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http://www.ncbi.nlm.nih.gov/pubmed/28988716 | 1. Mol Ther. 2018 Jan 3;26(1):105-114. doi: 10.1016/j.ymthe.2017.08.019. Epub
2017 Sep 7.
Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with
Reduced Asialoglycoprotein Receptor Expression.
Willoughby JLS(1), Chan A(1), Sehgal A(1), Butler JS(1), Nair JK(1), Racie T(1),
Shulga-Morskaya S(1), Nguyen T(1), Qian K(1), Yucius K(1), Charisse K(1), van
Berkel TJC(2), Manoharan M(1), Rajeev KG(1), Maier MA(1), Jadhav V(1),
Zimmermann TS(3).
Author information:
(1)Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
(2)Division of Biopharmaceutics, Leiden Academic Center for Drug Research, 2300
RA Leiden, the Netherlands.
(3)Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA. Electronic address:
tzimmermann@alnylam.com.
The hepatocyte-specific asialoglycoprotein receptor (ASGPR) is an ideal
candidate for targeted drug delivery to the liver due to its high capacity for
substrate clearance from circulation together with its well-conserved expression
and function across species. The development of GalNAc-siRNA conjugates, in
which a synthetic triantennary N-acetylgalactosamine-based ligand is conjugated
to chemically modified siRNA, has enabled efficient, ASGPR-mediated delivery to
hepatocytes. To investigate the potential impact of variations in receptor
expression on the efficiency of GalNAc-siRNA conjugate delivery, we evaluated
the pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates in multiple
pre-clinical models with reduced receptor expression. Despite greater than 50%
reduction in ASGPR levels, GalNAc conjugate activity was retained, suggesting
that the remaining receptor capacity was sufficient to mediate efficient uptake
of potent GalNAc-siRNAs at pharmacologically relevant dose levels. Collectively,
our data support a broad application of the GalNAc-siRNA technology for hepatic
targeting, including disease states where ASGPR expression may be reduced.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2017.08.019
PMCID: PMC5762979
PMID: 28988716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30820542 | 1. Nucleic Acids Res. 2019 Apr 23;47(7):3306-3320. doi: 10.1093/nar/gkz140.
Safety evaluation of 2'-deoxy-2'-fluoro nucleotides in GalNAc-siRNA conjugates.
Janas MM(1), Zlatev I(1), Liu J(1), Jiang Y(1), Barros SA(1), Sutherland JE(1),
Davis WP(1), Liu J(1), Brown CR(1), Liu X(1), Schlegel MK(1), Blair L(1), Zhang
X(1), Das B(1), Tran C(1), Aluri K(1), Li J(1), Agarwal S(1), Indrakanti R(1),
Charisse K(1), Nair J(1), Matsuda S(1), Rajeev KG(1), Zimmermann T(1),
Sepp-Lorenzino L(1), Xu Y(1), Akinc A(1), Fitzgerald K(1), Vaishnaw AK(1), Smith
PF(1), Manoharan M(1), Jadhav V(1), Wu JT(1), Maier MA(1).
Author information:
(1)Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate
backbone are frequently used to confer drug-like properties. Because
2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their
safety profile was assessed when used in revusiran and ALN-TTRSC02, two short
interfering RNAs (siRNAs), of the same sequence but different chemical
modification pattern and metabolic stability, conjugated to an
N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes.
Exposure to 2'-F-monomer metabolites was low and transient in rats and humans.
In vitro, 2'-F-nucleoside 5'-triphosphates were neither inhibitors nor preferred
substrates for human polymerases, and no obligate or non-obligate chain
termination was observed. Modest effects on cell viability and mitochondrial DNA
were observed in vitro in a subset of cell types at high concentrations of
2'-F-nucleosides, typically not attained in vivo. No apparent functional impact
on mitochondria and no significant accumulation of 2'-F-monomers were observed
after weekly administration of two GalNAc-siRNA conjugates in rats for ∼2 years.
Taken together, the results support the conclusion that 2'-F nucleotides can be
safely applied for the design of metabolically stabilized therapeutic
GalNAc-siRNAs with favorable potency and prolonged duration of activity allowing
for low dose and infrequent dosing.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkz140
PMCID: PMC6468299
PMID: 30820542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31303442 | 1. Mol Ther. 2019 Sep 4;27(9):1547-1557. doi: 10.1016/j.ymthe.2019.06.009. Epub
2019 Jun 29.
Enhanced Potency of GalNAc-Conjugated Antisense Oligonucleotides in
Hepatocellular Cancer Models.
Kim Y(1), Jo M(2), Schmidt J(2), Luo X(2), Prakash TP(3), Zhou T(2), Klein S(2),
Xiao X(2), Post N(4), Yin Z(5), MacLeod AR(6).
Author information:
(1)Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad,
CA 92010, USA. Electronic address: ykim@ionisph.com.
(2)Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad,
CA 92010, USA.
(3)Department of Medicinal Chemistry, Ionis Pharmaceuticals Inc., Carlsbad, CA
92010, USA.
(4)Department of Pharmacokinetics, Ionis Pharmaceuticals Inc., Carlsbad, CA
92010, USA.
(5)Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second
Military Medical University, Shanghai, China.
(6)Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad,
CA 92010, USA. Electronic address: rmacleod@ionisph.com.
Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target
difficult-to-drug protein classes by targeting their corresponding mRNAs.
Significantly enhanced ASO activity has been achieved by the targeted delivery
of ASOs to selected tissues. One example is the targeted delivery of ASOs to
hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO,
which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we
have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach
to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The
activity of GalNAc-conjugated ASOs was superior to that of the unconjugated
parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (-) cells.
Both human- and mouse-derived HCC displayed reduced levels of ASGR, however,
despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency
in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both
enhanced antisense activity and antitumor activity in the
diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced
ASO activity in human circulating tumor cells from HCC patients, demonstrating
the potential of this approach in primary human HCC tumor cells. Taken together,
these results provide a strong rationale for a potential therapeutic use of
GalNAc-conjugated ASOs for the treatment of HCC.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2019.06.009
PMCID: PMC6731179
PMID: 31303442 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26011654 | 1. Bioconjug Chem. 2015 Aug 19;26(8):1451-5. doi:
10.1021/acs.bioconjchem.5b00265. Epub 2015 Jun 10.
Efficient Synthesis and Biological Evaluation of 5'-GalNAc Conjugated Antisense
Oligonucleotides.
Østergaard ME(1), Yu J(1), Kinberger GA(1), Wan WB(1), Migawa MT(1), Vasquez
G(1), Schmidt K(1), Gaus HJ(1), Murray HM(1), Low A(1), Swayze EE(1), Prakash
TP(1), Seth PP(1).
Author information:
(1)Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010,
United States.
Conjugation of triantennary N-acetyl galactosamine (GalNAc) to oligonucleotide
therapeutics results in marked improvement in potency for reducing gene targets
expressed in hepatocytes. In this report we describe a robust and efficient
solution-phase conjugation strategy to attach triantennary GalNAc clusters (mol.
wt. ∼2000) activated as PFP (pentafluorophenyl) esters onto 5'-hexylamino
modified antisense oligonucleotides (5'-HA ASOs, mol. wt. ∼8000 Da). The
conjugation reaction is efficient and was used to prepare GalNAc conjugated ASOs
from milligram to multigram scale. The solution phase method avoids loading of
GalNAc clusters onto solid-support for automated synthesis and will facilitate
evaluation of GalNAc clusters for structure activity relationship (SAR) studies.
Furthermore, we show that transfer of the GalNAc cluster from the 3'-end of an
ASO to the 5'-end results in improved potency in cells and animals.
DOI: 10.1021/acs.bioconjchem.5b00265
PMID: 26011654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36345805 | 1. J Peripher Nerv Syst. 2022 Dec;27(4):228-237. doi: 10.1111/jns.12519. Epub
2022 Nov 16.
Liver-directed drugs for transthyretin-mediated amyloidosis.
Brannagan TH 3rd(1), Berk JL(2), Gillmore JD(3), Maurer MS(4), Waddington-Cruz
M(5), Fontana M(3), Masri A(6), Obici L(7), Brambatti M(8), Baker BF(8), Hannan
LA(8), Buchele G(8), Viney NJ(8), Coelho T(9), Nativi-Nicolau J(10).
Author information:
(1)Peripheral Neuropathy Center, Columbia University, Vagelos College of
Physicians and Surgeons, New York, New York, USA.
(2)Amyloidosis Center, Boston University School of Medicine, Boston,
Massachusetts, USA.
(3)National Amyloidosis Centre, University College London, Royal Free Hospital,
London, UK.
(4)Cardiac Amyloidosis Program, Division of Cardiology, Columbia College of
Physicians and Surgeons, New York, New York, USA.
(5)National Amyloidosis Referral Center-CEPARM, University Hospital, Federal
University of Rio de Janeiro, Rio de Janeiro, Brazil.
(6)Cardiac Amyloidosis Program, Knight Cardiovascular Institute, Oregon Health &
Science University, Portland, Oregon, USA.
(7)Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San
Matteo, Pavia, Italy.
(8)Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
(9)Department of Neurosciences, Centro Hospitalar Universitário do Porto, Porto,
Portugal.
(10)Division of Heart Failure and Transplant, Mayo Clinic, Jacksonville,
Florida, USA.
Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized,
progressively debilitating, fatal disease caused by the aggregation and
extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple
organs and tissues throughout the body. TTR is predominantly synthesized by the
liver and normally circulates as a homotetramer, while misfolded monomers
aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to
reduce the amount of TTR produced by the liver using drugs that directly target
the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing
tools act to reduce TTR production, describing strategies for improved targeted
delivery of these agents to hepatocytes where TTR is preferentially expressed.
Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed
RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing
tool reduces TTR expression by introducing nonsense mutations into the TTR gene.
Two strategies to facilitate tissue-specific delivery of these nucleic
acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid
nanoparticles (LNPs) that recruit apolipoprotein E support low-density
lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for
CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine
(GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the
asialoglycoprotein receptor. In summary, ATTR is a progressive disease with
various clinical manifestations due to TTR aggregation, deposition, and amyloid
formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation
(eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to
hepatocytes, the primary location of TTR synthesis.
© 2022 The Authors. Journal of the Peripheral Nervous System published by Wiley
Periodicals LLC on behalf of Peripheral Nerve Society.
DOI: 10.1111/jns.12519
PMCID: PMC10100204
PMID: 36345805 [Indexed for MEDLINE]
Conflict of interest statement: Thomas H. Brannagan 3rd has received consulting
income from Akcea, Alnylam and Ionis. Institutional support in the form of
clinical trial funding from Alnylam and Ionis. John L. Berk has received
consulting income from Corino Therapeutics, Ionis/Akcea, Alnylam,
Eidos/BridgeBio and Intellia. Institutional support through clinical trial
participation has been received from Alnylam, Ionis, Pfizer, Corino, and
Eidos/BridgeBio. Julian D. Gillmore is a consultant for Eidos, Ionis, Alnylam,
Pfizer and Intellia. Mathew S. Maurer has grant support from NIH—R01HL139671.
Consulting income from Eidos, Prothena, Ionis and Alnylam, Novo‐Nordisk and
Intellia. Institutional support in the form of clinical trial funding from
Pfizer, Attralus, Ionis, Eidos and Alnylam. Marcia Waddington‐Cruz received
honorariums from NHI, Prothena, FoldRx, Ionis, Pfizer, Alnylam, PTC and Genzyme
for travel expenses related to presentations at medical meetings, for acting as
a principal investigator in clinical trials and as a consultant member. Mariana
Fontana has received consultancy/advisory board income from Akcea, Alnylam,
Alexion, Intellia, Ionis, Pfizer, Eidos, Janssen, and Novo Nordisk, and salary
from the British Heart Foundation. Ahmad Masri receives research grants from
Pfizer, Akcea, Ionis and Ultromics and fees (consultant, honoraria) from Eidos,
Pfizer, Ionis, BMS, Attralus, Tenaya and Cytokinetics. Laura Obici received
speaker and consulting honoraria from Alnylam, SOBI, Akcea and Pfizer. Teresa
Coelho is a past and current investigator in clinical trials sponsored by
FoldRx, Pfizer, Alnylam, Ionis, Prothena and Eidos ‐ Institution was paid per
protocol. Consultant for Pfizer, Alnylam, Ionis, Akcea, Sobi, Eidos and Prothena
pro bono. Pfizer, Alnylam, Ionis and Biogen supported expenses with travel,
accommodation and registrations for scientific meetings. Jose Nativi‐Nicolau
received funding for research from Akcea/Ionis, Pfizer Inc and Eidos
Therapeutics, and consulting funding from Alnylam Pharmaceuticals, Pfizer Inc
and Akcea/Ionis. Brenda F. Baker, Nick Viney, Lisa A. Hannan, Michela Brambatti,
and Gustavo Buchele are employees and stockholders of Ionis Pharmaceuticals,
Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/28649135 | 1. Nat Rev Genet. 2017 Oct;18(10):613-623. doi: 10.1038/nrg.2017.47. Epub 2017
Jun 26.
Synthetic lethality and cancer.
O'Neil NJ(1), Bailey ML(1), Hieter P(1).
Author information:
(1)Michael Smith Laboratories, University of British Columbia, 2185 East Mall,
Vancouver, British Columbia V6T 1Z4, Canada.
A synthetic lethal interaction occurs between two genes when the perturbation of
either gene alone is viable but the perturbation of both genes simultaneously
results in the loss of viability. Key to exploiting synthetic lethality in
cancer treatment are the identification and the mechanistic characterization of
robust synthetic lethal genetic interactions. Advances in next-generation
sequencing technologies are enabling the identification of hundreds of
tumour-specific mutations and alterations in gene expression that could be
targeted by a synthetic lethality approach. The translation of synthetic
lethality to therapy will be assisted by the synthesis of genetic interaction
data from model organisms, tumour genomes and human cell lines.
DOI: 10.1038/nrg.2017.47
PMID: 28649135 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28129130 | 1. Mol Ther. 2017 Jan 4;25(1):71-78. doi: 10.1016/j.ymthe.2016.10.019. Epub 2017
Jan 4.
Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA
Conjugate.
Zimmermann TS(1), Karsten V(2), Chan A(2), Chiesa J(3), Boyce M(4), Bettencourt
BR(2), Hutabarat R(2), Nochur S(2), Vaishnaw A(2), Gollob J(2).
Author information:
(1)Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA. Electronic address:
tzimmermann@alnylam.com.
(2)Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
(3)Covance Clinical Research Unit Ltd., Leeds LS2 9LH, UK.
(4)Hammersmith Medicines Research Ltd., London NW10 7EW, UK.
Advancement of RNAi-based therapeutics depends on effective delivery to the site
of protein synthesis. Although intravenously administered, multi-component
delivery vehicles have enabled small interfering RNA (siRNA) delivery and
progression into clinical development, advances of single-component, systemic
siRNA delivery have been challenging. In pre-clinical models, attachment of a
triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates
hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated
gene silencing. In this phase 1 study, we assessed translation of this delivery
approach by evaluating the safety, tolerability, pharmacokinetics, and
pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin
(TTR). Subjects received a placebo or ascending doses of revusiran
subcutaneously ranging from 1.25-10 mg/kg in the single and 2.5-10 mg/kg in the
multiple ascending dose phases. Revusiran was generally well tolerated, with
transient, mild to moderate injection site reactions the most common
treatment-emergent adverse events. Doses of 2.5-10 mg/kg revusiran elicited a
significant reduction of serum TTR versus the placebo (p < 0.01), with mean TTR
reductions of approximately 90% observed with multiple dosing. These results
demonstrate translation of this novel delivery platform, enabling clinical
development of subcutaneously administered GalNAc-siRNAs for liver-based
diseases.
Copyright © 2017 The American Society of Gene and Cell Therapy. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymthe.2016.10.019
PMCID: PMC5363199
PMID: 28129130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21094158 | 1. FEBS Lett. 2011 Jan 3;585(1):1-6. doi: 10.1016/j.febslet.2010.11.024. Epub
2010 Nov 19.
Synthetic lethality: general principles, utility and detection using genetic
screens in human cells.
Nijman SM(1).
Author information:
(1)Research Center for Molecular Medicine of the Austrian Academy of Sciences
(CeMM), Vienna, Austria. snijman@cemm.oeaw.ac.at
Synthetic lethality occurs when the simultaneous perturbation of two genes
results in cellular or organismal death. Synthetic lethality also occurs between
genes and small molecules, and can be used to elucidate the mechanism of action
of drugs. This area has recently attracted attention because of the prospect of
a new generation of anti-cancer drugs. Based on studies ranging from yeast to
human cells, this review provides an overview of the general principles that
underlie synthetic lethality and relates them to its utility for identifying
gene function, drug action and cancer therapy. It also identifies the latest
strategies for the large-scale mapping of synthetic lethalities in human cells
which bring us closer to the generation of comprehensive human genetic
interaction maps.
Copyright © 2010 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.febslet.2010.11.024
PMCID: PMC3018572
PMID: 21094158 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30059974 | 1. Bioinformatics. 2019 Feb 15;35(4):701-702. doi: 10.1093/bioinformatics/bty673.
DiscoverSL: an R package for multi-omic data driven prediction of synthetic
lethality in cancers.
Das S(1), Deng X(1), Camphausen K(1), Shankavaram U(1).
Author information:
(1)Radiation Oncology Branch, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA.
SUMMARY: Synthetic lethality is a state when simultaneous loss of two genes is
lethal to a cancer cell, while the loss of the individual genes is not. We
developed an R package DiscoverSL to predict and visualize synthetic lethality
in cancers using multi-omic cancer data. Mutation, copy number alteration and
gene expression data from The Cancer Genome Atlas project were combined to
develop a multi-parametric Random Forest classifier. The effects of selectively
targeting the predicted synthetic lethal genes is tested in silico using shRNA
and drug screening data from cancer cell line databases. The clinical outcome in
patients with mutation in primary gene and over/under-expression in the
synthetic lethal gene is evaluated using Kaplan-Meier analysis. The method helps
to identify new therapeutic approaches by exploiting the concept of synthetic
lethality.
AVAILABILITY AND IMPLEMENTATION: DiscoverSL package with user manual and sample
workflow is available for download from github url:
https://github.com/shaoli86/DiscoverSL/releases/tag/V1.0 under GNU GPL-3.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
Published by Oxford University Press 2018.
DOI: 10.1093/bioinformatics/bty673
PMCID: PMC6378931
PMID: 30059974 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16110319 | 1. Nat Rev Cancer. 2005 Sep;5(9):689-98. doi: 10.1038/nrc1691.
The concept of synthetic lethality in the context of anticancer therapy.
Kaelin WG Jr(1).
Author information:
(1)Howard Hughes Medical Institute, 44 Binney Street, Mayer 457, Boston,
Massachusetts 02115, USA. william_kaelin@dfci.harvard.edu
Two genes are synthetic lethal if mutation of either alone is compatible with
viability but mutation of both leads to death. So, targeting a gene that is
synthetic lethal to a cancer-relevant mutation should kill only cancer cells and
spare normal cells. Synthetic lethality therefore provides a conceptual
framework for the development of cancer-specific cytotoxic agents. This paradigm
has not been exploited in the past because there were no robust methods for
systematically identifying synthetic lethal genes. This is changing as a result
of the increased availability of chemical and genetic tools for perturbing gene
function in somatic cells.
DOI: 10.1038/nrc1691
PMID: 16110319 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31675556 | 1. J Nutr Biochem. 2019 Dec;74:108227. doi: 10.1016/j.jnutbio.2019.108227. Epub
2019 Aug 31.
Curcumin functions as a MEK inhibitor to induce a synthetic lethal effect on
KRAS mutant colorectal cancer cells receiving targeted drug regorafenib.
Wu CS(1), Wu SY(2), Chen HC(1), Chu CA(3), Tang HH(4), Liu HS(5), Hong YR(6),
Huang CF(7), Huang GC(8), Su CL(9).
Author information:
(1)Department of Human Development and Family Studies, National Taiwan Normal
University, Taipei 106, Taiwan.
(2)Department of Human Development and Family Studies, National Taiwan Normal
University, Taipei 106, Taiwan; Graduate Program of Nutrition Science, School of
Life Science, National Taiwan Normal University, Taipei 106, Taiwan.
(3)Department of Microbiology and Immunology, College of Medicine, National
Cheng Kung University, Tainan 701, Taiwan.
(4)Graduate Program of Nutrition Science, School of Life Science, National
Taiwan Normal University, Taipei 106, Taiwan.
(5)Department of Microbiology and Immunology, College of Medicine, National
Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and
Signaling Research Center, College of Medicine, National Cheng Kung University,
Tainan 701, Taiwan.
(6)Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical
University, Kaohsiung 807, Taiwan; Department of Biochemistry, College of
Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
(7)Department of Biochemistry, College of Medicine, Kaohsiung Medical
University, Kaohsiung 807, Taiwan; Institute of Biopharmaceutical Sciences,
National Yang-Ming University, Taipei 112, Taiwan. Electronic address:
cyhuang5@ym.edu.tw.
(8)Division of Hemato-oncology, Department of Internal Medicine, Yuan's General
Hospital, Kaohsiung 802, Taiwan. Electronic address:
guanchenghuang@yahoo.com.tw.
(9)Department of Human Development and Family Studies, National Taiwan Normal
University, Taipei 106, Taiwan; Graduate Program of Nutrition Science, School of
Life Science, National Taiwan Normal University, Taipei 106, Taiwan. Electronic
address: chunlisu@ntnu.edu.tw.
Curcumin, a major yellow pigment and spice in turmeric and curry, has been
demonstrated to have an anticancer effect in human clinical trials. Mutation of
KRAS has been shown in 35%-45% of colorectal cancer, and regorafenib has been
approved by the US FDA to treat patients with colorectal cancer. Synthetic
lethality is a type of genetic interaction between two genes such that
simultaneous perturbations of the two genes result in cell death or a dramatic
decrease of cell viability, while a perturbation of either gene alone is not
lethal. Here, we reveal that curcumin significantly enhanced the growth
inhibition of regorafenib in human colorectal cancer HCT 116 cells (KRAS mutant)
to a greater extent than in human colorectal cancer HT-29 cells (KRAS
wild-type), producing an additive or synergistic effect in HCT 116 cells and
causing an antagonistic effect in HT-29 cells. Flow cytometric analysis showed
that the addition of curcumin elevated apoptosis and greatly increased autophagy
in HCT 116 cells but not in HT-29 cells. Mechanistically, curcumin behaved like
MEK-specific inhibitor (U0126) to enhance regorafenib-induced growth inhibition,
apoptosis and autophagy in HCT 116 cells. Our data suggest that curcumin may
target one more gene other than mutant KRAS to enhance regorafenib-induced
growth inhibition (synthetic lethality) in colorectal cancer HCT 116 cells,
indicating a possible role of curcumin in regorafenib-treated KRAS mutant
colorectal cancer.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jnutbio.2019.108227
PMID: 31675556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18586941 | 1. J Bacteriol. 2008 Sep;190(17):5841-54. doi: 10.1128/JB.00711-08. Epub 2008 Jun
27.
Synthetic lethality with the dut defect in Escherichia coli reveals layers of
DNA damage of increasing complexity due to uracil incorporation.
Ting H(1), Kouzminova EA, Kuzminov A.
Author information:
(1)Department of Microbiology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, USA.
