.S362151
PMCID: PMC9109892
PMID: 35585996
Conflict of interest statement: The authors report no conflicts of interest in
this work. |
http://www.ncbi.nlm.nih.gov/pubmed/34690074 | 1. Transfus Apher Sci. 2022 Feb;61(1):103289. doi: 10.1016/j.transci.2021.103289.
Epub 2021 Oct 9.
Successful therapeutic plasma exchange in a case with extremely severe
hypertriglyceridemia secondary to diabetic ketoacidosis concomitant with type IX
glycogen storage disease.
Kisioglu M(1), Yesilbas O(2), Guven B(3), Ceylaner S(4), Karaguzel G(5).
Author information:
(1)Department of Pediatrics, Karadeniz Technical University, Faculty of
Medicine, Trabzon, Turkey. Electronic address: [email protected].
(2)Department of Pediatric Critical Care Medicine, Karadeniz Technical
University, Faculty of Medicine, Trabzon, Turkey.
(3)Department of Pediatric Gastroenterology, Karadeniz Technical University,
Faculty of Medicine, Trabzon, Turkey.
(4)INTERGEN Genetic and Rare Diseases Diagnosis Research and Application Center,
Ankara, Turkey.
(5)Department of Pediatric Endocrinology, Karadeniz Technical University,
Faculty of Medicine, Trabzon, Turkey.
Herein, we aimed to present a child with extremely severe hypertriglyceridemia
(ESHTG) secondary to diabetic ketoacidosis concomitant with type IX glycogen
storage disease (GSD). Extremely severe hypertriglyceridemia (10 700 mg/dL) was
detected through the apparent lipemic appearance of the sampled blood in a
17-year-old male patient with severe diabetic ketoacidosis. In spite of insulin
infusion, the patient's clinical condition deteriorated to acute pancreatitis.
Single sessions of therapeutic plasma exchange (TPE) along with insulin
treatment have successfully intercepted the progression of the state of acute
pancreatitis. The patient was also diagnosed with type IX GSD on the basis of
the genetic analyses performed for the potential underlying metabolic diseases.
In conclusion, underlying metabolic diseases, such as glycogen storage disease,
should be investigated in patients with diabetic ketoacidosis accompanied by
severe hypertriglyceridemia. If ESHTG does not relieve despite insulin infusion,
and/or acute pancreatitis occurs as a complication, TPE should be kept in mind.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.transci.2021.103289
PMID: 34690074 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35963982 | 1. J Endocrinol Invest. 2023 Jan;46(1):173-179. doi: 10.1007/s40618-022-01897-1.
Epub 2022 Aug 13.
Therapeutic plasma exchange in hyperthyroidism prior to surgery.
Kirkizlar HO(1), Celik M(2).
Author information:
(1)Department of Hematology, Trakya University Medical Faculty, Edirne, Turkey.
[email protected].
(2)Department of Endocrinology, Trakya University Medical Faculty, Edirne,
Turkey.
PURPOSE: Therapeutic plasma exchange (TPE) is a treatment option to reduce
thyroid hormones in the event of contraindication or unresponsiveness to
antithyroid drugs (ATDs).
METHODS: We analyzed 11 patients with hyperthyroidism who received TPE prior to
surgery between January 2008 and December 2016 at our center.
RESULTS: In total, 41 processes were applied to 11 patients with
hyperthyroidism. The median age was 40 years, and 90.9% of the patients were
female. Seven patients had Graves' disease, while four had a toxic multinodular
goiter. The distribution of TPE indications comprised contraindication to ATDs
(64%) and insufficient response to ATDs (36%). An adequate response was not
obtained with TPE in two patients, and cholestyramine plus methimazole and Lugol
solution were applied. The median number of TPE sessions was 3. During the TPE
period, a β-blocker was applied concurrently except in one patient who was
contraindicated for the drug. The reduction in FT3 and FT4 hormones and the
increase in TSH levels were statistically significant after TPE application (p
values of 0.003, 0.033 and 0.008, respectively). Regarding adverse events of TPE
application, an allergic reaction was seen in one patient, while prolongation of
prothrombin time without any clinical findings was seen in another patient. Ten
patients underwent total thyroidectomy, and one patient underwent a
gynecological surgery procedure without any major complications.
CONCLUSION: The American Society for Apheresis guideline, which is the most
referenced guideline, mentions the utilization of TPE before thyroid surgery,
only in patients with thyrotoxicosis despite the wider necessity of this
treatment choice under the condition of uncontrolled hyperthyroidism prior to
any kind of surgery. We concluded that TPE is a reliable and effective
application in patients with hyperthyroidism before any surgical procedure,
according to our study results.
© 2022. The Author(s), under exclusive licence to Italian Society of
Endocrinology (SIE).
DOI: 10.1007/s40618-022-01897-1
PMID: 35963982 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35353437 | 1. Ther Apher Dial. 2022 Dec;26(6):1274-1280. doi: 10.1111/1744-9987.13844. Epub
2022 Apr 7.
Therapeutic plasma exchange for optic neuritis attacks in patients with
neuromyelitis optica spectrum disorders.
Gonzalez C(1)(2), Vargas D(1)(2), Contreras K(1), Garcia P(1)(3), Rodriguez
P(1)(3), Zarco L(1)(3), Navas C(2).
Author information:
(1)Department of Internal Medicine, Nephrology Unit, Neurology Unit, Hospital
Universitario San Ignacio, Bogota, Colombia.
(2)Nephrology, Neurology, Clínica Universitaria Colombia, Bogota, Colombia.
(3)Faculty of medicine, Pontificia Universidad Javeriana, Bogota, Colombia.
BACKGROUND: Optic neuritis (ON) causes several sequela. Aggressive treatment
with plasma exchange (TPE) is an option. This study describes improvement and
safety outcomes with TPE.
METHODS: We recruited adults with ON in neuromyelitis optica spectrum disorders
(NMOSD) patients treated with TPE. The primary outcome was an improvement in the
visual acuity scale (VOS). We described the data and used multivariate logistic
regression to identify factors associated with response.
RESULTS: Eighty-three patients received 558 TPE sessions. Mean age was
40.9 years (±13.7 years); 73.5% were women, 50.1% were first attack, and 10.7%
were bilateral. Median VOS: 5 (range [R], 2-7). Median time between onset and
TPE was 8 days (R, 1-32). By Keegan's criteria, 82.4% experience improvement and
78.3% improve in at least 1 point in VOS. Age and pre-TPE VOS were related to
improvement. Low fibrinogen occurs in 26% sessions.
CONCLUSION: TPE is effective and safety for ON in NMOSD patients. There is a
need for a clinical trial using a therapeutic equivalent.
© 2022 International Society for Apheresis and Japanese Society for Apheresis.
DOI: 10.1111/1744-9987.13844
PMID: 35353437 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35955999 | 1. J Clin Med. 2022 Jul 28;11(15):4383. doi: 10.3390/jcm11154383.
Total Plasma Exchange in Neuromuscular Junction Disorders-A Single-Center,
Retrospective Analysis of the Efficacy, Safety and Potential Diagnostic
Properties in Doubtful Diagnosis.
Totzeck A(1), Jahn M(2), Stolte B(1), Thimm A(1), Kleinschnitz C(1), Hagenacker
T(1).
Author information:
(1)Department of Neurology and Center for Translational Neuro- and Behavioral
Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen,
45147 Essen, Germany.
(2)Department of Nephrology, University Hospital Essen, University of
Duisburg-Essen, 45147 Essen, Germany.
Neuromuscular junction disorders (NJDs) are a heterogeneous group of diseases
including myasthenia gravis (MG). In some cases, patients are present with
myasthenic symptoms without evidence of autoimmune antibodies, making diagnosis
challenging. Total plasma exchange (TPE) has proven efficacy in NJDs. The
objective is to describe the safety and efficacy of TPE in NJD patients with
questionable disease activity or uncertain diagnosis in order to assess the
diagnostic potential of TPE. We report an observational, retrospective cohort
study of clinical routine data. All the data were derived from the electronic
medical records of the Department of Neurology at University Hospital Essen. We
searched for patients with NJDs between 1 July 2018 and 30 June 2021. Of the 303
patients who presented to the department with NJDs, 20 were treated with TPE; 9
patients did not show a measurable benefit from TPE (45%), 6 of whom were
diagnosed with seronegative MG. Of these, 3 (50%) had long-standing ocular
symptoms. There were decreases in the mean arterial pressure, hemoglobin,
hematocrit and fibrinogen during treatment, which were not considered clinically
relevant. In (seronegative) myasthenic patients, TPE may help to verify an
uncertain diagnosis or to reveal possible muscle damage, allowing unnecessary
therapy to be avoided.
DOI: 10.3390/jcm11154383
PMCID: PMC9369332
PMID: 35955999
Conflict of interest statement: A.T. and T.H. are members of the medical
advisory board of the German Myasthenia Society; A.T. received consultation
honoraria from Argenx. M.J., B.S. and A.TH. declare no conflicts of interest.
C.K. received speaker’s and or consultation honoraria from Alexion
Pharmaceuticals and Biogen; T.H. received speaker’s and or consultation
honoraria from Alexion Pharmaceuticals, Argenx, Novartis, Hormosan Pharma,
Biogen, Roche and Sanofi-Genzyme. |
http://www.ncbi.nlm.nih.gov/pubmed/17224307 | 1. Transfus Apher Sci. 2007 Feb;36(1):103-7. doi: 10.1016/j.transci.2006.06.008.
Epub 2007 Jan 16.
Therapeutic plasma exchange in the treatment of neuroimmunologic disorders:
review of 50 cases.
Yücesan C(1), Arslan O, Arat M, Yücemen N, Ayyildiz E, Ilhan O, Mutluer N.
Author information:
(1)Ankara University Faculty of Medicine, Ibni Sina Hospital, Department of
Neurology, Sihhiye, 06100 Ankara, Turkey.
Therapeutic plasma exchange (TPE) has been used for the treatment of neurologic
diseases in which autoimmunity plays a major role. We reviewed the medical
records of our patients who had consecutively been treated by TPE between
January 1998 and June 2000. Neurological indications included myasthenia gravis
(30 patients), multiple sclerosis attack (6 patients with remitting-relapsing
course and 3 patients with secondary progressive course), Guillain-Barrè
syndrome (6 patients), paraproteinemic neuropathy (2 patients), and chronic
inflammatory demyelinating neuropathy (CIDP), transverse myelitis due to
systemic lupus erythematosus, acute disseminated encephalomyelitis in one
patient each. Continuous flow cell separators were used for TPE. TPE was
generally given every other day for all of the patients and one plasma volume
was exchanged for each cycle. Although the patients with secondary progressive
multiple sclerosis (3 patients) and paraproteinemic neuropathy (2 patients) did
not show any improvement after TPE, other patients' targeted neurological
deficits were improved by TPE. During the TPE procedures, no patient had any
morbidity or mortality, and the complications were mild and manageable such as
hypotension, hypocalcemia and mild anemia; three patients had septicemia due to
the venous catheter used for TPE. TPE is an effective treatment in neurologic
diseases in which autoimmunity plays an important role in pathogenesis, and it
is safe when performed in experienced centers.
DOI: 10.1016/j.transci.2006.06.008
PMID: 17224307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32802495 | 1. Autoimmune Dis. 2020 Jul 31;2020:3484659. doi: 10.1155/2020/3484659.
eCollection 2020.
Therapeutic Plasma Exchange as a Treatment for Autoimmune Neurological Disease.
Nieto-Aristizábal I(1), Vivas ÁJ(1)(2), Ruiz-Montaño P(1)(2), Aragón CC(1),
Posso-Osorio I(1), Quiñones J(3)(4), Rivillas JA(2)(3), Tobón GJ(1).
Author information:
(1)GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina
Traslacional, Universidad Icesi and Fundación Valle del Lili, Cra. 98 18-49,
Cali, Colombia.
(2)Medical School, Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia.
(3)Department of Neurology, Fundación Valle del Lili, Cra. 98 18-49, Cali,
Colombia.
(4)Unit of Neuroimmunology, Fundación Valle del Lili, Cra. 98 18-49, Cali,
Colombia.
INTRODUCTION: Therapeutic plasma exchange (TPE) is commonly used as treatment of
certain autoimmune neurological diseases (ANDs), and its main objective is the
removal of pathogenic autoantibodies. Our aim was to describe the clinical
profile and the experience with the usage of TPE in patients with ANDs at our
institution.
METHODS: This is an observational retrospective study, including medical records
of patients with diagnosis of ANDs who received TPE, between 2011 and 2018.
Characteristics of TPE, such as number of cycles, type of replacement solution,
and adverse effects, were evaluated. The modified Rankin Scale (mRS) was applied
to measure the clinical response after the therapy.
RESULTS: 187 patients were included with the following diagnoses: myasthenia
gravis (MG), n = 70 (37%); Guillain-Barré syndrome (GBS), n = 53 (28.3%),
neuromyelitis optica spectrum disorders (NMOSD), n = 35 (18.7%); chronic
inflammatory demyelinating polyneuropathy (CIDP), n = 23 (12.2%); and autoimmune
encephalitis (AE), n = 6 (3.2%). The most used types of replacement solution
were albumin (n = 131, 70%) and succinylated gelatin (n = 45, 24%). All patients
received a median of five cycles (IQR 5-5). Hypotension and hydroelectrolytic
disorders were the main complications. After TPE, 99 patients (52.9%) showed
improvement in the mRS scores and a statistical significance (p < 0.05) was seen
between the admission score and after TPE for every diagnosis except for CIDP.
CONCLUSION: TPE has an adequate safety profile, and improvement in functionality
in treated patients reflects its effectiveness.
Copyright © 2020 Ivana Nieto-Aristizábal et al.
DOI: 10.1155/2020/3484659
PMCID: PMC7415086
PMID: 32802495
Conflict of interest statement: The authors declare that they have no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34904748 | 1. J Clin Apher. 2022 Feb;37(1):70-81. doi: 10.1002/jca.21953. Epub 2021 Dec 14.
Immunoadsorption and plasma exchange-Efficient treatment options for
neurological autoimmune diseases.
Boedecker SC(1), Luessi F(2), Engel S(2), Kraus D(1), Klimpke P(1), Holtz S(1),
Meinek M(1), Marczynski P(1), Weinmann A(1), Weinmann-Menke J(1).
Author information:
(1)Department of Nephrology, University Medical Centre Mainz of the Johannes
Gutenberg University Mainz, Mainz, Germany.
(2)Department of Neurology, University Medical Centre Mainz of the Johannes
Gutenberg University Mainz, Mainz, Germany.
BACKGROUND: Therapeutic plasma exchange (TPE) and immunoadsorption (IA) are
first or second line treatment options in patients with neurological autoimmune
diseases, including multiple sclerosis, neuromyelitis optica spectrum disorders
(NMSOD), chronic inflammatory demyelinating polyneuropathy, acute inflammatory
demyelinating polyradiculoneuropathy (Guillain-Barré syndrome), and autoimmune
encephalitis.
METHODS: In this prospective randomized controlled monocentric study, we
assessed safety and efficacy of therapy with IA or TPE in patients with
neurological autoimmune diseases. Treatment response was assessed using various
neurological scores as well by measuring immunoglobulin and cytokine
concentrations. Clinical outcome was evaluated by application of specific scores
for the underlying diseases.
RESULTS: A total of 32 patients were analyzed. Among these, 19 patients were
treated with TPE and 13 patients with IA. IA and TPE therapy showed a comparable
significant treatment response. In patients with MS and NMOSD, mean EDSS before
and after treatment showed a significant reduction after treatment with IA. We
observed a significant reduction of the pro-inflammatory cytokines IL-12, lL-17,
IL-6, INF-γ, and tumor necrosis factor alpha during IA treatment, whereas this
reduction was not seen in patients treated with TPE.
CONCLUSIONS: In summary, both IA and TPE were effective and safe procedures for
treating neurological autoimmune diseases. However, there was a trend towards
longer therapy response in patients treated with IA compared to TPE, possibly
related to a reduction in plasma levels of pro-inflammatory cytokines seen only
in the IA-treated group.
© 2021 The Authors. Journal of Clinical Apheresis published by Wiley Periodicals
LLC.
DOI: 10.1002/jca.21953
PMID: 34904748 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29882008 | 1. Acta Neurol Belg. 2018 Sep;118(3):451-458. doi: 10.1007/s13760-018-0961-5.
Epub 2018 Jun 7.
Overview of therapeutic plasma exchange in pediatric neurology: a single-center
experience.
Özkale M(1), Erol I(2), Özkale Y(3), Kozanoğlu İ(4).
Author information:
(1)Department of Pediatrics, Baskent University Faculty of Medicine, Adana Dr
Turgut Noyan Teaching and Medical Research Center, Baraj Yolu 1 Durak, Seyhan,
01120, Adana, Turkey.
(2)Department of Pediatric Neurology, Baskent University Faculty of Medicine, Dr
Turgut Noyan Teaching and Medical Research Center, Adana, Turkey.
(3)Department of Pediatrics, Baskent University Faculty of Medicine, Adana Dr
Turgut Noyan Teaching and Medical Research Center, Baraj Yolu 1 Durak, Seyhan,
01120, Adana, Turkey. [email protected].
(4)Department of Physiology, Baskent University Faculty of Medicine, Dr Turgut
Noyan Teaching and Medical Research Center, Adult Bone Marrow Transplantation
Center, Apheresis Unit, Adana, Turkey.
Erratum in
Acta Neurol Belg. 2018 Sep;118(3):527. doi: 10.1007/s13760-018-0968-y.
Therapeutic plasma exchange (TPE) is used in the treatment of neurological,
hematological, renal and autoimmune diseases with known or suspected immune
pathogenesis. In comparison with neurological diseases of adults, knowledge
about the use of TPE in children is incomplete. We report our experience on TPE
in children with neurological diseases in a single institution and describe the
underlying etiology, clinical course, treatment and outcome. We retrospectively
evaluated 22 consecutive children (12 girls, 10 boys, aged 2-16 years) who
underwent TPE in the pediatric intensive care unit between January 2010 and
January 2017. There were 135 TPE procedures with median 6 TPE sessions per
patient. Fresh frozen plasma was used as a replacement fluid in all cases. Most
common indications were inflammatory polyneuropathy followed by acquired
demyelinating diseases of the central nervous system. Other indications were
autoimmune encephalitis and paraneoplastic limbic encephalitis. No mortality was
recorded during TPE. The complication rate was 2.2% and consisted of transient
events like hypotension and allergic reactions. Therapetic plasma exchange is
one of the safe methods of treatment for neuroimmunological disorders in
children, with Guillain-Barré syndrome as the most common indication.
DOI: 10.1007/s13760-018-0961-5
PMID: 29882008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23619327 | 1. Transfus Apher Sci. 2013 Jun;48(3):349-52. doi: 10.1016/j.transci.2013.04.015.
Epub 2013 Apr 22.
Therapeutic plasma exchange in patients with neurological diseases: multicenter
retrospective analysis.
Kaya E(1), Keklik M, Sencan M, Yilmaz M, Keskin A, Kiki I, Erkurt MA, Sivgin S,
Korkmaz S, Okan V, Doğu MH, Unal A, Cetin M, Altuntaş F, Ilhan O.
Author information:
(1)Inonu University Medical School, Department of Hematology and Aphaeresis
Unit, Malatya, Turkey. [email protected]
Therapeutic plasma exchange (TPE), is a procedure, changing pathologic
substances in the plasma of patients with replacement fluid. TPE has an
increasing list of indications in recent years such as neurological, connective
tissue, hematological, nephrological, endocrinological and metabolic disorders.
We report our multicenter data about therapeutic plasma exchange in patients
with neurological diseases. Six University Hospitals' aphaeresis units medical
records about neurologic diseases were reviewed retrospectively. Hundred and
fifteen patients and 771 TPE sessions from six aphaeresis units' were included
to this study. Of the 115 patients, 53 (46%) were men and 62 (54%) were women.
