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http://www.ncbi.nlm.nih.gov/pubmed/34835034 | 1. Viruses. 2021 Nov 5;13(11):2228. doi: 10.3390/v13112228.
Curing Cats with Feline Infectious Peritonitis with an Oral Multi-Component Drug
Containing GS-441524.
Krentz D(1), Zenger K(1), Alberer M(2), Felten S(1), Bergmann M(1), Dorsch R(1),
Matiasek K(3), Kolberg L(2), Hofmann-Lehmann R(4), Meli ML(4), Spiri AM(4),
Horak J(5), Weber S(6), Holicki CM(6), Groschup MH(6)(7), Zablotski Y(1),
Lescrinier E(8), Koletzko B(5), von Both U(2)(9), Hartmann K(1).
Author information:
(1)Clinic of Small Animal Medicine, Centre for Clinical Veterinary Medicine, LMU
Munich, 80539 Munich, Germany.
(2)Division of Paediatric Infectious Diseases, Dr. von Hauner Children's
Hospital, University Hospital, LMU Munich, 80337 Munich, Germany.
(3)Section of Clinical and Comparative Neuropathology, Institute of Veterinary
Pathology, Centre for Clinical Veterinary Medicine, LMU Munich, 80539 Munich,
Germany.
(4)Clinical Laboratory, Department of Clinical Diagnostics and Services, and
Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, CH-8057
Zurich, Switzerland.
(5)Department Paediatrics, Division Metabolic and Nutritional Medicine, Dr. von
Hauner Children's Hospital, University Hospital, LMU Munich, 80337 Munich,
Germany.
(6)Institute of Novel and Emerging Infectious Diseases,
Friedrich-Loeffler-Institut, Greifswald-Insel Riems, 17493 Greifswald, Germany.
(7)German Center for Infection Research (DZIF), Partner Site
Hamburg-Luebeck-Borstel-Riems, Greifswald-Insel Riems, 17493 Greifswald,
Germany.
(8)Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, 3000
Leuven, Belgium.
(9)German Center for Infection Research (DZIF), Partner Site Munich, 80337
Munich, Germany.
Feline infectious peritonitis (FIP) caused by feline coronavirus (FCoV) is a
common dis-ease in cats, fatal if untreated, and no effective treatment is
currently legally available. The aim of this study was to evaluate efficacy and
toxicity of the multi-component drug Xraphconn® in vitro and as oral treatment
in cats with spontaneous FIP by examining survival rate, development of clinical
and laboratory parameters, viral loads, anti-FCoV antibodies, and adverse
effects. Mass spectrometry and nuclear magnetic resonance identified GS-441524
as an active component of Xraphconn®. Eighteen cats with FIP were prospectively
followed up while being treated orally for 84 days. Values of key parameters on
each examination day were compared to values before treatment initiation using
linear mixed-effect models. Xraphconn® displayed high virucidal activity in cell
culture. All cats recovered with dramatic improvement of clinical and laboratory
parameters and massive reduction in viral loads within the first few days of
treatment without serious adverse effects. Oral treatment with Xraphconn®
containing GS-441524 was highly effective for FIP without causing serious
adverse effects. This drug is an excellent option for the oral treatment of FIP
and should be trialed as potential effective treatment option for other severe
coronavirus-associated diseases across species.
DOI: 10.3390/v13112228
PMCID: PMC8621566
PMID: 34835034 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. The oral multi-component drug Xraphconn® was provided by Mutian
Life Sciences Limited, but Mutian played no role in the interpretation of study
data or the decision to submit the manuscript for publication. No commercial
conflict of interest exists as the information is solely for scientific
dissemination. |
http://www.ncbi.nlm.nih.gov/pubmed/29778200 | 1. Vet Microbiol. 2018 Jun;219:226-233. doi: 10.1016/j.vetmic.2018.04.026. Epub
2018 Apr 22.
The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis
(FIP) virus in tissue culture and experimental cat infection studies.
Murphy BG(1), Perron M(2), Murakami E(2), Bauer K(1), Park Y(2), Eckstrand C(1),
Liepnieks M(1), Pedersen NC(3).
Author information:
(1)Department of Pathology, Microbiology, and Immunology, School of Veterinary
Medicine, University of California, Davis, CA, USA.
(2)Gilead Sciences, Foster City, CA, USA.
(3)Center for Companion Animal Health, School of Veterinary Medicine, University
of California, One Shields Ave., Davis, CA, USA. Electronic address:
ncpedersen@ucdavis.edu.
Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus
disease of domestic cats. Recent studies of diseases caused by several RNA
viruses in people and other species indicate that antiviral therapy may be
effective against FIP in cats. The small molecule nucleoside analog GS-441524 is
a molecular precursor to a pharmacologically active nucleoside triphosphate
molecule. These analogs act as an alternative substrate and RNA-chain terminator
of viral RNA dependent RNA polymerase. We determined that GS-441524 was
non-toxic in feline cells at concentrations as high as 100 uM and effectively
inhibited FIPV replication in cultured CRFK cells and in naturally infected
feline peritoneal macrophages at concentrations as low as 1 uM. We determined
the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that
would sustain effective blood levels for 24 h. In an experimental FIPV infection
of cats, GS-441524 treatment caused a rapid reversal of disease signs and return
to normality with as little as two weeks of treatment in 10/10 cats and with no
apparent toxicity.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.vetmic.2018.04.026
PMCID: PMC7117434
PMID: 29778200 [Indexed for MEDLINE]
Conflict of interest statement: M. Perron, E. Murakami and Y. Park are employees
of Gilead Sciences, Inc., Foster City, CA, USA and hold stock interests in the
company. |
http://www.ncbi.nlm.nih.gov/pubmed/32456286 | 1. Viruses. 2020 May 24;12(5):576. doi: 10.3390/v12050576.
Antiviral Effects of Hydroxychloroquine and Type I Interferon on In Vitro Fatal
Feline Coronavirus Infection.
Takano T(1), Satoh K(1), Doki T(1), Tanabe T(2), Hohdatsu T(1).
Author information:
(1)Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan.
(2)Laboratory of Veterinary Microbiology, School of Veterinary Medicine,
Kitasato University, Towada, Aomori 034-8628, Japan.
Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and
mortality by the FIP virus (FIPV, virulent feline coronavirus). Several
antiviral drugs for FIP have been identified, but many of these are expensive
and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug
approved by several countries to treat malaria and immune-mediated diseases in
humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2,
dengue virus) have been confirmed. We investigated whether HCQ in association
with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 μM of
HCQ significantly inhibited the replication of types I and II FIPV.
Interestingly, the combination of 100 μM of HCQ and 104 U/mL of recombinant
feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral
activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω
are applicable for treatment of FIP. Further clinical studies are needed to
verify the combination of HCQ and rIFN-ω will be effective and safe treatment
for cats with FIP.
DOI: 10.3390/v12050576
PMCID: PMC7290745
PMID: 32456286 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36297266 | 1. Pathogens. 2022 Oct 20;11(10):1209. doi: 10.3390/pathogens11101209.
Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of
Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious
Peritonitis.
Roy M(1), Jacque N(2), Novicoff W(3), Li E(1), Negash R(1), Evans SJM(1).
Author information:
(1)Department of Veterinary Biosciences, College of Veterinary Medicine, The
Ohio State University, Columbus, OH 43210, USA.
(2)Independent Researcher, San Jose, CA 95123, USA.
(3)Departments of Orthopaedic Surgery and Public Health Sciences, School of
Medicine, University of Virginia, Charlottesville, VA 22903, USA.
Feline infectious peritonitis (FIP) is a complex and historically fatal disease,
though recent advances in antiviral therapy have uncovered potential treatments.
A newer therapeutic option, unlicensed molnupiravir, is being used as a
first-line therapy for suspect FIP and as a rescue therapy to treat cats who
have persistent or relapsed clinical signs of FIP after GS-441524 and/or GC376
therapy. Using owner-reported data, treatment protocols for 30 cats were
documented. The 26 cats treated with unlicensed molnupiravir as a rescue therapy
were treated with an average starting dosage of 12.8 mg/kg and an average ending
dosage of 14.7 mg/kg twice daily for a median of 12 weeks (IQR = 10-15). In
total, 24 of 26 cats were still living disease-free at the time of writing. One
cat was euthanized after completing treatment due to a prolonged seizure, and
the other cat underwent retreatment for relapsed clinical signs. Few adverse
effects were reported, with the most notable-folded ears (1), broken whiskers
(1), and severe leukopenia (1)-seen at dosages above 23 mg/kg twice daily. This
study provides a proof of principle for the use of molnupiravir in cats and
supports the need for future studies to further evaluate molnupiravir as a
potentially safe and effective therapy for FIP.
DOI: 10.3390/pathogens11101209
PMCID: PMC9612227
PMID: 36297266
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36387398 | 1. Front Vet Sci. 2022 Oct 28;9:1002488. doi: 10.3389/fvets.2022.1002488.
eCollection 2022.