Synthetic lethality is inviability of a double-mutant combination of two fully
viable single mutants, commonly interpreted as redundancy at an essential
metabolic step. The dut-1 defect in Escherichia coli inactivates dUTPase,
causing increased uracil incorporation in DNA and known synthetic lethalities
[SL(dut) mutations]. According to the redundancy logic, most of these SL(dut)
mutations should affect nucleotide metabolism. After a systematic search for
SL(dut) mutants, we did identify a single defect in the DNA precursor
metabolism, inactivating thymidine kinase (tdk), that confirmed the redundancy
explanation of synthetic lethality. However, we found that the bulk of mutations
interacting genetically with dut are in DNA repair, revealing layers of damage
of increasing complexity that uracil-DNA incorporation sends through the
chromosomal metabolism. Thus, we isolated mutants in functions involved in (i)
uracil-DNA excision (ung, polA, and xthA); (ii) double-strand DNA break repair
(recA, recBC, and ruvABC); and (iii) chromosomal-dimer resolution (xerC, xerD,
and ftsK). These mutants in various DNA repair transactions cannot be redundant
with dUTPase and instead reveal "defect-damage-repair" cycles linking unrelated
metabolic pathways. In addition, two SL(dut) inserts (phoU and degP) identify
functions that could act to support the weakened activity of the Dut-1 mutant
enzyme, suggesting the "compensation" explanation for this synthetic lethality.
We conclude that genetic interactions with dut can be explained by redundancy,
by defect-damage-repair cycles, or as compensation.
DOI: 10.1128/JB.00711-08
PMCID: PMC2519533
PMID: 18586941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32883316 | 1. J Hematol Oncol. 2020 Sep 3;13(1):118. doi: 10.1186/s13045-020-00956-5.
Advances in synthetic lethality for cancer therapy: cellular mechanism and
clinical translation.
Topatana W(1)(2), Juengpanich S(1)(2), Li S(1), Cao J(1), Hu J(1), Lee J(3),
Suliyanto K(2), Ma D(2), Zhang B(1), Chen M(4)(5), Cai X(6)(7)(8).
Author information:
(1)Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang
University, Hangzhou, 310016, China.
(2)School of Medicine, Zhejiang University, Hangzhou, 310058, China.
(3)Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, 310058, China.
(4)Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang
University, Hangzhou, 310016, China. mychen@zju.edu.cn.
(5)School of Medicine, Zhejiang University, Hangzhou, 310058, China.
mychen@zju.edu.cn.
(6)Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang
University, Hangzhou, 310016, China. srrsh_cxj@zju.edu.cn.
(7)School of Medicine, Zhejiang University, Hangzhou, 310058, China.
srrsh_cxj@zju.edu.cn.
(8)Key Laboratory of Endoscopic Technique Research of Zhejiang Province, No.3
East Qingchun Road, Hangzhou, 310016, China. srrsh_cxj@zju.edu.cn.
Synthetic lethality is a lethal phenomenon in which the occurrence of a single
genetic event is tolerable for cell survival, whereas the co-occurrence of
multiple genetic events results in cell death. The main obstacle for synthetic
lethality lies in the tumor biology heterogeneity and complexity, the inadequate
understanding of synthetic lethal interactions, drug resistance, and the
challenges regarding screening and clinical translation. Recently, DNA damage
response inhibitors are being tested in various trials with promising results.
This review will describe the current challenges, development, and opportunities
for synthetic lethality in cancer therapy. The characterization of potential
synthetic lethal interactions and novel technologies to develop a more effective
targeted drug for cancer patients will be explored. Furthermore, this review
will discuss the clinical development and drug resistance mechanisms of
synthetic lethality in cancer therapy. The ultimate goal of this review is to
guide clinicians at selecting patients that will receive the maximum benefits of
DNA damage response inhibitors for cancer therapy.
DOI: 10.1186/s13045-020-00956-5
PMCID: PMC7470446
PMID: 32883316 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there are no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24864230 | 1. Biomed Res Int. 2014;2014:196034. doi: 10.1155/2014/196034. Epub 2014 Apr 22.
Syn-lethality: an integrative knowledge base of synthetic lethality towards
discovery of selective anticancer therapies.
Li XJ(1), Mishra SK(1), Wu M(2), Zhang F(1), Zheng J(3).
Author information:
(1)Bioinformatics Research Centre (BIRC), School of Computer Engineering,
Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798.
(2)Institute for Infocomm Research (I2R), 1 Fusionopolis Way, Singapore 138632.
(3)Bioinformatics Research Centre (BIRC), School of Computer Engineering,
Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798 ; Genome
Institute of Singapore (GIS), Biopolis, Singapore 138672.
Synthetic lethality (SL) is a novel strategy for anticancer therapies, whereby
mutations of two genes will kill a cell but mutation of a single gene will not.
Therefore, a cancer-specific mutation combined with a drug-induced mutation, if
they have SL interactions, will selectively kill cancer cells. While numerous SL
interactions have been identified in yeast, only a few have been known in human.
There is a pressing need to systematically discover and understand SL
interactions specific to human cancer. In this paper, we present Syn-Lethality,
the first integrative knowledge base of SL that is dedicated to human cancer. It
integrates experimentally discovered and verified human SL gene pairs into a
network, associated with annotations of gene function, pathway, and molecular
mechanisms. It also includes yeast SL genes from high-throughput screenings
which are mapped to orthologous human genes. Such an integrative knowledge base,
organized as a relational database with user interface for searching and network
visualization, will greatly expedite the discovery of novel anticancer drug
targets based on synthetic lethality interactions. The database can be
downloaded as a stand-alone Java application.
DOI: 10.1155/2014/196034
PMCID: PMC4016865
PMID: 24864230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26451775 | 1. PLoS Comput Biol. 2015 Oct 9;11(10):e1004506. doi:
10.1371/journal.pcbi.1004506. eCollection 2015 Oct.
Connectivity Homology Enables Inter-Species Network Models of Synthetic
Lethality.
Jacunski A(1), Dixon SJ(2), Tatonetti NP(3).
Author information:
(1)Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia
University, New York, New York, United States of America; Department of Systems
Biology, Columbia University, New York, New York, United States of America.
(2)Department of Biological Sciences, Columbia University, New York, New York,
United States of America.
(3)Department of Systems Biology, Columbia University, New York, New York,
United States of America; Department of Biomedical Informatics, Columbia
University, New York, New York, United States of America; Department of
Medicine, Columbia University, New York, New York, United States of America.
Synthetic lethality is a genetic interaction wherein two otherwise nonessential
genes cause cellular inviability when knocked out simultaneously. Drugs can
mimic genetic knock-out effects; therefore, our understanding of promiscuous
drugs, polypharmacology-related adverse drug reactions, and multi-drug
therapies, especially cancer combination therapy, may be informed by a deeper
understanding of synthetic lethality. However, the colossal experimental burden
in humans necessitates in silico methods to guide the identification of
synthetic lethal pairs. Here, we present SINaTRA (Species-INdependent
TRAnslation), a network-based methodology that discovers genome-wide synthetic
lethality in translation between species. SINaTRA uses connectivity homology,
defined as biological connectivity patterns that persist across species, to
identify synthetic lethal pairs. Importantly, our approach does not rely on
genetic homology or structural and functional similarity, and it significantly
outperforms models utilizing these data. We validate SINaTRA by predicting
synthetic lethality in S. pombe using S. cerevisiae data, then identify over one
million putative human synthetic lethal pairs to guide experimental approaches.
We highlight the translational applications of our algorithm for drug discovery
by identifying clusters of genes significantly enriched for single- and
multi-drug cancer therapies.
DOI: 10.1371/journal.pcbi.1004506
PMCID: PMC4599967
PMID: 26451775 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34070674 | 1. Int J Mol Sci. 2021 May 25;22(11):5614. doi: 10.3390/ijms22115614.
Breast Cancer Predisposition Genes and Synthetic Lethality.
Neiger HE(1), Siegler EL(2), Shi Y(2).
Author information:
(1)College of Graduate Studies, California Northstate University, Elk Grove, CA
95757, USA.
(2)College of Medicine, California Northstate University, Elk Grove, CA 95757,
USA.
BRCA1 and BRCA2 are tumor suppressor genes with pivotal roles in the development
of breast and ovarian cancers. These genes are essential for DNA double-strand
break repair via homologous recombination (HR), which is a virtually error-free
DNA repair mechanism. Following BRCA1 or BRCA2 mutations, HR is compromised,
forcing cells to adopt alternative error-prone repair pathways that often result
in tumorigenesis. Synthetic lethality refers to cell death caused by
simultaneous perturbations of two genes while change of any one of them alone is
nonlethal. Therefore, synthetic lethality can be instrumental in identifying new
therapeutic targets for BRCA1/2 mutations. PARP is an established synthetic
lethal partner of the BRCA genes. Its role is imperative in the single-strand
break DNA repair system. Recently, Olaparib (a PARP inhibitor) was approved for
treatment of BRCA1/2 breast and ovarian cancer as the first successful synthetic
lethality-based therapy, showing considerable success in the development of
effective targeted cancer therapeutics. Nevertheless, the possibility of drug
resistance to targeted cancer therapy based on synthetic lethality necessitates
the development of additional therapeutic options. This literature review
addresses cancer predisposition genes, including BRCA1, BRCA2, and PALB2,
synthetic lethality in the context of DNA repair machinery, as well as available
treatment options.
DOI: 10.3390/ijms22115614
PMCID: PMC8198377
PMID: 34070674 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/16118434 | 1. Methods Mol Biol. 2006;313:171-92. doi: 10.1385/1-59259-958-3:171.
Synthetic genetic array analysis in Saccharomyces cerevisiae.
Tong AH, Boone C.
Synthetic lethality occurs when the combination of two mutations leads to an
inviable organism. Screens for synthetic lethal genetic interactions have been
used extensively to identify genes whose products buffer one another or impinge
on the same essential pathway. For the yeast Saccharomyces cerevisiae, we
developed a method termed Synthetic Genetic Array (SGA) analysis, which offers
an efficient approach for the systematic construction of double mutants and
enables a global analysis of synthetic lethal genetic interactions. In a typical
SGA screen, a query mutation is crossed to an ordered array of approx 5000
viable gene deletion mutants (representing approximately 80% of all yeast genes)
such that meiotic progeny harboring both mutations can be scored for fitness
defects. This array-based approach automates yeast genetic analysis in general
and can be easily adapted for a number of different screens, including genetic
suppression, plasmid shuffling, dosage lethality, or suppression.
DOI: 10.1385/1-59259-958-3:171
PMID: 16118434 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34050264 | 1. Exp Mol Med. 2021 May;53(5):835-847. doi: 10.1038/s12276-021-00635-6. Epub
2021 May 28.
Aurora kinase A, a synthetic lethal target for precision cancer medicine.
Mou PK(1), Yang EJ(1), Shi C(1), Ren G(1), Tao S(1), Shim JS(2)(3).
Author information:
(1)Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau
SAR, China.
(2)Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau
SAR, China. jsshim@um.edu.mo.
(3)MoE Frontiers Science Center for Precision Oncology, University of Macau,
Taipa, Macau SAR, China. jsshim@um.edu.mo.
Recent advances in high-throughput sequencing technologies and data science have
facilitated the development of precision medicine to treat cancer patients.
Synthetic lethality is one of the core methodologies employed in precision
cancer medicine. Synthetic lethality describes the phenomenon of the interplay
between two genes in which deficiency of a single gene does not abolish cell
viability but combined deficiency of two genes leads to cell death. In cancer
treatment, synthetic lethality is leveraged to exploit the dependency of cancer
cells on a pathway that is essential for cell survival when a tumor suppressor
is mutated. This approach enables pharmacological targeting of mutant tumor
suppressors that are theoretically undruggable. Successful clinical introduction
of BRCA-PARP synthetic lethality in cancer treatment led to additional
discoveries of novel synthetic lethal partners of other tumor suppressors,
including p53, PTEN, and RB1, using high-throughput screening. Recent work has
highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple
tumor suppressors. AURKA is a serine/threonine kinase involved in a number of
central biological processes, such as the G2/M transition, mitotic spindle
assembly, and DNA replication. This review introduces synthetic lethal
interactions between AURKA and its tumor suppressor partners and discusses the
potential of AURKA inhibitors in precision cancer medicine.
DOI: 10.1038/s12276-021-00635-6
PMCID: PMC8178373
PMID: 34050264 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/25171417 | 1. Cell. 2014 Aug 28;158(5):1199-1209. doi: 10.1016/j.cell.2014.07.027.
Predicting cancer-specific vulnerability via data-driven detection of synthetic
lethality.
Jerby-Arnon L(1), Pfetzer N(2), Waldman YY(3), McGarry L(2), James D(2), Shanks
E(2), Seashore-Ludlow B(4), Weinstock A(3), Geiger T(5), Clemons PA(4), Gottlieb
E(2), Ruppin E(6).
Author information:
(1)The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv
6997801, Israel. Electronic address: livnatje@post.tau.ac.il.
(2)Cancer Research UK, The Beatson Institute for Cancer Research, Switchback
Road, Glasgow G61 1BD, Scotland, UK.
(3)The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv
6997801, Israel.
(4)Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, 7
Cambridge Center, Cambridge, MA 02142, USA.
(5)The Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801,
Israel.
(6)The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv
6997801, Israel; The Sackler School of Medicine, Tel Aviv University, Tel Aviv
6997801, Israel. Electronic address: ruppin@post.tau.ac.il.
Comment in
Cancer Cell. 2014 Sep 8;26(3):306-308. doi: 10.1016/j.ccr.2014.08.008.
Synthetic lethality occurs when the inhibition of two genes is lethal while the
inhibition of each single gene is not. It can be harnessed to selectively treat
cancer by identifying inactive genes in a given cancer and targeting their
synthetic lethal (SL) partners. We present a data-driven computational pipeline
for the genome-wide identification of SL interactions in cancer by analyzing
large volumes of cancer genomic data. First, we show that the approach
successfully captures known SL partners of tumor suppressors and oncogenes. We
then validate SL predictions obtained for the tumor suppressor VHL. Next, we
construct a genome-wide network of SL interactions in cancer and demonstrate its
value in predicting gene essentiality and clinical prognosis. Finally, we
identify synthetic lethality arising from gene overactivation and use it to
predict drug efficacy. These results form a computational basis for exploiting
synthetic lethality to uncover cancer-specific susceptibilities.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2014.07.027
PMID: 25171417 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18789146 | 1. Genome Biol. 2008;9(9):R135. doi: 10.1186/gb-2008-9-9-r135. Epub 2008 Sep 12.
Modeling synthetic lethality.
Le Meur N(1), Gentleman R.
Author information:
(1)Division of Public Health Sciences, Fred Hutchinson Cancer Center Research,
Program in Computational Biology, Seattle, WA 98109, USA. nlemeur@fhcrc.org
BACKGROUND: Synthetic lethality defines a genetic interaction where the
combination of mutations in two or more genes leads to cell death. The
implications of synthetic lethal screens have been discussed in the context of
drug development as synthetic lethal pairs could be used to selectively kill
cancer cells, but leave normal cells relatively unharmed. A challenge is to
assess genome-wide experimental data and integrate the results to better
understand the underlying biological processes. We propose statistical and
computational tools that can be used to find relationships between synthetic
lethality and cellular organizational units.
RESULTS: In Saccharomyces cerevisiae, we identified multi-protein complexes and
pairs of multi-protein complexes that share an unusually high number of
synthetic genetic interactions. As previously predicted, we found that synthetic
lethality can arise from subunits of an essential multi-protein complex or
between pairs of multi-protein complexes. Finally, using multi-protein complexes
allowed us to take into account the pleiotropic nature of the gene products.
CONCLUSIONS: Modeling synthetic lethality using current estimates of the yeast
interactome is an efficient approach to disentangle some of the complex
molecular interactions that drive a cell. Our model in conjunction with applied
statistical methods and computational methods provides new tools to better
characterize synthetic genetic interactions.
DOI: 10.1186/gb-2008-9-9-r135
PMCID: PMC2592713
PMID: 18789146 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21737609 | 1. Cancer Genomics Proteomics. 2011 Jul-Aug;8(4):159-71.
Synthetic lethality-based targets for discovery of new cancer therapeutics.
Weidle UH(1), Maisel D, Eick D.
Author information:
(1)Roche Diagnostics, Division Pharma, Penzberg, Germany.
ulrich.weidle@roche.com
Synthetic lethality is based on the incompatibility of cell survival with the
loss of function of two or more genes, not with loss of function of a single
gene. If targets of synthetic lethality are deregulated or mutated in cancer
cells, the strategy of synthetic lethality can result in significant increase of
therapeutic efficacy and a favourable therapeutic window. In this review, we
discuss synthetic lethality based on deficient DNA repair mechanisms, activating
mutations of RAS, loss of function mutations of the tumor suppressor genes p53,
Rb and von Hippel-Lindau, and disruption of interactive protein kinase networks
in the context of development of new anticancer agents.
PMID: 21737609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30125975 | 1. J Cell Biochem. 2019 Jan;120(1):405-416. doi: 10.1002/jcb.27395. Epub 2018 Aug
20.
Identification of synthetic lethality based on a functional network by using
machine learning algorithms.
Li J(1), Lu L(2), Zhang YH(3), Liu M(4), Chen L(4), Huang T(3), Cai YD(1).
Author information:
(1)School of Life Sciences, Shanghai University, Shanghai, China.
(2)Department of Radiology, Columbia University Medical Center, New York.
(3)Institute of Health Sciences, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai, China.
(4)College of Information Engineering, Shanghai Maritime University, Shanghai,
China.
Synthetic lethality is the synthesis of mutations leading to cell death.
Tumor-specific synthetic lethality has been targeted in research to improve
cancer therapy. With the advances of techniques in molecular biology, such as
RNAi and CRISPR/Cas9 gene editing, efforts have been made to systematically
identify synthetic lethal interactions, especially for frequently mutated genes
in cancers. However, elucidating the mechanism of synthetic lethality remains a
challenge because of the complexity of its influencing conditions. In this
study, we proposed a new computational method to identify critical functional
features that can accurately predict synthetic lethal interactions. This method
incorporates several machine learning algorithms and encodes protein-coding
genes by an enrichment system derived from gene ontology terms and Kyoto
Encyclopedia of Genes and Genomes pathways to represent their functional
features. We built a random forest-based prediction engine by using 2120
selected features and obtained a Matthews correlation coefficient of 0.532. We
examined the top 15 features and found that most of them have potential roles in
synthetic lethality according to previous studies. These results demonstrate the
ability of our proposed method to predict synthetic lethal interactions and
provide a basis for further characterization of these particular genetic
combinations.
© 2018 Wiley Periodicals, Inc.
DOI: 10.1002/jcb.27395
PMID: 30125975 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26085504 | 1. Bioinformatics. 2015 Oct 15;31(20):3299-305. doi:
10.1093/bioinformatics/btv352. Epub 2015 Jun 17.
Fast-SL: an efficient algorithm to identify synthetic lethal sets in metabolic
networks.
Pratapa A(1), Balachandran S(2), Raman K(1).
Author information:
(1)Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences
and.
(2)Department of Computer Science and Engineering, Indian Institute of
Technology Madras, Chennai 600 036, India.
MOTIVATION: Synthetic lethal sets are sets of reactions/genes where only the
simultaneous removal of all reactions/genes in the set abolishes growth of an
organism. Previous approaches to identify synthetic lethal genes in genome-scale
metabolic networks have built on the framework of flux balance analysis (FBA),
extending it either to exhaustively analyze all possible combinations of genes
or formulate the problem as a bi-level mixed integer linear programming (MILP)
problem. We here propose an algorithm, Fast-SL, which surmounts the
computational complexity of previous approaches by iteratively reducing the
search space for synthetic lethals, resulting in a substantial reduction in
running time, even for higher order synthetic lethals.
RESULTS: We performed synthetic reaction and gene lethality analysis, using
Fast-SL, for genome-scale metabolic networks of Escherichia coli, Salmonella
enterica Typhimurium and Mycobacterium tuberculosis. Fast-SL also rigorously
identifies synthetic lethal gene deletions, uncovering synthetic lethal triplets
that were not reported previously. We confirm that the triple lethal gene sets
obtained for the three organisms have a precise match with the results obtained
through exhaustive enumeration of lethals performed on a computer cluster. We
also parallelized our algorithm, enabling the identification of synthetic lethal
gene quadruplets for all three organisms in under 6 h. Overall, Fast-SL enables
an efficient enumeration of higher order synthetic lethals in metabolic
networks, which may help uncover previously unknown genetic interactions and
combinatorial drug targets.
AVAILABILITY AND IMPLEMENTATION: The MATLAB implementation of the algorithm,
compatible with COBRA toolbox v2.0, is available at
https://github.com/RamanLab/FastSL CONTACT: kraman@iitm.ac.in
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author 2015. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com.
DOI: 10.1093/bioinformatics/btv352
PMID: 26085504 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36069976 | 1. Cancer Res. 2022 Nov 2;82(21):4044-4057. doi: 10.1158/0008-5472.CAN-21-4443.
VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma.
Shields JA(1), Meier SR(1), Bandi M(1), Mulkearns-Hubert EE(2), Hajdari N(2),
Ferdinez MD(1), Engel JL(1), Silver DJ(2), Shen B(1), Zhang W(1), Hubert CG(2),
Mitchell K(2), Shakya S(2), Zhao SC(1), Bejnood A(1), Zhang M(1), Tjin Tham Sjin
R(1), Wilker E(1), Lathia JD(2), Andersen JN(1), Chen Y(1), Li F(1), Weber B(1),
Huang A(1), Emmanuel N(1).
Author information:
(1)Tango Therapeutics, Boston, Massachusetts.
(2)Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Synthetic lethality is a genetic interaction that results in cell death when two
genetic deficiencies co-occur but not when either deficiency occurs alone, which
can be co-opted for cancer therapeutics. Pairs of paralog genes are among the
most straightforward potential synthetic-lethal interactions by virtue of their
redundant functions. Here, we demonstrate a paralog-based synthetic lethality by
targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of
VRK2, which is silenced by promoter methylation in approximately two thirds of
GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in
decreased activity of the downstream substrate barrier to autointegration factor
(BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF
activity following VRK1 knockdown caused nuclear lobulation, blebbing, and
micronucleation, which subsequently resulted in G2-M arrest and DNA damage. The
VRK1-VRK2 synthetic-lethal interaction was dependent on VRK1 kinase activity and
was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell
line-derived xenograft and patient-derived xenograft models, knockdown of VRK1
led to robust tumor growth inhibition. These results indicate that inhibiting
VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated
GBM.
SIGNIFICANCE: A paralog synthetic-lethal interaction between VRK1 and VRK2
sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity,
supporting VRK1 as a drug discovery target in this disease.
©2022 The Authors; Published by the American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-21-4443
PMCID: PMC9627132
PMID: 36069976 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19690570 | 1. Mol Syst Biol. 2009;5:301. doi: 10.1038/msb.2009.56. Epub 2009 Aug 18.
Genome-scale gene/reaction essentiality and synthetic lethality analysis.
Suthers PF(1), Zomorrodi A, Maranas CD.
Author information:
(1)Department of Chemical Engineering, The Pennsylvania State University,
University Park, PA 16802, USA.
Comment in
doi: 10.1038/msb200957.
Synthetic lethals are to pairs of non-essential genes whose simultaneous
deletion prohibits growth. One can extend the concept of synthetic lethality by
considering gene groups of increasing size where only the simultaneous
elimination of all genes is lethal, whereas individual gene deletions are not.
We developed optimization-based procedures for the exhaustive and targeted
enumeration of multi-gene (and by extension multi-reaction) lethals for
genome-scale metabolic models. Specifically, these approaches are applied to
iAF1260, the latest model of Escherichia coli, leading to the complete
identification of all double and triple gene and reaction synthetic lethals as
well as the targeted identification of quadruples and some higher-order ones.
Graph representations of these synthetic lethals reveal a variety of motifs
ranging from hub-like to highly connected subgraphs providing a birds-eye view
of the avenues available for redirecting metabolism and uncovering complex
patterns of gene utilization and interdependence. The procedure also enables the
use of falsely predicted synthetic lethals for metabolic model curation. By
analyzing the functional classifications of the genes involved in synthetic
lethals, we reveal surprising connections within and across clusters of
orthologous group functional classifications.