The median age was 50 (range: 5-85) years. Of these patients 58.3% were
Guillain-Barre syndrome (GBS), 17.4% were acute disseminated encephalomyelitis
(ADEM), 10.4% were chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP), 7% were multiple sclerosis, 6.1% were myasthenia gravis (MG) and 0.9%
were Wilson disease (WD). The median number of TPE sessions per patient was 5
(range 1-72). Human albumin was used as a replacement fluid in 66% and fresh
frozen plasma was used in 34% of cases. TPE was done through central venous
catheters in 66%, and peripheral venous access in 34% of patients. Some
complications were seen in patients (18.3%) during TPE sessions. These
complications were, complications related to catheter placement procedure
(8.7%), hypotension (3.5%), hypocalcaemia (3.5%) and allergic reactions (1.7%).
The complication ratios were 2.7% in total 771 TPE procedures. TPE procedure was
terminated in 6% of sessions depending on these complications. Overall responses
to TPE were noted in 89.5% of patients. In conclusion; Therapeutic plasma
exchange is an effective treatment option in several neurologic diseases.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.transci.2013.04.015
PMID: 23619327 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28194064 | 1. Indian J Hematol Blood Transfus. 2017 Mar;33(1):97-105. doi:
10.1007/s12288-016-0661-3. Epub 2016 Feb 22.
Therapeutic Plasma Exchange in Patients with Neurologic Disorders: Review of 63
Cases.
Tombak A(1), Uçar MA(1), Akdeniz A(1), Yilmaz A(2), Kaleagası H(2), Sungur
MA(3), Tiftik EN(1).
Author information:
(1)Department of Hematology, Mersin University Faculty of Medicine, Çiftlikköy
Kampüsü, Mersin, Turkey.
(2)Department of Neurology, Mersin University Faculty of Medicine, Mersin,
Turkey.
(3)Department of Biostatistics, Duzce University, Düzce, Turkey.
Therapeutic plasma exchange (TPE) is a procedure that reduces circulating
autoantibodies of the patients. TPE is commonly used in neurological disorders
where autoimmunity plays a major role. We report our experience with regard to
the indications, adverse events and outcomes of plasma exchange in neurological
disorders. Sixty-three patients were included to this retrospective study.
Median age was 48 years (range 1-85), there was a predominance of males.
Neurological indications included Guillain-Barrè syndrome (n = 22), myasthenia
gravis (n = 21), chronic inflammatory demyelinating polyneuropathy (n = 7),
polymyositis (n = 3), multifocal motor neuropathy (n = 2), acute disseminated
encephalomyelitis (n = 2), neuromyelitis optica (n = 2), multiple sclerosis
(n = 2), limbic encephalitis (n = 1) and transverse myelitis (n = 1). TPE was
frontline therapy in 57 % of the patients (n = 36). Total number of TPE sessions
was 517; median number of sessions per patient was 8 (range 1-66). TPE was done
through a central venous access in 97 % and through a peripheral venous access
in 3 % of the patients. Human albumin was used as replacement fluid in 49 %,
hydroxyethyl starch (HES) in 49 % and fresh frozen plasma in 2 % of the cases.
Adverse reactions were recorded in 60 % of the patients. Total ratio of
complications in 517 TPE procedures was 10.8 % and these were mild and
manageable such as allergic reactions and hypotension. Overall response rate was
81 %. Interestingly, complication and response rates were similar in both HES
and human albumin groups. We conclude that TPE is an effective treatment in
neurologic diseases in which autoimmunity plays an important role in the
pathogenesis and HES can be used instead of albumin as replacement fluid in
these disorders, since it is cost-effective, has similar efficacy and
complication rates.
DOI: 10.1007/s12288-016-0661-3
PMCID: PMC5280851
PMID: 28194064 |
http://www.ncbi.nlm.nih.gov/pubmed/18331814 | 1. Transfus Apher Sci. 2008 Apr;38(2):109-15. doi: 10.1016/j.transci.2007.11.002.
Epub 2008 Mar 10.
Therapeutic plasma exchange in patients with neurologic diseases: retrospective
multicenter study.
Kaynar L(1), Altuntas F, Aydogdu I, Turgut B, Kocyigit I, Hacioglu SK,
Ismailogullari S, Turgut N, Erkurt MA, Sari I, Oztekin M, Solmaz M, Eser B,
Ersoy AO, Unal A, Cetin M.
Author information:
(1)Erciyes Medical School, Department of Hematology and Apheresis Unit, 38039
Kayseri, Turkey.
Therapeutic plasma exchange (TPE) is commonly used in many neurological
disorders where an immune etiology was known or suspected. We report our
experience with TPE performed for neuroimmunologic disorders at four university
hospitals. The study was a retrospective review of the medical records of
neurological patients (n=57) consecutively treated with TPE between April 2006
and May 2007. TPE indications in neurological diseases included Guillain-Barrè
Syndrome (GBS) (n=41), myasthenia gravis (MG) (n=11), acute disseminated
encephalomyelitis (ADEM) (n=3), chronic inflammatory demyelinating
polyneuropathy (CIDP) (n=1) and multiple sclerosis (MS) (n=1). Patient median
age was 49; there was a predominance of males. Twenty-two patients had a history
of other therapy including intravenous immunoglobulin (IVIG), steroid,
azothioprin, and pridostigmine prior to TPE. Another 35 patients had not
received any treatment prior to TPE. All patients were classified according to
the Hughes functional grading scores pre- and first day post-TPE for early
clinical evaluation of patients. The TPE was carried out 1-1.5 times at the
predicted plasma volume every other day. Two hundred and ninety-four procedures
were performed on 57 patients. The median number of TPE sessions per patient was
five, and the median processed plasma volume was 3075mL for each cycle. Although
the pre-TPE median Hughes score of all patients was 4, it had decreased to grade
1 after TPE. While the pre-TPE median Hughes score for GBS and MG patients was
4, post-TPE scores were decreased to grade 1. Additionally, there was a
statistically significant difference between post-TPE Hughes score for GBS
patients with TPE as front line therapy and patients receiving IVIG as front
line therapy (1 vs. 3.5; p=0.034). Although there was no post-TPE improvement in
Hughes scores in patients with ADEM and CIDP, patients with MS had an improved
Hughes score from 4 to 1. Mild and manageable complications such as hypotension
and hypocalcemia were also observed. TPE may be preferable for controlling
symptoms of neuroimmunological disorders in early stage of the disease,
especially with GBS.
DOI: 10.1016/j.transci.2007.11.002
PMID: 18331814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33884210 | 1. J Pediatr Intensive Care. 2021 Jun;10(2):106-109. doi: 10.1055/s-0040-1714098.
Epub 2020 Jul 20.
Therapeutic Plasma Exchange Application in Children Requires Individual
Decision.
Atay G(1), Demirkol D(1)(2).
Author information:
(1)Department of Pediatric Intensive Care, Faculty of Medicine, Istanbul
University, Istanbul, Turkey.
(2)Child Health Institute, Istanbul University, Istanbul, Turkey.
Therapeutic plasma exchange (TPE) is a treatment administered with the aim of
removing a pathogenic material or compound causing morbidity in a variety of
neurologic, hematologic, renal, and autoimmune diseases. In this study, we aimed
to assess the indications, efficacy, reliability, complications, and treatment
response of pediatric patients for TPE. This retrospective study analyzed data
from 39 patients aged from 0 to 18 years who underwent a total of 172 TPE
sessions from January 2015 to April 2018 in a tertiary pediatric intensive care
unit. Indications for TPE were, in order of frequency, macrophage activation
syndrome (28.2%, n = 11), renal transplantation rejection (15.4%, n = 6),
liver failure (15.4%, n = 6), Guillain-Barre's syndrome (15%, n = 6),
hemolytic uremic syndrome (7.7%, n = 3), acute demyelinating disease (7.7%, n
= 3), septic shock (5.1%, n = 2), and intoxication (5.1%, n = 2). No patient
had any adverse event related to the TPE during the procedure. The TPE session
was ended prematurely in one patient due to insufficient vascular access and
lack of blood flow (2.6%). In the long term, thrombosis due to the indwelling
central catheter occurred (5.1%, n = 2). TPE appears to be an effective
first-stage or supplementary treatment in a variety of diseases, may be safely
used in pediatric patients, and there are significant findings that its area of
use will increase. In experienced hands and when assessed carefully, it appears
that the rate of adverse reactions and vascular access problems may be low
enough to be negligible.
Thieme. All rights reserved.
DOI: 10.1055/s-0040-1714098
PMCID: PMC8052102
PMID: 33884210
Conflict of interest statement: Conflict of Interest None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/31029610 | 1. Transfus Apher Sci. 2019 Jun;58(3):266-272. doi:
10.1016/j.transci.2019.04.011. Epub 2019 Apr 19.
Therapeutic apheresis in neurological, nephrological and gastrointestinal
diseases.
Chegini A(1), Ahmadi Karvigh S(2), Rahbar M(2), Sharifi Rayeni A(2).
Author information:
(1)Blood Transfusion Research Center, High Institute for Research and Education
in Transfusion Medicine,Tehran, Iran. Electronic address: [email protected].
(2)Sina hospital, Tehran university of medical science, Tehran, Iran.
Therapeutic plasma exchange (TPE) is a process in which plasma containing
antibodies, immune complexes, inflammatory moderators, paraproteins and other
toxins which are believed to be the cause of disease is removed from a patient.
TPE is the first-line treatment (category I, level 1A) in all forms of Acute
inflammatory demyelinating polyradiculoneuropathy disease (axonal, demyelinating
and miller-fisher variant) as well as in acute myasthenic crisis, chronic
inflammatory demyelinating polyradiculoneuropathy and Paraproteinemic
neuropathies (category I, level 1B). Moreover, TPE in kidney diseases, for
instance: desensitization in renal transplantation(ABO compatible) (living
donor)and desensitization in deceased donor, desensitization in renal
transplantation(ABO incompatible) (living donor), thrombotic microangiopathy
complement Mediated (Factor H autoantibodies), Focal segmental
glomerulosclerosis(recurrent in transplanted kidney), ANCA-associated rapidly
progressive glomerulonephritis(Dialysis dependence, DAH), Anti-Glomerular
basement membrane disease Goodpasture's syndrome)(DAH,Dialysis-independence,)
has been utilized as an initial treatment. (category I) TPE has been used as the
key therapeutic modality to reduce anti-A or anti-B antibody titers in the liver
peri-transplant period with the goal of preventing rejection and facilitating
graft survival. Also, plasma exchange is the first-line therapy in Wilson's
disease (category I, level1C).
Copyright © 2019. Published by Elsevier Ltd.
DOI: 10.1016/j.transci.2019.04.011
PMID: 31029610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23619323 | 1. Transfus Apher Sci. 2013 Jun;48(3):335-9. doi: 10.1016/j.transci.2013.04.012.
Epub 2013 Apr 23.
Therapeutic plasma-exchange in hematologic disease: results from a single center
in Eastern Anatolia.
Erkurt MA(1), Kuku I, Kaya E, Ozgen U, Berber I, Koroglu M, Ozgül M.
Author information:
(1)Inonu University, Faculty of Medicine, Department of Hematology and Apheresis
Unit, Malatya, Turkey. [email protected]
Therapeutic plasma-exchange (TPE) is used as primary and adjunctive therapy in
treatment of several hematologic diseases. We retrospectively evaluated the
results of TPE in hematologic diseases during 2008-2012. A total of 301 TPE
procedures were performed in 44 patients (19 male and 25 female, with mean age
of 50.6±15years). Fifteen of 44 patients had thrombotic thrombocytopenic purpura
(TTP), 14 patients had HELLP syndrome (Hemolysis Elevated Liver enzymes, Low
Platelet count), 10 patients had multiple myeloma-hyperviscosity and the rest
five patients had snake bite. Fresh frozen plasma (FFP) was used as replacement
fluid. Complete response (CR) was achieved on 13 patients (87%) in primarily
TTP. CR was achieved in all other three diseases. Total complications were
detected in 8.1% of the TPE procedures. Adverse events (AEs), were seen in 5.4%
of all procedures. None of the patients died from any complication. AE occurred
in 4% (Grade-I), 1% (Grade-II), and 0.3% (Grade-III) of the procedures. The most
common AE were nausea/vomiting, hypotension, pruritus and abdominal pain. TPE is
effectively and safely carried out in our center in hematologic diseases.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.transci.2013.04.012
PMID: 23619323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30924130 | 1. Br J Haematol. 2019 Jul;186(2):207-219. doi: 10.1111/bjh.15903. Epub 2019 Mar
28.
The role of plasma exchange in the management of autoimmune disorders.
Zanatta E(1), Cozzi M(2), Marson P(3), Cozzi F(1).
Author information:
(1)Rheumatology Unit, Department of Medicine, Padova University Hospital,
Padova, Italy.
(2)Nephrology and Dialysis Unit, Department of Medicine, ASUITS, Trieste, Italy.
(3)Apheresis Unit, Department of Transfusion Medicine, Padova University
Hospital, Padova, Italy.
Therapeutic plasma exchange (TPE) has been mainly used in the treatment of
autoimmune diseases. The main mechanisms of action of TPE include the removal of
circulating autoantibodies, immune complexes, complement components, cytokines
and adhesion molecules, along with sensitization of antibody-producing cells to
immunosuppressant agents. TPE is useful in autoimmune haematological, renal,
rheumatic and neurological diseases, and is recommended for acute disorders,
together with relapsed or worsened chronic diseases that are often unresponsive
to conventional treatments. The American Society for Apheresis and the British
Society of Haematology have published guidelines on the clinical use of
apheresis procedures, indicating the different levels of efficacy of TPE. Based
on the evidence from current literature and our personal experience, this review
discusses the indications and the suggested regimens for TPE in autoimmune
haematological and non-haematological disorders.
© 2019 British Society for Haematology and John Wiley & Sons Ltd.
DOI: 10.1111/bjh.15903
PMID: 30924130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10619926 | 1. Artif Organs. 1999 Dec;23(12):1079-87. doi: 10.1046/j.1525-1594.1999.06187.x.
Plasmapheresis with a substitution solution of human serum protein (5%) versus
plasmapheresis with a substitution solution of human albumin (5%) in patients
suffering from autoimmune diseases.
Bambauer R(1), Arnold A.
Author information:
(1)Institute of Blood Purification, Homburg/Saar, Germany.
Therapeutic plasma exchange (TPE) has been used extensively for over 2 decades
to treat a variety of autoimmune and congenital diseases and is now widely
accepted. The primary objective of this study was to compare the clinical
efficacy of two plasma exchange preparations, human serum protein (HSP) and
human albumin (HA). Twenty-four patients in the following disease categories
underwent TPE using either HSP (Biseko, 5%) or HA (5%): systemic lupus
erythematosus, 8; glomerulonephritis, 8; myasthenia gravis, 2;
Guillain-Barré-syndrome, 2; recurrent iritis, 1; pemphigoid, 1; uveitis, 1; and
vascular retinitis, 1. There was no statistically significant difference in the
average number of TPEs needed in the HSP group (13.5) and HA (13.8) measured
over the first 6 weeks of treatment. The secondary parameters, in particular the
immunological parameters IgG and IgA, provided evidence that plasma exchange
with HSP may have some advantages over HA, and confirmatory studies in a larger
group of patients are indicated. Adverse events during TPE occurred in both the
HAS group (4 patients) and the HA group (4 patients). However, patients in the
HSP group were older (12.3 years), were suffering from more complicated
autoimmune diseases, and the number of occasions (days) on which these were
reported (6 days) was less than in the HA group (11 days). One patient in the HA
group died from septic-toxic circulatory collapse on Day 49 due to an infection
with resistant strains of Staphylococcus aureus. Infections in other patients
did not occur; all showed considerable improvement in their symptoms and
completed the study in good general condition.
DOI: 10.1046/j.1525-1594.1999.06187.x
PMID: 10619926 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16382247 | 1. Ann Acad Med Singap. 2005 Nov;34(10):615-24.
Plasma filtration.
Tan HK(1), Hart G.
Author information:
(1)Department of Renal Medicine, Singapore General Hospital, Singapore, and
University of Melbourne, Victoria, Australia. [email protected]
Therapeutic plasma exchange (TPE) or plasmapheresis involves the separation of
plasma from whole blood. In so doing, plasma-borne humoral disease mediators are
removed from the body. This can attenuate the course and severity of the
underlying disease. Diseases that can be treated with TPE are classified into
the following categories: (1) endocrinological, (2) neurological, (3)
renal/rheumatological, and (4) haematological. TPE is adjuvant in most of these
settings. Disease-specific pharmacological treatment remains the cornerstone of
treatment in many of these conditions. Plasma separation can be achieved with
either (1) centrifugation (CF) or (2) membrane plasma filtration (PF). The
latter is the focus of this review. It can be performed using either a
continuous renal replacement therapy (CRRT) or haemodialysis (HD) machine.
Standard plasma filtration has also been modified to incorporate sorbent
technology which obviates the need for plasma volume replacement fluids. Larger
clinical issues such as timing of initiation and intensity of therapy are
examined.
PMID: 16382247 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34261138 | 1. Semin Liver Dis. 2021 Nov;41(4):476-494. doi: 10.1055/s-0041-1730971. Epub
2021 Jul 14.
Plasma Exchange in Acute and Acute on Chronic Liver Failure.
Maiwall R(1), Sarin SK(1).
Author information:
(1)Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi,
India.
Liver failure in the context of acute (ALF) and acute on chronic liver failure
(ACLF) is associated with high mortality in the absence of a liver transplant.
For decades, therapeutic plasma exchange (TPE) is performed for the management
of immune-mediated diseases. TPE has emerged as an attractive extracorporeal
blood purification technique in patients with ALF and ACLF. The basic premise of
using TPE is to remove the toxic substances which would allow recovery of native
liver functions by facilitating liver regeneration. In recent years, encouraging
data have emerged, suggesting the benefits of TPE in patients with liver
failure. TPE has emerged as an attractive liver support device for the failing
liver until liver transplantation or clinical recovery. The data in patients
with ALF suggest routine use of high-volume TPE, while the data for such a
strategy are less robust for patients with ACLF.
Thieme. All rights reserved.
DOI: 10.1055/s-0041-1730971
PMID: 34261138 [Indexed for MEDLINE]
Conflict of interest statement: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/31719176 | 1. mBio. 2019 Nov 12;10(6):e02232-19. doi: 10.1128/mBio.02232-19.
Diversity in lac Operon Regulation among Diverse Escherichia coli Isolates
Depends on the Broader Genetic Background but Is Not Explained by Genetic
Relatedness.
Phillips KN(1), Widmann S(1), Lai HY(2), Nguyen J(1), Ray JCJ(3), Balázsi G(4),
Cooper TF(5)(2).
Author information:
(1)Department of Biology and Biochemistry, University of Houston, Houston,
Texas, USA.
(2)School of Natural and Computational Science, Massey University, Auckland, New
Zealand.
(3)Center for Computational Biology and Department of Molecular Biosciences,
University of Kansas, Lawrence, Kansas, USA.
(4)Laufer Center for Physical and Quantitative Biology and Department of
Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA.
(5)Department of Biology and Biochemistry, University of Houston, Houston,
Texas, USA [email protected].
Transcription of bacterial genes is controlled by the coordinated action of cis-
and trans-acting regulators. The activity and mode of action of these regulators
can reflect different requirements for gene products in different environments.
A well-studied example is the regulatory function that integrates the
environmental availability of glucose and lactose to control the Escherichia
colilac operon. Most studies of lac operon regulation have focused on a few
closely related strains. To determine the range of natural variation in lac
regulatory function, we introduced a reporter construct into 23 diverse E. coli
strains and measured expression with combinations of inducer concentrations. We
found a wide range of regulatory functions. Several functions were similar to
the one observed in a reference lab strain, whereas others depended weakly on
the presence of cAMP. Some characteristics of the regulatory function were
explained by the genetic relatedness of strains, indicating that differences
varied on relatively short time scales. The regulatory characteristics explained
by genetic relatedness were among those that best predicted the initial growth
of strains following transition to a lactose environment, suggesting a role for
selection. Finally, we transferred the lac operon, with the lacI regulatory
gene, from five natural isolate strains into a reference lab strain. The
regulatory function of these hybrid strains revealed the effect of local and
global regulatory elements in controlling expression. Together, this work
demonstrates that regulatory functions can be varied within a species and that
there is variation within a species to best match a function to particular
environments.IMPORTANCE The lac operon of Escherichia coli is a classic model
for studying gene regulation. This study has uncovered features such as the
environmental input logic controlling gene expression, as well as gene
expression bistability and hysteresis. Most lac operon studies have focused on a
few lab strains, and it is not known how generally those findings apply to the
diversity of E. coli strains. We examined the environmental dependence of lac
gene regulation in 20 natural isolates of E. coli and found a wide range of
regulatory responses. By transferring lac genes from natural isolate strains
into a common reference strain, we found that regulation depends on both the lac
genes themselves and on the broader genetic background, indicating potential for
still-greater regulatory diversity following horizontal gene transfer. Our
results reveal that there is substantial natural variation in the regulation of
the lac operon and indicate that this variation can be ecologically meaningful.