Effect of GS-441524 in combination with the 3C-like protease inhibitor GC376 on
the treatment of naturally transmitted feline infectious peritonitis.
Lv J(1), Bai Y(1), Wang Y(1), Yang L(1), Jin Y(1), Dong J(1).
Author information:
(1)College of Veterinary Medicine, China Agricultural University, Beijing,
China.
OBJECTIVES: The main objectives of this study were to investigate the efficacy
of the nucleotide analog GS-441524 in combination with the 3C-like protease
inhibitor GC376 for the treatment of naturally aquired feline infectious
peritonitis (FIP) and to test whether their combination shortens the dosing
period and improves the cure rate.
METHODS: In total, 46 FIP-affected cats were enrolled in this experiment,
including 36 with wet FIP (29 with abdominal effusion, six with thoracic
effusion, and one with thoracic+abdominal effusion), and 10 with dry FIP. The
cats were aged from 3 to 96 months. Thoracic+abdominal effusion, lymph-node
puncture fluid and perirenal puncture fluid was collected from the affected cats
for qPCR testing, and all 46 cats were positive for feline coronavirus (FCoV).
The cats divided into different dose groups, all treated for 4 weeks: group 1
(GS-441524, 5 mg/kg.sc.q.24 h; GC376, 20 mg/kg.sc.q.12 h), group 2 (GS-441524,
2.5 mg/kg.sc.q.24 h; GC376, 20 mg/kg.sc.q.12 h), group 3 (GS-441524, 2.5
mg/kg.sc.q.24 h; GC376, 10 mg/kg.sc.q.12 h), and group 4 (GS-441524, 5
mg/kg.sc.q.24 h; GC376, 10 mg/kg.sc.q.12 h).
RESULTS: After the 4-week combination treatment, 45 of the 46 (97.8%) cats
survived, and 43 of those became clinically normal. Two cats required longer (7
to 12 weeks) treatment to achieve full recovery. As of writing (10 months after
completion of the trial), all 45 cats were alive and no relapse was observed.
CONCLUSIONS AND RELEVANCE: GS-441524 combined with GC376 can be safely and
effectively used to treat FIP and reduces the treatment period to 4 weeks, with
an excellent cure rate.
Copyright © 2022 Lv, Bai, Wang, Yang, Jin and Dong.
DOI: 10.3389/fvets.2022.1002488
PMCID: PMC9650422
PMID: 36387398
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32903584 | 1. Front Public Health. 2020 Aug 13;8:473. doi: 10.3389/fpubh.2020.00473.
eCollection 2020.
Modeling the Onset of Symptoms of COVID-19.
Larsen JR(1)(2), Martin MR(3), Martin JD(4), Kuhn P(2), Hicks JB(2).
Author information:
(1)Quantitative and Computational Biology, Department of Biological Science,
University of Southern California, Los Angeles, CA, United States.
(2)USC Michelson Center for Convergent Bioscience, University of Southern
California, Los Angeles, CA, United States.
(3)Nexus Development PA LLC, Redwood City, CA, United States.
(4)NanoCarrier Co., Ltd., Chiba, Japan.
COVID-19 is a pandemic viral disease with catastrophic global impact. This
disease is more contagious than influenza such that cluster outbreaks occur
frequently. If patients with symptoms quickly underwent testing and contact
tracing, these outbreaks could be contained. Unfortunately, COVID-19 patients
have symptoms similar to other common illnesses. Here, we hypothesize the order
of symptom occurrence could help patients and medical professionals more quickly
distinguish COVID-19 from other respiratory diseases, yet such essential
information is largely unavailable. To this end, we apply a Markov Process to a
graded partially ordered set based on clinical observations of COVID-19 cases to
ascertain the most likely order of discernible symptoms (i.e., fever, cough,
nausea/vomiting, and diarrhea) in COVID-19 patients. We then compared the
progression of these symptoms in COVID-19 to other respiratory diseases, such as
influenza, SARS, and MERS, to observe if the diseases present differently. Our
model predicts that influenza initiates with cough, whereas COVID-19 like other
coronavirus-related diseases initiates with fever. However, COVID-19 differs
from SARS and MERS in the order of gastrointestinal symptoms. Our results
support the notion that fever should be used to screen for entry into facilities
as regions begin to reopen after the outbreak of Spring 2020. Additionally, our
findings suggest that good clinical practice should involve recording the order
of symptom occurrence in COVID-19 and other diseases. If such a systemic
clinical practice had been standard since ancient diseases, perhaps the
transition from local outbreak to pandemic could have been avoided.
Copyright © 2020 Larsen, Martin, Martin, Kuhn and Hicks.