DOI: 10.1038/msb.2009.56
PMCID: PMC2736653
PMID: 19690570 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34589394 | 1. Acta Pharm Sin B. 2021 Sep;11(9):2738-2748. doi: 10.1016/j.apsb.2021.01.002.
Epub 2021 Jan 7.
Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and
strategy.
Li K(1), You J(1), Wu Q(1), Meng W(2), He Q(1)(3)(4), Yang B(1)(3), Zhu C(1),
Cao J(1)(3)(4).
Author information:
(1)Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of
Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou 310058, China.
(2)Affiliated Hangzhou First People's Hospital, Zhejiang University School of
Medicine, Hangzhou 310058, China.
(3)Innovation Institute for Artificial Intelligence in Medicine, Zhejiang
University, Hangzhou 310058, China.
(4)Cancer Center of Zhejiang University, Hangzhou 310058, China.
Synthetic lethality is a proven effective antitumor strategy that has attracted
great attention. Large-scale screening has revealed many synthetic lethal
genetic phenotypes, and relevant small-molecule drugs have also been implemented
in clinical practice. Increasing evidence suggests that CDKs, constituting a
kinase family predominantly involved in cell cycle control, are synthetic lethal
factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which
facilitate numerous antitumor treatment options based on CDK-related synthetic
lethality. In this review, we focus on the synthetic lethal phenotype and
mechanism related to CDKs and summarize the preclinical and clinical discoveries
of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor
compounds for strategic synthesis lethality in the future.
© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica,
Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
DOI: 10.1016/j.apsb.2021.01.002
PMCID: PMC8463275
PMID: 34589394
Conflict of interest statement: No potential conflicts of interest were
disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/20976469 | 1. Hum Genet. 2010 Dec;128(6):567-75. doi: 10.1007/s00439-010-0900-x. Epub 2010
Oct 26.
Synthetic lethal interactions for the development of cancer therapeutics:
biological and methodological advancements.
Mizuarai S(1), Kotani H.
Author information:
(1)Department of Oncology, Tsukuba Research Institute, Banyu Pharmaceutical Co.,
Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.
Synthetic lethal interaction is defined as a combination of two mutations that
is lethal when present in the same cell; each individual mutation is non-lethal.
Synthetic lethal interactions attract attention in cancer research fields since
the discovery of synthetic lethal genes with either oncogenes or tumor
suppressor genes (TSGs) provides novel cancer therapeutic targets. Due to the
selective lethal effect on cancer cells harboring specific genetic alterations,
it is expected that targeting synthetic lethal genes would provide wider
therapeutic windows compared with cytotoxic chemotherapeutics. Here, we review
the current status of the application of synthetic lethal screening in cancer
research fields from biological and methodological viewpoints. Very recent
studies seeking to identify synthetic lethal genes with K-RAS and p53, which are
known to be the most frequently occurring oncogenes and TSGs, respectively, are
introduced. Among the accumulating amount of research on synthetic lethal
interactions, the synthetic lethality between BRCA1/2 and PARP1 inhibition has
been clinically proven. Thus, both preclinical and clinical data showing a
preferential anti-tumor effect on BRCA1/2 deficient tumors by a PARP1 inhibitor
are the best examples of the synthetic lethal approach of cancer therapeutics.
Finally, methodological progress regarding synthetic lethal screening, including
barcode shRNA screening and in vivo synthetic lethal screening, is described.
Given the fact that an increasing number of synthetic lethal genes for major
cancerous genes have been validated in preclinical studies, this intriguing
approach awaits clinical verification of preferential benefits for cancer
patients with specific genetic alterations as a clear predictive factor for
tumor response.
DOI: 10.1007/s00439-010-0900-x
PMID: 20976469 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31671773 | 1. Cancers (Basel). 2019 Oct 29;11(11):1682. doi: 10.3390/cancers11111682.
SL-BioDP: Multi-Cancer Interactive Tool for Prediction of Synthetic Lethality
and Response to Cancer Treatment.
Deng X(1)(2), Das S(3), Valdez K(4)(5), Camphausen K(6), Shankavaram U(7).
Author information:
(1)Bioinformatics core facility, Radiation Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
dengx@mail.nih.gov.
(2)Frederick National Laboratory for Cancer Research, Leidos Biomedical
Research, Inc., Frederick, MD 21702, USA. dengx@mail.nih.gov.
(3)Bioinformatics core facility, Radiation Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
shaoli.das@nih.gov.
(4)Bioinformatics core facility, Radiation Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
kristin.valdez@nih.gov.
(5)Frederick National Laboratory for Cancer Research, Leidos Biomedical
Research, Inc., Frederick, MD 21702, USA. kristin.valdez@nih.gov.
(6)Bioinformatics core facility, Radiation Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
camphauk@mail.nih.gov.
(7)Bioinformatics core facility, Radiation Oncology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
uma@mail.nih.gov.
Synthetic lethality exploits the phenomenon that a mutation in a cancer gene is
often associated with new vulnerability which can be uniquely targeted
therapeutically, leading to a significant increase in favorable outcome. DNA
damage and survival pathways are among the most commonly mutated networks in
human cancers. Recent data suggest that synthetic lethal interactions between a
tumor defect and a DNA repair pathway can be used to preferentially kill tumor
cells. We recently published a method, DiscoverSL, using multi-omic cancer data,
that can predict synthetic lethal interactions of potential clinical relevance.
Here, we apply the generality of our models in a comprehensive web tool called
Synthetic Lethality Bio Discovery Portal (SL-BioDP) and extend the cancer types
to 18 cancer genome atlas cohorts. SL-BioDP enables a data-driven computational
approach to predict synthetic lethal interactions from hallmark cancer pathways
by mining cancer's genomic and chemical interactions. Our tool provides queries
and visualizations for exploring potentially targetable synthetic lethal
interactions, shows Kaplan-Meier plots of clinical relevance, and provides in
silico validation using short hairpin RNA (shRNA) and drug efficacy data. Our
method would thus shed light on mechanisms of synthetic lethal interactions and
lead to the discovery of novel anticancer drugs.
DOI: 10.3390/cancers11111682
PMCID: PMC6895978
PMID: 31671773
Conflict of interest statement: The authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31627702 | 1. Klin Onkol. 2019 Fall;32(Supplementum 3):19-24. doi: 10.14735/amko20193S.
Synthetic Lethality - Its Current Application and Potential in Oncological
Treatment.
[Article in English]
Bortlíková L, Müller P, Vojtěšek B, Rak V, Svoboda M.
BACKGROUND: Synthetic lethality is a gene interaction where a defect in one of
the interacting genes is compatible with cell viability, whereas the disruption
of both genes leads to cell death. The discovery of the lethal effect of
poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutant cells has opened
an important direction in the development of targeted therapy in oncology. The
PARP inhibitor olaparib has become the first registered drug for recurrent
high-grade serous ovarian cancer treatment based on synthetic lethality that has
reached the clinic. Current research focuses on the combination of PARP
inhibitors and inhibitors of kinases, which control the cell cycle, to prevent
or overcome resistance to PARP inhibitors. There are also ongoing clinical
trials which examine PARP inhibitor treatment in other types of cancers
including tumours presenting the so-called BRCAness phenotype. Screenings for
new synthetic lethalities which could serve as potential targets for new drug
development have improved with the CRISPR/Cas9 technology, but another key
problem persists in the screening efforts, namely the incomplete penetrance of
synthetic lethality throughout a tumour cell population.
PURPOSE: This paper summarises the current application of synthetic lethality
principles in oncology and discusses the challenges in research focused on
potential new drugs based on synthetic lethality.
DOI: 10.14735/amko20193S
PMID: 31627702 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24893124 | 1. J Med Chem. 2014 Oct 9;57(19):7859-73. doi: 10.1021/jm500415t. Epub 2014 Jun
13.
Development of synthetic lethality anticancer therapeutics.
Fang B(1).
Author information:
(1)Department of Thoracic and Cardiovascular Surgery, Unit 1489, The University
of Texas MD Anderson Cancer Center , 1515 Holcombe Boulevard, Houston, Texas
77030, United States.
The concept of synthetic lethality (the creation of a lethal phenotype from the
combined effects of mutations in two or more genes) has recently been exploited
in various efforts to develop new genotype-selective anticancer therapeutics.
These efforts include screening for novel anticancer agents, identifying novel
therapeutic targets, characterizing mechanisms of resistance to targeted
therapy, and improving efficacies through the rational design of combination
therapy. This review discusses recent developments in synthetic lethality
anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for
BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers,
and small molecule agents targeting RAS gene mutant cancers. Because cancers are
caused by mutations in multiple genes and abnormalities in multiple signaling
pathways, synthetic lethality for a specific tumor suppressor gene or oncogene
is likely cell context-dependent. Delineation of the mechanisms underlying
synthetic lethality and identification of treatment response biomarkers will be
critical for the success of synthetic lethality anticancer therapy.
DOI: 10.1021/jm500415t
PMCID: PMC4205018
PMID: 24893124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30682083 | 1. PLoS One. 2019 Jan 25;14(1):e0210859. doi: 10.1371/journal.pone.0210859.
eCollection 2019.
Synthetic lethality guiding selection of drug combinations in ovarian cancer.
Heinzel A(1)(2), Marhold M(3), Mayer P(1), Schwarz M(3), Tomasich E(3), Lukas
A(1), Krainer M(3), Perco P(1)(4).
Author information:
(1)Emergentec biodevelopment GmbH, Vienna, Austria.
(2)Department of Internal Medicine III, Medical University of Vienna, Vienna,
Austria.
(3)Department of Oncology, Division of Internal Medicine I, Medical University
of Vienna, Vienna, Austria.
(4)Department of Internal Medicine IV, Medical University of Innsbruck,
Innsbruck, Austria.
BACKGROUND: Synthetic lethality describes a relationship between two genes where
single loss of either gene does not trigger significant impact on cell
viability, but simultaneous loss of both gene functions results in lethality.
Targeting synthetic lethal interactions with drug combinations promises
increased efficacy in tumor therapy.
MATERIALS AND METHODS: We established a set of synthetic lethal interactions
using publicly available data from yeast screens which were mapped to their
respective human orthologs using information from orthology databases. This set
of experimental synthetic lethal interactions was complemented by a set of
predicted synthetic lethal interactions based on a set of protein meta-data like
e.g. molecular pathway assignment. Based on the combined set, we evaluated drug
combinations used in late stage clinical development (clinical phase III and IV
trials) or already in clinical use for ovarian cancer with respect to their
effect on synthetic lethal interactions. We furthermore identified a set of drug
combinations currently not being tested in late stage ovarian cancer clinical
trials that however have impact on synthetic lethal interactions thus being
worth of further investigations regarding their therapeutic potential in ovarian
cancer.
RESULTS: Twelve of the tested drug combinations addressed a synthetic lethal
interaction with the anti-VEGF inhibitor bevacizumab in combination with
paclitaxel being the most studied drug combination addressing the synthetic
lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations
for example holds the combination of the PARP inhibitor olaparib and paclitaxel,
which showed efficacy in phase II clinical studies.
CONCLUSION: A set of drug combinations currently not tested in late stage
ovarian cancer clinical trials was identified having impact on synthetic lethal
interactions thus being worth of further investigations regarding their
therapeutic potential in ovarian cancer.
DOI: 10.1371/journal.pone.0210859
PMCID: PMC6347359
PMID: 30682083 [Indexed for MEDLINE]
Conflict of interest statement: AL is managing partner of emergentec
biodevelopment GmbH, Austria. AH, PP, and PM at the time of performing the
analysis were employees of emergentec biodevelopment GmbH. Commercial
affiliation does not alter our adherence to PLOS ONE policies on sharing data
and materials. All authors declare that they have no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/27113746 | 1. Curr Cancer Drug Targets. 2017;17(4):304-310. doi:
10.2174/1568009616666160426122736.
Synthetic Lethal Interactions in Cancer Therapy.
Geng X(1), Wang X(2), Zhu D(3), Ying S(1).
Author information:
(1)Department of Respiratory and Critical Care Medicine, Second Affiliated
Hospital, Institute of Respiratory Diseases, Zhejiang University School of
Medicine, Hangzhou, China.
(2)Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou,
China.
(3)Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua
Hospital of Zhejiang University, Jinhua, China.
BACKGROUND: Silencing of two or more complementary signaling pathways can lead
to cell death, while loss of any single genetic function does not show a severe
phnotype, this kind of inter action is coined as "synthetic lethality".
Nowadays, synthetic lethality has become a widely used anti-cancer strategy.
METHOD: We reviewed the synthetic lethal interactions exploited in anticancer
therapies before 2016.
CONCLUSION: Synthetic lethality is a well proved anticancer strategy and more
synthetic lethal interactions is being translated into clinical cancer
therapies.
Copyright© Bentham Science Publishers; For any queries, please email at
epub@benthamscience.org.
DOI: 10.2174/1568009616666160426122736
PMID: 27113746 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30594981 | 1. J Microbiol. 2019 Jan;57(1):9-17. doi: 10.1007/s12275-019-8475-2. Epub 2018
Dec 29.
Synthetic lethal interaction between oxidative stress response and DNA damage
repair in the budding yeast and its application to targeted anticancer therapy.
Choi JE(1)(2), Chung WH(3)(4).
Author information:
(1)College of Pharmacy, Duksung Women's University, Seoul, 01369, Republic of
Korea.
(2)Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of
Korea.
(3)College of Pharmacy, Duksung Women's University, Seoul, 01369, Republic of
Korea. whchung23@duksung.ac.kr.
(4)Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of
Korea. whchung23@duksung.ac.kr.
Synthetic lethality is an extreme form of negative genetic epistasis that arises
when a combination of functional deficiency in two or more genes results in cell
death, whereas none of the single genetic perturbations are lethal by
themselves. This unconventional genetic interaction is a modification of the
concept of essentiality that can be exploited for the purpose of targeted cancer
therapy. The yeast Saccharomyces cerevisiae has been pivotally used for early
large-scale synthetic lethal screens due to its experimental advantages, but
recent advances in gene silencing technology have now made direct
high-throughput analysis possible in higher organisms. Identification of
tumor-specific alterations and characterization of the mechanistic principles
underlying synthetic lethal interaction are the key to applying synthetic
lethality to clinical cancer treatment by enabling genome-driven oncological
research. Here, we provide emerging ideas on the synthetic lethal interactions
in budding yeast, particularly between cellular processes responsible for
oxidative stress response and DNA damage repair, and discuss how they can be
appropriately utilized for context-dependent cancer therapeutics.
DOI: 10.1007/s12275-019-8475-2
PMID: 30594981 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34454516 | 1. Mol Cancer. 2021 Aug 28;20(1):111. doi: 10.1186/s12943-021-01405-8.
Uncovering cancer vulnerabilities by machine learning prediction of synthetic
lethality.
Benfatto S(#)(1), Serçin Ö(#)(1), Dejure FR(#)(1), Abdollahi A(2), Zenke FT(3),
Mardin BR(4).
Author information:
(1)BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg,
Germany.
(2)Division of Molecular and Translational Radiation Oncology, National Centre
for Tumour Diseases (NCT), Heidelberg University Hospital, 69120, Heidelberg,
Germany.
(3)Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA,
Frankfurter Str. 250, 64293, Darmstadt, Germany.
(4)BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg,
Germany. mardin@bio.mx.
(#)Contributed equally
BACKGROUND: Synthetic lethality describes a genetic interaction between two
perturbations, leading to cell death, whereas neither event alone has a
significant effect on cell viability. This concept can be exploited to
specifically target tumor cells. CRISPR viability screens have been widely
employed to identify cancer vulnerabilities. However, an approach to
systematically infer genetic interactions from viability screens is missing.
METHODS: Here we describe PAn-canceR Inferred Synthetic lethalities (PARIS), a
machine learning approach to identify cancer vulnerabilities. PARIS predicts
synthetic lethal (SL) interactions by combining CRISPR viability screens with
genomics and transcriptomics data across hundreds of cancer cell lines profiled
within the Cancer Dependency Map.
RESULTS: Using PARIS, we predicted 15 high confidence SL interactions within 549
DNA damage repair (DDR) genes. We show experimental validation of an SL
interaction between the tumor suppressor CDKN2A, thymidine phosphorylase (TYMP)
and the thymidylate synthase (TYMS), which may allow stratifying patients for
treatment with TYMS inhibitors. Using genome-wide mapping of SL interactions for
DDR genes, we unraveled a dependency between the aldehyde dehydrogenase ALDH2
and the BRCA-interacting protein BRIP1. Our results suggest BRIP1 as a potential
therapeutic target in ~ 30% of all tumors, which express low levels of ALDH2.
CONCLUSIONS: PARIS is an unbiased, scalable and easy to adapt platform to
identify SL interactions that should aid in improving cancer therapy with
increased availability of cancer genomics data.
© 2021. The Author(s).
DOI: 10.1186/s12943-021-01405-8
PMCID: PMC8401190
PMID: 34454516 [Indexed for MEDLINE]
Conflict of interest statement: Frank T. Zenke is an employee of Merck KGaA,
Darmstadt, Germany. Salvatore Benfatto, Francesca R. Dejure, Özdemirhan Serçin,
and Balca R. Mardin are employees of BioMed X Institute (GmbH), Heidelberg,
Germany. Amir Abdollahi is an academic mentor at BioMed X Institute and receives
research grants from Merck KGaA. |
http://www.ncbi.nlm.nih.gov/pubmed/34590269 | 1. Methods Mol Biol. 2021;2381:39-56. doi: 10.1007/978-1-0716-1740-3_2.
Mapping Synthetic Dosage Lethal Genetic Interactions in Saccharomyces
cerevisiae.
Hamza A(1), Amitzi L(1), Duffy S(1), Hieter P(2).
Author information:
(1)Michael Smith Laboratories, University of British Columbia, Vancouver, BC,
Canada.
(2)Michael Smith Laboratories, University of British Columbia, Vancouver, BC,
Canada. hieter@msl.ubc.ca.
Synthetic dosage lethality (SDL) is a type of genetic interaction that occurs
when increasing the expression of a gene causes a fitness defect, such as
lethality, in a specific mutant background but has little effect on fitness in a
wild-type background. SDL genetic interactions discovered in model organisms
such as the budding yeast, Saccharomyces cerevisiae , represent candidate
genetic interactions that may be conserved in human cells. In some cases, SDL
genetic interactions can be applied to study the biological implications of
genes overexpressed in cancer and to discover potential anticancer therapeutic
drug targets. Here, we provide a protocol for screening a query overexpression
gene against ordered arrays of yeast mutant strains to identify mutations that
sensitize yeast to increased dosage of a specific gene product. We outline
applications and procedures for screening with an inducibly overexpressed
wild-type gene, a common feature of cancer cells, or with an inducibly
overexpressed gene carrying a dominant-negative missense mutation as a model of
protein-inhibitor interactions. This high-throughput screening platform is
adapted from synthetic genetic array (SGA) technology and enables the generation
of large-scale SDL genetic interaction networks that can be applied to study
gene/pathway function and to identify cross-species cancer-relevant processes.
© 2021. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-1740-3_2
PMID: 34590269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26427375 | 1. Biol Direct. 2015 Oct 1;10:57. doi: 10.1186/s13062-015-0086-1.
Inferring synthetic lethal interactions from mutual exclusivity of genetic
events in cancer.
Srihari S(1), Singla J(2), Wong L(3), Ragan MA(4).
Author information:
(1)Institute for Molecular Bioscience, The University of Queensland, St. Lucia,
Queensland, 4072, Australia.
(2)Department of Computer Science and Engineering, Indian Institute of
Technology Roorkee, Uttarakhand, 247667, India.
(3)Department of Computer Science, National University of Singapore, Singapore,
117417, Singapore. wongls@comp.nus.edu.sg.
(4)Institute for Molecular Bioscience, The University of Queensland, St. Lucia,
Queensland, 4072, Australia. m.ragan@uq.edu.au.
BACKGROUND: Synthetic lethality (SL) refers to the genetic interaction between
two or more genes where only their co-alteration (e.g. by mutations,
amplifications or deletions) results in cell death. In recent years, SL has
emerged as an attractive therapeutic strategy against cancer: by targeting the
SL partners of altered genes in cancer cells, these cells can be selectively
killed while sparing the normal cells. Consequently, a number of studies have
attempted prediction of SL interactions in human, a majority by extrapolating SL
interactions inferred through large-scale screens in model organisms. However,
these predicted SL interactions either do not hold in human cells or do not
include genes that are (frequently) altered in human cancers, and are therefore
not attractive in the context of cancer therapy.
RESULTS: Here, we develop a computational approach to infer SL interactions
directly from frequently altered genes in human cancers. It is based on the
observation that pairs of genes that are altered in a (significantly) mutually
exclusive manner in cancers are likely to constitute lethal combinations. Using
genomic copy-number and gene-expression data from four cancers, breast,
prostate, ovarian and uterine (total 3980 samples) from The Cancer Genome Atlas,
we identify 718 genes that are frequently amplified or upregulated, and are
likely to be synthetic lethal with six key DNA-damage response (DDR) genes in
these cancers. By comparing with published data on gene essentiality (~16000
genes) from ten DDR-deficient cancer cell lines, we show that our identified
genes are enriched among the top quartile of essential genes in these cell
lines, implying that our inferred genes are highly likely to be (synthetic)
lethal upon knockdown in these cell lines. Among the inferred targets are
tousled-like kinase 2 (TLK2) and the deubiquitinating enzyme
ubiquitin-specific-processing protease 7 (USP7) whose overexpression correlates
with poor survival in cancers.
CONCLUSION: Mutual exclusivity between frequently occurring genetic events
identifies synthetic lethal combinations in cancers. These identified genes are
essential in cell lines, and are potential candidates for targeted cancer
therapy. Availability: http://bioinformatics.org.au/tools-data/underMutExSL
DOI: 10.1186/s13062-015-0086-1
PMCID: PMC4590705
PMID: 26427375 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23447678 | 1. J Cell Sci. 2013 May 1;126(Pt 9):2004-13. doi: 10.1242/jcs.121301. Epub 2013
Feb 27.
Deregulated G1-S control and energy stress contribute to the synthetic-lethal
interactions between inactivation of RB and TSC1 or TSC2.
Gordon GM(1), Zhang T, Zhao J, Du W.
Author information:
(1)Ben May Department for Cancer Research, The University of Chicago, 929 E.
57th Street, Chicago, IL 60637, USA.
Synthetic lethality is a potential strategy for cancer treatment by specifically
promoting the death of cancer cells with particular defects such as the loss of
the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB
and TSC2 induces synergistic apoptosis during the development of Drosophila
melanogaster and in cancer cells. However, the in vivo mechanism of this
synthetic-lethal interaction is not clear. Here, we show that synergistic cell
death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/gig,
respectively, or overexpress Rheb and dE2F1, are correlated with synergistic
defects in G1-S control, which causes cells to accumulate DNA damage.
Coexpression of the G1-S inhibitor Dap, but not the G2-M inhibitor dWee1,
decreases DNA damage and reduces cell death. In addition, we show that rbf and
dtsc1 mutant cells are under energy stress, are sensitive to decreased energy
levels and depend on the cellular energy stress-response pathway for survival.
Decreasing mitochondrial ATP synthesis by inactivating cova or abrogating the
energy-stress response by removing the metabolic regulator LKB1 both enhance the
elimination of cells lacking either rbf or dtsc1. These observations, in
conjunction with the finding that deregulation of TORC1 induces activation of
JNK, indicate that multiple cellular stresses are induced and contribute to the
synthetic-lethal interactions between RB and TSC1/TSC2 inactivation. The
insights gained from this study suggest new approaches for targeting
RB-deficient cancers.