Copyright © 2019 Phillips et al.
DOI: 10.1128/mBio.02232-19
PMCID: PMC6851279
PMID: 31719176 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26415599 | 1. BMC Bioinformatics. 2015 Sep 29;16:311. doi: 10.1186/s12859-015-0720-z.
PROKARYO: an illustrative and interactive computational model of the lactose
operon in the bacterium Escherichia coli.
Esmaeili A(1), Davison T(2), Wu A(3), Alcantara J(4), Jacob C(5)(6).
Author information:
(1)Department of Computer Science, Faculty of Science, University of Calgary,
2500 University Drive NW, Calgary, T2N 1N4, Canada. [email protected].
(2)Department of Computer Science, Faculty of Science, University of Calgary,
2500 University Drive NW, Calgary, T2N 1N4, Canada. [email protected].
(3)Department of Computer Science, Faculty of Science, University of Calgary,
2500 University Drive NW, Calgary, T2N 1N4, Canada. [email protected].
(4)Department of Microbiology, Immunology and Infectious Diseases, Cumming
School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N
4N1, Canada. [email protected].
(5)Department of Computer Science, Faculty of Science, University of Calgary,
2500 University Drive NW, Calgary, T2N 1N4, Canada. [email protected].
(6)Department of Biochemistry and Molecular Biology, Cumming School of Medicine,
University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Canada.
[email protected].
BACKGROUND: We are creating software for agent-based simulation and
visualization of bio-molecular processes in bacterial and eukaryotic cells. As a
first example, we have built a 3-dimensional, interactive computer model of an
Escherichia coli bacterium and its associated biomolecular processes. Our
illustrative model focuses on the gene regulatory processes that control the
expression of genes involved in the lactose operon. Prokaryo, our agent-based
cell simulator, incorporates cellular structures, such as plasma membranes and
cytoplasm, as well as elements of the molecular machinery, including RNA
polymerase, messenger RNA, lactose permease, and ribosomes.
RESULTS: The dynamics of cellular 'agents' are defined by their rules of
interaction, implemented as finite state machines. The agents are embedded
within a 3-dimensional virtual environment with simulated physical and
electrochemical properties. The hybrid model is driven by a combination of (1)
mathematical equations (DEQs) to capture higher-scale phenomena and (2)
agent-based rules to implement localized interactions among a small number of
molecular elements. Consequently, our model is able to capture phenomena across
multiple spatial scales, from changing concentration gradients to one-on-one
molecular interactions. We use the classic gene regulatory mechanism of the
lactose operon to demonstrate our model's resolution, visual presentation, and
real-time interactivity. Our agent-based model expands on a sophisticated
mathematical E. coli metabolism model, through which we highlight our model's
scientific validity.
CONCLUSION: We believe that through illustration and interactive exploratory
learning a model system like Prokaryo can enhance the general understanding and
perception of biomolecular processes. Our agent-DEQ hybrid modeling approach can
also be of value to conceptualize, illustrate, and--eventually--validate cell
experiments in the wet lab.
DOI: 10.1186/s12859-015-0720-z
PMCID: PMC4587781
PMID: 26415599 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34367115 | 1. Front Microbiol. 2021 Jul 21;12:709259. doi: 10.3389/fmicb.2021.709259.
eCollection 2021.
The Selective Advantage of the lac Operon for Escherichia coli Is Conditional on
Diet and Microbiota Composition.
Pinto C(1), Melo-Miranda R(2), Gordo I(3), Sousa A(2).
Author information:
(1)CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de
Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
(2)Department of Medical Sciences, Institute of Biomedicine (iBiMED), University
of Aveiro, Aveiro, Portugal.
(3)Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Erratum in
Front Microbiol. 2023 Nov 27;14:1332365. doi: 10.3389/fmicb.2023.1332365.
The lac operon is one of the best known gene regulatory circuits and constitutes
a landmark example of how bacteria tune their metabolism to nutritional
conditions. It is nearly ubiquitous in Escherichia coli strains justifying the
use of its phenotype, the ability to consume lactose, for species
identification. Lactose is the primary sugar found in milk, which is abundant in
mammals during the first weeks of life. However, lactose is virtually
non-existent after the weaning period, with humans being an exception as many
consume dairy products throughout their lives. The absence of lactose during
adulthood in most mammals and the rarity of lactose in the environment, means
that the selective pressure for maintaining the lac operon could be weak for
long periods of time. Despite the ability to metabolize lactose being a hallmark
of E. coli's success when colonizing its primary habitat, the mammalian
intestine, the selective value of this trait remains unknown in this ecosystem
during adulthood. Here we determine the competitive advantage conferred by the
lac operon to a commensal strain of E. coli when colonizing the mouse gut. We
find that its benefit, which can be as high as 11%, is contingent on the
presence of lactose in the diet and on the presence of other microbiota members
in the gut, but the operon is never deleterious. These results help explaining
the pervasiveness of the lac operon in E. coli, but also its polymorphism, as
lac-negative E. coli strains albeit rare can naturally occur in the gut.
Copyright © 2021 Pinto, Melo-Miranda, Gordo and Sousa.
DOI: 10.3389/fmicb.2021.709259
PMCID: PMC8333865
PMID: 34367115
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34953812 | 1. Biophys J. 2022 Jan 18;121(2):183-192. doi: 10.1016/j.bpj.2021.12.027. Epub
2021 Dec 23.
Switching off: The phenotypic transition to the uninduced state of the lactose
uptake pathway.
Bhogale PM(1), Sorg RA(2), Veening JW(3), Berg J(4).
Author information:
(1)University of Cologne, Institute for Biological Physics, Köln, Germany.
(2)Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology
Institute, Center for Synthetic Biology, University of Groningen, Groningen, the
Netherlands.
(3)Department of Fundamental Microbiology, Faculty of Biology and Medicine,
Lausanne, Switzerland.
(4)University of Cologne, Institute for Biological Physics, Köln, Germany.
Electronic address: [email protected].
The lactose uptake pathway of E. coli is a paradigmatic example of
multistability in gene regulatory circuits. In the induced state of the lac
pathway, the genes comprising the lac operon are transcribed, leading to the
production of proteins that import and metabolize lactose. In the uninduced
state, a stable repressor-DNA loop frequently blocks the transcription of the
lac genes. Transitions from one phenotypic state to the other are driven by
fluctuations, which arise from the random timing of the binding of ligands and
proteins. This stochasticity affects transcription and translation, and
ultimately molecular copy numbers. Our aim is to understand the transition from
the induced to the uninduced state of the lac operon. We use a detailed
computational model to show that repressor-operator binding and unbinding,
fluctuations in the total number of repressors, and inducer-repressor binding
and unbinding all play a role in this transition. Based on the timescales on
which these processes operate, we construct a minimal model of the transition to
the uninduced state and compare the results with simulations and experimental
observations. The induced state turns out to be very stable, with a transition
rate to the uninduced state lower than 2×10-9 per minute. In contrast to the
transition to the induced state, the transition to the uninduced state is well
described in terms of a 2D diffusive system crossing a barrier, with the
diffusion rates emerging from a model of repressor unbinding.
Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.bpj.2021.12.027
PMCID: PMC8790241
PMID: 34953812 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34346508 | 1. Int J Cancer. 2021 Nov 15;149(10):1787-1800. doi: 10.1002/ijc.33758. Epub 2021
Aug 16.
Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis
in colorectal cancer.
Mochizuki Y(1)(2), Funayama R(1), Shirota M(3), Kikukawa Y(1), Ohira M(1),
Karasawa H(2), Kobayashi M(1)(2), Ohnuma S(2), Unno M(2), Nakayama K(1).
Author information:
(1)Department of Cell Proliferation, ART, Graduate School of Medicine, Tohoku
University, Sendai, Japan.
(2)Department of Surgery, Graduate School of Medicine, Tohoku University,
Sendai, Japan.
(3)Division of Interdisciplinary Medical Science, ART, Graduate School of
Medicine, Tohoku University, Sendai, Japan.
The splicing of microexons (very small exons) is frequently dysregulated in the
brain of individuals with autism spectrum disorder. However, little is known of
the patterns, regulatory mechanisms and roles of microexon splicing in cancer.
We here examined the transcriptome-wide profile of microexon splicing in matched
colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons
comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between
CRC and normal tissue. The 21 genes harboring the differentially spliced
microexons were enriched in gene ontology terms related to cell adhesion and
migration. RNA interference-mediated knockdown experiments identified two
splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC
cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing
pre-mRNAs and to control their splicing in such cells. Differential microexon
splicing was shown to be due, at least in part, to altered expression of RBFOX2
and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found
that changes in the pattern of microexon splicing were associated with CRC
metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1
might influence CRC metastasis through the regulation of microexon splicing.
© 2021 UICC.
DOI: 10.1002/ijc.33758
PMID: 34346508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24299589 | 1. Neuroradiol J. 2007 Feb 28;20(1):48-55. doi: 10.1177/197140090702000108. Epub
2007 Feb 28.
Leigh Syndrome: an MR Study of Three Cases.
Cecchini S(1), Regnicolo L, Polonara G, Sallei M, Cesaroni E, Tavoni MA, Zamponi
N.
Author information:
(1)Department of Radiology, Azienda Ospedaliero-Universitaria Ospedali Riuniti
Umberto I, G.Salesi, G.M. Lancisi; Ancona, Italy - [email protected].
Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is the most
common childhood mitochondrial encephalopathy, accounting for more than 50% of
cases in this age group. Its estimated incidence is 1:40,000 - 1:77,000 liveborn
infants a year. LS is a rare progressive multisystem fatal disorder inherited by
autosomal recessive, X-linked and maternal transmission. Clinical onset is
predominantly in the first two years of life (average: six months); 50% of
patients die within a year, even though there are later- and even adult-onset
forms with a more protracted evolution. LS is due to a deficit of various
respiratory chain and Krebs cycle enzymes resulting in insufficient production
of adenosine triphosphate (ATP), in particular cytochrome-c-oxidase (COX),
pyruvate carboxylase, pyruvate dehydrogenase complex and complex I of the
respiratory chain, which share an autosomal recessive and X-linked mode of
transmission. Cases with maternal inheritance (MILS) are due to a mitochondrial
DNA (mtDNA) point mutation. LS is clinically heterogeneous in relation to the
severity of the metabolic dysfunction and is characterized by muscle involvement
and especially CNS disorders, particularly psychomotor retardation, ocular
symptoms, hypotonia and pyramidal signs. Death is most commonly due to
respiratory failure, status epilepticus and sudden coma. The major
neuropathological findings, first described by Leigh in 1951, are symmetrical
foci of spongy necrosis associated with vessel proliferation and reactive
gliosis in basal nuclei, brainstem and thalamus grey matter. The neuronal
metabolic alteration can also affect the white matter, resulting in delayed
myelination or hypomyelination. The diagnosis rests on clinical signs, elevated
CSF lactate, pyruvate and alanine, and biochemical and neuroradiological data.
We describe two patients with LS studied with morphological MR associated with
diffusion and spectroscopy techniques to assess the diagnostic potential of
standard MR imaging and establish whether the association of functional MR
methods can improve its diagnostic accuracy. A case of LS with a post-mortem MR
study is also described. Three patients with a diagnosis of LS based on
clinical, CSF and laboratory data were studied on a GE SIGNA EXCITE 1.5 T unit
using an eight-channel phased-array head coil to acquire standard sequences (SE
T1; TSE DP T2; FLAIR) and echo-planar diffusion-weighted sequences (DWI; b= 1000
s/mm2) with calculation of ADC maps. The spectroscopic study used single-voxel
(TE/TR ms = 144/1500) and multi-voxel techniques (TE/TR ms = 144/1000) at the
level of the basal nuclei. Bilateral and symmetrical involvement of basal nuclei
grey matter with T2 hyperintensity was a consistent finding in the morphological
MR study. In one patient, associated white matter involvement with T2
hyperintensity in periventricular and retrotrigonal areas reflected delayed
myelination or hypomyelination. The deep grey matter changes, sometimes
associated with white matter lesions, suggested a diagnosis of subacute
necrotizing encephalomyelopathy, in line with the literature. Acute-phase ADC
values in affected areas were lower than those of normal grey and white matter
and displayed signal hyperintensity on DWI. Reduced ADC values are associated
with restricted water diffusivity typical of cytotoxic edema. Spectroscopy
showed a high lactate peak, reflecting altered anaerobic glycolysis, and a
reduced NAA peak in affected areas, which are however non-specific findings. The
most informative study in these patients is standard MR associated with
functional techniques, which can confirm the diagnosis obtained with
morphological imaging.
DOI: 10.1177/197140090702000108
PMID: 24299589 |
http://www.ncbi.nlm.nih.gov/pubmed/34584848 | 1. Urol Case Rep. 2021 Sep 14;39:101839. doi: 10.1016/j.eucr.2021.101839.
eCollection 2021 Nov.
Zinner's syndrome: Case report of a rare maldevelopment in the male
genitourinary tract.
Almuhanna AM(1), Alsuhaibani S(2), Almesned R(3), Almatar A(4), Alali H(4).
Author information:
(1)Urology Department, King Fahad Hospital, Al-Ahsa, Saudi Arabia.
(2)U rology Department, King Fahad Hospital, Imam Abdulrahman Bin Faisal
University, Saudi Arabia.
(3)Urology Department, King Faisal Specials Hospital, Riyadh, Saudi Arabia.
(4)Urology Department, King Fahad Specials Hospital, Dammam, Saudi Arabia.
Zinner syndrome is a rare congenital malformation of the urogenital tract. It is
due anomaly in the developmental of Wolffian duct. Zinner syndrome comprises
triad of seminal vesicle cyst, unilateral renal agenesis and ipsilateral
ejaculatory duct obstruction. It is frequently associated with infertility.
Herein we are highlighting a case of a 35 years-old male, a father of 4
biological children who presented to our clinic due to right hemiscrotal pain,
associated with post ejaculation pain.
© 2021 The Authors. Published by Elsevier Inc.
DOI: 10.1016/j.eucr.2021.101839
PMCID: PMC8455976
PMID: 34584848 |
http://www.ncbi.nlm.nih.gov/pubmed/34891476 | 1. Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021:1086-1091. doi:
10.1109/EMBC46164.2021.9630940.
Modeling Gene Expression: Lac operon.
Velazco S, Kambo D, Yu K, Saha A, Beckman E, Mysore N, Cauwenberghs G.
Gene regulation is an essential process for cell development, having a profound
effect in dictating cell functions. Bacterial genes are often regulated through
inducible systems like the Lac operon which plays an important role in cell
metabolism. An accurate model of its regulation can reveal the dynamics of gene
expression. In this paper, a mathematical model of this system is constructed by
focusing on regulation by the Lac repressor. The results show, as expected, that
the concentration of lactose approaches zero while glucose concentration
approaches the initial concentration of lactose by the action of
β-galactosidase, expressed by the Lac operon. Addition of PD control improves
stability of the system, with the phase margin increasing from 45° to 90°.
Modeling the dynamics of gene expression in inducible operons like Lac operon
can be essential for its applications in the production of recombinant proteins
and its potential usage in gene therapy.
DOI: 10.1109/EMBC46164.2021.9630940
PMID: 34891476 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34504629 | 1. Radiol Case Rep. 2021 Aug 30;16(11):3380-3382. doi:
10.1016/j.radcr.2021.08.012. eCollection 2021 Nov.
A rare case of Zinner syndrome: Triad of unilateral renal agenesis, ipsilateral
seminal vesicle cyst and ejaculatory duct obstruction.
Karki P(1), Manandhar S(1), Kharel A(1).
Author information:
(1)Department of Radiology and Imaging, Patan Academy of Health Sciences, P. O.
Box 26500, Lalitpur, Nepal.
A rare triad of Wolffian duct anomaly known as Zinner syndrome includes
unilateral renal agenesis with ipsilateral seminal vesicle cyst and ejaculatory
duct obstruction. It is often diagnosed in third and fourth decades of life.
Patient presents with dysuria, perineal pain, infertility and painful
ejaculation. The aim of this case report is to show the importance of the
radiological imaging on diagnosis of Zinner syndrome. MRI being the modality of
the choice for the confirmation of the diagnosis is vital in further management
of the syndrome.
© 2021 The Authors. Published by Elsevier Inc. on behalf of University of
Washington.
DOI: 10.1016/j.radcr.2021.08.012
PMCID: PMC8411213
PMID: 34504629 |
http://www.ncbi.nlm.nih.gov/pubmed/32991910 | 1. Urology. 2021 Mar;149:e44-e47. doi: 10.1016/j.urology.2020.09.024. Epub 2020
Sep 28.
Seminal Vesicle Cysts With Upper Urinary Tract Abnormalities: A Single-center
Case Series of Pediatric Zinner Syndrome.
Takemura K(1), Sato A(2), Morizawa Y(2), Kufukihara R(2), Iwasa S(2), Satoh
H(3).
Author information:
(1)Department of Pediatric Urology and Kidney Transplants, Tokyo Metropolitan
Children's Medical Center, Tokyo, Japan; Department of Urology, Tokyo
Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo,
Japan. Electronic address: [email protected].
(2)Department of Pediatric Urology and Kidney Transplants, Tokyo Metropolitan
Children's Medical Center, Tokyo, Japan.
(3)Department of Pediatric Urology and Kidney Transplants, Tokyo Metropolitan
Children's Medical Center, Tokyo, Japan. Electronic address:
[email protected].
Seminal vesicle cysts are usually congenital and frequently accompanied by upper
urinary tract abnormalities due to mesonephric duct maldevelopment. Zinner
syndrome, first described in 1914, refers to a triad of features consisting of
seminal vesicle cysts, ejaculatory duct obstruction, and unilateral (mostly
ipsilateral) renal agenesis. We herein present four pediatric patients with
Zinner syndrome diagnosed at a children's medical center. A remnant ureteral
structure was observed in three (75%) patients. Interestingly, a multicystic
dysplastic kidney was present in one (25%) patient before it eventually
disappeared. These findings suggest possible involvement of renal dysgenesis
rather than agenesis in Zinner syndrome.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.urology.2020.09.024
PMID: 32991910 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34527910 | 1. Med Pharm Rep. 2021 Aug;94(Suppl No 1):S47-S50. doi: 10.15386/mpr-2229. Epub
2021 Aug 10.
Zinner syndrome - case report.
Militaru V(1)(2), Mihaly ZA(3), Ilea C(4), Coman M(5), Stanciu M(5), Crisan
N(3)(6), Coman I(6).
Author information:
(1)5 Medical Department, Iuliu Hatieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania.
(2)Internal Medicine Department, Cluj-Napoca Municipal Hospital, Romania.
(3)Urology Department, Cluj-Napoca Municipal Hospital, Romania.
(4)Emergency Medicine Department, Cluj-Napoca Municipal Hospital, Romania.
(5)Radiology Department, Cluj-Napoca Municipal Hospital, Romania.
(6)2 Urology Department, Iuliu Hatieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania.
We present the case of a 51-year-old male with Zinner syndrome, which is a rare
disease, resulting from an abnormal evolution of the mesonephric (Wolffian)
duct. It consists in cystic dilations of one seminal vesicle and/or ejaculatory
duct and ipsilateral renal agenesis. It leads to symptoms related to urination,
ejaculation, even infertility, and to low-abdomen and perineal pain. The
diagnosis is set by ultrasonography, CT scan and, mainly, MRI. Usually it is
treated conservatively, but certain cases require surgery, nowadays minimally
invasive.