DOI: 10.3389/fpubh.2020.00473
PMCID: PMC7438535
PMID: 32903584 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36119462 | 1. Mediterr J Hematol Infect Dis. 2022 Sep 1;14(1):e2022065. doi:
10.4084/MJHID.2022.065. eCollection 2022.
Comparison of the Clinical and Laboratory Features of COVID and Influenza in
Children.
Pata D(1)(2), Buonsenso D(1)(2)(3), Valentini P(1).
Author information:
(1)Department of Woman and Child Health and Public Health, Fondazione
Policlinico Universitario A. Gemelli, Rome, Italy.
(2)Global Health Research Institute, Istituto di Igiene, Università Cattolica
del Sacro Cuore, Roma, Italia.
(3)Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e
Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.
BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by
SARS-CoV-2 and has a clinical presentation ranging from an asymptomatic course
to flu-like syndrome up to respiratory failure. Seasonal Influenza, due to the
influenza viruses and very common in children, can cause symptoms similar to
COVID-19. In order to identify clinical and laboratory characteristics that
allow healthcare workers to differentiate COVID-19 from Influenza, we performed
a systematic review of the existing literature on the pediatric age. Methods.
The research was done via PubMed for articles published from March 2020 to
October 2021, combining the MeSH words "COVID-19" and "Influenza" and "Children"
and considering the suggestions of the PRISMA Group.
RESULTS: The most frequently described symptoms were fever and cough in both
groups. In most studies, high fever, cough, nasal congestion or rhinorrhea,
vomiting, and muscle pain were detected more frequently in the Influenza group.
Regarding the value of laboratory tests, the results were mixed. Almost all
studies reported significantly lower levels of C-reactive protein and
procalcitonin in the COVID-19 group than in the Influenza group. In most
manuscripts, COVID-19 had a milder course than Influenza.
CONCLUSIONS: No symptoms are characteristic of a single infectious agent, with
flu-like disorders being the most common. In addition, laboratory tests do not
help in the differential diagnosis; however, they show a limited inflammatory
response in COVID-19, which could explain the fewer complications compared to
adulthood, with a less severe clinical course.
DOI: 10.4084/MJHID.2022.065
PMCID: PMC9448268
PMID: 36119462
Conflict of interest statement: Competing interests: The authors declare no
conflict of Interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34226206 | 1. Thorax. 2022 Feb;77(2):154-163. doi: 10.1136/thoraxjnl-2021-216949. Epub 2021
Jul 5.
Clinical phenotypes and outcomes of SARS-CoV-2, influenza, RSV and seven other
respiratory viruses: a retrospective study using complete hospital data.
Hedberg P(1)(2), Karlsson Valik J(2)(3), van der Werff S(2)(3), Tanushi H(3),
Requena Mendez A(2)(3), Granath F(3), Bell M(4)(5), Mårtensson J(4)(5), Dyrdak
R(6)(7), Hertting O(8)(9), Färnert A(2)(3), Ternhag A(2)(3), Naucler P(2)(3).
Author information:
(1)Department of Microbiology, Tumor and Cell Biology, Karolinska Institute,
Stockholm, Sweden Pontus.hedberg@ki.se.
(2)Department of Infectious Diseases, Karolinska University Hospital, Stockholm,
Sweden.
(3)Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
(4)Department of Physiology and Pharmacology, Karolinska Institute, Stockholm,
Sweden.
(5)Department of Perioperative Medicine and Intensive Care, Karolinska
University Hospital, Stockholm, Sweden.
(6)Department of Microbiology, Tumor and Cell Biology, Karolinska Institute,
Stockholm, Sweden.
(7)Department of Clinical Microbiology, Karolinska University Hospital,
Stockholm, Sweden.
(8)Department of Women's and Children's Health, Karolinska Institute, Stockholm,
Sweden.
(9)Department of Paediatric Infectious Diseases, Astrid Lindgren's Hospital,
Karolinska University Hospital, Stockholm, Sweden.
BACKGROUND: An understanding of differences in clinical phenotypes and outcomes
COVID-19 compared with other respiratory viral infections is important to
optimise the management of patients and plan healthcare. Herein we sought to
investigate such differences in patients positive for SARS-CoV-2 compared with
influenza, respiratory syncytial virus (RSV) and other respiratory viruses.
METHODS: We performed a retrospective cohort study of hospitalised adults and
children (≤15 years) who tested positive for SARS-CoV-2, influenza virus A/B,
RSV, rhinovirus, enterovirus, parainfluenza viruses, metapneumovirus, seasonal
coronaviruses, adenovirus or bocavirus in a respiratory sample at admission
between 2011 and 2020.