DOI: 10.1242/jcs.121301
PMCID: PMC3666254
PMID: 23447678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30971823 | 1. Nature. 2019 Apr;568(7753):551-556. doi: 10.1038/s41586-019-1102-x. Epub 2019
Apr 10.
WRN helicase is a synthetic lethal target in microsatellite unstable cancers.
Chan EM(#)(1)(2), Shibue T(#)(1), McFarland JM(1), Gaeta B(1), Ghandi M(1),
Dumont N(1), Gonzalez A(1), McPartlan JS(1), Li T(2), Zhang Y(2), Bin Liu J(2),
Lazaro JB(3), Gu P(4), Piett CG(5), Apffel A(1), Ali SO(1)(2), Deasy R(1),
Keskula P(1), Ng RWS(1)(2), Roberts EA(3), Reznichenko E(3), Leung L(1), Alimova
M(1), Schenone M(1), Islam M(1)(2), Maruvka YE(1)(6), Liu Y(1)(2), Roper J(7),
Raghavan S(1)(2), Giannakis M(1)(2), Tseng YY(1), Nagel ZD(1)(5), D'Andrea A(3),
Root DE(1), Boehm JS(1), Getz G(1)(6), Chang S(4)(8)(9), Golub TR(1)(10)(11),
Tsherniak A(1), Vazquez F(#)(12)(13), Bass AJ(#)(14)(15).
Author information:
(1)Broad Institute of Harvard and MIT, Cambridge, MA, USA.
(2)Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston, MA, USA.
(3)Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA.
(4)Department of Laboratory Medicine, Yale University School of Medicine, New
Haven, CT, USA.
(5)Department of Environmental Health, Harvard T. H. Chan School of Public
Health, Boston, MA, USA.
(6)Massachusetts General Hospital Cancer Center, Boston, MA, USA.
(7)Department of Medicine, Division of Gastroenterology, Duke University,
Durham, NC, USA.
(8)Department of Pathology, Yale University School of Medicine, New Haven, CT,
USA.
(9)Department of Molecular Biophysics and Biochemistry, Yale University School
of Medicine, New Haven, CT, USA.
(10)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA.
(11)Howard Hughes Medical Institute, Chevy Chase, MD, USA.
(12)Broad Institute of Harvard and MIT, Cambridge, MA, USA.
vazquez@broadinstitute.org.
(13)Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA. vazquez@broadinstitute.org.
(14)Broad Institute of Harvard and MIT, Cambridge, MA, USA.
adam_bass@dfci.harvard.edu.
(15)Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA. adam_bass@dfci.harvard.edu.
(#)Contributed equally
Comment in
Nature. 2019 Apr;568(7753):463-464. doi: 10.1038/d41586-019-01086-w.
Nat Rev Cancer. 2019 Jun;19(6):305. doi: 10.1038/s41568-019-0147-3.
Cancer Discov. 2019 Jul;9(7):OF6. doi: 10.1158/2159-8290.CD-NB2019-055.
Synthetic lethality-an interaction between two genetic events through which the
co-occurrence of these two genetic events leads to cell death, but each event
alone does not-can be exploited for cancer therapeutics1. DNA repair processes
represent attractive synthetic lethal targets, because many cancers exhibit an
impairment of a DNA repair pathway, which can lead to dependence on specific
repair proteins2. The success of poly(ADP-ribose) polymerase 1 (PARP-1)
inhibitors in cancers with deficiencies in homologous recombination highlights
the potential of this approach3. Hypothesizing that other DNA repair defects
would give rise to synthetic lethal relationships, we queried dependencies in
cancers with microsatellite instability (MSI), which results from deficient DNA
mismatch repair. Here we analysed data from large-scale silencing screens using
CRISPR-Cas9-mediated knockout and RNA interference, and found that the RecQ DNA
helicase WRN was selectively essential in MSI models in vitro and in vivo, yet
dispensable in models of cancers that are microsatellite stable. Depletion of
WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle
arrest selectively in MSI models. MSI cancer models required the helicase
activity of WRN, but not its exonuclease activity. These findings show that WRN
is a synthetic lethal vulnerability and promising drug target for MSI cancers.
DOI: 10.1038/s41586-019-1102-x
PMCID: PMC6580861
PMID: 30971823 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interest A.J.B. receives research
funding from Merck and Novartis. D.E.R. receives research funding from the
Functional Genomics Consortium (Abbvie, Jannsen, Merck, Vir) and is a director
of Addgene. A.T. consults for Tango Therapeutics. T.R.G. has advised Foundation
Medicine, Glaxo SmithKline, Sherlock Biosciences, Forma Therapeutics. A.D.A.
consults for Lilly Oncology, EMD Serono, Intellia Therapeutics, Sierra Oncology,
Formation Biologics, Cyteir Therapeutics, consults and holds stock in Ideaya,
and co-founded and holds stock in Cedilla Therapeutics. G.G. receives research
funding from IBM and Pharmacyclics and is an inventor on multiple patent
applications related to bioinformatic tools, including applications related to
MuTect, ABSOLUTE, MSMuTect, MSMutSig and MSIClass. Y.E.M. is an inventor on
patent applications related to the bioinformatic tools, MSMuTect, MSMutSig and
MSIClass. The Broad Institute filed a US patent application related to the
target described in this manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/26516187 | 1. Nucleic Acids Res. 2016 Jan 4;44(D1):D1011-7. doi: 10.1093/nar/gkv1108. Epub
2015 Oct 29.
SynLethDB: synthetic lethality database toward discovery of selective and
sensitive anticancer drug targets.
Guo J(1), Liu H(2), Zheng J(3).
Author information:
(1)School of Computer Engineering, Nanyang Technological University, Singapore
639798, Singapore.
(2)School of Computer Engineering, Nanyang Technological University, Singapore
639798, Singapore Lab of Information Management, Changzhou University, Jiangsu
213164, China hliu@cczu.edu.cn.
(3)School of Computer Engineering, Nanyang Technological University, Singapore
639798, Singapore Genome Institute of Singapore (GIS), Biopolis, Singapore
138672, Singapore ZhengJie@ntu.edu.sg.
Synthetic lethality (SL) is a type of genetic interaction between two genes such
that simultaneous perturbations of the two genes result in cell death or a
dramatic decrease of cell viability, while a perturbation of either gene alone
is not lethal. SL reflects the biologically endogenous difference between cancer
cells and normal cells, and thus the inhibition of SL partners of genes with
cancer-specific mutations could selectively kill cancer cells but spare normal
cells. Therefore, SL is emerging as a promising anticancer strategy that could
potentially overcome the drawbacks of traditional chemotherapies by reducing
severe side effects. Researchers have developed experimental technologies and
computational prediction methods to identify SL gene pairs on human and a few
model species. However, there has not been a comprehensive database dedicated to
collecting SL pairs and related knowledge. In this paper, we propose a
comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/),
which contains SL pairs collected from biochemical assays, other related
databases, computational predictions and text mining results on human and four
model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a
confidence score was calculated by integrating individual scores derived from
different evidence sources. We also developed a statistical analysis module to
estimate the druggability and sensitivity of cancer cells upon drug treatments
targeting human SL partners, based on large-scale genomic data, gene expression
profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To
help users access and mine the wealth of the data, we developed other practical
functionalities, such as search and filtering, orthology search, gene set
enrichment analysis. Furthermore, a user-friendly web interface has been
implemented to facilitate data analysis and interpretation. With the integrated
data sets and analytics functionalities, SynLethDB would be a useful resource
for biomedical research community and pharmaceutical industry.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkv1108
PMCID: PMC4702809
PMID: 26516187 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26431531 | 1. PLoS One. 2015 Oct 2;10(10):e0139435. doi: 10.1371/journal.pone.0139435.
eCollection 2015.
The Overexpression of FEN1 and RAD54B May Act as Independent Prognostic Factors
of Lung Adenocarcinoma.
Hwang JC(1), Sung WW(2), Tu HP(3), Hsieh KC(4), Yeh CM(5), Chen CJ(6), Tai
HC(5), Hsu CT(7), Shieh GS(8), Chang JG(9), Yeh KT(10), Liu TC(11).
Author information:
(1)Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung
Medical University, Kaohsiung, Taiwan; Department of Pathology, Lin Shin
Hospital, Taichung, Taiwan.
(2)School of Medicine, Chung Shan Medical University, Taichung, Taiwan;
Department of Medical Education, Chung Shan Medical University Hospital,
Taichung, Taiwan; Department of Medical Technology, Jen-Teh Junior College of
Medicine, Nursing and Management, Miaoli, Taiwan.
(3)Department of Public Health and Environmental Medicine, School of Medicine,
College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
(4)Division of Thoracic Surgery, Department of Surgery, E-Da Hospital,
Kaohsiung, Taiwan.
(5)Department of Surgical Pathology, Changhua Christian Hospital, Changhua,
Taiwan.
(6)School of Medicine, Chung Shan Medical University, Taichung, Taiwan;
Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing
and Management, Miaoli, Taiwan; Department of Surgical Pathology, Changhua
Christian Hospital, Changhua, Taiwan.
(7)Department of Pathology, E-Da Hospital and I-SHOU University, Kaohsiung,
Taiwan.
(8)Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
(9)Department of Laboratory Medicine, and Center of RNA Biology and Clinical
Application, China Medical University Hospital, China Medical University,
Taichung, Taiwan.
(10)School of Medicine, Chung Shan Medical University, Taichung, Taiwan;
Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan.
(11)Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung
Medical University, Kaohsiung, Taiwan; Division of Hematology/Oncology,
Department of Internal Medicine, Kaohsiung Medical University Hospital,
Kaohsiung, Taiwan.
Synthetic lethality arises when a combination of mutations in two or more genes
leads to cell death. However, the prognostic role of concordant overexpression
of synthetic lethality genes in protein level rather than a combination of
mutations is not clear. In this study, we explore the prognostic role of
combined overexpression of paired genes in lung adenocarcinoma. We used
immunohistochemical staining to investigate 24 paired genes in 93 lung
adenocarcinoma patients and Kaplan-Meier analysis and Cox proportional hazards
models to evaluate their prognostic roles. Among 24 paired genes, only FEN1
(Flap endonuclease 1) and RAD54B (RAD54 homolog B) were overexpressed in lung
adenocarcinoma patients with poor prognosis. Patients with expression of both
FEN1 and RAD54B were prone to have advanced nodal involvement and significantly
poor prognosis (HR = 2.35, P = 0.0230). These results suggest that intensive
follow up and targeted therapy might improve clinical outcome for patients who
show expression of both FEN1 and RAD54B.
DOI: 10.1371/journal.pone.0139435
PMCID: PMC4592204
PMID: 26431531 [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/29421999 | 1. Curr Med Chem. 2019;26(8):1446-1482. doi: 10.2174/0929867325666180201114306.
DNA Double Strand Break Repair - Related Synthetic Lethality.
Toma M(1), Skorski T(2), Sliwinski T(1).
Author information:
(1)Laboratory of Medical Genetics, Faculty of Biology and Environmental
Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
(2)Department of Microbiology and Immunology, 3400 North Broad Street, Temple
University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.
Cancer is a heterogeneous disease with a high degree of diversity between and
within tumors. Our limited knowledge of their biology results in ineffective
treatment. However, personalized approach may represent a milestone in the field
of anticancer therapy. It can increase specificity of treatment against tumor
initiating cancer stem cells (CSCs) and cancer progenitor cells (CPCs) with
minimal effect on normal cells and tissues. Cancerous cells carry multiple
genetic and epigenetic aberrations which may disrupt pathways essential for cell
survival. Discovery of synthetic lethality has led a new hope of creating
effective and personalized antitumor treatment. Synthetic lethality occurs when
simultaneous inactivation of two genes or their products causes cell death
whereas individual inactivation of either gene is not lethal. The effectiveness
of numerous anti-tumor therapies depends on induction of DNA damage therefore
tumor cells expressing abnormalities in genes whose products are crucial for DNA
repair pathways are promising targets for synthetic lethality. Here, we discuss
mechanistic aspects of synthetic lethality in the context of deficiencies in DNA
double strand break repair pathways. In addition, we review clinical trials
utilizing synthetic lethality interactions and discuss the mechanisms of
resistance.
Copyright© Bentham Science Publishers; For any queries, please email at
epub@benthamscience.net.
DOI: 10.2174/0929867325666180201114306
PMID: 29421999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36446128 | 1. ACS Biomater Sci Eng. 2022 Dec 12;8(12):5210-5220. doi:
10.1021/acsbiomaterials.2c01073. Epub 2022 Nov 29.
Nanoparticle-Mediated PRDX2 Inhibition for Specific Targeting of CHK2-Null
Colorectal Cancer.
Ahmad A(1), Prakash R(2), Khan MS(3), Altwaijry N(3), Asghar MN(4), Raza SS(2),
Khan R(1).
Author information:
(1)Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge
City, Sector-81, Mohali140306, Punjab, India.
(2)Laboratory for Stem Cell & Restorative Neurology, Department of
Biotechnology, Era's Lucknow Medical College Hospital, Sarfarazganj,
Lucknow226003, Uttar Pradesh, India.
(3)Department of Biochemistry, College of Sciences, King Saud University,
Riyadh, Riyadh Province11451, Saudi Arabia.
(4)Department of Medical Biology, University of Québec at Trois-Rivieres,
Trois-Rivieres, QuébecG9A 5H7, Canada.
Synthetic lethality is a pragmatic targeted cancer therapy approach in which
cancer cells harboring genetic alterations are exploited for the specific
killing of cancer cells. Earlier, we have established a synthetic lethal (SL)
interaction between two genes that are CHK2 and PRDX2 in colorectal cancer (CRC)
cells. The SL interaction between CHK2 and PRDX2 resulted in selective targeting
of CHK2-defective CRC cells. N-Carbamoyl alanine (NCA) is a PRDX2 inhibitor and
is a peptide-like organic compound, which degrades after oral administration in
harsh gastric pH. To overcome the limitations of NCA, a chitosan-based
nanocarrier was developed for the entrapment of NCA. In this study, we targeted
the SL interaction between PRDX2 and CHK2 using NCA-loaded chitosan
nanoparticles (NCA-Chit NPs) to selectively inhibit the CHK2-null HCT116 cells.
NCA-Chit NPs were assessed for various physicochemical characterizations such as
the hydrodynamic diameter (size), zeta potential, and polydispersity index using
a Zetasizer. Additionally, morphological studies for the shape and size of NPs
were confirmed by transmission electron microscopy, scanning electron
microscopy, and atomic force microscopy. Cellular uptake of NPs was confirmed
using confocal microscopy, which exhibited that nanoparticles were able to
internalize into the HCT116 cells. Blank Chit NPs were found to be
cytocompatible as they did not exert any cytotoxic effects on hTERT, L929, and
Caco-2 cells (intestinal epithelial cells). Importantly, NCA-Chit NPs were quite
hemocompatible also. In the form of an NCA-chitosan nanoformulation, the
efficacy was enhanced by about 8 times compared to free form of NCA towards
selective killing of CHK2-null HCT116 cells as compared to HCT116 cells. The
chitosan-based nanoformulation for NCA was developed to augment the efficacy of
the NCA for enhanced cell death of colorectal cancer cells having CHK2 defects.
DOI: 10.1021/acsbiomaterials.2c01073
PMID: 36446128 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29171189 | 1. IUBMB Life. 2017 Dec;69(12):929-937. doi: 10.1002/iub.1696.
Synthetic lethality in DNA repair network: A novel avenue in targeted cancer
therapy and combination therapeutics.
Bhattacharjee S(1), Nandi S(1).
Author information:
(1)Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Synthetic lethality refers to a lethal phenotype that results from the
simultaneous disruptions of two genes, while the disruption of either gene alone
is viable. Many DNA double strand break repair (DSBR) genes have synthetic
lethal relationships with oncogenes and tumor suppressor genes, which can be
exploited for targeted cancer therapy, an approach referred to as combination
therapy. DNA double-strand breaks (DSBs) are one of the most toxic lesions to a
cell and can be repaired by non-homologous end joining (NHEJ) or homologous
recombination (HR). HR and NHEJ genes are particularly attractive targets for
cancer therapy because these genes have altered expression patterns in cancer
cells when compared with normal cells and these genetic abnormalities can be
targeted for selectively killing cancer cells. Here, we review recent advances
in the development of small molecule inhibitors against HR and NHEJ genes to
induce synthetic lethality and address the future directions and clinical
relevance of this approach. © 2017 IUBMB Life, 69(12):929-937, 2017.
© 2017 International Union of Biochemistry and Molecular Biology.
DOI: 10.1002/iub.1696
PMID: 29171189 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35170959 | 1. J Am Chem Soc. 2022 Mar 2;144(8):3696-3705. doi: 10.1021/jacs.1c12697. Epub
2022 Feb 16.
Rapid Inhibitor Discovery by Exploiting Synthetic Lethality.
Muscato JD(1), Morris HG(1), Mychack A(1), Rajagopal M(1)(2), Baidin V(2),
Hesser AR(1), Lee W(1), İnecik K(1), Wilson LJ(3), Kraml CM(3), Meredith TC(1),
Walker S(1)(2).
Author information:
(1)Department of Microbiology, Harvard University, 77 Avenue Louis Pasteur,
Boston, Massachusetts 02115, United States.
(2)Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford
Street, Cambridge, Massachusetts 02138, United States.
(3)Lotus Separations LLC, B20 Frick Chemistry Laboratory, Princeton, New Jersey
08544, United States.
Synthetic lethality occurs when inactivation of two genes is lethal but
inactivation of either single gene is not. This phenomenon provides an
opportunity for efficient compound discovery. Using differential growth screens,
one can identify biologically active compounds that selectively inhibit proteins
within the synthetic lethal network of any inactivated gene. Here, based purely
on synthetic lethalities, we identified two compounds as the only possible
inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis from a
screen of ∼230,000 compounds. Both compounds proved to inhibit the
glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is
required for β-lactam resistance in methicillin-resistant S. aureus (MRSA), and
the inhibitors restored sensitivity to oxacillin in a highly resistant S. aureus
strain. As no other compounds were pursued as possible LTA glycolipid assembly
inhibitors, this work demonstrates the extraordinary efficiency of screens that
exploit synthetic lethality to discover compounds that target specified
pathways. The general approach should be applicable not only to other bacteria
but also to eukaryotic cells.
DOI: 10.1021/jacs.1c12697
PMCID: PMC9012225
PMID: 35170959 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/26630128 | 1. Expert Opin Biol Ther. 2016;16(2):161-72. doi: 10.1517/14712598.2016.1110141.
Epub 2015 Dec 2.
Current views on inducing synthetic lethal RNAi responses in the treatment of
cancer.
Kacsinta AD(1), Dowdy SF(1).
Author information:
(1)a Department of Cellular and Molecular Medicine , UCSD School of Medicine ,
La Jolla , CA , USA.
INTRODUCTION: Cancer cells arise from normal cells that have incurred mutations
in oncogenes and tumor suppressor genes. The mutations are often unique and not
readily found in normal cells, giving rise to the opportunity of exploiting
these mutations to induce synthetic lethality. Synthetic lethality occurs when
inhibition or mutation in two or more separate genes leads to cell death while
inhibition or mutations of either gene alone has no lethal effect on the cell.
Using RNA interference (RNAi) to identify synthetic lethality has become a
growingly popular screening approach.
AREAS COVERED: In this review, we cover the use of RNAi therapeutics to induce
synthetic lethality in cancer. Additionally, we discuss several select small
molecule inhibitors that were identified or verified by RNAi that induce
synthetic lethality in specific cancers. We also discuss the identification of
novel synthetic lethal combinations and the cancer model that the combination
was validated in. Lastly, we discuss RNAi delivery vehicles.
EXPERT OPINION: While RNAi therapeutics have great potential to treat cancer,
due to the siRNA delivery problem, RNAi remains more commonly used as a tool,
rather than a therapeutic. However, with emerging technological advances in the
field of RNAi therapeutics, it is only a matter of time before RNAi-induced
synthetic lethal clinical studies are initiated in cancer patients.
DOI: 10.1517/14712598.2016.1110141
PMID: 26630128 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33795234 | 1. Cancer Discov. 2021 Jul;11(7):1626-1635. doi: 10.1158/2159-8290.CD-20-1503.
Epub 2021 Apr 1.
Synthetic Lethality in Cancer Therapeutics: The Next Generation.
Setton J(1), Zinda M(2), Riaz N(1), Durocher D(3)(4), Zimmermann M(5), Koehler
M(2), Reis-Filho JS(1), Powell SN(6).
Author information:
(1)Memorial Sloan Kettering Cancer Center, New York, New York.
(2)Repare Therapeutics, Cambridge, Massachusetts.
(3)Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto,
Ontario, Canada.
(4)Department of Molecular Genetics, University of Toronto, Toronto, Ontario,
Canada.
(5)Repare Therapeutics, St-Laurent, Quebec, Canada.
(6)Memorial Sloan Kettering Cancer Center, New York, New York.
powells@mskcc.org.
Synthetic lethality (SL) provides a conceptual framework for tackling targets
that are not classically "druggable," including loss-of-function mutations in
tumor suppressor genes required for carcinogenesis. Recent technological
advances have led to an inflection point in our understanding of genetic
interaction networks and ability to identify a wide array of novel SL drug
targets. Here, we review concepts and lessons emerging from first-generation
trials aimed at testing SL drugs, discuss how the nature of the targeted lesion
can influence therapeutic outcomes, and highlight the need to develop clinical
biomarkers distinct from those based on the paradigms developed to target
activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of
loss of function of tumor suppressor and DNA repair genes, as well as of
amplification and/or overexpression of genes that cannot be targeted directly. A
next generation of tumor-specific alterations targetable through SL has emerged
from high-throughput CRISPR technology, heralding not only new opportunities for
drug development, but also important challenges in the development of optimal
predictive biomarkers.
©2021 American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-20-1503
PMCID: PMC8295179
PMID: 33795234 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest: MZ, MZ and MK are
employees and shareholders of Repare Therapeutics. DD is a shareholder in Repare
Therapeutics. JSR-F reports receiving personal/consultancy fees from Goldman
Sachs, Paige.AI and Repare Therapeutics, membership of the scientific advisory
boards of VolitionRx, Repare Therapeutics and Paige.AI, membership of the Board
of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific
advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis,
Genentech and InVicro. SNP is a medical board advisor to Varian, Philips,
AstraZeneca, and XRAD therapeutics. All other authors declare no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33992077 | 1. BMC Bioinformatics. 2021 May 15;22(1):250. doi: 10.1186/s12859-021-04168-7.
Identifying collateral and synthetic lethal vulnerabilities within the
DNA-damage response.
Pinoli P(1), Srihari S(2), Wong L(3), Ceri S(4).
Author information:
(1)Department of Electronic, Information and Bioengineering, Politecnico di
Milano, Piazza Leonardo da Vinci 32, Milan, Italy. pietro.pinoli@polimi.it.
(2)Institute for Molecular Bioscience, The University of Queensland, St Lucia,
QLD, Australia.
(3)School of Computing, National University of Singapore, Computing Drive 13,
Singapore, Singapore.
(4)Department of Electronic, Information and Bioengineering, Politecnico di
Milano, Piazza Leonardo da Vinci 32, Milan, Italy.
BACKGROUND: A pair of genes is defined as synthetically lethal if defects on
both cause the death of the cell but a defect in only one of the two is
compatible with cell viability. Ideally, if A and B are two synthetic lethal
genes, inhibiting B should kill cancer cells with a defect on A, and should have
no effects on normal cells. Thus, synthetic lethality can be exploited for
highly selective cancer therapies, which need to exploit differences between
normal and cancer cells.