DOI: 10.15386/mpr-2229
PMCID: PMC8411814
PMID: 34527910 |
http://www.ncbi.nlm.nih.gov/pubmed/33462046 | 1. BMJ Case Rep. 2021 Jan 18;14(1):e239254. doi: 10.1136/bcr-2020-239254.
A wide spectrum of rare clinical variants of Zinner syndrome.
Talwar HS(1), Mittal A(1), Narain TA(1), Panwar VK(2).
Author information:
(1)Urology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand,
India.
(2)Urology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand,
India [email protected].
Congenital malformations of the seminal vesicles (SVs) are rare and are
associated with abnormalities of the ipsilateral urinary tracts as
embryologically both the ureteral buds and SVs arise from the mesonephric ducts.
The triad of SV cysts, ipsilateral renal agenesis and ejaculatory duct
obstruction is known as the Zinner syndrome. We, herein, present three very rare
presentations of Zinner syndrome. Case 1 presented with haematuria, and was
found to have a large SV cyst with stones and underwent a robotic cyst excision.
Case 2 presented with primary infertility, and was found to have a variant of
Zinner syndrome. Case 3 was a known case of chronic kidney disease on
maintenance haemodialysis who presented with fever and oliguria. He was found to
have Zinner syndrome and underwent aspiration of SV abscess. To the best of our
knowledge, such varying presentations of Zinner syndrome have been rarely
reported thus far.
© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and
permissions. Published by BMJ.
DOI: 10.1136/bcr-2020-239254
PMCID: PMC7813347
PMID: 33462046 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/32421805 | 1. Nucleic Acids Res. 2020 Jul 2;48(W1):W275-W286. doi: 10.1093/nar/gkaa394.
IRIS3: integrated cell-type-specific regulon inference server from single-cell
RNA-Seq.
Ma A(1), Wang C(1), Chang Y(1), Brennan FH(2), McDermaid A(3)(4), Liu B(5),
Zhang C(6), Popovich PG(2), Ma Q(1).
Author information:
(1)Department of Biomedical Informatics, College of Medicine, The Ohio State
University, Columbus, OH 43210, USA.
(2)Department of Neuroscience, Center for Brain and Spinal Cord Repair, Belford
Center for Spinal Cord Injury, The Ohio State University Wexner Medical Center,
Columbus, OH 43210, USA.
(3)Imagenetics, Sanford Health, Sioux Falls, SD 57104, USA.
(4)Department of Internal Medicine, Sanford School of Medicine, University of
South Dakota, Vermillion, SD 57069, USA.
(5)School of Mathematics, Shandong University, Jinan 250100, China.
(6)Department of Medical & Molecular Genetics, Indiana University, School of
Medicine, Indianapolis, IN 46202, USA.
A group of genes controlled as a unit, usually by the same repressor or
activator gene, is known as a regulon. The ability to identify active regulons
within a specific cell type, i.e., cell-type-specific regulons (CTSR), provides
an extraordinary opportunity to pinpoint crucial regulators and target genes
responsible for complex diseases. However, the identification of CTSRs from
single-cell RNA-Seq (scRNA-Seq) data is computationally challenging. We
introduce IRIS3, the first-of-its-kind web server for CTSR inference from
scRNA-Seq data for human and mouse. IRIS3 is an easy-to-use server empowered by
over 20 functionalities to support comprehensive interpretations and graphical
visualizations of identified CTSRs. CTSR data can be used to reliably
characterize and distinguish the corresponding cell type from others and can be
combined with other computational or experimental analyses for biomedical
studies. CTSRs can, therefore, aid in the discovery of major regulatory
mechanisms and allow reliable constructions of global transcriptional regulation
networks encoded in a specific cell type. The broader impact of IRIS3 includes,
but is not limited to, investigation of complex diseases hierarchies and
heterogeneity, causal gene regulatory network construction, and drug
development. IRIS3 is freely accessible from https://bmbl.bmi.osumc.edu/iris3/
with no login requirement.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkaa394
PMCID: PMC7319566
PMID: 32421805 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22235300 | 1. PLoS One. 2012;7(1):e29496. doi: 10.1371/journal.pone.0029496. Epub 2012 Jan
3.
Genomic arrangement of regulons in bacterial genomes.
Zhang H(1), Yin Y, Olman V, Xu Y.
Author information:
(1)Computational Systems Biology Laboratory, Department of Biochemistry and
Molecular Biology and Institute of Bioinformatics, University of Georgia,
Athens, Georgia, United States of America.
Regulons, as groups of transcriptionally co-regulated operons, are the basic
units of cellular response systems in bacterial cells. While the concept has
been long and widely used in bacterial studies since it was first proposed in
1964, very little is known about how its component operons are arranged in a
bacterial genome. We present a computational study to elucidate of the
organizational principles of regulons in a bacterial genome, based on the
experimentally validated regulons of E. coli and B. subtilis. Our results
indicate that (1) genomic locations of transcriptional factors (TFs) are under
stronger evolutionary constraints than those of the operons they regulate so
changing a TF's genomic location will have larger impact to the bacterium than
changing the genomic position of any of its target operons; (2) operons of
regulons are generally not uniformly distributed in the genome but tend to form
a few closely located clusters, which generally consist of genes working in the
same metabolic pathways; and (3) the global arrangement of the component operons
of all the regulons in a genome tends to minimize a simple scoring function,
indicating that the global arrangement of regulons follows simple organizational
principles.
DOI: 10.1371/journal.pone.0029496
PMCID: PMC3250446
PMID: 22235300 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/30052770 | 1. Bioinformatics. 2019 Feb 15;35(4):636-642. doi: 10.1093/bioinformatics/bty658.
MR4Cancer: a web server prioritizing master regulators for cancer.
Ru B(1), Tong Y(1), Zhang J(1).
Author information:
(1)School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
MOTIVATION: During cancer stage transition, a master regulator (MR) refers to
the key gene controlling cancer initiation and progression by orchestrating the
associated target genes (termed as its regulon). Due to their inherent
importance, MRs can serve as critical biomarkers for cancer diagnosis and
prognosis, and therapeutic targets. However, it is challenging to infer key MRs
that might explain gene expression profile changes between two groups due to
lack of context-specific regulons, whose expression level can collectively
reflect the activity of likely MRs. There is also a need to design an
easy-to-use tool of MR identification for research community.
RESULTS: First, we generated cancer-specific regulons for 26 cancer types by
analyzing high-throughput omics data from TCGA, and extracted noncancer-specific
regulons from public databases. We subsequently developed a web server
MR4Cancer, integrating the regulons with statistical inference to identify and
prioritize MRs driving a phenotypic divergence of interest. Based on the input
gene list (e.g. differentially expressed genes) or expression profile with two
groups, MR4Cancer outputs ranked MRs by enrichment testing against the
predefined regulons. Gene Ontology and canonical pathway analyses are also
conducted to elucidate the function of likely MRs. Moreover, MR4Cancer provides
dynamic network visualization for MR-target relations, and users can
interactively interrogate the network to produce new hypotheses and high-quality
figures for publication. Finally, the presented case studies highlighted the
performance of MR4Cancer. We expect this user-friendly and powerful web tool
will provide researchers novel insights into tumorigenesis and therapeutic
intervention.
AVAILABILITY AND IMPLEMENTATION: http://cis.hku.hk/MR4Cancer.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author 2018. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
DOI: 10.1093/bioinformatics/bty658
PMID: 30052770 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32854400 | 1. Genes (Basel). 2020 Aug 25;11(9):995. doi: 10.3390/genes11090995.
Beyond Trees: Regulons and Regulatory Motif Characterization.
Xia X(1)(2).
Author information:
(1)Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
(2)Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada.
Trees and their seeds regulate their germination, growth, and reproduction in
response to environmental stimuli. These stimuli, through signal transduction,
trigger transcription factors that alter the expression of various genes leading
to the unfolding of the genetic program. A regulon is conceptually defined as a
set of target genes regulated by a transcription factor by physically binding to
regulatory motifs to accomplish a specific biological function, such as the
CO-FT regulon for flowering timing and fall growth cessation in trees. Only with
a clear characterization of regulatory motifs, can candidate target genes be
experimentally validated, but motif characterization represents the weakest
feature of regulon research, especially in tree genetics. I review here relevant
experimental and bioinformatics approaches in characterizing transcription
factors and their binding sites, outline problems in tree regulon research, and
demonstrate how transcription factor databases can be effectively used to aid
the characterization of tree regulons.
DOI: 10.3390/genes11090995
PMCID: PMC7564462
PMID: 32854400 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32817385 | 1. mSystems. 2020 Aug 18;5(4):e00511-20. doi: 10.1128/mSystems.00511-20.
Systematic Reconstruction of the Complete Two-Component Sensorial Network in
Staphylococcus aureus.
Rapun-Araiz B(#)(1), Haag AF(#)(2), De Cesare V(3), Gil C(1), Dorado-Morales
P(1), Penades JR(4), Lasa I(5).
Author information:
(1)Laboratory of Microbial Pathogenesis, Navarrabiomed, Complejo Hospitalario de
Navarra (CHN)-Universidad Pública de Navarra (UPNA), IDISNA, Pamplona, Spain.
(2)Institute of Infection, Immunity and Inflammation, University of Glasgow,
Glasgow, Scotland, United Kingdom [email protected] [email protected].
(3)MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee,
Dundee, Scotland, United Kingdom.
(4)Institute of Infection, Immunity and Inflammation, University of Glasgow,
Glasgow, Scotland, United Kingdom.
(5)Laboratory of Microbial Pathogenesis, Navarrabiomed, Complejo Hospitalario de
Navarra (CHN)-Universidad Pública de Navarra (UPNA), IDISNA, Pamplona, Spain
[email protected] [email protected].
(#)Contributed equally
In bacteria, adaptation to changes in the environment is mainly controlled
through two-component signal transduction systems (TCSs). Most bacteria contain
dozens of TCSs, each of them responsible for sensing a different range of
signals and controlling the expression of a repertoire of target genes
(regulon). Over the years, identification of the regulon controlled by each
individual TCS in different bacteria has been a recurrent question. However,
limitations associated with the classical approaches used have left our
knowledge far from complete. In this report, using a pioneering approach in
which a strain devoid of the complete nonessential TCS network was
systematically complemented with the constitutively active form of each response
regulator, we have reconstituted the regulon of each TCS of S. aureus in the
absence of interference between members of the family. Transcriptome sequencing
(RNA-Seq) and proteomics allowed us to determine the size, complexity, and
insulation of each regulon and to identify the genes regulated exclusively by
one or many TCSs. This gain-of-function strategy provides the first description
of the complete TCS regulon in a living cell, which we expect will be useful to
understand the pathobiology of this important pathogen.IMPORTANCE Bacteria are
able to sense environmental conditions and respond accordingly. Their sensorial
system relies on pairs of sensory and regulatory proteins, known as
two-component systems (TCSs). The majority of bacteria contain dozens of TCSs,
each of them responsible for sensing and responding to a different range of
signals. Traditionally, the function of each TCS has been determined by
analyzing the changes in gene expression caused by the absence of individual
TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial
system to introduce, one by one, the active form of every TCS. This
gain-of-function strategy allowed us to identify the changes in gene expression
conferred by each TCS without interference of other members of the family.
Copyright © 2020 Rapun-Araiz et al.
DOI: 10.1128/mSystems.00511-20
PMCID: PMC7438023
PMID: 32817385 |
http://www.ncbi.nlm.nih.gov/pubmed/26975728 | 1. Sci Rep. 2016 Mar 15;6:23030. doi: 10.1038/srep23030.
Bacterial regulon modeling and prediction based on systematic cis regulatory
motif analyses.
Liu B(1), Zhou C(1), Li G(1), Zhang H(2), Zeng E(3)(4)(5), Liu Q(6), Ma Q(7)(5).
Author information:
(1)School of Mathematics, Shandong University, Jinan, Shandong, China.
(2)Systems Biology and Biomedical Informatics (SBBI) Laboratory University of
Nebraska-Lincoln, Lincoln, NE 68588-0115, USA.
(3)Department of Biology, University of South Dakota, Vermillion, SD 57069, USA.
(4)Department of Computer Science, University of South Dakota, Vermillion, SD
57069, USA.
(5)BioSNTR, Brookings, SD, USA.
(6)Department of Bioinformatics, School of Life Sciences and Technology, Tongji
University, Shanghai, China.
(7)Department of Plant Science, South Dakota State University, Brookings, SD,
57006, USA.
Regulons are the basic units of the response system in a bacterial cell, and
each consists of a set of transcriptionally co-regulated operons. Regulon
elucidation is the basis for studying the bacterial global transcriptional
regulation network. In this study, we designed a novel co-regulation score
between a pair of operons based on accurate operon identification and cis
regulatory motif analyses, which can capture their co-regulation relationship
much better than other scores. Taking full advantage of this discovery, we
developed a new computational framework and built a novel graph model for
regulon prediction. This model integrates the motif comparison and clustering
and makes the regulon prediction problem substantially more solvable and
accurate. To evaluate our prediction, a regulon coverage score was designed
based on the documented regulons and their overlap with our prediction; and a
modified Fisher Exact test was implemented to measure how well our predictions
match the co-expressed modules derived from E. coli microarray gene-expression
datasets collected under 466 conditions. The results indicate that our program
consistently performed better than others in terms of the prediction accuracy.
This suggests that our algorithms substantially improve the state-of-the-art,
leading to a computational capability to reliably predict regulons for any
bacteria.
DOI: 10.1038/srep23030
PMCID: PMC4792141
PMID: 26975728 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15231752 | 1. Genome Res. 2004 Jul;14(7):1362-73. doi: 10.1101/gr.2242604.
Regulog analysis: detection of conserved regulatory networks across bacteria:
application to Staphylococcus aureus.
Alkema WB(1), Lenhard B, Wasserman WW.
Author information:
(1)Center for Genomics and Bioinformatics, Karolinska Institutet, Stockholm,
Sweden.
A transcriptional regulatory network encompasses sets of genes (regulons) whose
expression states are directly altered in response to an activating signal,
mediated by trans-acting regulatory proteins and cis-acting regulatory
sequences. Enumeration of these network components is an essential step toward
the creation of a framework for systems-based analysis of biological processes.
Profile-based methods for the detection of cis-regulatory elements are often
applied to predict regulon members, but they suffer from poor specificity. In
this report we describe Regulogger, a novel computational method that uses
comparative genomics to eliminate spurious members of predicted gene regulons.
Regulogger produces regulogs, sets of coregulated genes for which the regulatory
sequence has been conserved across multiple organisms. The quantitative method
assigns a confidence score to each predicted regulog member on the basis of the
degree of conservation of protein sequence and regulatory mechanisms. When
applied to a reference collection of regulons from Escherichia coli, Regulogger
increased the specificity of predictions up to 25-fold over methods that use
cis-element detection in isolation. The enhanced specificity was observed across
a wide range of biologically meaningful parameter combinations, indicating a
robust and broad utility for the method. The power of computational pattern
discovery methods coupled with Regulogger to unravel transcriptional networks
was demonstrated in an analysis of the genome of Staphylococcus aureus. A total
of 125 regulogs were found in this organism, including both well-defined
functional groups and a subset with unknown functions.
Copyright 2004 Cold Spring Harbor Laboratory Press ISSN
DOI: 10.1101/gr.2242604
PMCID: PMC442153
PMID: 15231752 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16813171 | 1. Mol Biol (Mosk). 2006 May-Jun;40(3):524-32.
[ClusterTree-RS: the binary tree algorithm for identification of co-regulated
genes by clustering regulatory signals].
[Article in Russian]
Stavrovskaia ED, Makeev VIu, Mironov AA.
Identification of groups of co-regulated genes (regulons) is an important part
of studying transcriptional regulation. One possible approach is to cluster
regulatory sites that were found using experimental or computational techniques,
such as phylogenetic footprinting. This strategy doesn't require a priori
knowledge about co-regulation and allows finding putative new members of known
groups of co-regulated genes (i.e. a new regulon). Also, it allows finding new
putative regulons, which is especially important for poorly annotated genomes.
We have developed ClusterTree-RS, an algorithm for clustering regulatory signals
using binary trees; it is presented in this paper along with some testing
results on simulated and real data. The algorithm is implemented in Java and
took about 2 hours 40 minutes to cluster 1500 input signals on a computer with
AMD Athlon 1.91 GHz CPU.
PMID: 16813171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35996994 | 1. Eur J Neurol. 2022 Dec;29(12):3556-3563. doi: 10.1111/ene.15528. Epub 2022 Sep
13.
Identification of UBA1 as the causative gene of an X-linked non-Kennedy
spinal-bulbar muscular atrophy.
Khani M(1)(2), Nafissi S(2)(3), Shamshiri H(2)(3), Moazzeni H(1), Taheri H(1),
Sadeghi M(4), Salehi N(5), Chitsazian F(6), Elahi E(1)(2).
Author information:
(1)School of Biology, College of Science, University of Tehran, Tehran, Iran.
(2)Iranian Neuromusclar Research Center, Tehran University of Medical Sciences,
Tehran, Iran.
(3)Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran.
(4)National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.
(5)School of Biological Science, Institute for Research in Fundamental Sciences
(IPM), Tehran, Iran.
(6)Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
BACKGROUND AND PURPOSE: Spinal-bulbar muscular atrophy (SBMA) (Kennedy's
disease) is a motor neuron disease. Kennedy's disease is nearly exclusively
caused by mutations in the androgen receptor encoding gene (AR). The results of
studies aimed at identification of the genetic cause of a disease that best
approximates SBMA in a pedigree (four patients) without mutations in AR are
reported.
METHODS: Clinical investigations included thorough neurological and
non-neurological examinations and testing. Genetic analysis was performed by
exome sequencing using standard protocols. UBA1 mutations were modeled on the
crystal structure of UBA1.
RESULTS: The clinical features of the patients are described in detail. A
missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable
cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on
chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like
modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the
ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause
infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation
identified here and the XL-SMA causative mutations were shown to affect amino
acids positioned in the vicinity of UBA1's ATP binding site and to cause
structural changes.
CONCLUSION: UBA1 was identified as a novel SBMA causative gene. The gene affects
protein homeostasis which is one of most important components of the pathology
of neurodegeneration. The contribution of this same gene to the etiology of
XL-SMA is discussed.
© 2022 European Academy of Neurology.
DOI: 10.1111/ene.15528
PMID: 35996994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29298167 | 1. Clin Neuropharmacol. 2018 Jan/Feb;41(1):28-30. doi:
10.1097/WNF.0000000000000262.
Newly Developed Skin Picking After Methylphenidate Treatment in Attention
Deficit Hyperactivity Disorder: Possible Mechanisms.
Kara T, Akaltun İ.
Dermatillomania is characterized by excessive and repeated skin picking
sufficient to damage cutaneous tissue, but with no underlying dermatological
disease. The condition appears as an independent diagnosis in the
Obsessive-Compulsive and Related Disorders category in the Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition. A psychiatric pathology
is generally reported to accompany this symptom. Attention deficit hyperactivity
disorder (ADHD) is a potentially lifelong condition involving inattentiveness,
hyperactivity, and impulsiveness. Attention deficit hyperactivity disorder is
one of the most common childhood psychiatric disorders. Treatment includes
medication, psychotherapy, and psychosocial therapies. Psychostimulants
constitute the basis of treatment of children with ADHD worldwide. We describe a
case of skin picking developing after methylphenidate therapy for ADHD. Possible
explanations of methylphenidate and skin picking are reviewed in the light of
the current literature.
DOI: 10.1097/WNF.0000000000000262
PMID: 29298167 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31825805 | 1. Biochim Biophys Acta Gene Regul Mech. 2020 Jun;1863(6):194472. doi:
10.1016/j.bbagrm.2019.194472. Epub 2019 Dec 9.
Which came first, the transcriptional regulator or its target genes? An
evolutionary perspective into the construction of eukaryotic regulons.
Trefflich S(1), Dalmolin RJS(2), Ortega JM(3), Castro MAA(4).