RESULTS: A total of 6321 adult (1721 SARS-CoV-2) and 6379 paediatric (101
SARS-CoV-2) healthcare episodes were included in the study. In adults,
SARS-CoV-2 positivity was independently associated with younger age, male sex,
overweight/obesity, diabetes and hypertension, tachypnoea as well as better
haemodynamic measurements, white cell count, platelet count and creatinine
values. Furthermore, SARS-CoV-2 was associated with higher 30-day mortality as
compared with influenza (adjusted HR (aHR) 4.43, 95% CI 3.51 to 5.59), RSV (aHR
3.81, 95% CI 2.72 to 5.34) and other respiratory viruses (aHR 3.46, 95% CI 2.61
to 4.60), as well as higher 90-day mortality, ICU admission, ICU mortality and
pulmonary embolism in adults. In children, patients with SARS-CoV-2 were older
and had lower prevalence of chronic cardiac and respiratory diseases compared
with other viruses.
CONCLUSIONS: SARS-CoV-2 is associated with more severe outcomes compared with
other respiratory viruses, and although associated with specific patient and
clinical characteristics at admission, a substantial overlap precludes
discrimination based on these characteristics.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/thoraxjnl-2021-216949
PMCID: PMC8260304
PMID: 34226206 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/33615750 | 1. J Zhejiang Univ Sci B. 2021 Feb 15;22(2):87-98. doi: 10.1631/jzus.B2000479.
Comparison of COVID-19 and influenza characteristics.
Bai Y(1), Tao X(2).
Author information:
(1)Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan 430022,
China.
(2)Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan 430022,
China. taoxn2004@163.com.
The emergence of coronavirus disease 2019 (COVID-19) not only poses a serious
threat to the health of people worldwide but also affects the global economy.
The outbreak of COVID-19 began in December 2019, at the same time as the
influenza season. However, as the treatments and prognoses of COVID-19 and
influenza are different, it is important to accurately differentiate these two
different respiratory tract infections on the basis of their respective
early-stage characteristics. We reviewed official documents and news released by
the National Health Commission of the People's Republic of China, the Chinese
Center for Disease Control and Prevention (China CDC), the United States CDC,
and the World Health Organization (WHO), and we also searched the PubMed, Web of
Science, Excerpta Medica database (Embase), China National Knowledge
Infrastructure (CNKI), Wanfang, preprinted bioRxiv and medRxiv databases for
documents and guidelines from earliest available date up until October 3rd,
2020. We obtained the latest information about COVID-19 and influenza and
summarized and compared their biological characteristics, epidemiology, clinical
manifestations, pathological mechanisms, treatments, and prognostic factors. We
show that although COVID-19 and influenza are different in many ways, there are
numerous similarities; thus, in addition to using nucleic acid-based polymerase
chain reaction (PCR) and antibody-based approaches, clinicians and
epidemiologists should distinguish between the two using their respective
characteristics in early stages. We should utilize experiences from other
epidemics to provide additional guidance for the treatment and prevention of
COVID-19.
DOI: 10.1631/jzus.B2000479
PMCID: PMC7885750
PMID: 33615750 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35078478 | 1. BMC Vet Res. 2022 Jan 25;18(1):55. doi: 10.1186/s12917-022-03153-3.
ERDRP-0519 inhibits feline coronavirus in vitro.
Camero M(1), Lanave G(2), Catella C(1), Lucente MS(1), Sposato A(1), Mari V(1),
Tempesta M(1), Martella V(1), Buonavoglia A(3).
Author information:
(1)Department of Veterinary Medicine, University of Bari, Valenzano, Italy.
(2)Department of Veterinary Medicine, University of Bari, Valenzano, Italy.
gianvito.lanave@uniba.it.
(3)Freelance, Bari, Italy.
BACKGROUND: Coronaviruses (CoVs) are major human and animal pathogens and
antiviral drugs are pursued as a complementary strategy, chiefly if vaccines are
not available. Feline infectious peritonitis (FIP) is a fatal systemic disease
of felids caused by FIP virus (FIPV), a virulent pathotype of feline enteric
coronavirus (FeCoV). Some antiviral drugs active on FIPV have been identified,
but they are not available in veterinary medicine. ERDRP-0519 (ERDRP) is a
non-nucleoside inhibitor, targeting viral RNA polymerase, effective against
morbilliviruses in vitro and in vivo.