RESULTS: In this paper, we present a new method for predicting synthetic lethal
(SL) gene pairs. As neighbouring genes in the genome have highly correlated
profiles of copy number variations (CNAs), our method clusters proximal genes
with a similar CNA profile, then predicts mutually exclusive group pairs, and
finally identifies the SL gene pairs within each group pairs. For
mutual-exclusion testing we use a graph-based method which takes into account
the mutation frequencies of different subjects and genes. We use two different
methods for selecting the pair of SL genes; the first is based on the gene
essentiality measured in various conditions by means of the "Gene Activity
Ranking Profile" GARP score; the second leverages the annotations of gene to
biological pathways.
CONCLUSIONS: This method is unique among current SL prediction approaches, it
reduces false-positive SL predictions compared to previous methods, and it
allows establishing explicit collateral lethality relationship of gene pairs
within mutually exclusive group pairs.
DOI: 10.1186/s12859-021-04168-7
PMCID: PMC8126165
PMID: 33992077 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/31811941 | 1. Drug Discov Today. 2020 Feb;25(2):305-320. doi: 10.1016/j.drudis.2019.11.014.
Epub 2019 Dec 4.
Synthetic lethality: a step forward for personalized medicine in cancer.
Jariyal H(1), Weinberg F(2), Achreja A(2), Nagarath D(3), Srivastava A(4).
Author information:
(1)National Institute of Pharmaceutical Education and Research (NIPER),
Ahmedabad, India.
(2)Department of Biomedical Engineering, University of Michigan, USA.
(3)Department of Biomedical Engineering, University of Michigan, USA. Electronic
address: dnagrath@umich.edu.
(4)National Institute of Pharmaceutical Education and Research (NIPER),
Ahmedabad, India. Electronic address: akshay.srivastava@niperahm.ac.in.
Erratum in
Drug Discov Today. 2021 Aug;26(8):2077. doi: 10.1016/j.drudis.2020.07.016.
Synthetic lethality occurs between two genes when silencing of either gene alone
enables viable outcomes but inhibition of both is lethal. Understanding
context-dependent functioning of synthetic lethality allows therapeutic
targeting in cancer. Furthermore, the paradigm shift toward precision medicine
to treat cancer necessitates the establishment of biomarkers to help determine
which patient populations might respond to specific drug combinations.
Elucidating synthetically lethal gene combinations in cancer could establish
clinically relevant drug combinations as well as biomarkers to better treat
patients. Here, we have reviewed the recent synthetically lethal gene
combinations in preclinical and clinical settings and discuss how this approach
could help reveal potential biomarkers.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.drudis.2019.11.014
PMID: 31811941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22864477 | 1. Nat Cell Biol. 2012 Sep;14(9):958-65. doi: 10.1038/ncb2556. Epub 2012 Aug 5.
Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal
progenitors suppresses retinoblastoma formation.
Nittner D(1), Lambertz I, Clermont F, Mestdagh P, Köhler C, Nielsen SJ,
Jochemsen A, Speleman F, Vandesompele J, Dyer MA, Schramm A, Schulte JH, Marine
JC.
Author information:
(1)Laboratory for Molecular Cancer Biology, Center for the Biology of Disease,
VIB, 3000 Leuven, Belgium.
Comment in
Nat Rev Cancer. 2012 Oct;12(10):657. doi: 10.1038/nrc3358.
Synthetic lethality is a promising strategy for specific targeting of cancer
cells that carry mutations that are absent in normal cells. This approach may
help overcome the challenge associated with targeting dysfunctional tumour
suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting
prevents retinoblastoma formation in mice by synthetic lethality with combined
inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient
tumour suppressor, its complete loss of function is selected against during
tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient
retinal progenitor cells harbouring an intact p53 pathway, but not in the
absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92
cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92
inactivation suppresses retinoblastoma formation in mice and co-silencing of
miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma
cells. These data provide an explanation for the selective pressure against loss
of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may
potentially represent a general approach for synthetic lethal targeting of
cancer cells that harbour specific cancer-inducing genotypes.
DOI: 10.1038/ncb2556
PMID: 22864477 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34322164 | 1. US Ophthalmic Rev. 2020 Fall;13(2):76-79. doi: 10.17925/usor.2020.13.2.76.
Epub 2020 Dec 23.
Suprachoroidal Injection of Triamcinolone- Review of a Novel Treatment for
Macular Edema Caused by Noninfectious Uveitis.
Price KW(1), Albini TA(2), Yeh S(1)(3).
Author information:
(1)Department of Ophthalmology, Emory University School of Medicine, Atlanta,
GA, USA.
(2)Bascom Palmer Eye Institute, University of Miami Miller School of Medicine,
Miami, FL, USA.
(3)Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE,
USA.
Macular edema is the most frequent cause of visual deterioration in
noninfectious uveitis. The treatment of noninfectious uveitis with associated
macular edema commonly includes systemic or locally administered
corticosteroids, with long-term use limited by significant side effects. The
need for a treatment with an improved safety profile has driven the development
of a novel ophthalmic therapy: a proprietary triamcinolone acetonide suspension
(CLS-TA) administered in the suprachoroidal space (XIPERE™; Clearside
Biomedical, Alpharetta, GA, USA). Suprachoroidal delivery of corticosteroids
allows higher steroid concentration in the posterior segment and decreases the
risk of other adverse ocular events. Recent results from the PEACHTREE trial
(ClinicalTrials.gov Identifier: NCT02595398), a phase III trial with two
suprachoroidal injections of CLS-TA at 0 and 12 weeks with follow up lasting 24
weeks, showed the significant improvement in visual acuity and reduction in
central subfield thickness, all without increasing the risk of elevated
intraocular pressure or accelerated cataract progression.
DOI: 10.17925/usor.2020.13.2.76
PMCID: PMC8315419
PMID: 34322164 |
http://www.ncbi.nlm.nih.gov/pubmed/35929940 | 1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Aug 10;39(8):877-880. doi:
10.3760/cma.j.cn511374-20210025-00163.
[Genetic analysis for a child with comorbid X-linked ichthyosis and Duchenne
muscular dystrophy].
[Article in Chinese]
Zhang C(1), Hao S, Hui L, Feng X, Chen X, Wang X, Zheng L, Liu F, Zhou B, Zhang
Q.
Author information:
(1)Medical Genetics Center, Gansu Maternal and Child Health Care Hospital,
Lanzhou, Gansu 730050, China. 0929zhangqh@163.com.
OBJECTIVE: To carry out pedigree analysis for a rare child with comorbid
X-linked ichthyosis (XLI) and Duchenne muscular dystrophy (DMD).
METHODS: Whole exome sequencing (WES) and multiple ligation-dependent probe
amplification (MLPA) were used to detect potential deletions in the STS and DMD
genes.
RESULTS: The proband was found to harbor hemizygous deletion of the STS gene and
exons 48 to 54 of the DMD gene.
CONCLUSION: The child has comorbid XLI and DMD, which is extremely rare.
DOI: 10.3760/cma.j.cn511374-20210025-00163
PMID: 35929940 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35218518 | 1. J Mol Neurosci. 2022 May;72(5):1098-1107. doi: 10.1007/s12031-022-01980-5.
Epub 2022 Feb 26.
Genetic Analysis of Forty MLPA-Negative Duchenne Muscular Dystrophy Patients by
Whole-Exome Sequencing.
Zamani GR(#)(1), Mohammadi MF(#)(2), Tavasoli AR(1)(3), Ashrafi MR(1),
Hosseinpour S(4), Ghabeli H(1), Pourbakhtyaran E(1), Haghighi R(1), Hosseiny
SMM(5), Mohammadi P(6), Heidari M(7).
Author information:
(1)Department of Pediatric Neurology, Pediatrics Center of Excellence,
Children's Medical Center, Myelin Disorders Clinic, Tehran University of Medical
Sciences, Tehran, Iran.
(2)Department of Cell and Molecular Sciences, Faculty of Biological Sciences,
Kharazmi University, Tehran, Iran.
(3)Jefferson Institute of Molecular Medicine, Thomas Jefferson University,
Philadelphia, USA.
(4)Department of Pediatric Neurology, Vali-E-Asr Hospital, Imam Khomeini
Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
(5)Department of Pediatric Neurology, School of Medicine, Hamadan University of
Medical Sciences, Hamadan, Iran.
(6)Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares
University, Postal Code, Jalah-Al Ahmad Hwy, 14117-1316, Tehran, Iran.
Pouria.mohammaditmu@gmail.com.
(7)Department of Pediatric Neurology, Pediatrics Center of Excellence,
Children's Medical Center, Myelin Disorders Clinic, Tehran University of Medical
Sciences, Tehran, Iran. m-heidari@sina.tums.ac.ir.
(#)Contributed equally
This manuscript aimed to determine the underlying point mutations causing
Duchenne muscular dystrophy (DMD) in a heterogeneous group of Iranian patients,
who are clinically suspected. Whole-exome sequencing was utilized to detect
disease-causing variants in 40 MLPA-negative DMD patients. Disease-causing
variants were detected in the DMD gene in 36/40 of the patients (90%), and 4/40
of them (10%) remained undiagnosed. WES analysis revealed that nonsense variant
was the most common type in our study (23/36 of the cases). Besides, 12/36 of
the cases had frameshift variant, and one of the patients had a likely
pathogenic splice variant in the DMD gene. Carrier testing revealed that 21/40
of the mothers had the identified variant. Therefore, most variants were
inherited (58.3%), while 19/40 were de novo (41. 7%). The present study has
demonstrated the importance of performing WES to detect disease-causing point
mutations in MLPA-negative DMD patients and to identify carrier females. Due to
regulatory challenges, the clinical development of therapeutic approaches is
time-consuming and may not be available to all patients shortly. Therefore, it
appears that the techniques used to accurately detect disease-causing variants
in carrier mothers are a more efficient solution to prevent the increased
prevalence of DMD.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s12031-022-01980-5
PMID: 35218518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34327855 | 1. Mol Genet Genomic Med. 2021 Sep;9(9):e1759. doi: 10.1002/mgg3.1759. Epub 2021
Jul 29.
MLPA followed by target-NGS to detect mutations in the dystrophin gene of
Peruvian patients suspected of DMD/DMB.
Guevara-Fujita ML(1), Huaman-Dianderas F(1), Obispo D(1), Sánchez R(1),
Barrenechea V(1), Rojas-Málaga D(1)(2), Estrada-Cuzcano A(1)(3), Trubnykova
M(4), Cornejo-Olivas M(5)(6), Marca V(5), Gallardo B(4), Dueñas-Roque M(7),
Protzel A(7), Castañeda C(8), Abarca H(4), Celis L(9), La Serna-Infantes J(10),
Fujita R(1).
Author information:
(1)Centro de Genética y Biología Molecular, Instituto de Investigación, Facultad
de Medicina Humana, Universidad de San Martín de Porres, Lima, Peru.
(2)Laboratório de Genética Molecular, Serviço de Genética Médica, Hospital de
Clínicas de Porto Alegre, Rio Grande do Sul, Brazil.
(3)Paris-Saclay Institute of Neuroscience, CERTO-Retina France, CNRS, Université
Paris-Saclay, Orsay, 91405, France.
(4)Servicio de Genética y Errores Innatos del Metabolismo del Instituto Nacional
de Salud del Niño, Lima, Peru.
(5)Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas,
Lima, Peru.
(6)Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru.
(7)Hospital Nacional Edgardo Rebagliati Martins, EsSalud, Lima, Peru.
(8)Hospital Nacional Cayetano Heredia, Lima, Peru.
(9)Servicio de Genética, Instituto de Salud del Niño San Borja, Lima, Peru.
(10)GenoCenter, Lima, Peru.
BACKGROUND: We report the molecular analysis of the DMD gene in a group of
Peruvian patients with Duchenne/Becker dystrophinopathy. This is the first study
to thoroughly characterize mutations in this population.
METHODS: We used the combination of multiplex ligation-dependent probe
amplification (MLPA) and sequencing analysis of the DMD gene. We recruited
Peruvian patients in 2 years from reference national hospitals. We performed DNA
tests in 152 patients, checking first exon deletion/duplication by MLPA, and
subsequently, if negative, samples were sequenced to detect point mutations.
RESULTS: The average age for diagnosis was 9.8 years, suggesting a delay for
timely diagnosis and care. We found causal DMD mutations in 125 patients: 72
(57.6%) exon deletions/duplications (41.6% deletions, 16.0% duplications), and
53 (42.4%) point mutations (27.2% nonsense, 9.6% small indels, and 5.6% splice
site).
CONCLUSION: Due to our genetic background, we expected a higher number of novel
and recurrent causal mutations in our sample. Results showed 16% of novel
mutations, similar to other well-studied populations.
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley
Periodicals LLC.
DOI: 10.1002/mgg3.1759
PMCID: PMC8457708
PMID: 34327855 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that no conflict of interest
could be perceived as prejudicial to the impartiality of the reported research. |
http://www.ncbi.nlm.nih.gov/pubmed/12022080 | 1. Rev Neurol. 2002 Feb 1-15;34(3):278-81.
[Diagnostic techniques described in the study of Duchenne/Becker muscular
dystrophy].
[Article in Spanish]
Montejo-Pujadas Y(1), Zaldívar-Vaillant T, Acevedo-López AM.
Author information:
(1)Departamento de Neurogen tica; Instituto Nacional de Neurolog a y Neurocirug
a, La Habana, 10400, Cuba. yuset@infomed.sld.cu
INTRODUCTION: Duchenne/Becker muscular dystrophy (DMD/B) is one of the commonest
myopathies, with an incidence of 1/3,500 male live births. It is characterized
by the slow degeneration of muscle fibres, so that the patient has become an
invalid by the age of 10 years, followed by death from respiratory or cardiac
failure. It has a sex linked recessive mode of inheritance.
DEVELOPMENT: The gene causing this disorder is the DMD gene and is found on the
short arm of the X chromosome. The commonest mutations of this gene are
deletions. Many molecular techniques for study of the disorder have been
developed over the years. These include the Southern Blot, polymerase chain
reaction (PCR), use of the Short Tandem Repeat (STR), polymorphic length
restriction fragments (RFLP), Western Blot for the study of the protein and
others.
CONCLUSIONS: In this paper we review the diagnostic tests most widely used in
this disease. These have permitted improved study of the various families
affected and thus improved the quality of life of the families at risk.
PMID: 12022080 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33734897 | 1. Genet Test Mol Biomarkers. 2021 Mar;25(3):218-226. doi:
10.1089/gtmb.2020.0246.
Whole-Exome Sequencing Identifies Small Mutations in Pakistani Muscular
Dystrophy Patients.
Zehravi M(1), Wahid M(1)(2), Ashraf J(3), Fatima T(1)(4).
Author information:
(1)Dow Research Institute of Biotechnology and Biomedical Sciences, Dow
University of Health Sciences, Karachi, Pakistan.
(2)Department of Pathology, Dow International Medical College, Dow University of
Health Sciences, Karachi, Pakistan.
(3)Department of Neurosurgery, Dow University of Health Sciences, Karachi,
Pakistan.
(4)Dow College of Biotechnology, Dow University of Health Sciences, Karachi,
Pakistan.
Background: Muscular dystrophies are a heterogeneous group of inherited
disorders that cannot be diagnosed clinically due to overlapping clinical
phenotypes. Whole-exome sequencing is considered as the diagnostic strategy of
choice in these cases. In this study we aimed to determine the mutational
spectrum of multiplex ligation-dependent probe amplification (MLPA)-negative
muscular dystrophy patients in Pakistan using whole-exome sequencing.
Subsequently the mutations identified via WES were used to screen additional
dystrophinopathy patients by Sanger sequencing. Materials and Methods: DNA
extracted from the peripheral blood of three MLPA-negative muscular dystrophy
patients was sent for whole-exome sequencing. The identified variants in these 3
patients were then checked in 18 dystrophinopathy patients using Sanger
sequencing. Results: Four missense variants and one nonsense variant in the
Duchenne muscular dystrophy (DMD) gene were detected. WES diagnosed a DMD
patient carrying a nonsense variant c.4375C>T (rs398123953) who can benefit from
Ataluren therapy. The other two patients carried missense variant (c.572G>T) in
the YARS2 gene (rs11539445) labeling them as patients of MLASA (myopathy, lactic
acidosis, and sideroblastic anemia). The identified missense and nonsense
variants in the DMD gene were detected in 18 clinically diagnosed
dystrophinopathy patients using Sanger sequencing. Three missense variants were
detected in our cohort of 18 dystrophinopathy patients. One missense variant
c.3406A>T (rs3827462) and a nonsense variant c.4375C>T (rs398123953) were not
detected in our cohort of 18 dystrophinopathy patients. Conclusions: Whole-exome
sequencing identified a nonsense variant in Pakistani muscular dystrophy
patients, which is amenable to treatment by Ataluren and a missense variant in
YARS2 gene responsible for causing MLASA.
DOI: 10.1089/gtmb.2020.0246
PMID: 33734897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36281417 | 1. Heliyon. 2022 Oct 14;8(10):e11071. doi: 10.1016/j.heliyon.2022.e11071.
eCollection 2022 Oct.
A pilot study of newborn screening for Duchenne muscular dystrophy in Guangzhou.
Jia X(1), Jiang X(1), Huang Y(1).
Author information:
(1)Department of Guangzhou Newborn Screening Center, Guangzhou Women and
Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
BACKGROUND: To estimate the overall situation of Duchenne muscular dystrophy
(DMD) screening in newborns in Guangzhou, China.
METHOD: A total of 62553 newborns including 44268 males and 18285 females were
screened for DMD by measuring muscle specific creatine kinase isoform (CK-MM)
concentrations using the GSP® Neonatal CK-MM kit based on time-resolved
immunofluorescence. We recalled positive cases and recollected dried blood spots
(DBS) for retest of CK-MM. The newborns with retest positive result were
recalled again for serum creatine kinase (CK) and multiplex ligation-dependent
probe amplification (MLPA) test. Whole exon sequencing was performed when MLPA
test was negative.
RESULTS: Four males were diagnosed with DMD. The incidence of males was 1/11067.
No DMD patient was found in female. There were significant differences of CK-MM
concentration between male and female newborns. Among gestational age (GA),
birth weight (BW) and age at sampling, linear regression analysis showed that
CK-MM concentration was much more closely correlated with GA and age at
sampling.
CONCLUSIONS: CK-MM concentration is affected by gender, GA, BW and age at
sampling. The efficiency of DMD screening might be improved by adjusting a
multitier cut-off value according to GA and age at sampling. DMD newborn
screening should be male priority.
© 2022 Published by Elsevier Ltd.
DOI: 10.1016/j.heliyon.2022.e11071
PMCID: PMC9587328
PMID: 36281417
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30453357 | 1. Neuropediatrics. 2019 Feb;50(1):41-45. doi: 10.1055/s-0038-1675626. Epub 2018
Nov 19.
Diagnostic Pathway to Nonsense Mutation Dystrophinopathy: A Tertiary-Center,
Retrospective Experience.
Ardıçlı D(1), Haliloğlu G(1), Alikaşifoğlu M(2)(3), Topaloğlu H(1).
Author information:
(1)Department of Pediatric Neurology, Hacettepe University Children's Hospital,
Ankara, Turkey.
(2)Department of Medical Genetics, Hacettepe University Children's Hospital,
Ankara, Turkey.
(3)Genetics Diagnostic Center, DAMAGEN, Ankara, Turkey.
Up to 15% of Duchenne's muscular dystrophy (DMD) is caused by nonsense mutations
(nm-DMD). In this study, we aimed to evaluate the age at diagnosis,
presentations, and diagnostic approach in 43 nm-DMD boys. The mean age at
presentation and diagnosis was 3 years and 4 years, respectively. Presenting
signs or symptoms were asymptomatic creatine kinase (CK) elevation (40%), muscle
weakness (30%), motor delay (18%), and walking difficulties (12%). Multiplex
polymerase chain reaction (PCR) of the most commonly deleted exons were negative
(n = 17), and muscle biopsy was consistent with dystrophinopathy (n = 24). In
all patients, multiplex ligation-dependent probe amplification (MLPA) followed
by direct sequencing of all exons, revealed nm-DMD. Mean age at genetic
diagnosis was 6 years 8 months. Patients were evaluated in two-time periods,
between 2006 and 2011 (Group I: n = 10) and 2011 and 2017 (Group II: n = 33).
The mean age at diagnosis/genetic confirmation in Group I and in Group II was 3
years 9 months/10 years, and 4 years 1 month/5 years 9 months, respectively.
Most frequently performed first step diagnostic tests in Group I and Group II
were muscle biopsy and MLPA.Our study reflects the change in the age at genetic
diagnosis and diagnostic approach to nm-DMD depending on the advances and
availability of genetic testing.
Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0038-1675626
PMID: 30453357 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/24300647 | 1. S Afr Med J. 2013 Oct 10;103(12 Suppl 1):999-1004. doi: 10.7196/samj.7274.
Genetic testing for Duchenne/Becker muscular dystrophy in Johannesburg, South
Africa.
Kerr R(1), Robinson C, Essop FB, Krause A.
Author information:
(1)Division of Human Genetics, School of Pathology, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa.
robyn.kerr@nhls.ac.za.
BACKGROUND: Genetic testing for Duchenne/Becker muscular dystrophy (DMD/BMD)
mutations initially involved multiplex polymerase chain reaction (mPCR), which
targeted two mutation hotspots in the gene and detected deletions in affected
males. A newer technology, multiplex ligation-dependent probe amplification
(MLPA), was introduced for diagnostic testing in 2007.
OBJECTIVES: To evaluate MLPA relative to mPCR as a technique for DMD/BMD
diagnostic testing and to establish whether the mutation profile in affected
individuals differs between different South African ethnic groups. METHODS; From
January 2000 - May 2007, genetic diagnostic testing for DMD/BMD was undertaken
in 128 male patients using mPCR. From May 2007 onwards, MLPA replaced this
technique and 261 males were investigated. MLPA is a kit-based technology
available from MRC-Holland.Results. Of the 128 and 261 probands tested using
mPCR and MLPA, respectively, 31% and 34% were found to carry a deletion
mutation. Further, MLPA could detect duplication mutations (11.5%), complex
rearrangements (1.5%) and small mutations (1.5%). In black patients, deletion
mutations were found to cluster in the 3' region of the gene. No
population-specific pathogenic mutations were found.
CONCLUSIONS: The mutation detection rate for mPCR and MLPA is similar for
deletion mutations, but MLPA proved to be a better diagnostic approach as it
could detect other types of mutations as well, including duplications, complex
rearrangements and small mutations. MLPA could also diagnose mutation status in
at-risk female relatives, which is not possible with mPCR.
DOI: 10.7196/samj.7274
PMID: 24300647 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25271841 | 1. Curr Protoc Hum Genet. 2014 Oct 1;83:9.25.1-29. doi:
10.1002/0471142905.hg0925s83.
Molecular diagnosis of Duchenne muscular dystrophy.
Nallamilli BR(1), Ankala A, Hegde M.
Author information:
(1)Department of Human Genetics, Emory University School of Medicine, Atlanta,
Georgia.
Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular
disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The
mutation spectrum of DMD is unique in that 65% of causative mutations are
intragenic deletions, with intragenic duplications and point mutations (along
with other sequence variants) accounting for 6% to 10% and 30% to 35%,
respectively. The strategy for molecular diagnostic testing for DMD involves
initial screening for deletions/duplications using microarray-based comparative
genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for
sequence variants. Recently, next-generation sequencing (NGS)-based targeted
gene analysis has become clinically available for detection of point mutations
and other sequence variants (small insertions, deletions, and indels). This unit
initially discusses the strategic algorithm for establishing a molecular
diagnosis of DMD and later provides detailed protocols of current molecular
diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing,
and NGS-based sequencing assay.
Copyright © 2014 John Wiley & Sons, Inc.