Author information:
(1)Graduate Program in Bioinformatics, Institute of Biological Sciences, Federal
University of Minas Gerais, Belo Horizonte 31270-901, Brazil; Bioinformatics and
Systems Biology Laboratory, Federal University of Paraná, Curitiba 81520-260,
Brazil.
(2)Bioinformatics Multidisciplinary Environment, Federal University of Rio
Grande do Norte, Natal 59078-400, Brazil.
(3)Graduate Program in Bioinformatics, Institute of Biological Sciences, Federal
University of Minas Gerais, Belo Horizonte 31270-901, Brazil.
(4)Bioinformatics and Systems Biology Laboratory, Federal University of Paraná,
Curitiba 81520-260, Brazil. Electronic address: [email protected].
Eukaryotic regulons are regulatory units formed by a set of genes under the
control of the same transcription factor (TF). Despite the functional
plasticity, TFs are highly conserved and recognize the same DNA sequences in
different organisms. One of the main factors that confer regulatory specificity
is the distribution of the binding sites of the TFs along the genome, allowing
the configuration of different transcriptional regulatory networks (TRNs) from
the same regulator. A similar scenario occurs between tissues of the same
organism, where a TRN can be rewired by epigenetic factors, modulating the
accessibility of the TF to its binding sites. In this article we discuss
concepts that can help to formulate testable hypotheses about the construction
of regulons, exploring the presence and absence of the elements that form a TRN
throughout the evolution of an ancestral lineage. This article is part of a
Special Issue entitled: Transcriptional Profiles and Regulatory Gene Networks
edited by Dr. Federico Manuel Giorgi and Dr. Shaun Mahony.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2019.194472
PMID: 31825805 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that there are no competing interests associated with this manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/32773451 | 1. Curr Opin Neurol. 2020 Oct;33(5):629-634. doi: 10.1097/WCO.0000000000000856.
Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and
avenues for treatment.
Grunseich C(1), Fischbeck KH.
Author information:
(1)National Institutes of Health, Bethesda, Maryland, USA.
PURPOSE OF REVIEW: The aim of this study was to illustrate the current
understanding and avenues for developing treatment in spinal and bulbar muscular
atrophy (SBMA), an inherited neuromuscular disorder caused by a CAG
trinucleotide repeat expansion in the androgen receptor (AR) gene.
RECENT FINDINGS: Important advances have been made in characterizing the
molecular mechanism of the disease, including the disruption of protein
homeostasis, intracellular trafficking and signalling pathways. Biomarkers such
as MRI quantification of muscle volume and fat fraction have been used to track
disease progression, and will be useful in future clinical studies. Therapies
tested and under development have been based on diverse strategies, including
targeting mutant AR gene expression, stability and activity, and pathways that
mitigate disease toxicity.
SUMMARY: We provide an overview of the recent advances in understanding the SBMA
disease mechanism and highlight efforts to translate these insights into well
tolerated and effective therapy.
DOI: 10.1097/WCO.0000000000000856
PMCID: PMC7748295
PMID: 32773451 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest There are no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20689246 | 1. Neurodegener Dis. 2011;8(1-2):25-34. doi: 10.1159/000313682. Epub 2010 Aug 4.
Prenatal flutamide enhances survival in a myogenic mouse model of spinal bulbar
muscular atrophy.
Johansen JA(1), Troxell-Smith SM, Yu Z, Mo K, Monks DA, Lieberman AP, Breedlove
SM, Jordan CL.
Author information:
(1)Neuroscience Program, Michigan State University, East Lansing, MI 48109, USA.
[email protected]
BACKGROUND: Spinal bulbar muscular atrophy (SBMA) is caused by a CAG repeat
expansion mutation in the androgen receptor (AR) gene, and mutant AR is presumed
to act in motoneurons to cause SBMA. However, we found that mice overexpressing
wild-type (wt) AR solely in skeletal muscle fibers display the same
androgen-dependent disease phenotype as when mutant AR is broadly expressed,
challenging the assumptions that only an expanded AR can induce disease and that
SBMA is strictly neurogenic. We have previously reported that AR toxicity was
ligand dependent in our model, and that very few transgenic (tg) males survived
beyond birth.
METHODS: We tested whether the AR antagonist flutamide could block perinatal
toxicity. tg males were treated prenatally with flutamide and assessed for
survival and motor behavior in adulthood.
RESULTS: Prenatal treatment with flutamide rescued tg male pups from perinatal
death, and, as adults, such perinatally rescued tg males showed an SBMA
phenotype that was comparable to that of previously described untreated tg
males. Moreover, tg males carrying a mutant endogenous allele for AR--the
testicular feminization mutation (tfm)--and thus having functional AR only in
muscle fibers nevertheless displayed the same androgen-dependent disease
phenotype as adults.
CONCLUSIONS: These mice represent an excellent model to study the myogenic
contribution to SBMA as they display many of the core features of disease as
other mouse models. These data demonstrate that AR acting exclusively in muscle
fibers is sufficient to induce SBMA symptoms and that flutamide is protective
perinatally.
Copyright © 2010 S. Karger AG, Basel.
DOI: 10.1159/000313682
PMCID: PMC3030474
PMID: 20689246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34608100 | 1. Curr Opin Allergy Clin Immunol. 2021 Dec 1;21(6):590-596. doi:
10.1097/ACI.0000000000000793.
Thymic stromal lymphopoietin and alarmins as possible therapeutical targets for
asthma.
Salvati L(1), Maggi L, Annunziato F, Cosmi L.
Author information:
(1)Department of Experimental and Clinical Medicine, University of Florence,
Florence, Italy.
PURPOSE OF REVIEW: Overview of epithelial cytokines, particularly thymic stromal
lymphopoietin (TSLP), released by the airway epithelium and the effects of their
inhibition on the outcomes of patients with asthma.
RECENT FINDINGS: The epithelial cytokines are early mediators at the top of the
inflammatory cascade and are attractive therapeutic targets to prevent
exacerbations and improve lung function in patients with type 2 and nontype 2
asthma.
SUMMARY: Clinical trials demonstrated that tezepelumab, an anti-TSLP monoclonal
antibody, is a promising alternative treatment for asthma that is effective also
in nontype 2 asthma. The PATHWAY and NAVIGATOR trials have assessed its effects
in improving outcomes on broad clinically diverse populations. The
identification of biomarkers will help to predict potential responders and help
in asthma treatment personalization.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/ACI.0000000000000793
PMCID: PMC9722372
PMID: 34608100 [Indexed for MEDLINE]
Conflict of interest statement: There are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34572294 | 1. Biomedicines. 2021 Aug 29;9(9):1108. doi: 10.3390/biomedicines9091108.
Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological
Therapies of Severe Asthma.
Pelaia C(1), Pelaia G(2), Longhini F(2), Crimi C(3), Calabrese C(4), Gallelli
L(1), Sciacqua A(2), Vatrella A(5).
Author information:
(1)Department of Health Sciences, University "Magna Graecia" of Catanzaro, Viale
Europa-Località Germaneto, 88100 Catanzaro, Italy.
(2)Department of Medical and Surgical Sciences, University "Magna Graecia" of
Catanzaro, 88100 Catanzaro, Italy.
(3)Department of Clinical and Experimental Medicine, University of Catania,
95131 Catania, Italy.
(4)Department of Translational Medical Sciences, University of Campania "Luigi
Vanvitelli", 80131 Naples, Italy.
(5)Department of Medicine, Surgery, and Dentistry, University of Salerno, 84084
Salerno, Italy.
Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP),
interleukin-33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by
airway epithelium and exert a prominent role in asthma pathobiology. In
particular, several environmental factors such as allergens, cigarette smoking,
airborne pollutants, and infectious agents trigger the release of alarmins,
which in turn act as upstream activators of pro-inflammatory pathways underlying
type 2 (T2-high) asthma. Indeed, alarmins directly activate group 2 innate
lymphoid cells (ILC2), eosinophils, basophils, and mast cells and also stimulate
dendritic cells to drive the commitment of naïve T helper (Th) cells towards the
Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable
targets for add-on therapies of severe asthma. Within this context, the fully
human anti-TSLP monoclonal antibody tezepelumab has been evaluated in very
promising randomized clinical trials. Tezepelumab and other anti-alarmins are
thus likely to become, in the near future, valuable therapeutic options for the
biological treatment of uncontrolled severe asthma.
DOI: 10.3390/biomedicines9091108
PMCID: PMC8465735
PMID: 34572294
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34572466 | 1. Biomedicines. 2021 Sep 21;9(9):1281. doi: 10.3390/biomedicines9091281.
The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in
Asthma: A Systematic Review.
Calzetta L(1), Aiello M(1), Frizzelli A(1), Bertorelli G(1), Ritondo BL(2),
Rogliani P(2), Chetta A(1).
Author information:
(1)Respiratory Disease and Lung Function Unit, Department of Medicine and
Surgery, University of Parma, 43126 Parma, Italy.
(2)Unit of Respiratory Medicine, Department of Experimental Medicine, University
of Rome "Tor Vergata", 00133 Rome, Italy.
Airway hyperresponsiveness (AHR) represents a central pathophysiological
hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue
implicated in the onset of AHR. ASM also exerts pro-inflammatory and
immunomodulatory actions, by secreting a wide range of cytokines and chemokines.
In asthma pathogenesis, the overexpression of several type 2 inflammatory
mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with
ASM hyperreactivity, all of which can be targeted by humanized monoclonal
antibodies (mAbs). Therefore, the aim of this review was to systematically
assess evidence across the literature on mAbs for the treatment of asthma with
respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab,
benralizumab, dupilumab, and tezepelumab were found to be effective in
modulating the contractility of the ASM and preventing the AHR, but no available
studies concerning the impact of reslizumab on the ASM were identified from the
literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate
the ASM in asthma, by specifically blocking the interaction between IgE, IL-4,
and TSLP, and their receptors are located on the surface of ASM cells.
Conversely, mepolizumab and benralizumab have prevalently indirect impacts
against AHR by targeting eosinophils and other immunomodulatory effector cells
promoting inflammatory processes. AHR has been suggested as the main treatable
trait towards precision medicine in patients suffering from eosinophilic asthma,
therefore, well-designed head-to-head trials are needed to compare the efficacy
of those mAbs that directly target ASM contractility specifically against the
AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.
DOI: 10.3390/biomedicines9091281
PMCID: PMC8468486
PMID: 34572466
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33368307 | 1. J Clin Pharmacol. 2021 Jul;61(7):901-912. doi: 10.1002/jcph.1803. Epub 2021
Jan 16.
Pharmacokinetic and Pharmacodynamic Modeling of Tezepelumab to Guide Phase 3
Dose Selection for Patients With Severe Asthma.
Ly N(1), Zheng Y(1), Griffiths JM(2), van der Merwe R(3), Agoram B(1), Parnes
JR(4), Roskos L(5).
Author information:
(1)Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology
and Safety Sciences, BioPharmaceuticals R and D, AstraZeneca, South San
Francisco, California, USA.
(2)Translational Science and Experimental Medicine, Research and Early
Development, Respiratory and Immunology, BioPharmaceuticals R and D,
AstraZeneca, Gaithersburg, Maryland, USA.
(3)Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R and
D, AstraZeneca, Cambridge, UK.
(4)Amgen, Thousand Oaks, California, USA.
(5)Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology
and Safety Sciences, BioPharmaceuticals R and D, AstraZeneca, Gaithersburg,
Maryland, USA.
Tezepelumab is a human monoclonal antibody that blocks thymic stromal
lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the
phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab
significantly reduced exacerbations in adults with severe, uncontrolled asthma.
We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling to guide
tezepelumab dose selection for phase 3 trials in patients with severe asthma. PK
data from 7 clinical studies were used to develop a population PK model.
Population PK-PD models were developed to characterize the relationship between
tezepelumab PK and asthma exacerbation rate (AER) and fractional exhaled nitric
oxide (FeNO) levels (using phase 2b PD data only). Tezepelumab PK were well
described by a 2-compartment model with first-order absorption; PK parameter
estimates were consistent with those of other immunoglobulin G2 antibodies.
PK-PD models predicted that subcutaneous dosing at 210 mg every 4 weeks was
associated with ≈90% of the maximum drug effect of tezepelumab on AER and FeNO;
further dose increases were not expected to result in additional, clinically
meaningful treatment benefit. No clinically significant covariates of treatment
effects on AER and FeNO were identified. Population PK simulations,
exposure-response relationships and safety profiles of tezepelumab at doses up
to 280 mg every 2 weeks suggested that no dose adjustment based on body weight
or for adolescents was required. These results support the selection of 210 mg
every 4 weeks subcutaneously as the dose for phase 3 studies of tezepelumab in
adults and adolescents with severe asthma.
© 2020, The American College of Clinical Pharmacology.
DOI: 10.1002/jcph.1803
PMID: 33368307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34606305 | 1. Ann Intern Med. 2021 Oct;174(10):JC115. doi: 10.7326/ACPJ202110190-115. Epub
2021 Oct 5.
In severe, uncontrolled asthma, tezepelumab reduced exacerbations and improved
asthma control at 1 y.
Taleb AA(1), Badgett RG(1).
Author information:
(1)University of Kansas School of Medicine, Wichita, Kansas, USA (A.A.T.,
R.G.B.).
Comment on
N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975.
Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents
with severe, uncontrolled asthma. N Engl J Med. 2021;384:1800-9. 33979488.
DOI: 10.7326/ACPJ202110190-115
PMID: 34606305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31993419 | 1. Front Cell Dev Biol. 2020 Jan 14;7:377. doi: 10.3389/fcell.2019.00377.
eCollection 2019.
Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression
and Cell Fate.
Arnold PR(1)(2), Wells AD(3), Li XC(2).
Author information:
(1)Texas A&M Health Science Center, College of Medicine, Bryan, TX, United
States.
(2)Immunobiology and Transplant Sciences, Department of Surgery, Houston
Methodist Hospital, Houston, TX, United States.
(3)Department of Pathology and Laboratory Medicine, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, United States.
Enhancers are cis-regulatory elements in the genome that cooperate with
promoters to control target gene transcription. Unlike promoters, enhancers are
not necessarily adjacent to target genes and can exert their functions
regardless of enhancer orientations, positions and spatial segregations from
target genes. Thus, for a long time, the question as to how enhancers act in a
temporal and spatial manner attracted considerable attention. The recent
discovery that enhancers are also abundantly transcribed raises interesting
questions about the exact roles of enhancer RNA (eRNA) in gene regulation. In
this review, we highlight the process of enhancer transcription and the diverse
features of eRNA. We review eRNA functions, which include enhancer-promoter
looping, chromatin modifying, and transcription regulating. As eRNA are
transcribed from active enhancers, they exhibit tissue and lineage specificity,
and serve as markers of cell state and function. Finally, we discuss the unique
relationship between eRNA and super enhancers in phase separation wherein eRNA
may contribute significantly to cell fate decisions.
Copyright © 2020 Arnold, Wells and Li.
DOI: 10.3389/fcell.2019.00377
PMCID: PMC6971116
PMID: 31993419 |
http://www.ncbi.nlm.nih.gov/pubmed/22169023 | 1. Curr Opin Genet Dev. 2012 Apr;22(2):79-85. doi: 10.1016/j.gde.2011.11.001.
Epub 2011 Dec 12.
Enhancer and promoter interactions-long distance calls.
Krivega I(1), Dean A.
Author information:
(1)Laboratory of Cellular and Developmental Biology, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20982, United States.
In metazoans, enhancers of gene transcription must often exert their effects
over tens of kilobases of DNA. Over the past decade it has become clear that to
do this, enhancers come into close proximity with target promoters with the
looping away of intervening sequences. In a few cases proteins that are involved
in the establishment or maintenance of these loops have been revealed but how
the proper gene target is selected remains mysterious. Chromatin insulators had
been appreciated as elements that play a role in enhancer fidelity through their
enhancer blocking or barrier activity. However, recent work suggests more direct
participation of insulators in enhancer-gene interactions. The emerging view
begins to incorporate transcription activation by distant enhancers with large
scale nuclear architecture and subnuclear movement.
Published by Elsevier Ltd.
DOI: 10.1016/j.gde.2011.11.001
PMCID: PMC3342482
PMID: 22169023 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31285341 | 1. Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15062-15067. doi:
10.1073/pnas.1908962116. Epub 2019 Jul 8.
Large distances separate coregulated genes in living Drosophila embryos.
Heist T(1), Fukaya T(2)(3), Levine M(4)(5).
Author information:
(1)Lewis-Sigler Institute for Integrative Genomics, Princeton University,
Princeton, NJ 08544.
(2)Institute for Quantitative Biosciences, The University of Tokyo, 113-0032
Tokyo, Japan.
(3)Department of Life Sciences, Graduate School of Arts and Sciences, The
University of Tokyo, 113-0032 Tokyo, Japan.
(4)Lewis-Sigler Institute for Integrative Genomics, Princeton University,
Princeton, NJ 08544; [email protected].
(5)Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Transcriptional enhancers are short segments of DNA that switch genes on and off
in response to a variety of cellular signals. Many enhancers map quite far from
their target genes, on the order of tens or even hundreds of kilobases. There is
extensive evidence that remote enhancers are brought into proximity with their
target promoters via long-range looping interactions. However, the exact
physical distances of these enhancer-promoter interactions remain uncertain.
Here, we employ high-resolution imaging of living Drosophila embryos to
visualize the distances separating linked genes that are coregulated by a shared
enhancer. Cotransvection assays (linked genes on separate homologs) suggest a
surprisingly large distance during transcriptional activity: at least 100-200
nm. Similar distances were observed when a shared enhancer was placed into close
proximity with linked reporter genes in cis. These observations are consistent
with the occurrence of "transcription hubs," whereby clusters (or condensates)
of multiple RNA polymerase II complexes and associated cofactors are
periodically recruited to active promoters. The dynamics of this process might
be responsible for rapid fluctuations in the distances separating the
transcription of coregulated reporter genes during transvection. We propose that
enhancer-promoter communication depends on a combination of classical looping
and linking models.
DOI: 10.1073/pnas.1908962116
PMCID: PMC6660726
PMID: 31285341 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23525463 | 1. Nucleic Acids Res. 2013 May;41(9):4835-46. doi: 10.1093/nar/gkt188. Epub 2013
Mar 21.
High-throughput identification of long-range regulatory elements and their
target promoters in the human genome.
Hwang YC(1), Zheng Q, Gregory BD, Wang LS.
Author information:
(1)Genomics and Computational Biology Graduate Program, University of
Pennsylvania, Philadelphia, PA, USA.
Enhancer elements are essential for tissue-specific gene regulation during
mammalian development. Although these regulatory elements are often distant from
their target genes, they affect gene expression by recruiting transcription
factors to specific promoter regions. Because of this long-range action, the
annotation of enhancer element-target promoter pairs remains elusive. Here, we
developed a novel analysis methodology that takes advantage of Hi-C data to
comprehensively identify these interactions throughout the human genome. To do
this, we used a geometric distribution-based model to identify DNA-DNA
interaction hotspots that contact gene promoters with high confidence. We
observed that these promoter-interacting hotspots significantly overlap with
known enhancer-associated histone modifications and DNase I hypersensitive
sites. Thus, we defined thousands of candidate enhancer elements by
incorporating these features, and found that they have a significant propensity
to be bound by p300, an enhancer binding transcription factor. Furthermore, we
revealed that their target genes are significantly bound by RNA Polymerase II
and demonstrate tissue-specific expression. Finally, we uncovered that these
elements are generally found within 1 Mb of their targets, and often regulate
multiple genes. In total, our study presents a novel high-throughput workflow
for confident, genome-wide discovery of enhancer-target promoter pairs, which
will significantly improve our understanding of these regulatory interactions.
DOI: 10.1093/nar/gkt188
PMCID: PMC3643598
PMID: 23525463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35437236 | 1. Yi Chuan. 2022 Apr 20;44(4):275-288. doi: 10.16288/j.yczz.21-440.
The regulatory mechanisms by enhancers during cancer initiation and progression.
Qi SH(1)(2), Wang QL(1)(2), Zhang JY(1)(2), Liu Q(1)(2), Li CY(1)(2)(3)(4).