RESULTS: The antiviral efficacy of ERDRP against a type II FIPV was evaluated in
vitro in Crandell Reese Feline Kidney (CRFK) cells. ERDRP significantly
inhibited replication of FIPV in a dose-dependent manner. Viral infectivity was
decreased by up to 3.00 logarithms in cell cultures whilst viral load, estimated
by quantification of nucleic acids, was reduced by nearly 3.11 logaritms.
CONCLUSIONS: These findings confirm that ERDRP is highly effective against a
CoV. Experiments will be necessary to assess whether ERDRP is suitable for
treatment of FIPV in vivo.
© 2022. The Author(s).
DOI: 10.1186/s12917-022-03153-3
PMCID: PMC8787031
PMID: 35078478 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33995342 | 1. Front Immunol. 2021 Apr 21;12:593595. doi: 10.3389/fimmu.2021.593595.
eCollection 2021.
Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic
Influenza A(H1N1).
Choreño-Parra JA(1)(2), Jiménez-Álvarez LA(2), Cruz-Lagunas A(2),
Rodríguez-Reyna TS(3), Ramírez-Martínez G(2), Sandoval-Vega M(4),
Hernández-García DL(5), Choreño-Parra EM(6), Balderas-Martínez YI(2),
Martinez-Sánchez ME(2), Márquez-García E(2), Sciutto E(7), Moreno-Rodríguez
J(8), Barreto-Rodríguez JO(9), Vázquez-Rojas H(9), Centeno-Sáenz GI(9),
Alvarado-Peña N(10), Salinas-Lara C(11), Sánchez-Garibay C(11), Galeana-Cadena
D(2), Hernández G(3), Mendoza-Milla C(12), Domínguez A(2)(13), Granados J(14),
Mena-Hernández L(15), Pérez-Buenfil LÁ(16), Domínguez-Cheritt G(13)(17),
Cabello-Gutiérrez C(18), Luna-Rivero C(19), Salas-Hernández J(20),
Santillán-Doherty P(21), Regalado J(21), Hernández-Martínez A(22), Orozco L(22),
Ávila-Moreno F(23), García-Latorre EA(1), Hernández-Cárdenas CM(5)(13), Khader
SA(24), Zlotnik A(25), Zúñiga J(2)(13).
Author information:
(1)Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional,
Mexico City, Mexico.
(2)Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades
Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
(3)Department of Immunology and Rheumatology, Instituto Nacional de Ciencias
Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
(4)Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de
México, Mexico City, Mexico.
(5)Intensive Care Unit, Instituto Nacional de Enfermedades Respiratorias Ismael
Cosío Villegas, Mexico City, Mexico.
(6)Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México,
Mexico City, Mexico.
(7)Department of Immunology, Instituto de Investigaciones Biomédicas,
Universidad Nacional Autónoma de México, Mexico City, Mexico.
(8)Direccion de Enseñanza e Investigación, Hospital Juárez de Mexico, Mexico
City, Mexico.
(9)Subdirección de Medicina, Instituto Nacional de Enfermedades Respiratorias
Ismael Cosío Villegas, Mexico City, Mexico.
(10)Coordinación de Infectología y Microbiología, Instituto Nacional de
Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
(11)Departamento de Neuropatología, Instituto Nacional de Neurología y
Neurocirugía "Manuel Velasco Suarez", Mexico City, Mexico.
(12)Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades
Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
(13)Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico
City, Mexico.
(14)Department of Transplantation, Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, Mexico City, Mexico.
(15)Department of Dermatology, Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, Mexico City, Mexico.
(16)Department of Education, Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán, Mexico City, Mexico.
(17)Critical Care Unit, Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán, Mexico City, Mexico.
(18)Department of Virology, Instituto Nacional de Enfermedades Respiratorias
Ismael Cosío Villegas, Mexico City, Mexico.
(19)Department of Pathology, Instituto Nacional de Enfermedades Respiratorias
Ismael Cosío Villegas, Mexico City, Mexico.
(20)General Direction, Instituto Nacional de Enfermedades Respiratorias Ismael
Cosío Villegas, Mexico City, Mexico.
(21)Department of Medical Direction, Instituto Nacional de Enfermedades
Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
(22)Laboratorio Inmunogenómica y Enfermedades Metabólicas, Instituto Nacional de
Medicina Genómica, Mexico City, Mexico.
(23)Biomedicine Research Unit (UBIMED), Lung Diseases and Cancer Epigenomics
Laboratory, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional
Autónoma de México (UNAM), Tlalnepantla de Baz, Mexico.
(24)Department of Molecular Microbiology, Washington University School of
Medicine in St Louis, St Louis, MO, United States.