DOI: 10.1002/0471142905.hg0925s83
PMID: 25271841 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23381834 | 1. J Mol Neurosci. 2013 Jun;50(2):314-6. doi: 10.1007/s12031-013-9971-1. Epub
2013 Feb 5.
Evolution of molecular diagnosis of Duchenne muscular dystrophy.
Itto AB(1), Hamzi K, Bellayou H, Itri M, Slassi I, Nadifi S.
Author information:
(1)Neuropediatrics Department, Ibn Rochd Hospital, Casablanca, Morocco.
benittoa@yahoo.fr
Duchenne muscular dystrophy (DMD) is the commonest of the muscular dystrophies.
The DMD gene (DMD) is the biggest human gene and the most common molecular
defect in the DMD gene, accounting for approximately 65 % of cases of DMD, is
the deletion of one or more exons. The most basic method still in regular use
involves multiplex PCR of the exons, known to be most commonly deleted. The
multiplex is relatively simple. Quantitative analysis of all exons of the gene
and multiplex ligation-dependent probe amplification have brought about an
improvement in mutation detection rate, as they will detect all exon scale
deletions as well as duplications, widely used to detect exonic and intronic
mutations. As a sensitive and discriminative tool, MLPA can be used for prenatal
testing. A more recent development in quantitative analysis is the use of
oligonucleotide-based array comparative genomic hybridization.
DOI: 10.1007/s12031-013-9971-1
PMID: 23381834 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33552634 | 1. J Pediatr Genet. 2021 Mar;10(1):23-28. doi: 10.1055/s-0040-1713850. Epub 2020
Jul 8.
Next-Generation Sequencing in a Cohort of Asian Indian Patients with the
Duchenne Muscular Dystrophy Phenotype: Diagnostic Yield and Mutation Spectrum.
Nerakh G(1), Ranganath P(1), Murugan S(2).
Author information:
(1)Department of Medical Genetics, Nizam's Institute of Medical Sciences,
Hyderabad, Telangana, India.
(2)MedGenome Labs Ltd., Bengaluru, India.
Multiplex ligation-dependent probe amplification (MLPA) detects exonic deletions
and duplications in the DMD gene in around 65 to 70% of patients with the
Duchenne muscular dystrophy (DMD) phenotype. This study looks at the diagnostic
yield of next-generation sequencing (NGS) and the mutation spectrum in an Asian
Indian cohort of MLPA-negative cases with the DMD phenotype. NGS-based
sequencing of DMD gene was done in 28 MLPA-negative cases (25 male probands with
the DMD phenotype and 3 obligate carrier mothers of deceased affected male
patients) and disease-causing variants were identified in 19 (67.9%) of these
cases. Further molecular testing in four of the remaining nine cases revealed
gene variants associated with limb girdle muscular dystrophies. Thus, NGS-based
multigene panel testing for muscular dystrophy-associated genes or clinical
exome sequencing rather than targeted DMD gene sequencing appears to be a more
cost-effective testing modality with better diagnostic yield, for MLPA-negative
patients with the DMD phenotype.
Thieme. All rights reserved.
DOI: 10.1055/s-0040-1713850
PMCID: PMC7853918
PMID: 33552634
Conflict of interest statement: Conflict of Interest None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35359537 | 1. Ann Indian Acad Neurol. 2021 Nov-Dec;24(6):873-878. doi:
10.4103/aian.AIAN_126_21. Epub 2021 Aug 20.
Duchenne Muscular Dystrophy: Genetic and Clinical Profile in the Population of
Rajasthan, India.
Goyal M(1), Gupta A(1), Agarwal K(1), Kapoor S(2), Kumar S(2).
Author information:
(1)Department of Pediatrics, SMS Medical College, Jaipur, Rajasthan, India.
(2)Division of Genetics, Department of Pediatrics, Maulana Azad Medical College,
New Delhi, India.
BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular
dystrophy that affects young boys and is caused by mutation of the dystrophin
gene located over X chromosome.
MATERIALS AND METHODS: In this prospective study, 120 clinically diagnosed DMD
patients were tested for exon deletions, duplication or point mutation.
RESULTS: Of the 120 clinically suspected DMD patients, the diagnosis of DMD was
confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of
onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120
cases were confirmed by genetic testing and six were by absence of staining for
dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication
in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion
located at a distal hot spot region. Single exon deletion was found in 16.5%.
Distal hotspot exons 47, 48 and 50 were the commonly deleted exons.
CONCLUSIONS: In our study, 94.8% cases showed genetic change in the DMD gene.
Muscle biopsy was the choice of investigation in earlier days. Detection of DMD
by DNA based method eliminates the need to do an invasive procedure for
diagnosis. Hence the genetic testing should be the investigation of choice in
suspected cases of DMD. The pattern of deletion, obtained in the population of
Rajasthan was similar when compared with other ethnic groups of the Indian
population. It would be helpful for researchers to develop drugs specific to
exons or for ongoing mutation-specific therapies.
Copyright: © 2006 - 2021 Annals of Indian Academy of Neurology.
DOI: 10.4103/aian.AIAN_126_21
PMCID: PMC8965960
PMID: 35359537
Conflict of interest statement: There are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/26037351 | 1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Jun;32(3):363-6. doi:
10.3760/cma.j.issn.1003-9406.2015.03.013.
[Genetic testing and prenatal diagnosis for eight families affected with
Duchenne muscular dystrophy].
[Article in Chinese]
Li Y(1), Zhang J, Xu Y, Guo F, Xu H, Yan F, Ren J, Wang D, Chen B.
Author information:
(1)Department of Obstetrics and Gynecology, Xijing Hospital, the 4th Military
Medical University, Xi'an, Shaanxi 710032, P.R.China. zhzhhao@163.com.
OBJECTIVE: To optimize the methods for genetic detection and prenatal diagnosis
of Duchenne muscular dystrophy (DMD).
METHODS: Denaturing high-performance liquid chromatography (DHPLC), multiplex
PCR (mPCR), sequencing and other molecular techniques were used in combination
for molecular diagnosis of 8 cases diagnosed as DMD.
RESULTS: Among the 8 cases, 4 have carried large deletions, 3 have point
mutations, among which 6 were of de novo type. Prenatal diagnosis were offered
for 5 families, the results showed that none of the fetuses had carried large
deletions or point mutations. The pregnancies had continued and healthy babies
were born.
CONCLUSION: Combined use of short tandem repeat, DHPLC, mPCR and sequencing can
improve the detection of DMD gene mutations. By establishing and optimizing
genetic and prenatal diagnostic methods, accurate genetic counseling can be
provided for families affected with DMD.
DOI: 10.3760/cma.j.issn.1003-9406.2015.03.013
PMID: 26037351 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2669113 | 1. Riv Neurol. 1989 Jan-Feb;59(1):8-14.
[Present-day clinico-genetic framework of Duchenne's muscular dystrophy].
[Article in Italian]
Meola G(1).
Author information:
(1)Istituto di Clinica Neurologica, Centro Dino Ferrari, Università, Milano.
The authors emphasize the importance of adding a genetic criterion to the
definition of Duchenne dystrophy. The clinical characteristics, however, on the
basis of recent molecular genetic studies, are sufficiently precise to make the
condition heterogeneous: two types of Duchenne dystrophy, with or without mental
retardation in affected boys; muscular dystrophy in girls with mild symptomatic
weakness in "manifesting carriers" up to severe myopathy in girls, found to be
associated with reciprocal chromosomal translocation (X-autosome), always at the
same site, Xp21. Diagnostic use of Xp21 probes is now as necessary as EMG,
muscle biopsy and serum CK assay for the definition of Duchenne muscular
dystrophy.
PMID: 2669113 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8745379 | 1. J Child Neurol. 1996 Jan;11(1):13-20. doi: 10.1177/088307389601100103.
Dystrophinopathies: clarification and complication.
Samaha FJ(1), Quinlan JG.
Author information:
(1)Department of Neurology, University of Cincinnati Medical Center, OH 45267,
USA.
The purpose of this review is to analyze the clinical applications of a
remarkable series of advances made in molecular genetics, primarily with regard
to Becker muscular dystrophy. A new classification is required to clarify such
syndromes as Duchenne and Becker muscular dystrophy. Dystrophinopathies can be
seen in patients with early onset and a severe course (Duchenne muscular
dystrophy), patients with later onset and milder weakness (Becker muscular
dystrophy), patients with myalgia and cramp syndrome, and patients with dilated
cardiomyopathies. Dystrophin testing in muscle is the most sensitive test for
identification of dystrophinopathy patients, although gene deletion studies can
make the diagnosis in most cases.
DOI: 10.1177/088307389601100103
PMID: 8745379 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33660024 | 1. Hautarzt. 2021 Apr;72(4):295-298. doi: 10.1007/s00105-021-04777-6. Epub 2021
Mar 3.
[Hyperplasia-associated cutaneous paraneoplasia].
[Article in German; Abstract available in German from the publisher]
Schmidt MF(1), Schaller M(2), Schmitt LC(3).
Author information:
(1)Klinik für Dermatologie und Allergologie, Hautklinik, Universitätsklinikum
Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland.
(2)Universitäts-Hautklinik Tübingen, Eberhard Karls Universität Tübingen,
Tübingen, Deutschland.
(3)Klinik für Dermatologie und Allergologie, Hautklinik, Universitätsklinikum
Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland. lschmitt@ukaachen.de.
BACKGROUND: Hyperplasia-associated cutaneous paraneoplasia is an important
differential diagnosis in everyday clinical practice. An early diagnosis of the
underlying tumor disease can significantly improve the patient's prognosis.
PATHOGENESIS: Hyperplasia is probably mainly cytokine-mediated. The primary
tumor and/or the metastases release growth factors and transcription factors
which, via epidermal growth factors, lead to hyperproliferation of
keratinocytes.
ACANTHOSIS NIGRICANS MALIGNA: Symmetrical mainly intertriginous
hyperpigmentation with partially verrucous hyperplasia and lichenification
mostly in association with gastric adenocarcinoma. Special forms are florid
cutaneous papillomatosis and tripe palms. Pseudoacanthosis nigricans is to be
distinguished (metabolic and hormonal disorders). LESER-TRéLAT SYNDROME:
Eruptive occurrence of seborrheic keratosis associated with visceral tumors.
ACROKERATOSIS BAZEX: Erythema and scaling initially at the bridge of the nose,
ear helix and acra with later spread, associated with tumors of the upper
aerodigestive system. It should be clinically differentiated from psoriasis.
THERAPY: The treatment of the primary tumor is decisive, which also leads to
a decrease of cutaneous symptoms. Reappreance suggests tumor recurrence.
Publisher: ZUSAMMENFASSUNG: HINTERGRUND: Hyperplasie-assoziierte obligate kutane
Paraneoplasien stellen eine wichtige Differenzialdiagnose im klinischen Alltag
dar. Durch eine frühzeitige Diagnosestellung der zugrunde liegenden
Tumorerkrankung kann die Prognose des Patienten entscheidend verbessert werden.
PATHOGENESE: Die Hyperplasie ist wahrscheinlich vor allem zytokinvermittelt. Der
Primärtumor und/oder die Metastasen schütten Wachstumsfaktoren und
Transkriptionsfaktoren aus, die über Bindung an epidermale Rezeptoren zu
Hyperproliferation von Keratinozyten führen.
ACANTHOSIS NIGRICANS MALIGNA: Auffallend sind symmetrische, vor allem
intertriginöse Hyperpigmentierungen mit teilweise verrukösen Hyperplasien und
Lichenifikation meist in Assoziation mit Adenokarzinomen des Magens.
Sonderformen sind die floride kutane Papillomatose und „tripe palms“.
Abzugrenzen ist die Pseudoacanthosis nigricans bei Stoffwechsel- und hormonellen
Störungen. LESER-TRéLAT-SYNDROM: Es kommt zu einem eruptiven Auftreten von
Verrucae seborrhoicae assoziiert mit viszeralen Tumoren.
ACROKERATOSIS BAZEX: Charakteristisch sind Erythem und Schuppung an den
initialen Prädilektionsstellen Nasenrücken, Ohrhelix und Akren mit späterer
Ausbreitung bei Tumoren des oberen Aerodigestivsystems. Klinisch ist die
Acrokeratosis Bazex von einer Psoriasis abzugrenzen.
THERAPIE: Entscheidend ist die Behandlung des Primärtumors, wodurch es auch zum
Rückgang der Hautsymptome kommt. Rekurrenz spricht für ein Tumorrezidiv.
DOI: 10.1007/s00105-021-04777-6
PMID: 33660024 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33603399 | 1. Onco Targets Ther. 2021 Feb 10;14:951-957. doi: 10.2147/OTT.S290124.
eCollection 2021.
Malignant Acanthosis Nigricans with Recurrent Bladder Cancer: A Case Report and
Review of Literature.
Zhang R(1), Jiang M(1), Lei W(1), Wang A(1).
Author information:
(1)Department of Dermatology, The Second Hospital of Dalian Medical University,
Dalian, Liaoning, 116027, People's Republic of China.
Acanthosis nigricans (AN) is a rare cutaneous condition that may be a
manifestation of certain endocrinological or autoimmune diseases, as well as a
potential marker for underlying undiagnosed cancer. AN is classified as either
benign or malignant based on its clinical associations. Malignant acanthosis
nigricans (MAN), which tends to be extensive and develops rapidly, is considered
to be a paraneoplastic syndrome associated with advanced cancer, commonly
accompanied by intra-abdominal malignancies. Bladder cancer with AN concomitant
with tripe palms (TP) and/or mucosal involvement is relatively rare and, to our
knowledge, only seven cases of AN with bladder cancer have been reported in the
English literature. However, to date, there have been no reports of bladder
cancer with AN concomitant with TP, skin and mucosal involvement. Here, we
present a case of a 71-year-old male diagnosed with AN coexisting with recurrent
bladder cancer and simultaneous TP and oral AN. In addition, we provide a brief
review of the available literature on this topic. Early recognition of skin
features associated with internal malignancies provides an opportunity for early
diagnosis, treatment of the internal malignancy and monitoring of tumor
recurrence.
© 2021 Zhang et al.
DOI: 10.2147/OTT.S290124
PMCID: PMC7882790
PMID: 33603399
Conflict of interest statement: The authors declare no conflicts of interest in
this work. |
http://www.ncbi.nlm.nih.gov/pubmed/33344554 | 1. World J Clin Cases. 2020 Nov 26;8(22):5632-5638. doi:
10.12998/wjcc.v8.i22.5632.
Malignant acanthosis nigricans with Leser-Trélat sign and tripe palms: A case
report.
Wang N(1), Yu PJ(2), Liu ZL(1), Zhu SM(2), Zhang CW(3).
Author information:
(1)Graduate School, Qinghai University, Xining 810016, Qinghai Province, China.
(2)Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai
University, Xining 810000, Qinghai Province, China.
(3)Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai
University, Xining 810000, Qinghai Province, China. xtoof@sina.com.
BACKGROUND: Acanthosis nigricans (AN), Leser-Trélat sign, and tripe palm are all
skin diseases. To date, reports of these appearing as a paraneoplastic syndrome
in a gastric cancer patient are quite rare.
CASE SUMMARY: We report the case of a 61-year-old man with darkened skin color
in the face and torso with no obvious inducement after 1 year of treatment for
Riehl's melanosis. He had 40 brown maculopapular eruptions on his face and the
top of his head with obvious itching. Papillary wart-like hyperkeratosis with
dark brown pigmentation was also observed on both sides of the areola. He had
papilloma-like lesions on the face, around the orbit, and on the neck. His
bilateral palms had small, smooth, papillary projections with millet-like
appearance. Histopathological examination of the skin showed that the patient
was suffering from AN, tripe palms, and Leser-Trélat sign. Gastroscopy showed
the patient's cardia was affected, and pathological biopsy revealed that he had
moderate-to-poorly differentiated adenocarcinoma. Computed tomography test
results showed that his cardia wall had thickened. Based on these histological
and skin characteristics, the patient was diagnosed with gastric cancer with AN,
tripe palms, and Leser-Trélat sign.
CONCLUSION: Researchers should follow up on patients with malignant AN,
Leser-Trélat sign, and tripe palms.
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights
reserved.
DOI: 10.12998/wjcc.v8.i22.5632
PMCID: PMC7716325
PMID: 33344554
Conflict of interest statement: Conflict-of-interest statement: Our authors
declare that we have no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33074559 | 1. Cancer Rep (Hoboken). 2021 Feb;4(1):e1307. doi: 10.1002/cnr2.1307. Epub 2020
Oct 19.
Tripe palms and Malignant Acanthosis Nigricans: More than a diagnostic pointer.
Kumar P(1), Mukundan MK(2), Sehrawat A(1), Sundriyal D(1).
Author information:
(1)Department of Medical Oncology Haematology, All India Institute of Medical
Sciences, Rishikesh, India.
(2)Department of General Medicine, All India Institute of Medical Sciences,
Rishikesh, India.
BACKGROUND: Tripe palms (TP) is one of the rare cutaneous paraneoplastic
manifestations of various intra-abdominal malignancies. TP and malignant
acanthosis nigricans (MAN) occur together and may precede even years before the
index cancer. Though rare, the clinical significance of TP and MAN holds
significance as an indicator of internal malignancy.
CASE: Here, we describe 71-year, postmenopausal female with ovarian cancer who
presented to us with a history of dyspepsia, abdominal distension, and weight
loss. On detailed history and evaluation, it was found that she had TP and MAN
4 years before diagnosis.
CONCLUSION: The unique presentation preceding the primary illness necessitates
extensive early work-up to look for malignancy and the initial consideration for
surgery due to the tumor biology in such patients.
© 2020 The Authors. Cancer Reports published by Wiley Periodicals LLC.
DOI: 10.1002/cnr2.1307
PMCID: PMC7941556
PMID: 33074559 [Indexed for MEDLINE]
Conflict of interest statement: The authors have stated explicitly that there
are no conflicts of interest in connection with this article. |
http://www.ncbi.nlm.nih.gov/pubmed/30736994 | 1. Semin Diagn Pathol. 2019 Jul;36(4):211-228. doi: 10.1053/j.semdp.2019.01.001.
Epub 2019 Jan 31.
Cutaneous paraneoplastic syndromes.
Wick MR(1), Patterson JW(2).
Author information:
(1)PRW Laboratories, Charlottesville, VA, United State. Electronic address:
mrwick1@usa.net.
(2)PRW Laboratories, Charlottesville, VA, United State.
A variety of cutaneous abnormalities can be seen in patients with malignant
diseases, some of which are infectious, with others representing direct
involvement of the skin by the underlying disorder. Yet another group of lesions
can be regarded as associated markers of the malignant process, and, as such,
are termed "paraneoplastic." This review considers the latter collection of
conditions, grouping them by the generic type of malignancy that is usually
linked to the paraneoplasia. Some of the processes show a predominant
association with alimentary tract malignancies (acanthosis nigricans,
acrodermatitis paraneoplastica, florid cutaneous papillomatosis, necrolytic
migratory erythema, palmoplantar keratoderma, pancreatic fat necrosis, and
pityriasis rotunda). Others are usually linked to a hematolymphoid malignancy
(acquired ichthyosis, exfoliative erythroderma, necrobiotic xanthogranuloma,
pemphigus paraneoplastica, plane xanthoma, pyoderma gangrenosum, scleromyxedema,
Sweet syndrome, and leukocytoclastic vasculitis). Finally, yet another
collection of paraneoplastic skin disorders can associate themselves with
anatomically-diverse malignancies (Leser-Trelat syndrome, Trousseau syndrome,
dermatomyositis, erythema gyratum repens, hypertrichosis lanuginosa acquisita,
papuloerythroderma of Ofuji, tripe palms, and multicentric
reticulohistiocytosis). Recognition of these processes by the pathologist can be
a valuable step in the characterization of underlying malignant diseases.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1053/j.semdp.2019.01.001
PMID: 30736994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16767465 | 1. Psychol Res. 2007 Sep;71(5):583-90. doi: 10.1007/s00426-006-0068-0. Epub 2006
Jun 10.
Gaze behaviour in hereditary prosopagnosia.
Schwarzer G(1), Huber S, Grüter M, Grüter T, Gross C, Hipfel M, Kennerknecht I.
Author information:
(1)University of Giessen, Otto-Behaghel-Strasse 10F, 35394 Giessen, Germany.
gudrun.schwarzer@psychol.uni-giessen.de
Prosopagnosia is the inability to recognize someone by the face alone in the
absence of sensory or intellectual impairment. In contrast to the acquired form
of prosopagnosia we studied the congenital form. Since we could recently show
that this form is inherited as a simple monogenic trait we called it hereditary
form. To determine whether not only face recognition and neuronal processing but
also the perceptual acquisition of facial information is specific to
prosopagnosia, we studied the gaze behaviour of four hereditary prosopagnosics
in comparison to matched control subjects. This rarely studied form of
prosopagnosia ensures that deficits are limited to face recognition. Whereas the
control participants focused their gaze on the central facial features, the
hereditary prosopagnosics showed a significantly different gaze behaviour. They
had a more dispersed gaze and also fixated external facial features. Thus, the
face recognition impairment of the hereditary prosopagnosics is reflected in
their gaze behaviour.
DOI: 10.1007/s00426-006-0068-0
PMID: 16767465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19429021 | 1. Neurosci Lett. 2009 Apr 10;453(3):135-40. doi: 10.1016/j.neulet.2009.02.021.
Epub 2009 Feb 14.
Visual mental imagery in congenital prosopagnosia.
Grüter T(1), Grüter M, Bell V, Carbon CC.
Author information:
(1)University of Bamberg, Faculty of Humanities, Department of General
Psychology and Methodology, 96047 Bamberg, Germany.
Congenital prosopagnosia (cPA) is a selective impairment in the visual learning
and recognition of faces without detectable brain damage or malformation. There
is evidence that it can be inherited in an autosomal dominant mode of
inheritance. We assessed the capacity for visual mental imagery in 53 people
with cPA using an adapted Marks' VVIQ (Vividness of Visual Imaging
Questionnaire). The mean score of the prosopagnosic group showed the lowest
mental imagery scores ever published for a non-brain damaged group. In a
subsample of 12 people with cPA, we demonstrated that the cPA is a deficit of
configural face processing. We suggest that the 'VVIQ-PA' (VVIQ-Prosopagnosia)
questionnaire can help to confirm the diagnosis of cPA. Poor mental imagery, a
configural face processing impairment and clinical prosopagnosia should be
considered as symptoms of a yet poorly understood hereditary cerebral
dysfunction.
DOI: 10.1016/j.neulet.2009.02.021
PMID: 19429021 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36202621 | 1. Cogn Neuropsychol. 2022 May-Jun;39(3-4):196-207. doi:
10.1080/02643294.2022.2119838.
Atypical prosopagnosia following right hemispheric stroke: A 23-year follow-up
study with M.T.
Schroeger A(1)(2)(3), Kaufmann JM(2)(4), Zäske R(2)(4), Kovács G(4)(5), Klos
T(6), Schweinberger SR(2)(4).
Author information:
(1)Department of Psychology, Faculty of Psychology and Sports Science, Justus
Liebig University, Giessen, Germany.
(2)Department for General Psychology and Cognitive Neuroscience, Institute of
Psychology, Friedrich Schiller University, Jena, Germany.
(3)Department for the Psychology of Human Movement and Sport, Institute of Sport
Science, Friedrich Schiller University, Jena, Germany.
(4)DFG Research Unit Person Perception, Friedrich Schiller University, Jena,
Germany.
(5)Biological Psychology and Cognitive Neurosciences, Institute of Psychology,
Friedrich Schiller University, Jena, Germany.
(6)Kliniken am Europakanal, Erlangen, Germany.