Author information:
(1)School of Engineering Medicine, Beihang University, Beijing 100191, China.
(2)School of Biological Science and Medical Engineering, Beihang University,
Beijing 100191, China.
(3)Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,
Beihang University, Beijing 100191, China.
(4)Key Laboratory of Big Data-Based Precision Medicine (Ministry of Industry and
Information Technology), Beihang University, Beijing 100191, China.
Enhancer is a DNA sequence, and mainly acts in cis to regulate gene
transcription. Due to the uncertainty in both location and distance between
enhancers and their target genes, it is more complex and difficult to study the
underlying regulatory mechanism of enhancers. Accumulating evidences indicate
that enhancers are closely associated with the occurrence and development of
diseases, such as cancer. Therefore, the studies of enhancers in cancer will be
helpful to deeply unravel cancer pathogenesis and to promote the development of
antitumor drugs. The related research is with great social significance and
economic value. Currently, the identification of enhancers is insufficient. The
regulatory mechanisms by enhancers during the initiation and progression of
cancer and other diseases have not been fully delineated. In this review, we
provide an overview of enhancers, super enhancers and their properties, followed
by a description of enhancer prediction and identification at the genome-wide
level. Finally, we summarize the regulatory roles of enhancers during diseases
such as cancer in recent years, thereby providing a reference for the future
exploration on enhancer regulatory mechanisms as well as cancer diagnosis and
treatment.
Publisher:
增强子是一段具有转录调控功能的DNA序列,主要通过顺式调控方式发挥作用。由于增强子及其调控基因在位置和距离上的不确定性,大大增加了研究增强子作用机制的复杂性和困难性。越来越多的证据表明,增强子与癌症等疾病的发生发展密切相关,因此开展癌症相关增强子的研究,将有助于全面解析癌症发病机制,并推动抗肿瘤药物的高效研发,具有重要的社会意义和经济价值。目前对于增强子的鉴定不充分,增强子在癌症和其他疾病中的发生发展调控机制尚未得到完整的解析。本文主要对增强子和超级增强子及其特性进行介绍,并在全基因组水平上对增强子的预测和鉴定进行了描述,最后总结了近年来增强子在癌症等疾病发生过程中所发挥的调控作用,从而为未来解析增强子调控机制以及癌症的诊断和治疗提供参考。.
DOI: 10.16288/j.yczz.21-440
PMID: 35437236 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27932455 | 1. Nucleic Acids Res. 2017 Apr 7;45(6):3017-3030. doi: 10.1093/nar/gkw1220.
Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops
is not required to sustain transcription.
Rahman S(1), Zorca CE(1), Traboulsi T(1)(2), Noutahi E(1), Krause MR(3), Mader
S(1)(2), Zenklusen D(1).
Author information:
(1)Département de Biochimie et Médecine Moléculaire, Université de Montréal,
Montréal, QC H3T 1J4, Canada.
(2)Institute for Research in Immunology and Cancer, Université de Montréal,
Montréal, QC H3T 1J4, Canada.
(3)Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4,
Canada.
Enhancers are intergenic DNA elements that regulate the transcription of target
genes in response to signaling pathways by interacting with promoters over large
genomic distances. Recent studies have revealed that enhancers are
bi-directionally transcribed into enhancer RNAs (eRNAs). Using single-molecule
fluorescence in situ hybridization (smFISH), we investigated the eRNA-mediated
regulation of transcription during estrogen induction in MCF-7 cells. We
demonstrate that eRNAs are localized exclusively in the nucleus and are induced
with similar kinetics as target mRNAs. However, eRNAs are mostly nascent at
enhancers and their steady-state levels remain lower than those of their cognate
mRNAs. Surprisingly, at the single-allele level, eRNAs are rarely co-expressed
with their target loci, demonstrating that active gene transcription does not
require the continuous transcription of eRNAs or their accumulation at
enhancers. When co-expressed, sub-diffraction distance measurements between
nascent mRNA and eRNA signals reveal that co-transcription of eRNAs and mRNAs
rarely occurs within closed enhancer-promoter loops. Lastly, basal eRNA
transcription at enhancers, but not E2-induced transcription, is maintained upon
depletion of MLL1 and ERα, suggesting some degree of chromatin accessibility
prior to signal-dependent activation of transcription. Together, our findings
suggest that eRNA accumulation at enhancer-promoter loops is not required to
sustain target gene transcription.
© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkw1220
PMCID: PMC5389544
PMID: 27932455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23424115 | 1. Pac Symp Biocomput. 2013:92-102.
Epigenomic model of cardiac enhancers with application to genome wide
association studies.
Sahu AD(1), Aniba R, Chang YP, Hannenhalli S.
Author information:
(1)Center for Bioinformatics and Computational Biology, University of Maryland,
College park, MD 20742, USA.
Mammalian gene regulation is often mediated by distal enhancer elements, in
particular, for tissue specific and developmental genes. Computational
identification of enhancers is difficult because they do not exhibit clear
location preference relative to their target gene and also because they lack
clearly distinguishing genomic features. This represents a major challenge in
deciphering transcriptional regulation. Recent ChIP-seq based genome-wide
investigation of epigenomic modifications have revealed that enhancers are often
enriched for certain epigenomic marks. Here we utilize the epigenomic data in
human heart tissue along with validated human heart enhancers to develop a
Support Vector Machine (SVM) model of cardiac enhancers. Cross-validation
classification accuracy of our model was 84% and 92% on positive and negative
sets respectively with ROC AUC = 0.92. More importantly, while P300 binding has
been used as gold standard for enhancers, our model can distinguish P300-bound
validated enhancers from other P300-bound regions that failed to exhibit
enhancer activity in transgenic mouse. While GWAS studies reveal polymorphic
regions associated with certain phenotypes, they do not immediately provide
causality. Next, we hypothesized that genomic regions containing a GWAS SNP
associated with a cardiac phenotype might contain another SNP in a cardiac
enhancer, which presumably mediates the phenotype. Starting with a comprehensive
set of SNPs associated with cardiac phenotypes in GWAS studies, we scored other
SNPs in LD with the GWAS SNP according to its probability of being an enhancer
and choose one with best score in the LD as enhancer. We found that our
predicted enhancers are enriched for known cardiac transcriptional regulator
motifs and are likely to regulate the nearby gene. Importantly, these tendencies
are more favorable for the predicted enhancers compared with an approach that
uses P300 binding as a marker of enhancer activity.
PMCID: PMC3581590
PMID: 23424115 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26100358 | 1. Genomics. 2015 Sep;106(3):137-139. doi: 10.1016/j.ygeno.2015.06.002. Epub 2015
Jun 19.
Recent advances in functional assays of transcriptional enhancers.
Babbitt CC(1), Markstein M(2), Gray JM(3).
Author information:
(1)Department of Biology, University of Massachusetts, Amherst, United States.
Electronic address: [email protected].
(2)Department of Biology, University of Massachusetts, Amherst, United States.
(3)Department of Genetics, Harvard Medical School, United States.
In this special edition of Genomics, we present reviews of the current state of
the field in identifying and functionally understanding transcriptional
enhancers in cells and developing tissues. Typically several enhancers
coordinate the expression of an individual target gene, each controlling that
gene's expression in specific cell types at specific times. Until recently,
identifying each gene's enhancers had been challenging because enhancers do not
occupy prescribed locations relative to their target genes. Recently there have
been powerful advances in DNA sequencing and other technologies that make it
possible to identify the majority of enhancers in virtually any cell type of
interest. The reviews in this edition of Genomics highlight some of these new
and powerful approaches.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygeno.2015.06.002
PMCID: PMC4556128
PMID: 26100358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32958948 | 1. Nat Struct Mol Biol. 2020 Nov;27(11):1032-1040. doi:
10.1038/s41594-020-0493-6. Epub 2020 Sep 21.
Single-gene imaging links genome topology, promoter-enhancer communication and
transcription control.
Li J(1), Hsu A(1)(2), Hua Y(1), Wang G(1), Cheng L(1), Ochiai H(3)(4), Yamamoto
T(3)(4), Pertsinidis A(5).
Author information:
(1)Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York,
NY, USA.
(2)Department of Molecular, Cellular, and Developmental Biology, University of
Michigan, Ann Arbor, MI, USA.
(3)Program of Mathematical and Life Sciences, Graduate School of Integrated
Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan.
(4)Genome Editing Innovation Center, Hiroshima University, Higashi-Hiroshima,
Hiroshima, Japan.
(5)Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York,
NY, USA. [email protected].
Transcription activation by distal enhancers is essential for cell-fate
specification and maintenance of cellular identities. How long-range gene
regulation is physically achieved, especially within complex regulatory
landscapes of non-binary enhancer-promoter configurations, remains elusive.
Recent nanoscopy advances have quantitatively linked promoter kinetics and ~100-
to 200-nm-sized clusters of enhancer-associated regulatory factors (RFs) at
important developmental genes. Here, we further dissect mechanisms of RF
clustering and transcription activation in mouse embryonic stem cells. RF
recruitment into clusters involves specific molecular recognition of cognate DNA
and chromatin-binding sites, suggesting underlying cis-element clustering.
Strikingly, imaging of tagged genomic loci, with ≤1 kilobase and ~20-nanometer
precision, in live cells, reveals distal enhancer clusters over the extended
locus in frequent close proximity to target genes-within RF-clustering
distances. These high-interaction-frequency enhancer-cluster 'superclusters'
create nano-environments wherein clustered RFs activate target genes, providing
a structural framework for relating genome organization, focal RF accumulation
and transcription activation.
DOI: 10.1038/s41594-020-0493-6
PMCID: PMC7644657
PMID: 32958948 [Indexed for MEDLINE]
Conflict of interest statement: COMPETING INTERESTS The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/19675130 | 1. Development. 2009 Sep;136(18):3067-75. doi: 10.1242/dev.036426. Epub 2009 Aug
12.
Enhancer-promoter communication at the Drosophila engrailed locus.
Kwon D(1), Mucci D, Langlais KK, Americo JL, DeVido SK, Cheng Y, Kassis JA.
Author information:
(1)Laboratory of Molecular Genetics, Eunice Kennedy Shriver National Institute
of Child Health and Human Development, National Institutes of Health, Bethesda,
MD 20892, USA.
Enhancers are often located many tens of kilobases away from the promoter they
regulate, sometimes residing closer to the promoter of a neighboring gene. How
do they know which gene to activate? We have used homing P[en] constructs to
study the enhancer-promoter communication at the engrailed locus. Here we show
that engrailed enhancers can act over large distances, even skipping over other
transcription units, choosing the engrailed promoter over those of neighboring
genes. This specificity is achieved in at least three ways. First, early acting
engrailed stripe enhancers exhibit promoter specificity. Second, a proximal
promoter-tethering element is required for the action of the imaginal disc
enhancer(s). Our data suggest that there are two partially redundant
promoter-tethering elements. Third, the long-distance action of engrailed
enhancers requires a combination of the engrailed promoter and sequences within
or closely linked to the promoter proximal Polycomb-group response elements.
These data show that multiple mechanisms ensure proper enhancer-promoter
communication at the Drosophila engrailed locus.
DOI: 10.1242/dev.036426
PMCID: PMC2730364
PMID: 19675130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32038719 | 1. Front Genet. 2020 Jan 21;10:1372. doi: 10.3389/fgene.2019.01372. eCollection
2019.
4See: A Flexible Browser to Explore 4C Data.
Ben Zouari Y(1)(2)(3)(4), Platania A(1)(2)(3)(4), Molitor AM(1)(2)(3)(4), Sexton
T(1)(2)(3)(4).
Author information:
(1)Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch,
France.
(2)CNRS UMR7104, Illkirch, France.
(3)INSERM U1258, Illkirch, France.
(4)University of Strasbourg, Illkirch, France.
It is established that transcription of many metazoan genes is regulated by
distal regulatory sequences beyond the promoter. Enhancers have been identified
at up to megabase distances from their regulated genes, and/or proximal to or
within the introns of unregulated genes. The unambiguous identification of the
target genes of newly identified regulatory elements can thus be challenging.
Well-studied enhancers have been found to come into direct physical proximity
with regulated genes, presumably by the formation of chromatin loops. Chromosome
conformation capture (3C) derivatives that assess the frequency of proximity
between different genetic elements is thus a popular method for exploring gene
regulation by distal regulatory elements. For studies of chromatin loops and
promoter-enhancer communication, 4C (circular chromosome conformation capture)
is one of the methods of choice, optimizing cost (required sequencing depth),
throughput, and resolution. For ease of visual inspection of 4C data we present
4See, a versatile and user-friendly browser. 4See allows 4C profiles from the
same bait to be flexibly plotted together, allowing biological replicates to
either be compared, or pooled for comparisons between different cell types or
experimental conditions. 4C profiles can be integrated with gene tracks, linear
epigenomic profiles, and annotated regions of interest, such as called
significant interactions, allowing rapid data exploration with limited
computational resources or bioinformatics expertise.
Copyright © 2020 Ben Zouari, Platania, Molitor and Sexton.
DOI: 10.3389/fgene.2019.01372
PMCID: PMC6985583
PMID: 32038719 |
http://www.ncbi.nlm.nih.gov/pubmed/30704404 | 1. BMC Bioinformatics. 2019 Jan 31;20(1):60. doi: 10.1186/s12859-019-2655-2.
InTAD: chromosome conformation guided analysis of enhancer target genes.
Okonechnikov K(1)(2), Erkek S(1)(2)(3)(4), Korbel JO(3), Pfister SM(1)(2)(5),
Chavez L(6).
Author information:
(1)Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg,
Germany.
(2)Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany.
(3)Genome Biology Unit, European Molecular Biology Laboratory (EMBL),
Heidelberg, Germany.
(4)Izmir Biomedicine and Genome Center, Izmir, Turkey.
(5)Department of Pediatric Hematology and Oncology, Heidelberg University
Hospital, Heidelberg, Germany.
(6)Department of Medicine, Division of Medical Genetics, University of
California San Diego (UCSD), San Diego, USA. [email protected].
BACKGROUND: High-throughput technologies for analyzing chromosome conformation
at a genome scale have revealed that chromatin is organized in topologically
associated domains (TADs). While TADs are relatively stable across cell types,
intra-TAD activities are cell type specific. Epigenetic profiling of different
tissues and cell-types has identified a large number of non-coding epigenetic
regulatory elements ('enhancers') that can be located far away from coding
genes. Linear proximity is a commonly chosen criterion for associating enhancers
with their potential target genes. While enhancers frequently regulate the
closest gene, unambiguous identification of enhancer regulated genes remains to
be a challenge in the absence of sample matched chromosome conformation data.
RESULTS: To associate enhancers with their target genes, we have previously
developed and applied a method that tests for significant correlations between
enhancer and gene expressions across a cohort of samples. To limit the number of
tests, we constrain this analysis to gene-enhancer pairs embedded in the same
TAD, where information on TAD boundaries is borrowed from publicly available
chromosome conformation capturing ('Hi-C') data. We have now implemented this
method as an R Bioconductor package 'InTAD' and verified the software package by
reanalyzing available enhancer and gene expression data derived from ependymoma
brain tumors.
CONCLUSION: The open-source package InTAD is an easy-to-use software tool for
identifying proximal and distal enhancer target genes by leveraging information
on correlated expression of enhancers and genes that are located in the same
TAD. InTAD can be applied to any heterogeneous cohort of samples analyzed by a
combination of gene expression and epigenetic profiling techniques and
integrates either public or custom information of TAD boundaries.
DOI: 10.1186/s12859-019-2655-2
PMCID: PMC6357397
PMID: 30704404 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/22183586 | 1. Methods Mol Biol. 2012;833:29-45. doi: 10.1007/978-1-61779-477-3_3.
Monitoring the effects of chromatin remodelers on long-range interactions in
vivo.
Kiefer CM(1), Dean A.
Author information:
(1)Laboratory of Cellular and Developmental Biology, National Institutes of
Health, Bethesda, MD, USA.
In metazoans transcriptional enhancers and their more complex relatives, locus
control regions, are often located at great linear distances from their target
genes. In addition, these elements frequently activate different members of gene
families in temporal sequence or in different tissues. These issues have
complicated understanding the mechanisms underlying long-range gene activation.
Advances in primarily technical approaches, such as chromosome conformation
capture (3C) and its derivatives have now solidified the idea that distant
regulatory elements achieve proximity with their target genes when they are
activating them. Furthermore, these approaches are now allowing genome-wide
views of chromosome interactions that are likely to include regulatory,
structural, and organization aspects from which we will be able to understand
more about nuclear structure. At the base of these advances are experimental
approaches to localize protein-binding sites in chromatin, to assess remodeling
of chromatin and to measure interaction frequency between distant sites.
Examples of these approaches comprise this review.
DOI: 10.1007/978-1-61779-477-3_3
PMID: 22183586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29583027 | 1. Epigenomics. 2018 Apr 1;10(4):483-498. doi: 10.2217/epi-2017-0157. Epub 2018
Mar 27.
Enhancer talk.
Snetkova V(1)(2), Skok JA(1).
Author information:
(1)Department of Pathology, New York University School of Medicine, 550 First
Avenue, MSB 599, New York, NY 10016, USA.
(2)MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Enhancers are short noncoding segments of DNA (100-1000 bp) that control the
temporal and spatial activity of genes in an orientation-independent manner.
They can be separated from their target genes by large distances and are thus
known as distal regulatory elements. One consequence of the variability in the
distance separating enhancers and their target promoters is that it is difficult
to determine which elements are involved in the regulation of a particular gene.
Moreover, enhancers can be found in clusters in which multiple regulatory
elements control expression of the same target gene. However, little is known
about how the individual elements contribute to gene expression. Here, we
describe how chromatin conformation promotes and constraints enhancer activity.
Further, we discuss enhancer clusters and what is known about the contribution
of individual elements to the regulation of target genes. Finally, we examine
the reliability of different methods used to identify enhancers.
DOI: 10.2217/epi-2017-0157
PMCID: PMC5925435
PMID: 29583027 [Indexed for MEDLINE]
Conflict of interest statement: Financial & competing interests disclosure JA
Skok is supported by NIH grant R35GM122515, 4P30CA016087-36 Cancer Center
Support Grant NIH/NCI (Neel) and 2R01CA140729-06A1 NIH/NCI (Carroll). The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this
manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/12426570 | 1. Nat Genet. 2002 Dec;32(4):623-6. doi: 10.1038/ng1051. Epub 2002 Nov 11.
Long-range chromatin regulatory interactions in vivo.
Carter D(1), Chakalova L, Osborne CS, Dai YF, Fraser P.
Author information:
(1)Laboratory of Chromatin and Gene Expression, Developmental Genetics
Programme, The Babraham Institute, Cambridge CB2 4AT, UK.
Communication between distal chromosomal elements is essential for control of
many nuclear processes. For example, genes in higher eukaryotes often require
distant enhancer sequences for high-level expression. The mechanisms proposed
for long-range enhancer action fall into two basic categories. Non-contact
models propose that enhancers act at a distance to create a favorable
environment for gene transcription, or act as entry sites or nucleation points
for factors that ultimately communicate with the gene. Contact models propose
that communication occurs through direct interaction between the distant
enhancer and the gene by various mechanisms that 'loop out' the intervening
sequences. Although much attention has focused on contact models, the existence
and nature of long-range interactions is still controversial and speculative, as
there is no direct evidence that distant sequences physically interact in vivo.
Here, we report the development of a widely applicable in situ technique to tag
and recover chromatin in the immediate vicinity of an actively transcribed gene.
We show that the classical enhancer element, HS2 of the prototypical locus
control region (LCR) of the beta-globin gene cluster, is in close physical
proximity to an actively transcribed HBB (beta-globin) gene located over 50 kb
away in vivo, suggesting a direct regulatory interaction. The results give
unprecedented insight into the in vivo structure of the LCR-gene interface and
provide the first direct evidence of long-range enhancer communication.
DOI: 10.1038/ng1051
PMID: 12426570 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36071071 | 1. Sci Rep. 2022 Sep 7;12(1):15183. doi: 10.1038/s41598-022-19099-3.