(25)Department of Physiology & Biophysics School of Medicine, Institute for
Immunology, University of California, Irvine, CA, United States.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative
agent of coronavirus disease 2019 (COVID-19), is a global health threat with the
potential to cause severe disease manifestations in the lungs. Although COVID-19
has been extensively characterized clinically, the factors distinguishing
SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the
clinical, histopathological, and immunological characteristics of patients with
COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of
respiratory symptoms, increased tissue injury markers, and a histological
pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients.
Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology
were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by
higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and
sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by
increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels,
along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data
suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory
response that is different from the immune response against pandemic influenza
A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical
and immune factors to differentiate both diseases. These findings might be
relevant for the ongoing and future influenza seasons in the Northern
Hemisphere, which are historically unique due to their convergence with the
COVID-19 pandemic.
Copyright © 2021 Choreño-Parra, Jiménez-Álvarez, Cruz-Lagunas, Rodríguez-Reyna,
Ramírez-Martínez, Sandoval-Vega, Hernández-García, Choreño-Parra,
Balderas-Martínez, Martinez-Sánchez, Márquez-García, Sciutto, Moreno-Rodríguez,
Barreto-Rodríguez, Vázquez-Rojas, Centeno-Sáenz, Alvarado-Peña, Salinas-Lara,
Sánchez-Garibay, Galeana-Cadena, Hernández, Mendoza-Milla, Domínguez, Granados,
Mena-Hernández, Pérez-Buenfil, Domínguez-Cheritt, Cabello-Gutiérrez,
Luna-Rivero, Salas-Hernández, Santillán-Doherty, Regalado, Hernández-Martínez,
Orozco, Ávila-Moreno, García-Latorre, Hernández-Cárdenas, Khader, Zlotnik and
Zúñiga.
DOI: 10.3389/fimmu.2021.593595
PMCID: PMC8115405
PMID: 33995342 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. The reviewer (MC) has declared
a shared affiliation, with no collaboration with the author (SK), to the
handling editor, at the time of review. |
http://www.ncbi.nlm.nih.gov/pubmed/32881022 | 1. J Med Virol. 2021 Mar;93(3):1548-1555. doi: 10.1002/jmv.26486. Epub 2020 Sep
29.
A comparative study on the clinical features of COVID-19 with non-SARS-CoV-2
respiratory viral infections.
Tan JY(1), Sim XYJ(2)(3), Wee LE(2)(3), Chua YY(2), Cherng BPZ(2), Ng IM(3),
Conceicao EP(1)(2)(3), Wong TJ(4), Yang Y(3), Aung MK(3), Ling ML(3),
Venkatachalam I(2)(3).
Author information:
(1)Department of Internal Medicine, Singapore General Hospital, Singapore.
(2)Department of Infectious Diseases, Singapore General Hospital, Singapore.
(3)Department of Infection Prevention and Epidemiology, Singapore General
Hospital, Singapore.
(4)National Dental Research Institute Singapore, National Dental Centre
Singapore, Singapore.
During this coronavirus disease 2019 (COVID-19) pandemic, physicians have the
important task of risk stratifying patients who present with acute respiratory
illnesses. Clinical presentation of COVID-19, however, can be difficult to
distinguish from other respiratory viral infections. Thus, identifying clinical
features that are strongly associated with COVID-19 in comparison to other
respiratory viruses can aid risk stratification and testing prioritization
especially in situations where resources for virological testing and resources
for isolation facilities are limited. In our retrospective cohort study
comparing the clinical presentation of COVID-19 and other respiratory viral
infections, we found that anosmia and dysgeusia were symptoms independently
associated with COVID-19 and can be important differentiating symptoms in
patients presenting with acute respiratory illness. On the other hand,
laboratory abnormalities and radiological findings were not statistically
different between the two groups. In comparing outcomes, patients with COVID-19
were more likely to need high dependency or intensive care unit care and had a
longer median length of stay. With our findings, we emphasize that
epidemiological risk factors and clinical symptoms are more useful than
laboratory and radiological abnormalities in differentiating COVID-19 from other
respiratory viral infections.
© 2020 Wiley Periodicals LLC.
DOI: 10.1002/jmv.26486
PMID: 32881022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33799985 | 1. Pathogens. 2021 Mar 7;10(3):312. doi: 10.3390/pathogens10030312.
In Vitro Effects of Doxycycline on Replication of Feline Coronavirus.
Dunowska M(1), Ghosh S(1).
Author information:
(1)School of Veterinary Science, Massey University, Palmerston North 4410, New
Zealand.