Most findings on prosopagnosia to date suggest preserved voice recognition in
prosopagnosia (except in cases with bilateral lesions). Here we report a
follow-up examination on M.T., suffering from acquired prosopagnosia following a
large unilateral right-hemispheric lesion in frontal, parietal, and anterior
temporal areas excluding core ventral occipitotemporal face areas. Twenty-three
years after initial testing we reassessed face and object recognition skills
[Henke, K., Schweinberger, S. R., Grigo, A., Klos, T., & Sommer, W. (1998).
Specificity of face recognition: Recognition of exemplars of non-face objects in
prosopagnosia. Cortex, 34(2), 289-296]; [Schweinberger, S. R., Klos, T., &
Sommer, W. (1995). Covert face recognition in prosopagnosia - A dissociable
function? Cortex, 31(3), 517-529] and additionally studied voice recognition.
Confirming the persistence of deficits, M.T. exhibited substantial impairments
in famous face recognition and memory for learned faces, but preserved face
matching and object recognition skills. Critically, he showed substantially
impaired voice recognition skills. These findings are congruent with the ideas
that (i) prosopagnosia after right anterior temporal lesions can persist over
long periods > 20 years, and that (ii) such lesions can be associated with both
facial and vocal deficits in person recognition.
DOI: 10.1080/02643294.2022.2119838
PMID: 36202621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20657764 | 1. PLoS One. 2010 Jul 21;5(7):e11482. doi: 10.1371/journal.pone.0011482.
The early time course of compensatory face processing in congenital
prosopagnosia.
Stollhoff R(1), Jost J, Elze T, Kennerknecht I.
Author information:
(1)Max Planck Institute for Mathematics in the Sciences, Leipzig, Germany.
rainer.stollhoff@mis.mpg.de
BACKGROUND: Prosopagnosia is a selective deficit in facial identification which
can be either acquired, (e.g., after brain damage), or present from birth
(congenital). The face recognition deficit in prosopagnosia is characterized by
worse accuracy, longer reaction times, more dispersed gaze behavior and a strong
reliance on featural processing.
METHODS/PRINCIPAL FINDINGS: We introduce a conceptual model of an
apperceptive/associative type of congenital prosopagnosia where a deficit in
holistic processing is compensated by a serial inspection of isolated,
informative features. Based on the model proposed we investigated performance
differences in different face and shoe identification tasks between a group of
16 participants with congenital prosopagnosia and a group of 36 age-matched
controls. Given enough training and unlimited stimulus presentation
prosopagnosics achieved normal face identification accuracy evincing longer
reaction times. The latter increase was paralleled by an equally-sized increase
in stimulus presentation times needed achieve an accuracy of 80%. When the
inspection time of stimuli was limited (50 ms to 750 ms), prosopagnosics only
showed worse accuracy but no difference in reaction time. Tested for the ability
to generalize from frontal to rotated views, prosopagnosics performed worse than
controls across all rotation angles but the magnitude of the deficit didn't
change with increasing rotation. All group differences in accuracy, reaction or
presentation times were selective to face stimuli and didn't extend to shoes.
CONCLUSIONS/SIGNIFICANCE: Our study provides a characterization of congenital
prosopagnosia in terms of early processing differences. More specifically,
compensatory processing in congenital prosopagnosia requires an inspection of
faces that is sufficiently long to allow for sequential focusing on informative
features. This characterization of dysfunctional processing in prosopagnosia
further emphasizes fast and holistic information encoding as two defining
characteristics of normal face processing.
DOI: 10.1371/journal.pone.0011482
PMCID: PMC2908115
PMID: 20657764 [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/17981784 | 1. Front Biosci. 2008 Jan 1;13:3150-8. doi: 10.2741/2916.
Congenital prosopagnosia--a common hereditary cognitive dysfunction in humans.
Kennerknecht I(1), Pluempe N, Welling B.
Author information:
(1)Institut fuer Humangenetik, Westfaelische Wilhelms Universitaet, Muenster,
Germany. kennerk@uni-muenster.de
The apparent selectivity of agnosia for faces is termed prosopagnosia or face
blindness. This cognitive dysfunction can be seen after traumatic
events--involving at least the right occipital temporal region--or very
frequently congenital in the absence of any detectable lesions. The familiarity
of congenital prosopagnosia was studied in two independently ascertained
collections of subjects with prosopagnosia. One was an unselected group of
pupils and students who underwent a questionnaire based screening. The others
were self reported subjects after having heard for the first time about the
phenomenon of prosopagnosia from mass media citing our studies and/or from our
homepage (www.prosopagnosia.de). Those who agreed with consecutive studies of
their family members had mostly one or more prosopagnosic first degree
relatives. The segregation patterns derived from 39 families are compatible with
autosomal dominant inheritance. Hence, mutation(s) in one gene are sufficient
for manifestation of the phenotype. Still fitting the concept of autosomal
dominant inheritance, we have evidence for a slightly reduced penetrance (4
normal transmitters from distinct families) and one or two de novo mutations.
DOI: 10.2741/2916
PMID: 17981784 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19334306 | 1. J Neuropsychol. 2008 Mar;2(1):79-97. doi: 10.1348/174866407x231001.
Neural and genetic foundations of face recognition and prosopagnosia.
Grüter T(1), Grüter M, Carbon CC.
Author information:
(1)University of Vienna, Faculty of Psychology, Vienna, Austria
Faces are of essential importance for human social life. They provide valuable
information about the identity, expression, gaze, health, and age of a person.
Recent face-processing models assume highly interconnected neural structures
between different temporal, occipital, and frontal brain areas with several
feedback loops. A selective deficit in the visual learning and recognition of
faces is known as prosopagnosia, which can be found both in acquired and
congenital form. Recently, a hereditary sub-type of congenital prosopagnosia
with a very high prevalence rate of 2.5% has been identified. Recent research
results show that hereditary prosopagnosia is a clearly circumscribed
face-processing deficit with a characteristic set of clinical symptoms.
Comparing face processing of people of prosopagnosia with that of controls can
help to develop a more conclusive and integrated model of face processing. Here,
we provide a summary of the current state of face processing research. We also
describe the different types of prosopagnosia and present the set of typical
symptoms found in the hereditary type. Finally, we will discuss the implications
for future face recognition research.
DOI: 10.1348/174866407x231001
PMID: 19334306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20689639 | 1. Adv Cogn Psychol. 2010 Jul 1;6:23-34. doi: 10.2478/v10053-008-0074-4.
Configural and featural processing in humans with congenital prosopagnosia.
Lobmaier JS(1), Bölte J, Mast FW, Dobel C.
Author information:
(1)School of Psychology, University of St Andrews, Scotland.
Prosopagnosia describes the failure to recognize faces, a deficiency that can be
devastating in social interactions. Cases of acquired prosopagnosia have often
been described over the last century. In recent years, more and more cases of
congenital prosopagnosia (CP) have been reported. In the present study we tried
to determine possible cognitive characteristics of this impairment. We used
scrambled and blurred images of faces, houses, and sugar bowls to separate
featural processing strategies from configural processing strategies. This
served to investigate whether congenital prosopagnosia results from
process-specific deficiencies, or whether it is a face-specific impairment.
Using a delayed matching paradigm, 6 individuals with CP and 6 matched healthy
controls indicated whether an intact test stimulus was the same identity as a
previously presented scrambled or blurred cue stimulus. Analyses of d values
indicated that congenital prosopagnosia is a face-specific deficit, but that
this shortcoming is particularly pronounced for processing configural facial
information.
DOI: 10.2478/v10053-008-0074-4
PMCID: PMC2916664
PMID: 20689639 |
http://www.ncbi.nlm.nih.gov/pubmed/19823580 | 1. PLoS One. 2009 Oct 12;4(10):e7414. doi: 10.1371/journal.pone.0007414.
Impairments of biological motion perception in congenital prosopagnosia.
Lange J(1), de Lussanet M, Kuhlmann S, Zimmermann A, Lappe M, Zwitserlood P,
Dobel C.
Author information:
(1)Institute of Clinical Neuroscience and Medical Psychology,
Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
joachim.lange@med.uni-duesseldorf.de
Prosopagnosia is a deficit in recognizing people from their faces. Acquired
prosopagnosia results after brain damage, developmental or congenital
prosopagnosia (CP) is not caused by brain lesion, but has presumably been
present from early childhood onwards. Since other sensory, perceptual, and
cognitive abilities are largely spared, CP is considered to be a
stimulus-specific deficit, limited to face processing. Given that recent
behavioral and imaging studies indicate a close relationship of face and
biological-motion perception in healthy adults, we hypothesized that biological
motion processing should be impaired in CP. Five individuals with CP and ten
matched healthy controls were tested with diverse biological-motion stimuli and
tasks. Four of the CP individuals showed severe deficits in biological-motion
processing, while one performed within the lower range of the controls. A
discriminant analysis classified all participants correctly with a very high
probability for each participant. These findings demonstrate that in CP,
impaired perception of faces can be accompanied by impaired biological-motion
perception. We discuss implications for dedicated and shared mechanisms involved
in the perception of faces and biological motion.
DOI: 10.1371/journal.pone.0007414
PMCID: PMC2756626
PMID: 19823580 [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/16817175 | 1. Am J Med Genet A. 2006 Aug 1;140(15):1617-22. doi: 10.1002/ajmg.a.31343.
First report of prevalence of non-syndromic hereditary prosopagnosia (HPA).
Kennerknecht I(1), Grueter T, Welling B, Wentzek S, Horst J, Edwards S, Grueter
M.
Author information:
(1)Institute of Human Genetics, Westfälische Wilhelms-Universität, Münster,
Germany. kennerk@uni-muenster.de
Acquired prosopagnosia (PA) is a rare condition after, for example, a stroke or
brain injury. The congenital form of PA is generally considered to be even less
common. Beside a few single case reports and anecdotal mentioning of familial
cases no data on the epidemiology exists. Following a questionnaire-based
screening in local secondary schools and at our medical faculty, candidates
suspicious for PA underwent a semi-structured interview followed by examinations
of first degree relatives. Among 689 local pupils and medical students of our
university we found 17 with congenital PA. This corresponds to a prevalence rate
of 2.47% (95% CI 1.31-3.63). The frequency is among the highest known for a
monogenic disorder. All those index subjects (n = 14) of the target group who
agreed to further examinations of their family members had other first degree
relatives with the same cognitive disorder. This study provides epidemiological
evidence that congenital PA is a very common cognitive disorder which almost
always runs in families. The segregation pattern of this hereditary
prosopagnosia (HPA) is fully compatible with autosomal dominant inheritance.
Copyright 2006 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.31343
PMID: 16817175 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30947609 | 1. Cogn Neuropsychol. 2019 Feb-Mar;36(1-2):54-84. doi:
10.1080/02643294.2019.1593821. Epub 2019 Apr 4.
Object recognition in acquired and developmental prosopagnosia.
Barton JJS(1), Albonico A(1), Susilo T(2), Duchaine B(3), Corrow SL(1)(4).
Author information:
(1)a Departments of Medicine (Neurology), Ophthalmology and Visual Sciences,
Psychology , University of British Columbia , Vancouver , Canada.
(2)b School of Psychology , Victoria University of Wellington , Wellington , New
Zealand.
(3)c Department of Psychological and Brain Sciences , Dartmouth College ,
Hanover , NH , USA.
(4)d Department of Psychology , Bethel University , Minneapolis , MN , USA.
Whether face and object recognition are dissociated in prosopagnosia continues
to be debated: a recent review highlighted deficiencies in prior studies
regarding the evidence for such a dissociation. Our goal was to study cohorts
with acquired and developmental prosopagnosia with a complementary battery of
tests of object recognition that address prior limitations, as well as
evaluating for residual effects of object expertise. We studied 15 subjects with
acquired and 12 subjects with developmental prosopagnosia on three tests: the
Old/New Tests, the Cambridge Bicycle Memory Test, and the Expertise-adjusted
Test of Car Recognition. Most subjects with developmental prosopagnosia were
normal on the Old/New Tests: for acquired prosopagnosia, subjects with
occipitotemporal lesions often showed impairments while those with anterior
temporal lesions did not. Ten subjects showed a putative classical dissociation
between the Cambridge Face and Bicycle Memory Tests, seven of whom had normal
reaction times. Both developmental and acquired groups showed reduced car
recognition on the expertise-adjusted test, though residual effects of expertise
were still evident. Two subjects with developmental prosopagnosia met criteria
for normal object recognition across all tests. We conclude that strong evidence
for intact object recognition can be found in a few subjects but the majority
show deficits, particularly those with the acquired form. Both acquired and
developmental forms show residual but reduced object expertise effects.
DOI: 10.1080/02643294.2019.1593821
PMID: 30947609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30389553 | 1. Neuropsychologia. 2018 Dec;121:106-121. doi:
10.1016/j.neuropsychologia.2018.10.018. Epub 2018 Oct 31.
Tests of whole upright face processing in prosopagnosia: A literature review.
Robotham RJ(1), Starrfelt R(2).
Author information:
(1)Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A,
1353 Copenhagen, Denmark.
(2)Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A,
1353 Copenhagen, Denmark. Electronic address: randi.starrfelt@psy.ku.dk.
Prosopagnosia refers to an acquired or developmental deficit in face
recognition. This neuropsychological impairment has received increasing
attention over the last decade, in particular because of an increased scientific
interest in developmental prosopagnosia. Studies investigating prosopagnosia
have used a variety of different clinical and experimental tests to assess face
processing abilities. With such a large variety of assessment methods available,
test selection can be challenging. Some previous works have aimed to provide an
overview of tests used to diagnose prosopagnosia. However, no overview that is
based on a structured review of the literature is available. We review the
literature to identify tests that have been used to assess the processing of
whole upright faces in acquired and developmental prosopagnosia over the last
five years (2013-2017). We not only review tests that have been used for
diagnostic purposes, but also tests that have been used for experimental
purposes. Tests are categorised according to i) their experimental designs and,
ii) the stage of face processing that they assess. On this basis, we discuss
considerations regarding test designs for future studies. A visual illustration
providing a structured overview of paradigms available for testing the
processing of whole upright faces is provided. This visual illustration can be
used to inform test selection when designing a study and to apply a structured
approach to interpreting findings from the literature. The different approaches
to assessment of face processing in prosopagnosia have been necessary and
fruitful in generating data and hypotheses about the cause of face processing
deficits. However, impairments at different levels of face processing have often
been interpreted as reflecting a deficit in the recognition stage of face
processing. Based on the data now available on prosopagnosia, we advocate for a
more structured approach to assessment, which may facilitate a better
understanding of the key deficits in prosopagnosia and of the level(s) of face
processing that are impaired.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropsychologia.2018.10.018
PMID: 30389553 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33832676 | 1. Handb Clin Neurol. 2021;178:175-193. doi: 10.1016/B978-0-12-821377-3.00006-4.
Prosopagnosia and disorders of face processing.
Barton JJS(1), Davies-Thompson J(2), Corrow SL(3).
Author information:
(1)Departments of Medicine (Neurology), Ophthalmology and Visual Sciences, and
Psychology, University of British Columbia, Vancouver, BC, Canada. Electronic
address: jasonbarton@shaw.ca.
(2)Face Research Swansea, Department of Psychology, Swansea University, Sketty,
United Kingdom.
(3)Visual Cognition Lab, Department of Psychology, Bethel University, St. Paul,
MN, United States.
Face recognition is a form of expert visual processing. Acquired prosopagnosia
is the loss of familiarity for facial identity and has several functional
variants, namely apperceptive, amnestic, and associative forms. Acquired forms
are usually caused by either occipitotemporal or anterior temporal lesions,
right or bilateral in most cases. In addition, there is a developmental form,
whose functional and structural origins are still being elucidated. Despite
their difficulties with recognizing faces, some of these subjects still show
signs of covert recognition, which may have a number of explanations. Other
aspects of face perception can be spared in prosopagnosic subjects. Patients
with other types of face processing difficulties have been described, including
impaired expression processing, impaired lip-reading, false familiarity for
faces, and a people-specific amnesia. Recent rehabilitative studies have shown
some modest ability to improve face perception in prosopagnosic subjects through
perceptual training protocols.
Copyright © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/B978-0-12-821377-3.00006-4
PMID: 33832676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24389150 | 1. Front Biosci (Elite Ed). 2014 Jan 1;6(1):159-74. doi: 10.2741/e699.
Acquired prosopagnosia: structural basis and processing impairments.
Davies-Thompson J(1), Pancaroglu R(1), Barton J(1).
Author information:
(1)Department of Medicine (Neurology), and Department of Ophthalmology and
Visual Sciences, University of British Columbia, Canada.
Cognitive models propose a hierarchy of parallel processing stages in face
perception, and functional neuroimaging shows a network of regions involved in
face processing. Reflecting this, acquired prosopagnosia is not a single entity
but a family of disorders with different anatomic lesions and different
functional deficits. One classic distinction is between an apperceptive variant,
in which there is impaired perception of facial structure, and an
associative/amnestic variant, in which perception is relatively intact, with
subsequent problems matching perception to facial memories, because of either
disconnection or loss of those memories. These disorders also have to be
distinguished from people-specific amnesia, a multimodal impairment, and
prosop-anomia, in which familiarity with faces is preserved but access to names
is disrupted. These different disorders can be conceived as specific deficits at
different processing stages in cognitive models, and suggests that these
functional stages may have distinct neuroanatomic substrates. It remains to be
seen whether a similar anatomic and functional variability is present in
developmental prosopagnosia.
DOI: 10.2741/e699
PMID: 24389150 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21366884 | 1. J Neuropsychol. 2011 Mar;5(Pt 1):1-14. doi: 10.1348/174866410X500116.
Holistic processing impairment can be restricted to faces in acquired
prosopagnosia: evidence from the global/local Navon effect.
Busigny T(1), Rossion B.
Author information:
(1)Unité de Cognition et Développement, Faculté de Psychologie et des Sciences d
l'Education, Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
thomas.busigny@uclouvain.be
Previous studies have shown that acquired prosopagnosia is characterized by
impairment at holistic/configural processing. However, this view is essentially
supported by studies performed with patients whose face recognition difficulties
are part of a more general visual (integrative) agnosia. Here, we tested the
patient PS, a case of acquired prosopagnosia whose face-specific recognition
difficulties have been related to the inability to process individual faces
holistically (absence of inversion, composite, and whole-part effects with
faces). Here, we show that in contrast to this impairment, the patient presents
with an entirely normal response profile in a Navon hierarchical letter task:
she was as fast as normal controls, faster to identify global than local
letters, and her sensitivity to global interference during identification of
local letters was at least as large as normal observers. These observations
indicate that holistic processing as measured with global/local interference in
the Navon paradigm is functionally distinct from the ability to perceive an
individual face holistically.
©2010 The British Psychological Society.
DOI: 10.1348/174866410X500116
PMID: 21366884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27115682 | 1. Curr Biol. 2016 Apr 25;26(8):R312-3. doi: 10.1016/j.cub.2016.01.008.
Developmental prosopagnosia.
Cook R(1), Biotti F(2).
Author information:
(1)Social Perception Research Group, Department of Psychology, City University
London, Whiskin Street, London EC1R 0JD, UK. Electronic address:
Richard.Cook.1@city.ac.uk.
(2)Social Perception Research Group, Department of Psychology, City University
London, Whiskin Street, London EC1R 0JD, UK.
A Quick guide to developmental prosopagnosia, a condition definied by problems
in recognising faces that, in contrast with acquired prosopagnosia, develop in
the absence of manifest brain injury.
Copyright © 2016 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cub.2016.01.008
PMID: 27115682 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32648048 | 1. Neurol Sci. 2021 Feb;42(2):613-623. doi: 10.1007/s10072-020-04581-5. Epub 2020
Jul 10.
Selective defects of face familiarity associated to a left temporo-occipital
lesion.
Papagno C(1)(2), Barvas E(3), Tettamanti M(4), Gainotti G(5)(6).
Author information:
(1)Center for Neurocognitive Rehabilitation (CeRiN) and Center for Mind/Brain
Sciences (CIMeC), University of Trento, Via Matteo Del Ben, 5/b, 38068,
Rovereto, TN, Italy. costanza.papagno@unimib.it.
(2)Department of Psychology, University of Milano-Bicocca, Milan, Italy.
costanza.papagno@unimib.it.
(3)Center for Neurocognitive Rehabilitation (CeRiN) and Center for Mind/Brain
Sciences (CIMeC), University of Trento, Via Matteo Del Ben, 5/b, 38068,
Rovereto, TN, Italy.
(4)Center for Mind/Brain Sciences (CIMeC), University of Trento, Rovereto,
Italy.
(5)Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.
(6)Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia
Foundation, Rome, Italy.
Acquired prosopagnosia is usually a consequence of bilateral or right hemisphere
lesions and is often associated with topographical disorientation and
dyschromatopsia. Left temporo-occipital lesions sometimes result in a face
recognition disorder but in a context of visual object agnosia with spared
familiarity feelings for faces, usually in left-handers. We describe a patient
with a left temporo-occipital hemorrhagic lesion unexpectedly resulting in a
deficit of face familiarity, which could represent a mild form of associative
prosopagnosia. Our patient failed to feel familiarity feelings even with very
well-known famous faces but had neither visual object agnosia nor defects with
semantics or naming of celebrities. This was confirmed even when the patient was
re-tested a year later. We speculate that a graded lateralization of face
processing could be at the basis of occasional cases of prosopagnosia.
DOI: 10.1007/s10072-020-04581-5
PMCID: PMC7843582
PMID: 32648048 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31231507 | 1. F1000Res. 2019 May 31;8:F1000 Faculty Rev-765. doi:
10.12688/f1000research.18492.1. eCollection 2019.
Progress in perceptual research: the case of prosopagnosia.
Albonico A(1), Barton J(1).
Author information:
(1)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Sciences, Psychology, University of
British Columbia, Vancouver, Canada.
Prosopagnosia is an impairment in the ability to recognize faces and can be
acquired after a brain lesion or occur as a developmental variant. Studies of
prosopagnosia make important contributions to our understanding of face
processing and object recognition in the human visual system. We review four
areas of advances in the study of this condition in recent years. First are
issues surrounding the diagnosis of prosopagnosia, including the development and
evaluation of newer tests and proposals for diagnostic criteria, especially for
the developmental variant. Second are studies of the structural basis of
prosopagnosia, including the application of more advanced neuroimaging
techniques in studies of the developmental variant. Third are issues concerning
the face specificity of the defect in prosopagnosia, namely whether other object
processing is affected to some degree and in particular the status of visual
word processing in light of recent predictions from the "many-to-many
hypothesis". Finally, there have been recent rehabilitative trials of perceptual
learning applied to larger groups of prosopagnosic subjects that show that face
impairments are not immutable in this condition.
DOI: 10.12688/f1000research.18492.1
PMCID: PMC6556982
PMID: 31231507 [Indexed for MEDLINE]
Conflict of interest statement: No competing interests were disclosed.No
competing interests were disclosed.No competing interests were disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/18523592 | 1. PLoS One. 2008 Jun 4;3(6):e2326. doi: 10.1371/journal.pone.0002326.
Early left-hemispheric dysfunction of face processing in congenital
prosopagnosia: an MEG study.
Dobel C(1), Putsche C, Zwitserlood P, Junghöfer M.
Author information:
(1)Institute for Biomagnetism and Biosignalanalysis, Münster University
Hospital, Münster, Germany. cdobel@uni-muenster.de
BACKGROUND: Congenital prosopagnosia is a severe face perception impairment
which is not acquired by a brain lesion and is presumably present from birth. It
manifests mostly by an inability to recognise familiar persons.
Electrophysiological research has demonstrated the relevance to face processing
of a negative deflection peaking around 170 ms, labelled accordingly as N170 in
the electroencephalogram (EEG) and M170 in magnetoencephalography (MEG). The
M170 was shown to be sensitive to the inversion of faces and to familiarity--two
factors that are assumed to be crucial for congenital prosopagnosia. In order to
locate the cognitive dysfunction and its neural correlates, we investigated the
time course of neural activity in response to these manipulations.