A machine learning technique for identifying DNA enhancer regions utilizing
CIS-regulatory element patterns.
Butt AH(1), Alkhalifah T(2), Alturise F(3), Khan YD(1).
Author information:
(1)Department of Computer Science, School of Systems and Technology, University
of Management and Technology, Lahore, Pakistan.
(2)Department of Computer, College of Science and Arts in Ar Rass, Qassim
University, Ar Rass, Saudi Arabia. [email protected].
(3)Department of Computer, College of Science and Arts in Ar Rass, Qassim
University, Ar Rass, Saudi Arabia.
Enhancers regulate gene expression, by playing a crucial role in the synthesis
of RNAs and proteins. They do not directly encode proteins or RNA molecules. In
order to control gene expression, it is important to predict enhancers and their
potency. Given their distance from the target gene, lack of common motifs, and
tissue/cell specificity, enhancer regions are thought to be difficult to predict
in DNA sequences. Recently, a number of bioinformatics tools were created to
distinguish enhancers from other regulatory components and to pinpoint their
advantages. However, because the quality of its prediction method needs to be
improved, its practical application value must also be improved. Based on
nucleotide composition and statistical moment-based features, the current study
suggests a novel method for identifying enhancers and non-enhancers and
evaluating their strength. The proposed study outperformed state-of-the-art
techniques using fivefold and tenfold cross-validation in terms of accuracy. The
accuracy from the current study results in 86.5% and 72.3% in enhancer site and
its strength prediction respectively. The results of the suggested methodology
point to the potential for more efficient and successful outcomes when
statistical moment-based features are used. The current study's source code is
available to the research community at https://github.com/csbioinfopk/enpred .
© 2022. The Author(s).
DOI: 10.1038/s41598-022-19099-3
PMCID: PMC9452539
PMID: 36071071 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33837536 | 1. Physiol Plant. 2021 Dec;173(4):1382-1391. doi: 10.1111/ppl.13421. Epub 2021
Apr 21.
Enhancers as potential targets for engineering salinity stress tolerance in crop
plants.
Jain M(1), Garg R(2).
Author information:
(1)School of Computational and Integrative Sciences, Jawaharlal Nehru
University, New Delhi, India.
(2)Department of Life Sciences, School of Natural Sciences, Shiv Nadar
University, Gautam Buddha Nagar, Uttar Pradesh, India.
Enhancers represent noncoding regulatory regions of the genome located distantly
from their target genes. They regulate gene expression programs in a
context-specific manner via interacting with promoters of one or more target
genes and are generally associated with transcription factor binding sites and
epi(genomic)/chromatin features, such as regions of chromatin accessibility and
histone modifications. The enhancers are difficult to identify due to the
modularity of their associated features. Although enhancers have been studied
extensively in human and animals, only a handful of them has been identified in
few plant species till date due to nonavailability of plant-specific
experimental and computational approaches for their discovery. Being an
important regulatory component of the genome, enhancers represent potential
targets for engineering agronomic traits, including salinity stress tolerance in
plants. Here, we provide a review of the available experimental and
computational approaches along with the associated sequence and
chromatin/epigenetic features for the discovery of enhancers in plants. In
addition, we provide insights into the challenges and future prospects of
enhancer research in plant biology with emphasis on potential applications in
engineering salinity stress tolerance in crop plants.
© 2021 Scandinavian Plant Physiology Society.
DOI: 10.1111/ppl.13421
PMID: 33837536 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21831473 | 1. Trends Genet. 2011 Oct;27(10):433-9. doi: 10.1016/j.tig.2011.06.009. Epub 2011
Aug 9.
Noncoding RNAs and enhancers: complications of a long-distance relationship.
Orom UA(1), Shiekhattar R.
Author information:
(1)The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Spatial and temporal regulation of gene expression is achieved through
instructions provided by the distal transcriptional regulatory elements known as
enhancers. How enhancers transmit such information to their targets has been the
subject of intense investigation. Recent advances in high throughput analysis of
the mammalian transcriptome have revealed a surprising result indicating that a
large number of enhancers are transcribed to noncoding RNAs. Although long
noncoding RNAs were initially shown to confer epigenetic transcriptional
repression, recent studies have uncovered a role for a class of such transcripts
in gene-specific activation, often from distal genomic regions. In this review,
we discuss recent findings on the role of long noncoding RNAs in transcriptional
regulation, with an emphasis on new developments on the functional links between
long noncoding RNAs and enhancers.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tig.2011.06.009
PMCID: PMC4484734
PMID: 21831473 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36376800 | 1. BMC Bioinformatics. 2022 Nov 14;23(1):480. doi: 10.1186/s12859-022-05033-x.
iEnhancer-DCLA: using the original sequence to identify enhancers and their
strength based on a deep learning framework.
Liao M(1), Zhao JP(2), Tian J(1), Zheng CH(3)(4).
Author information:
(1)College of Mathematics and System Sciences, Xinjiang University, Ürümqi,
China.
(2)College of Mathematics and System Sciences, Xinjiang University, Ürümqi,
China. [email protected].
(3)College of Mathematics and System Sciences, Xinjiang University, Ürümqi,
China. [email protected].
(4)School of Computer Science and Technology, Anhui University, Hefei, China.
[email protected].
Enhancers are small regions of DNA that bind to proteins, which enhance the
transcription of genes. The enhancer may be located upstream or downstream of
the gene. It is not necessarily close to the gene to be acted on, because the
entanglement structure of chromatin allows the positions far apart in the
sequence to have the opportunity to contact each other. Therefore, identifying
enhancers and their strength is a complex and challenging task. In this article,
a new prediction method based on deep learning is proposed to identify enhancers
and enhancer strength, called iEnhancer-DCLA. Firstly, we use word2vec to
convert k-mers into number vectors to construct an input matrix. Secondly, we
use convolutional neural network and bidirectional long short-term memory
network to extract sequence features, and finally use the attention mechanism to
extract relatively important features. In the task of predicting enhancers and
their strengths, this method has improved to a certain extent in most evaluation
indexes. In summary, we believe that this method provides new ideas in the
analysis of enhancers.
© 2022. The Author(s).
DOI: 10.1186/s12859-022-05033-x
PMCID: PMC9664816
PMID: 36376800 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/25607649 | 1. Cell Cycle. 2015;14(2):253-60. doi: 10.4161/15384101.2014.977641.
Long ncRNA expression associates with tissue-specific enhancers.
Vučićević D(1), Corradin O, Ntini E, Scacheri PC, Ørom UA.
Author information:
(1)a Noncoding RNA Research Group; Max Planck Institute for Molecular Genetics ;
Berlin , Germany.
Comment in
Cell Cycle. 2015;14(11):1619-20. doi: 10.1080/15384101.2015.1032650.
Long non-coding RNAs (ncRNA) have recently been demonstrated to be expressed
from a subset of enhancers and to be required for the distant regulation of gene
expression. Several approaches to predict enhancers have been developed based on
various chromatin marks and occupancy of enhancer-binding proteins. Despite the
rapid advances in the field, no consensus how to define tissue specific
enhancers yet exists. Here, we identify 2,695 long ncRNAs annotated by ENCODE
(corresponding to 28% of all ENCODE annotated long ncRNAs) that overlap
tissue-specific enhancers. We use a recently developed algorithm to predict
tissue-specific enhancers, PreSTIGE, that is based on the H3K4me1 mark and
tissue specific expression of mRNAs. The expression of the long ncRNAs
overlapping enhancers is significantly higher when the enhancer is predicted as
active in a specific cell line, suggesting a general interdependency of active
enhancers and expression of long ncRNAs. This dependency is not identified using
previous enhancer prediction algorithms that do not account for expression of
their downstream targets. The predicted enhancers that overlap annotated long
ncRNAs generally have a lower ratio of H3K4me1 to H3K4me3, suggesting that
enhancers expressing long ncRNAs might be associated with specific epigenetic
marks. In conclusion, we demonstrate the tissue-specific predictive power of
PreSTIGE and provide evidence for thousands of long ncRNAs that are expressed
from active tissue-specific enhancers, suggesting a particularly important
functional relationship between long ncRNAs and enhancer activity in determining
tissue-specific gene expression.
DOI: 10.4161/15384101.2014.977641
PMCID: PMC4614992
PMID: 25607649 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31916476 | 1. RNA Biol. 2020 Nov;17(11):1550-1559. doi: 10.1080/15476286.2020.1712895. Epub
2020 Jan 19.
Enhancer RNAs in cancer: regulation, mechanisms and therapeutic potential.
Lee JH(1), Xiong F(1), Li W(1)(2).
Author information:
(1)Department of Biochemistry and Molecular Biology, McGovern Medical School,
University of Texas Health Science Center , Houston, TX, USA.
(2)Graduate School of Biomedical Sciences, University of Texas MD Anderson
Cancer Center and UTHealth , Houston, TX, USA.
Enhancers are distal genomic elements critical for gene regulation and cell
identify control during development and diseases. Many human cancers were found
to associate with enhancer malfunction, due to genetic and epigenetic
alterations, which in some cases directly drive tumour growth. Conventionally,
enhancers are known to provide DNA binding motifs to recruit transcription
factors (TFs) and to control target genes. However, recent progress found that
most, if not all, active enhancers pervasively transcribe noncoding RNAs that
are referred to as enhancer RNAs (eRNAs). Increasing evidence points to
functional roles of at least a subset of eRNAs in gene regulation in both normal
and cancer cells, adding new insights into the action mechanisms of enhancers.
eRNA expression was observed to be widespread but also specific to tumour types
and individual patients, serving as opportunities to exploit them as potential
diagnosis markers or therapeutic targets. In this review, we discuss the brief
history of eRNA research, their functional mechanisms and importance in cancer
gene regulation, as well as their therapeutic and diagnostic values in cancer.
We propose that further studies of eRNAs in cancer will offer a promising 'eRNA
targeted therapy' for human cancer intervention.
DOI: 10.1080/15476286.2020.1712895
PMCID: PMC7567500
PMID: 31916476 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported
by the authors. |
http://www.ncbi.nlm.nih.gov/pubmed/22555596 | 1. Nucleus. 2012 Mar 1;3(2):126-31. doi: 10.4161/nucl.19232. Epub 2012 Mar 1.
Chromatin signatures of active enhancers.
Spicuglia S(1), Vanhille L.
Author information:
(1)Inserm, UMR_S 928, TAGC, Marseille, France. [email protected]
Comment on
Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, Holota H,
et al. H3K4 tri-methylation provides an epigenetic signature of active
enhancers. EMBO J. 2011;30:4198–210. doi: 10.1038/emboj.2011.295.
Gene-distal cis-regulatory sequences, such as enhancers, are key contributors of
tissue-specific gene expression. In particular, enhancers can be located up to
hundreds of kilobases from the promoters that they control, making their
identification challenging. Thanks to the recent technological advances to map
histone modifications and chromatin-associated factors genome-wide, several
studies have begun to characterize chromatin signatures of active enhancers.
Here, we discuss some of these results and how they provide new insights into
the tissue-specific organization of enhancer repertoires.
DOI: 10.4161/nucl.19232
PMCID: PMC3383566
PMID: 22555596 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32952117 | 1. Yi Chuan. 2020 Sep 20;42(9):817-831. doi: 10.16288/j.yczz.20-097.
The identification of enhancers and its application in cancer studies.
Liu Q(1), Li CY(1)(2).
Author information:
(1)Beijing Advanced Innovation Center for Big Data-Based Precision Medicine &
School of Medical Sciences and Engineering, Beihang University, Beijing 100191,
China.
(2)Key Laboratory of Big Data-Based Precision Medicine (Beihang University),
Ministry of Industry and Information Technology, Beijing 100191, China.
Enhancers are a type of cis-acting DNA elements that enhance transcriptional
activity of target genes. However, the uncertainty in the orientation and
distance between enhancers and target genes could post significant difficulties
in identifying the target genes and the regulatory mechanisms of the enhancers.
Numerous studies have shown that the mutations and/or abnormalities in the
functions of enhancers are associated with development of diseases. A few
studies have reported that enhancers could activate cancer development or drug
resistance by promoting the expression of target genes. At present, enhancers
involved in carcinogenesis and drug resistance have not been fully identified,
and the underlying mechanism are still largely unknown. This paper summarizes
the main methods used in identifying and characterizing enhancers and analyzing
the regulatory mechanism at the genome-wide level. It further reviews the recent
research progress of enhancers in cancer diagnosis, treatment, and the
underlying mechanism during carcinogenesis, thereby providing a reference for
the screening of these enhancers involved in carcinogenesis and drug resistance
and exploring their regulatory mechanisms of target genes. It also provides a
new perspective for improving the diagnosis of cancer and insights for
formulating cancer therapeutic strategies.
Publisher:
增强子是一类增强靶基因转录活性的DNA顺式作用元件。但是增强子与靶基因的方向和距离不确定,大大增加了研究增强子调控的靶基因及其作用机制的困难。已有大量研究显示,增强子的突变或功能异常与疾病发生发展相关;仅有少量研究报道增强子通过促进靶基因的表达,引发癌症或产生抗药性。目前与癌症发生发展和在癌症治疗过程中抗药性产生相关的增强子尚未得到充分鉴定,这些增强子的调控机制也未得到充分解析。本文对目前可在全基因组水平上预测和鉴定增强子以及解析增强子调控机制的方法进行总结和对比,并对近几年增强子在肿瘤诊断、治疗和发生发展机制中的研究进展进行综述。期望本文为筛选与癌症发生发展相关的增强子和解析这些增强子的调控机制提供参考,为提高癌症的诊断和制定癌症的治疗策略提供新的视角。.
DOI: 10.16288/j.yczz.20-097
PMID: 32952117 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15809261 | 1. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R101-11. doi: 10.1093/hmg/ddi104.
Remote control of gene transcription.
West AG(1), Fraser P.
Author information:
(1)Division of Cancer Sciences and Molecular Pathology, University of Glasgow,
Western Infirmary, Glasgow, UK. [email protected]
In this review, we look at the most recent studies of DNA elements that function
over long genomic distances to regulate gene transcription and will discuss the
mechanisms genes employ to overcome the positive and negative influences of
their genomic neighbourhood in order to achieve accurate programmes of
expression. Enhancer elements activate high levels of transcription of linked
genes from distal locations. Recent technological advances have demonstrated
chromatin loop interactions between enhancers and their target promoters.
Moreover, there is increasing evidence that these dynamic interactions regulate
the repositioning of genes to foci of active transcription within the nucleus.
Enhancers have the potential to activate a number of neighbouring genes over a
large chromosomal region, hence, their action must be restricted in order to
prevent activation of non-target genes. This is achieved by specialized DNA
sequences, termed enhancer blockers (or insulators), that interfere with an
enhancer's ability to communicate with a target promoter when positioned between
the two. Here, we summarize current models of enhancer blocking activity and
discuss recent findings of how it can be dynamically regulated. It has become
clear that enhancer blocking elements should not be considered only as
structural elements on the periphery of gene loci, but as regulatory elements
that are crucial to the outcome of gene expression. The transcription potential
of a gene can also be susceptible to heterochromatic silencing originating from
its chromatin environment. Insulator elements can act as barriers to the spread
of heterochromatin. We discuss recent evidence supporting a number of
non-exclusive mechanisms of barrier action, which mostly describe the modulation
of chromatin structure or modification.
DOI: 10.1093/hmg/ddi104
PMID: 15809261 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34794294 | 1. J Coll Physicians Surg Pak. 2021 Dec;31(12):1494-1496. doi:
10.29271/jcpsp.2021.12.1494.
Spinal Muscular Atrophy with Respiratory Distress<br /> Type 1: A Novel Variant
of IGHMBP2 Gene.
Saeed M(1), Fawzy W(1), Al-Tala S(1), Magid TA(1), Ahmed H(1).
Author information:
(1)Department of Pediatric Medicine, King Fahad Armed Forces Hospital, Khamis
Mushait, Saudi Arabia.
Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an
exceptionally rare type of SMA. It results from disintegration of alpha motor
neurons of the spinal cord. Clinically, children affected with this disorder
present between the age of six weeks to six months with respiratory distress and
hypotonia. Most of the children die before the age of 13 months. Here, we report
a new variant in a female infant with SMARD1 having a novel IGHMBP2 gene
mutation. Despite supportive treatment, she died at the age of 5 months in
hospital. To the best of our knowledge, the variant has not been described in
the literature so far. Key Words: Spinal muscular atrophy with respiratory
distress type-1 (SMARD1), Hypotonia, respiratory distress, infants.
DOI: 10.29271/jcpsp.2021.12.1494
PMID: 34794294 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21258045 | 1. Brief Funct Genomics. 2011 Jan;10(1):3-10. doi: 10.1093/bfgp/elq033. Epub 2011
Jan 22.
In the loop: long range chromatin interactions and gene regulation.
Dean A(1).
Author information:
(1)Laboratory of Cellular and Developmental Biology, NIDDK, NIH, Building 50,
Room 3154, 50 South Drive, MSC 8028, Bethesda, MD 20892, USA.
[email protected]
Enhancers, silencer and insulators are DNA elements that play central roles in
regulation of the genome that are crucial for development and differentiation.
In metazoans, these elements are often separated from target genes by distances
that can reach 100 Kb. How regulation can be accomplished over long distances
has long been intriguing. Current data indicate that although the mechanisms by
which these diverse regulatory elements affect gene transcription may vary, an
underlying feature is the establishment of close contacts or chromatin loops.
With the generalization of this principle, new questions emerge, such as how the
close contacts are formed and stabilized and, importantly, how they contribute
to the regulation of transcriptional output at target genes. This review will
concentrate on examples where a functional role and a mechanistic understanding
has been explored for loops formed between genes and their regulatory elements
or among the elements themselves.
DOI: 10.1093/bfgp/elq033
PMCID: PMC3040559
PMID: 21258045 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8283989 | 1. Monatsschr Kinderheilkd. 1993 Nov;141(11):848-54.
[Spinal muscular atrophy in childhood. Possibilities and limits of clinical and
molecular genetic diagnosis].
[Article in German]
Zerres K(1), Rudnik-Schöneborn S, Röhrig D, Wirth B.
Author information:
(1)Institut für Humangenetik, Universität Bonn.
The proximal spinal muscular atrophies (SMA) are a clinically and genetically
heterogeneous group of neuromuscular disorders which are characterized by
selective degeneration of motor neurons in the spine and brainstem. The clinical
features resemble other muscle diseases, the diagnostic criteria of proximal SMA
have recently been defined by the International SMA Consortium. The
classification of the clinical picture in different subgroups is still a focus
of discussion. At present it seems likely that childhood onset SMA represents a
broad spectrum of various ages of onset and different degrees of disability.
Apart from different modes of inheritance, there is further evidence of
heterogeneity in proximal SMA. The autosomal recessive forms represent the
second frequent recessive disorder after cystic fibrosis, whereas autosomal
dominant inheritance is an exception in childhood onset SMA. There are no
convincing reports of X-linked SMA hitherto. With mapping of acute and chronic
forms of childhood SMA to chromosome 5q11.2-13.3 diagnosis by use of DNA markers
in affected families has become available. The current possibilities but also
problems and limitations of genotype analysis are discussed, with special regard
to the application of prenatal diagnosis. We report on the first experiences
with prenatal diagnosis in 37 SMA families.
PMID: 8283989 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30811991 | 1. Cell Rep. 2019 Feb 26;26(9):2419-2433.e3. doi: 10.1016/j.celrep.2019.02.002.
Positive and Negative Control of Enhancer-Promoter Interactions by Other DNA
Loops Generates Specificity and Tunability.
Hao N(1), Shearwin KE(2), Dodd IB(3).
Author information:
(1)Department of Molecular and Biomedical Science, The University of Adelaide,
Adelaide, SA 5005, Australia; CSIRO Synthetic Biology Future Science Platform,
Canberra, ACT 2601, Australia.
(2)Department of Molecular and Biomedical Science, The University of Adelaide,
Adelaide, SA 5005, Australia.
(3)Department of Molecular and Biomedical Science, The University of Adelaide,
Adelaide, SA 5005, Australia. Electronic address: [email protected].