METHODOLOGY: Seven individuals with congenital prosopagnosia and seven matched
controls participated in the experiment. To explore brain activity with high
accuracy in time, we recorded evoked magnetic fields (275 channel whole head
MEG) while participants were looking at faces differing in familiarity (famous
vs. unknown) and orientation (upright vs. inverted). The underlying neural
sources were estimated by means of the least square minimum-norm-estimation
(L2-MNE) approach.
PRINCIPAL FINDINGS: The behavioural data corroborate earlier findings on
impaired configural processing in congenital prosopagnosia. For the M170, the
overall results replicated earlier findings, with larger occipito-temporal brain
responses to inverted than upright faces, and more right- than left-hemispheric
activity. Compared to controls, participants with congenital prosopagnosia
displayed a general decrease in brain activity, primarily over left
occipitotemporal areas. This attenuation did not interact with familiarity or
orientation.
CONCLUSIONS: The study substantiates the finding of an early involvement of the
left hemisphere in symptoms of prosopagnosia. This might be related to an
efficient and overused featural processing strategy which serves as a
compensation of impaired configural processing.
DOI: 10.1371/journal.pone.0002326
PMCID: PMC2390849
PMID: 18523592 [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/7091286 | 1. Am J Ophthalmol. 1982 Jul;94(1):75-80. doi: 10.1016/0002-9394(82)90194-5.
Prosopagnosia.
Kay MC, Levin HS.
Three patients with prosopagnosia, and acquired inability to recognize familiar
faces usually resulting from cerebrovascular insufficiency, had left-sided
visual field defects and color vision abnormalities of central origin.
Prosopagnosia, although clinically associated with posterior right hemispheric
disease in most cases, represents a disconnection of both occipital poles from
the final processing center for facial recognition in the right temporal lobe.
This problem can profoundly affect everyday activities requiring visual
recognition.
DOI: 10.1016/0002-9394(82)90194-5
PMID: 7091286 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33392335 | 1. World J Clin Cases. 2020 Dec 26;8(24):6487-6498. doi:
10.12998/wjcc.v8.i24.6487.
Delayed diagnosis of prosopagnosia following a hemorrhagic stroke in an elderly
man: A case report.
Yuan Y(1), Huang F(1), Gao ZH(2), Cai WC(3), Xiao JX(1), Yang YE(1), Zhu PL(1).
Author information:
(1)Department of Geriatric Medicine, Fujian Provincial Hospital, Fuzhou 350001,
Fujian Province, China.
(2)Department of Ophthalmology, Fujian Provincial Hospital, Fuzhou 350001,
Fujian Province, China.
(3)Department of Radiology, Fujian Provincial Hospital, Fuzhou 350001, Fujian
Province, China.
BACKGROUND: Acquired prosopagnosia is a rare condition characterized by the loss
of familiarity with previously known faces and the inability to recognize new
ones. It usually occurs after the onset of brain lesions such as in a stroke.
The initial identification of prosopagnosia generally relies on a patient's
self-report, which can be challenging if it lacks an associated chief complaint.
There were few cases of prosopagnosia presenting purely as eye symptoms in the
previous literature confirmed by functional magnetic resonance imaging (MRI).
CASE SUMMARY: We present a case of delayed diagnosis of prosopagnosia after a
right hemisphere stroke in an elderly man whose chief complaint was persistent
and progressive "blurred vision" without facial recognition impairment.
Ophthalmic tests revealed a homonymous left upper quadrantanopia, with normal
visual acuity. He was found by accident to barely recognize familiar faces. The
patient showed severe deficit in face recognition and perception tests, and mild
memory loss in neuropsychological assessments. Further functional MRI revealed
the visual recognition deficits were face-specific. After behavioral
intervention, the patient started to rely on other cues to compensate for poor
facial recognition. His prosopagnosia showed no obvious improvement eight months
after the stroke, which had negative impact on his social network.
CONCLUSION: Our case demonstrates that the presentation of prosopagnosia can be
atypical, and visual difficulties might be a clinical manifestation solely of
prosopagnosia, which emphasizes the importance of routinely considering face
recognition impairment among elderly patients with brain lesions.
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights
reserved.
DOI: 10.12998/wjcc.v8.i24.6487
PMCID: PMC7760442
PMID: 33392335
Conflict of interest statement: Conflict-of-interest statement: The authors
declare that they have no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31750297 | 1. Front Bioeng Biotechnol. 2019 Nov 5;7:305. doi: 10.3389/fbioe.2019.00305.
eCollection 2019.
Classifying Promoters by Interpreting the Hidden Information of DNA Sequences
via Deep Learning and Combination of Continuous FastText N-Grams.
Le NQK(1), Yapp EKY(2), Nagasundaram N(3), Yeh HY(3).
Author information:
(1)Professional Master Program in Artificial Intelligence in Medicine, Taipei
Medical University, Taipei, Taiwan.
(2)Singapore Institute of Manufacturing Technology, Innovis, Singapore,
Singapore.
(3)Medical Humanities Research Cluster, School of Humanities, Nanyang
Technological University, Singapore, Singapore.
A promoter is a short region of DNA (100-1,000 bp) where transcription of a gene
by RNA polymerase begins. It is typically located directly upstream or at the 5'
end of the transcription initiation site. DNA promoter has been proven to be the
primary cause of many human diseases, especially diabetes, cancer, or
Huntington's disease. Therefore, classifying promoters has become an interesting
problem and it has attracted the attention of a lot of researchers in the
bioinformatics field. There were a variety of studies conducted to resolve this
problem, however, their performance results still require further improvement.
In this study, we will present an innovative approach by interpreting DNA
sequences as a combination of continuous FastText N-grams, which are then fed
into a deep neural network in order to classify them. Our approach is able to
attain a cross-validation accuracy of 85.41 and 73.1% in the two layers,
respectively. Our results outperformed the state-of-the-art methods on the same
dataset, especially in the second layer (strength classification). Throughout
this study, promoter regions could be identified with high accuracy and it
provides analysis for further biological research as well as precision medicine.
In addition, this study opens new paths for the natural language processing
application in omics data in general and DNA sequences in particular.
Copyright © 2019 Le, Yapp, Nagasundaram and Yeh.
DOI: 10.3389/fbioe.2019.00305
PMCID: PMC6848157
PMID: 31750297 |
http://www.ncbi.nlm.nih.gov/pubmed/26933872 | 1. Q J Exp Psychol (Hove). 2017 Feb;70(2):201-217. doi:
10.1080/17470218.2016.1161059. Epub 2016 Mar 31.
Eye-movement strategies in developmental prosopagnosia and "super" face
recognition.
Bobak AK(1), Parris BA(1), Gregory NJ(1), Bennetts RJ(1), Bate S(1).
Author information:
(1)a Department of Psychology, Faculty of Science and Technology , Bournemouth
University , Poole , UK.
Developmental prosopagnosia (DP) is a cognitive condition characterized by a
severe deficit in face recognition. Few investigations have examined whether
impairments at the early stages of processing may underpin the condition, and it
is also unknown whether DP is simply the "bottom end" of the typical
face-processing spectrum. To address these issues, we monitored the
eye-movements of DPs, typical perceivers, and "super recognizers" (SRs) while
they viewed a set of static images displaying people engaged in naturalistic
social scenarios. Three key findings emerged: (a) Individuals with more severe
prosopagnosia spent less time examining the internal facial region, (b) as
observed in acquired prosopagnosia, some DPs spent less time examining the eyes
and more time examining the mouth than controls, and (c) SRs spent more time
examining the nose-a measure that also correlated with face recognition ability
in controls. These findings support previous suggestions that DP is a
heterogeneous condition, but suggest that at least the most severe cases
represent a group of individuals that qualitatively differ from the typical
population. While SRs seem to merely be those at the "top end" of normal, this
work identifies the nose as a critical region for successful face recognition.
DOI: 10.1080/17470218.2016.1161059
PMID: 26933872 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19258451 | 1. Mol Biol Evol. 2009 Jun;26(6):1299-307. doi: 10.1093/molbev/msp040. Epub 2009
Mar 3.
Evolutionary forces act on promoter length: identification of enriched
cis-regulatory elements.
Kristiansson E(1), Thorsen M, Tamás MJ, Nerman O.
Author information:
(1)Department of Zoology, University of Gothenburg, Göteborg, Sweden.
erik.kristiansson@zool.gu.se
Transcription factors govern gene expression by binding to short DNA sequences
called cis-regulatory elements. These sequences are typically located in
promoters, which are regions of variable length upstream of the open reading
frames of genes. Here, we report that promoter length and gene function are
related in yeast, fungi, and plants. In particular, the promoters for
stress-responsive genes are in general longer than those of other genes.
Essential genes have, on the other hand, relatively short promoters. We utilize
these findings in a novel method for identifying relevant cis-regulatory
elements in a set of coexpressed genes. The method is shown to generate more
accurate results and fewer false positives compared with other common
procedures. Our results suggest that genes with complex transcriptional
regulation tend to have longer promoters than genes responding to few signals.
This phenomenon is present in all investigated species, indicating that
evolution adjust promoter length according to gene function. Identification of
cis-regulatory elements in Saccharomyces cerevisiae can be done with the web
service located at http://enricher.zool.gu.se.
DOI: 10.1093/molbev/msp040
PMID: 19258451 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33227813 | 1. Brief Bioinform. 2021 Jul 20;22(4):bbaa299. doi: 10.1093/bib/bbaa299.
Computational identification of eukaryotic promoters based on cascaded deep
capsule neural networks.
Zhu Y(1), Li F(2), Xiang D(3), Akutsu T(4), Song J(5), Jia C(6).
Author information:
(1)School of Science, Dalian Maritime University, China.
(2)Peter Doherty Institute for Infection and Immunity, The University of
Melbourne, Australia.
(3)Northwest A&F University, China.
(4)Bioinformatics Center, Institute for Chemical Research, Kyoto University.
(5)Biomedicine Discovery Institute and Department of Biochemistry and Molecular
Biology, Monash University, Melbourne, Australia.
(6)College of Science, Dalian Maritime University.
A promoter is a region in the DNA sequence that defines where the transcription
of a gene by RNA polymerase initiates, which is typically located proximal to
the transcription start site (TSS). How to correctly identify the gene TSS and
the core promoter is essential for our understanding of the transcriptional
regulation of genes. As a complement to conventional experimental methods,
computational techniques with easy-to-use platforms as essential bioinformatics
tools can be effectively applied to annotate the functions and physiological
roles of promoters. In this work, we propose a deep learning-based method termed
Depicter (Deep learning for predicting promoter), for identifying three specific
types of promoters, i.e. promoter sequences with the TATA-box (TATA model),
promoter sequences without the TATA-box (non-TATA model), and indistinguishable
promoters (TATA and non-TATA model). Depicter is developed based on an
up-to-date, species-specific dataset which includes Homo sapiens, Mus musculus,
Drosophila melanogaster and Arabidopsis thaliana promoters. A convolutional
neural network coupled with capsule layers is proposed to train and optimize the
prediction model of Depicter. Extensive benchmarking and independent tests
demonstrate that Depicter achieves an improved predictive performance compared
with several state-of-the-art methods. The webserver of Depicter is implemented
and freely accessible at https://depicter.erc.monash.edu/.
© The Author(s) 2020. Published by Oxford University Press. All rights reserved.
For Permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/bib/bbaa299
PMCID: PMC8522485
PMID: 33227813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24503515 | 1. Curr Opin Struct Biol. 2014 Apr;25:77-85. doi: 10.1016/j.sbi.2014.01.007. Epub
2014 Feb 4.
Role of DNA sequence based structural features of promoters in transcription
initiation and gene expression.
Bansal M(1), Kumar A(2), Yella VR(2).
Author information:
(1)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India. Electronic address: mb@mbu.iisc.ernet.in.
(2)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India.
Regulatory information for transcription initiation is present in a stretch of
genomic DNA, called the promoter region that is located upstream of the
transcription start site (TSS) of the gene. The promoter region interacts with
different transcription factors and RNA polymerase to initiate transcription and
contains short stretches of transcription factor binding sites (TFBSs), as well
as structurally unique elements. Recent experimental and computational analyses
of promoter sequences show that they often have non-B-DNA structural motifs, as
well as some conserved structural properties, such as stability, bendability,
nucleosome positioning preference and curvature, across a class of organisms.
Here, we briefly describe these structural features, the differences observed in
various organisms and their possible role in regulation of gene expression.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.sbi.2014.01.007
PMID: 24503515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36099980 | 1. Biosystems. 2022 Nov;221:104771. doi: 10.1016/j.biosystems.2022.104771. Epub
2022 Sep 12.
Genome-scale prediction of bacterial promoters.
Bernardino M(1), Beiko R(2).
Author information:
(1)Faculty of Computer Science, Dalhousie University, Halifax, Canada.
Electronic address: mr751465@dal.ca.
(2)Faculty of Computer Science, Dalhousie University, Halifax, Canada.
Electronic address: beiko@cs.dal.ca.
A key step in the transcription of RNA is the binding of the RNA polymerase
protein complex to a short promoter sequence that is typically upstream of the
gene to be expressed. Automated identification of promoters would serve as a
valuable complement to experimental validation in determining which genes are
likely to be expressed and when; however, promoter sequences are short and
highly variable, which makes them very difficult to accurately classify. The
many tools developed to identify promoters in DNA have generally been tested on
small and balanced subsets of genomic sequence, and the results may not reflect
their expected performance on genomes with millions of DNA base pairs where
promoters are likely to comprise less than ∼1% of the sequence. Here we
introduce Expositor, a neural-network-based method that uses different types of
DNA encodings and tunable sensitivity and specificity parameters. Expositor
showed higher sensitivity and precision on the E. coli K-12 MG1655 chromosome
than other tested approaches. Expositor predictions were more consistent in the
homologous subset of sequence from a strain of Salmonella than they were with
another strain of E. coli. We also examined the accuracy of Expositor in
distinguishing different classes of promoters and found that misclassification
between classes was consistent with the biological similarity between promoters.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.biosystems.2022.104771
PMID: 36099980 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25448745 | 1. J Steroid Biochem Mol Biol. 2015 Jan;145:121-30. doi:
10.1016/j.jsbmb.2014.11.006. Epub 2014 Nov 6.
Epigenetic modifications of gene promoter DNA in the liver of adult female mice
masculinized by testosterone.
Dkhil MA(1), Al-Quraishy S(2), Abdel-Baki AA(3), Ghanjati F(4), Arauzo-Bravo
MJ(5), Delic D(6), Wunderlich F(7).
Author information:
(1)Department of Zoology, College of Science, King Saud University, 11451
Riyadh, Saudi Arabia; Department of Zoology and Entomology, Faculty of Science,
Helwan University, Cairo, Egypt. Electronic address: mohameddkhil@yahoo.com.
(2)Department of Zoology, College of Science, King Saud University, 11451
Riyadh, Saudi Arabia.
(3)Department of Zoology, College of Science, King Saud University, 11451
Riyadh, Saudi Arabia; Department of Zoology, Faculty of Science, Beni-Suef
University, Beni-Suef, Egypt.
(4)Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University,
Duesseldorf, Germany.
(5)Computational Biology and Systems Biomedicine, Biodonostia Health Research
Institute, San Sebastion, Spain; IKERBASQUE, Basque Foundation for Science,
Bilbao, Spain.
(6)Department of Biology, Heinrich-Heine-University, Duesseldorf, Germany;
Boehringer-Ingelheim, Biberach, Germany.
(7)Department of Biology, Heinrich-Heine-University, Duesseldorf, Germany.
Testosterone (T) is known to masculinize the female phenotype of the liver,
evidenced as up- and down-regulated expressions of male- and female-predominant
genes, respectively, involved in hepatic metabolism. This study is aimed at
identifying epigenetic modifications of promoters of these differently expressed
genes in the liver after masculinization by T of adult female C57BL/6 mice using
methylated DNA immunoprecipitation and NimbleGen microarrays. Among the 17,354
promoters examined, 82 promoters in the liver have been identified to be
significantly changed by T (p<0.05), with 47 and 35 promoters exhibiting
increased and decreased DNA methylation, respectively. Most of these promoters
display the changes of DNA methylation in their Ups-regions, which are between
+500 and +2000 bp upstream from the transcription start site (TSS) of the genes.
Less T-induced modifications have been detected in the Cor-regions of the
promoters, i.e., +500 to -500 bp around the TSS. Only 13 and 7 Cor-promoters are
hyper- and hypo-methylated, respectively, among which are 10 hyper- and 5
hypo-methylated promoters of genes with annotated functions. Surprisingly, the
promoters are largely unmethylated in those genes whose expression has been
previously found to be permanently deregulated by T in the liver, as e.g. the
T-upregulated male-predominant genes Cyp7b1, Cyp2d9, Cyp4a10, Ugt2b1, Ugt2b38,
Hsd3b5, Slco1a1 as well as the T-downregulated female-predominant genes Cyp2b9,
Cyp2b13, Cyp3a41, Cyp3a44, Fmo3, Sult2a2, respectively. Though methylatable, the
promoter DNA of Ar, Esr1, and Esr2 remained unaffected by T. However, T
decreases DNA-methylation of the Cor-promoter region of Ddc encoding the
AR-coactivator dopa decarboxylase. Among the identified 15 Cor-promoters of
genes with annotated functions are also those of Defb43, Cst11, and Sele
involved in innate immunity. Our data support the view that T may exert
long-lasting epigenetic effects on functions of the liver-inherent immune
system.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jsbmb.2014.11.006
PMID: 25448745 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15899964 | 1. Genome Res. 2005 Jun;15(6):830-9. doi: 10.1101/gr.3430605. Epub 2005 May 17.
Direct isolation and identification of promoters in the human genome.
Kim TH(1), Barrera LO, Qu C, Van Calcar S, Trinklein ND, Cooper SJ, Luna RM,
Glass CK, Rosenfeld MG, Myers RM, Ren B.
Author information:
(1)Ludwig Institute for Cancer Research, University of California, San Diego, La
Jolla, California 92093, USA.
Transcriptional regulatory elements play essential roles in gene expression
during animal development and cellular response to environmental signals, but
our knowledge of these regions in the human genome is limited despite the
availability of the complete genome sequence. Promoters mark the start of every
transcript and are an important class of regulatory elements. A large, complex
protein structure known as the pre-initiation complex (PIC) is assembled on all
active promoters, and the presence of these proteins distinguishes promoters
from other sequences in the genome. Using components of the PIC as tags, we
isolated promoters directly from human cells as protein-DNA complexes and
identified the resulting DNA sequences using genomic tiling microarrays. Our
experiments in four human cell lines uncovered 252 PIC-binding sites in 44
semirandomly selected human genomic regions comprising 1% (30 megabase pairs) of
the human genome. Nearly 72% of the identified fragments overlap or immediately
flank 5' ends of known cDNA sequences, while the remainder is found in other
genomic regions that likely harbor putative promoters of unannotated
transcripts. Indeed, molecular analysis of the RNA isolated from one cell line
uncovered transcripts initiated from over half of the putative promoter
fragments, and transient transfection assays revealed promoter activity for a
significant proportion of fragments when they were fused to a luciferase
reporter gene. These results demonstrate the specificity of a genome-wide
analysis method for mapping transcriptional regulatory elements and also
indicate that a small, yet significant number of human genes remains to be
discovered.
DOI: 10.1101/gr.3430605
PMCID: PMC1142473
PMID: 15899964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34322164 | 1. US Ophthalmic Rev. 2020 Fall;13(2):76-79. doi: 10.17925/usor.2020.13.2.76.
Epub 2020 Dec 23.
Suprachoroidal Injection of Triamcinolone- Review of a Novel Treatment for
Macular Edema Caused by Noninfectious Uveitis.
Price KW(1), Albini TA(2), Yeh S(1)(3).
Author information:
(1)Department of Ophthalmology, Emory University School of Medicine, Atlanta,
GA, USA.
(2)Bascom Palmer Eye Institute, University of Miami Miller School of Medicine,
Miami, FL, USA.
(3)Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE,
USA.
Macular edema is the most frequent cause of visual deterioration in
noninfectious uveitis. The treatment of noninfectious uveitis with associated
macular edema commonly includes systemic or locally administered
corticosteroids, with long-term use limited by significant side effects. The
need for a treatment with an improved safety profile has driven the development
of a novel ophthalmic therapy: a proprietary triamcinolone acetonide suspension
(CLS-TA) administered in the suprachoroidal space (XIPERE™; Clearside
Biomedical, Alpharetta, GA, USA). Suprachoroidal delivery of corticosteroids
allows higher steroid concentration in the posterior segment and decreases the
risk of other adverse ocular events. Recent results from the PEACHTREE trial
(ClinicalTrials.gov Identifier: NCT02595398), a phase III trial with two
suprachoroidal injections of CLS-TA at 0 and 12 weeks with follow up lasting 24
weeks, showed the significant improvement in visual acuity and reduction in
central subfield thickness, all without increasing the risk of elevated
intraocular pressure or accelerated cataract progression.
DOI: 10.17925/usor.2020.13.2.76
PMCID: PMC8315419
PMID: 34322164 |
http://www.ncbi.nlm.nih.gov/pubmed/32327287 | 1. Neuromuscul Disord. 2020 Apr;30(4):315-328. doi: 10.1016/j.nmd.2020.03.001.
Epub 2020 Mar 12.
Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD
registry can be subdivided into 4 patterns of self-reported symptoms.
Banerji CRS(1), Cammish P(2), Evangelista T(2), Zammit PS(3), Straub V(2),
Marini-Bettolo C(2).
Author information:
(1)King's College London, Randall Centre for Cell and Molecular Biophysics, New
Hunt's House, Guy's Campus, London SE1 1UL, UK; Faculty of Medicine, Imperial
College London, Level 2, Faculty Building, South Kensington Campus, London SW7
2AZ, UK. Electronic address: christopher.2.banerji@kcl.ac.uk.
(2)John Walton Muscular Dystrophy Research Centre, Institute of Genetic
Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust,
Centre for Life, Newcastle NE1 3BZ, UK.
(3)King's College London, Randall Centre for Cell and Molecular Biophysics, New
Hunt's House, Guy's Campus, London SE1 1UL, UK.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant incurable
skeletal muscle disease. FSHD1 constitutes 95% of cases and is linked to
truncation of the D4Z4 macrosatellite at 4q35. In most cases the condition
initially presents with facial and proximal weakness of the upper limbs, but
over the course of the disease involves lower limb and truncal muscles. Weakness
is progressive and frequently asymmetric, which is a hallmark of the disease.
Here we performed an analysis of 643 FSHD1 patients in the UK FSHD patient
registry, investigating factors affecting rate of onset of 5 major FSHD
symptoms: facial, periscapular, foot dorsiflexor, hip girdle weakness, and
hearing loss. We found shorter D4Z4 repeat length associated with accelerated
onset of each symptom. Furthermore, paternal inheritance of the pathogenic
allele was associated with accelerated onset of foot dorsiflexor weakness, while
pregnancy and carrying multiple children to term was associated with slower
onset of all muscle symptoms. Lastly, we performed clustering analysis on age of
onset of the 4 muscle symptoms across 222 patients. We identified 4 clinical
presentations of FSHD1. A classical presentation (74%) and 3 facial sparing
phenotypes: a mild presentation (5%) with later facial and periscapular
involvement, an early shoulder presentation (10%) with accelerated periscapular
weakness and an early foot presentation (9%) with accelerated foot dorsiflexor
weakness. The mild presentation was associated with longer D4Z4 repeat lengths,
while the early foot presentation had a female bias. We note, however that
symptom progression differs significantly in these 4 clinical presentations
independently of D4Z4 repeat length and gender, motivating investigation of
further modifiers of FSHD1 severity.
Copyright © 2020 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2020.03.001
PMID: 32327287 [Indexed for MEDLINE] |