Enhancers are ubiquitous and critical gene-regulatory elements. However,
quantitative understanding of the role of DNA looping in the regulation of
enhancer action and specificity is limited. We used the Escherichia coli NtrC
enhancer-σ54 promoter system as an in vivo model, finding that NtrC activation
is highly sensitive to the enhancer-promoter (E-P) distance in the 300-6,000 bp
range. DNA loops formed by Lac repressor were able to strongly regulate enhancer
action either positively or negatively, recapitulating promoter targeting and
insulation. A single LacI loop combining targeting and insulation produced a
strong shift in specificity for enhancer choice between two σ54 promoters. A
combined kinetic-thermodynamic model was used to quantify the effect of
DNA-looping interactions on promoter activity and revealed that sensitivity to
E-P distance and to control by other loops is itself dependent on enhancer and
promoter parameters that may be subject to regulation.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2019.02.002
PMID: 30811991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2801018 | 1. Acta Neurol Scand. 1989 Sep;80(3):208-14. doi:
10.1111/j.1600-0404.1989.tb03864.x.
Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy.
Niebroj-Dobosz I(1), Hausmanowa-Petrusewicz I.
Author information:
(1)Department of Neurology, Medical School, Warsaw, Poland.
Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in
infantile and juvenile spinal muscular atrophy (SMA) was determined. The total
AChE activity was either normal or decreased in the childhood SMA (Type 1), the
other SMA groups and disease controls (ALS, X-linked SMA). In the majority of
SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found.
This was accompanied by changes in the other asymmetric and globular forms. The
latter was, however, not specific for SMA Type 1 cases. The ChE activity was
increased in the majority of SMA cases as well as disease controls. The
asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of
this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA
Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence
of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell
immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes
is obscure.
DOI: 10.1111/j.1600-0404.1989.tb03864.x
PMID: 2801018 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36000541 | 1. Future Oncol. 2022 Sep;18(29):3255-3266. doi: 10.2217/fon-2022-0595. Epub 2022
Aug 24.
HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of
HER2-positive gastroesophageal adenocarcinoma.
Tabernero J(1), Shen L(2), Elimova E(3), Ku G(4), Liu T(5), Shitara K(6), Lin
X(7), Boyken L(8), Li H(7), Grim J(8), Ajani J(9).
Author information:
(1)Vall d'Hebron Hospital Campus & Institute of Oncology (VHIO), UVic-UCC,
IOB-Quiron, Barcelona, 08035, Spain.
(2)Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis &
Translational Research (Ministry of Education/Beijing), Peking University Cancer
Hospital & Institute, Beijing, 102206, China.
(3)Princess Margaret Cancer Centre, Toronto, Ontario, M5G 2M9, Canada.
(4)Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
(5)National Cancer Center Hospital, Kashiwa, Chiba, 277-0882, Japan.
(6)Zhongshan Hospital, Shanghai, Shanghai, 200031, China.
(7)BeiGene (Shanghai) Co., Ltd., Shanghai, Shanghai, 200020, China.
(8)Zymeworks Inc., Vancouver, British Columbia, V5T 1G4, Canada.
(9)The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
HER2-positive gastroesophageal adenocarcinomas (GEAs) are common cancers with
high mortality and the treatment options for advanced/metastatic disease are
limited. Zanidatamab and tislelizumab are novel monoclonal antibodies targeting
HER2 and PD-1, respectively, and have shown encouraging antitumor activity in
early phase studies in multiple cancers, including GEA. Preliminary data
suggest that dual targeting of the HER2 and PD-1 pathways could further improve
upon the results achieved with targeting either pathway alone. Here, we describe
the design of HERIZON-GEA-01, a global, randomized, open-label,
active-comparator, Phase III study to evaluate and compare the efficacy and
safety of zanidatamab plus chemotherapy with or without tislelizumab to the
standard of care (trastuzumab plus chemotherapy) as first-line treatment for
patients with advanced/metastatic HER2-positive GEAs.
Plain Language Summary: HERIZON-GEA-01: A phase III study of zanidatamab +
chemotherapy ± tislelizumab for first-line treatment of advanced or metastatic
#HER2-positive gastroesophageal adenocarcinoma (GEA). Clinicaltrials.gov:
NCT05152147. #gastriccancer #stomachcancer @ZymeworksInc @BeiGeneGlobal Clinical
Trial Registration: NCT05152147 (ClinicalTrials.gov).
DOI: 10.2217/fon-2022-0595
PMID: 36000541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36400106 | 1. Lancet Oncol. 2022 Dec;23(12):1558-1570. doi: 10.1016/S1470-2045(22)00621-0.
Epub 2022 Nov 16.
Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced
or metastatic HER2-expressing or HER2-amplified cancers: a phase 1,
dose-escalation and expansion study.
Meric-Bernstam F(1), Beeram M(2), Hamilton E(3), Oh DY(4), Hanna DL(5), Kang
YK(6), Elimova E(7), Chaves J(8), Goodwin R(9), Lee J(10), Nabell L(11), Rha
SY(12), Mayordomo J(13), El-Khoueiry A(14), Pant S(15), Raghav K(15), Kim
JW(16), Patnaik A(2), Gray T(17), Davies R(17), Ozog MA(17), Woolery J(17), Lee
KW(16).
Author information:
(1)Department of Investigational Cancer Therapeutics, University of Texas MD
Anderson Cancer Center, Houston, TX, USA. Electronic address:
[email protected].
(2)START Center for Cancer Care, San Antonio, TX, USA.
(3)Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology,
Nashville, TN, USA.
(4)Department of Internal Medicine, Seoul National University Hospital, Seoul,
South Korea; Cancer Research Institute, Seoul National University College of
Medicine, Seoul, South Korea; Integrated Major in Innovative Medical Science,
Seoul National University Graduate School, Seoul, South Korea.
(5)USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Hoag Cancer
Centre, Newport Beach, CA, USA.
(6)Asan Medical Center, University of Ulsan, Seoul, South Korea.
(7)Princess Margaret Cancer Centre, Toronto, ON, Canada.
(8)Northwest Medical Specialties, Tacoma, WA, USA.
(9)Ottawa Hospital Cancer Centre, Ottawa Hospital Research Centre, Ottawa, ON,
Canada.
(10)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea.
(11)University of Alabama at Birmingham, Birmingham, AL, USA.
(12)Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South
Korea.
(13)University of Colorado Cancer Center, Aurora, CO, USA.
(14)USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
(15)Department of Investigational Cancer Therapeutics, University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(16)Seoul National University College of Medicine, Seoul National University
Bundang Hospital, Seongnam, South Korea.
(17)Zymeworks, Vancouver, BC, Canada.
BACKGROUND: HER2-targeted therapies have substantially improved outcomes for
patients with HER2-positive breast and gastric or gastro-oesophageal junction
cancers. Several other cancers exhibit HER2 expression or amplification,
suggesting that HER2-targeted agents can have broader therapeutic impact.
Zanidatamab is a humanised, bispecific monoclonal antibody directed against two
non-overlapping domains of HER2. The aim of this study was to evaluate the
safety and anti-tumour activity of zanidatamab across a range of solid tumours
with HER2 expression or amplification.
METHODS: This first-in-human, multicentre, phase 1, dose-escalation and
expansion trial included patients aged 18 years and older, with a life
expectancy of at least 3 months, with an Eastern Cooperative Oncology Group
performance status of 0 or 1, and locally advanced or metastatic,
HER2-expressing or HER2-amplified solid tumours of any kind who had received all
available approved therapies. The primary objectives of part 1 were to identify
the maximum tolerated dose, optimal biological dose, or recommended dose of
zanidatamab; all patients were included in the primary analyses. Part 1 followed
a 3 + 3 dose-escalation design, including different intravenous doses (from 5
mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective
of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy
in solid tumours. This trial is registered with ClinicalTrials.gov
(NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study
evaluates the use of zanidatamab in combination with chemotherapy and is
ongoing.
FINDINGS: Recruitment took place between Sept 1, 2016, and March 13, 2021. In
Part 1 (n=46), no dose-limiting toxicities were detected and the maximum
tolerated dose was not reached. The recommended dose for part 2 (n=22 for
biliary tract cancer; n=28 for colorectal cancer; and n=36 for other
HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal
cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent
treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%]
of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients;
all grade 1-2). The most frequent treatment-related adverse events in part 2 of
the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one
patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A
total of six grade 3 treatment-related adverse events were reported in four (3%)
of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients
had a confirmed objective response. There were no treatment-related deaths.
INTERPRETATION: These results support that HER2 is an actionable target in
various cancer histologies, including biliary tract cancer and colorectal
cancer. Evaluation of zanidatamab continues in ongoing studies.
FUNDING: Zymeworks.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00621-0
PMID: 36400106 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests FM-B reports consulting
or personal fees from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, DebioPharm,
eFFECTOR Therapeutics, F Hoffman-La Roche, Genentech, IBM Watson, Infinity
Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics,
OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seagen,
Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, and Chugai; advisory
board participation for Black Diamond, Biovica, Eisai, Immunomedics, Inflection
Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics,
OnCusp Therapeutics, Puma Biotechnology, Seagen, Silverback Therapeutics,
Spectrum Pharmaceuticals, and Zentalis; and research support, unrelated to this
work and paid to institution, from Aileron Therapeutics, AstraZeneca, Bayer
Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics,
Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech,
Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma
Biotechnology, and Taiho Pharmaceutical. EH reports consulting fees or research
grants outside of the scope of this work and paid to the institution from
AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive,
Arcus, ArQule, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Boehringer
Ingelheim, Clovis, Compugen, Curis, CytomX, Daiichi Sankyo, the Dana-Farber
Cancer Institute, Dantari, Deciphera, eFFECTOR Therapeutics, Eisai, Ellipses
Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, Greenwich LifeSciences,
H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte,
InvestisBio, iTeos, Jacobio, Janssen, Karyopharm, Leap Therapeutics, Lilly,
Loxo, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana,
Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis,
Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove,
Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr
Immunotherapeutics, Plexxikon, Puma Biotechnology, Radius Health, Regeneron,
Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen,
Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx,
Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Treadwell Therapeutics,
Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks. D-YO reports
consulting fees or Advisory Board participation for AstraZeneca, Novartis,
Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol
Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences,
IQVIA, and research support outside the scope of this work from AstraZeneca,
Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. Y-KK reports
consulting fees from ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics,
Daehwa, Blueprint, Surface Oncology, Bristol Myers Squibb, MSD, and Roche. EE
reports consulting fees from Bristol Myers Squibb, Zymeworks, Adaptimmune,
BeiGene; research support outside the scope of this work from Bristol Myers
Squibb, Zymeworks, and AstraZeneca; and a family member employedby Merck. RG
reports consulting fees or advisory board participation for Pfizer, Apobiologix,
Ipsen, Novartis, Eisai, Incyte, Bristol Myers Squibb, AstraZeneca, Merck, Roche,
and Advanced Accelerator Applications; and education grants from Pfizer,
Apobiologix, and Ipsen. SP reports consulting fees or advisory board
participation for Xencor, 4D Pharma, Zymeworks, Ipsen, Novartis, and Janssen;
research support outside the scope of this work and paid to institution from
Mirati Therapeutics, Pfizer, Lilly, Xencor, Novartis, Bristol Myers Squibb,
Ipsen, Astellas Pharma, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM
Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Zymeworks,
and BioNtech. KR reports personal fees from AstraZeneca, Bayer, Daiichi-Sankyo,
Eisai, and Seattle Genetics; and research support from Bayer, Daiichi-Sankyo,
Genentech/Roche, Guardant Health, Janssen, Lilly, and Medimmune outside the
submitted work. JWK reports consulting fees from AstraZeneca, BeiGene, Beyond
Bio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD, ONO, Sanofi-Aventis,
Servier, and TCUBEit. AP reports consulting or advisory fees from
Genentech/Roche, Merck, Bristol Myers Squibb, Bayer, Novartis, Seagen, Gilead
Sciences, Silverback Therapeutics, Daiichi, and HalioDx. TG, RD, and MAO report
employment by Zymeworks at the time of the study and ownership of Zymeworks
stock. JW reports employment by Zymeworks at the time of the study and ownership
of Seagen stock. K-WL reports consulting fees from ISU ABXIS, Bayer, Daiichi
Sankyo, Merck Sharp and Dohme, Bristol Myers Squibb, Vifor Pharma, Ono
Pharmaceutical, and Boryung; and research grants outside of the scope of this
work from AstraZeneca, Ono Pharmaceutical, Merck Sharp and Dohme, Merck KGaA,
Pfizer, BeiGene, Astellas Pharma, ALX Oncology, Macrogenetics, Five Prime
Therapeutics, Seagen, Bolt Therapeutics, Trishula Therapeutics, Oncologie,
Pharmacyclics, LSK BioPharma, MedPacto, Green Cross Corp, ABLBIO, Y-BIOLOGICS,
Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InventisBio, and Leap
Therapeutics. All other authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36459075 | 1. |
http://www.ncbi.nlm.nih.gov/pubmed/34626563 | 1. Lancet Gastroenterol Hepatol. 2021 Nov;6(11):956-969. doi:
10.1016/S2468-1253(21)00171-0.
Current and emerging therapies for advanced biliary tract cancers.
Kam AE(1), Masood A(2), Shroff RT(3).
Author information:
(1)Division of Hematology, Oncology and Cell Therapy, Rush University Medical
Center, Chicago, IL, USA. Electronic address: [email protected].
(2)Division of Hematology, Oncology and Cell Therapy, Rush University Medical
Center, Chicago, IL, USA.
(3)Division of Hematology and Oncology, University of Arizona Cancer Center,
Tucson, AZ, USA.
Comment in
Expert Rev Gastroenterol Hepatol. 2022 Apr;16(4):307-310. doi:
10.1080/17474124.2022.2055548.
Biliary tract cancers (cholangiocarcinomas and gallbladder cancers) are
increasing in incidence and have a poor prognosis. Most patients present with
advanced disease, for which the treatment is palliative chemotherapy. Over the
past few years, the genomic landscape of biliary tract cancers has been examined
and several targeted therapies have been developed. Molecular targets with
clinically meaningful activity include fibroblast growth factor receptor (FGFR),
isocitrate dehydrogenase (IDH), RAS-RAF-MEK (MAP2K1)-ERK (MAPK3), HER2 (also
known as ERBB2), DNA mismatch repair, and NTRK. Pemigatinib, a FGFR1-3
inhibitor, showed encouraging response rates and survival data as second-line
treatment and received US Food and Drug Administration (FDA) approval in April,
2020, for previously treated advanced or metastatic cholangiocarcinoma with
FGFR2 gene fusion or rearrangements. Ivosidenib, an IDH1 inhibitor, showed
improved progression-free survival versus placebo in second-line treatment in
the phase 3 ClarIDHy trial. Early phase trials of dabrafenib plus trametinib
(BRAF and MEK inhibition) and zanidatamab (a bispecific HER2-antibody) have
yielded encouraging response rates. Immunotherapy has mainly produced responses
in tumours with deficient mismatch repair or high microsatellite instability
(also known as dMMR or MSI-H) or higher PD-L1 score, or both. However, early
phase trials of immunotherapy plus chemotherapy in unselected patient
populations appear promising. NTRK inhibitors have also shown promise in early
phase trials of NTRK-fusion positive solid tumours, including
cholangiocarcinoma. In this Review, we discuss current and emerging therapies
for advanced biliary tract cancers, with a focus on molecularly targeted
therapy.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S2468-1253(21)00171-0
PMID: 34626563 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests RTS reports grants from
Merck, Exelixis Pharmaceuticals, Pieris, Taiho, and Rafael Pharmaceuticals, and
is an advisory board member for Seattle Genetics, QED Therapeutics, Debiopharm,
Agios, Clovis, and Incyte. AM reports grants from Tempus Labs. AEK declares no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36472472 | 1. MAbs. 2023 Jan-Dec;15(1):2153410. doi: 10.1080/19420862.2022.2153410.
Antibodies to watch in 2023.
Kaplon H(1), Crescioli S(2), Chenoweth A(2), Visweswaraiah J(3), Reichert JM(4).
Author information:
(1)Translational Medicine Department, Institut de Recherches Internationales
Servier Suresnes, France.
(2)St. John's Institute of Dermatology, School of Basic & Medical Biosciences,
King's College London, London UK.
(3)Drug Creation, Seismic Therapeutic, Cambridge MA USA.
(4)The Antibody Society Inc, Framingham, MA USA.
In this 14th installment of the annual Antibodies to Watch article series, we
discuss key events in commercial monoclonal antibody therapeutics development
that occurred in 2022 and forecast events that might occur in 2023. As of
mid-November, 12 antibody therapeutics had been granted first approvals in
either the United States or European Union (tebentafusp (Kimmtrak), faricimab
(Vabysmo), sutimlimab (Enjaymo), relatlimab (Opdualag), tixagevimab/cilgavimab
(Evusheld), mosunetuzumab (Lunsumio), teclistamab (TECVAYLI), spesolimab
(SPEVIGO), tremelimumab (Imjudo; combo with durvalumab), nirsevimab (Beyfortus),
mirvetuximab soravtansine (ELAHERE™), and teplizumab (TZIELD)), including 4
bispecific antibodies and 1 ADC. Based on FDA action dates, several additional
product candidates could be approved by the end of 2022. An additional seven
were first approved in China or Japan in 2022, including two bispecific
antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational
antibody therapeutics are undergoing review by regulatory agencies as of
mid-November 2022. Our data show that, with antibodies for COVID-19 excluded,
the late-stage commercial clinical pipeline grew by ~20% in the past year to
include nearly 140 investigational antibody therapeutics that were designed
using a wide variety of formats and engineering techniques. Of those in
late-stage development, marketing application submissions for at least 23 may
occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab,
linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab
deruxtecan, and tusamitamab ravtansine).
DOI: 10.1080/19420862.2022.2153410
PMCID: PMC9728470
PMID: 36472472 [Indexed for MEDLINE]
Conflict of interest statement: HK and JV are employed by companies that develop
antibody therapeutics. JMR is employed by The Antibody Society, a non-profit
trade association funded by corporate sponsors that develop antibody
therapeutics or provide services to companies that develop antibody
therapeutics, and she is Editor-in-Chief of mAbs, a biomedical journal focused
on topics relevant to antibody therapeutics development. Data in this
publication were collected from publicly available sources. |
http://www.ncbi.nlm.nih.gov/pubmed/8713055 | 1. Biochem J. 1996 Jul 15;317 ( Pt 2)(Pt 2):329-42. doi: 10.1042/bj3170329.
Multiple steps in the regulation of transcription-factor level and activity.
Calkhoven CF(1), Ab G.
Author information:
(1)Department of Biochemistry, University of Groningen, The Netherlands.
This review focuses on the regulation of transcription factors, many of which
are DNA-binding proteins that recognize cis-regulatory elements of target genes
and are the most direct regulators of gene transcription. Transcription factors
serve as integration centres of the different signal-transduction pathways
affecting a given gene. It is obvious that the regulation of these regulators
themselves is of crucial importance for differential gene expression during
development and in terminally differentiated cells. Transcription factors can be
regulated at two, principally different, levels, namely concentration and
activity, each of which can be modulated in a variety of ways. The
concentrations of transcription factors, as of intracellular proteins in
general, may be regulated at any of the steps leading from DNA to protein,
including transcription, RNA processing, mRNA degradation and translation. The
activity of a transcription factor is often regulated by (de) phosphorylation,
which may affect different functions, e.g. nuclear localization DNA binding and
trans-activation. Ligand binding is another mode of transcription-factor
activation. It is typical for the large super-family of nuclear hormone
receptors. Heterodimerization between transcription factors adds another
dimension to the regulatory diversity and signal integration. Finally,
non-DNA-binding (accessory) factors may mediate a diverse range of functions,
e.g. serving as a bridge between the transcription factor and the basal
transcription machinery, stabilizing the DNA-binding complex or changing the
specificity of the target sequence recognition. The present review presents an
overview of different modes of transcription-factor regulation, each illustrated
by typical examples.
DOI: 10.1042/bj3170329
PMCID: PMC1217492
PMID: 8713055 [Indexed for MEDLINE] |