Feline infectious peritonitis (FIP) is a sporadic fatal disease of cats caused
by a virulent variant of feline coronavirus (FCoV), referred to as FIP virus
(FIPV). Treatment options are limited, and most of the affected cats die or are
euthanized. Anecdotally, doxycycline has been used to treat FIP-affected cats,
but there are currently no data to support or discourage such treatment. The aim
of this study was to establish whether doxycycline inhibits replication of FIPV
in vitro. The virus was cultured in Crandell-Rees feline kidney cells with
various concentrations of doxycycline (0 to 50 µg/mL). The level of FIPV in
cultures was determined by virus titration and FCoV-specific
reverse-transcription quantitative PCR. Cell viability was also monitored. There
was no difference in the level of infectious virus or viral RNA between
doxycycline-treated and untreated cultures at 3, 12- and 18-hours
post-infection. However, at 24 h, the growth of FIPV was inhibited by
approximately two logs in cultures with >10 µg/mL doxycycline. This inhibition
was dose-dependent, with inhibitory concentration 50% (IC50) 4.1 µg/mL and IC90
5.4 µg/mL. Our data suggest that doxycycline has some inhibitory effect on FIPV
replication in vitro, which supports future clinical trials of its use for the
treatment of FIP-affected cats.
DOI: 10.3390/pathogens10030312
PMCID: PMC8001410
PMID: 33799985
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33135801 | 1. J Med Virol. 2021 Apr;93(4):2221-2226. doi: 10.1002/jmv.26645. Epub 2020 Nov
10.
The value of the platelet count and platelet indices in differentiation of
COVID-19 and influenza pneumonia.
Ozcelik N(1), Ozyurt S(1), Yilmaz Kara B(1), Gumus A(1), Sahin U(1).
Author information:
(1)Department of Chest Diseases, Recep Tayyip Erdogan University, Rıze, Turkey.
It is difficult to distinguish coronavirus disease-2019 (COVID-19) from other
viral respiratory tract infections owing to the similarities in clinical and
radiological findings. This study aims to determine the clinical importance of
platelet count and platelet indices in the differentiation of COVID-19 from
influenza and the value of these parameters in the differential diagnosis of
COVID-19. The medical records of the patients and the electronic patient
monitoring system were retrospectively analyzed. Demographic characteristics,
admission symptoms, laboratory findings, radiological involvement,
comorbidities, and mortality of the patients were recorded. Forty-three patients
diagnosed with influenza and 54 diagnosed with COVID-19 were included in the
study. The average age of the COVID-19 patients was lower than that of the
influenza patients (influenza: 60.5 years, COVID-19: 52.4 years;
pp = 0.024),.024), and the male gender was predominant in the COVID-19 group
(influenza: 42%, COVID-19: 56%). According to laboratory findings, the mean
platelet volume (MPV) and MPV/platelet ratio were statistically significantly
lower, whereas the eosinophil count and platelet distribution width levels were
significantly higher (p < 0.05) in the COVID-19 group. It was found that the
most common symptom in both groups was dyspnea and that the symptom was more
prevalent among influenza patients. In the diagnosis of COVID-19, the platelet
count and platelet indices are easily accessible, inexpensive, and important
parameters in terms of differential diagnosis and can help in the
differentiation of COVID-19 from influenza during seasonal outbreaks of the
latter.
© 2020 Wiley Periodicals LLC.
DOI: 10.1002/jmv.26645
PMID: 33135801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35412847 | 1. Microbiol Spectr. 2022 Apr 27;10(2):e0180721. doi: 10.1128/spectrum.01807-21.
Epub 2022 Apr 12.
Clinical Evaluation of BD Veritor SARS-CoV-2 and Flu A+B Assay for Point-Of-Care
System.
Christensen K(1), Ren H(2), Chen S(2), Cooper CK(1), Young S(3).
Author information:
(1)Becton, Dickinson and Company, BD Life Sciences-Integrated Diagnostic
Solutions, Sparks, Maryland, USA.
(2)Becton, Dickinson and Company, BD Life Sciences, San Diego, California, USA.
(3)Tricore Reference Laboratory, Albuquerque, New Mexico, USA.
Differential diagnosis of COVID-19 and/or influenza (flu) at point of care is
critical for efficient patient management and treatment of both these diseases.
The study presented here characterizes the BD Veritor System for Rapid Detection
of SARS-CoV-2 and Flu A+B ("Veritor SARS-CoV-2/Flu") triplex assay. The
performance for SARS-CoV-2 detection was determined using 298 specimens from
patients reporting COVID-19 symptoms within 7 days from symptom onset (DSO) in
comparison with the Lyra SARS-CoV-2 RT-PCR (reverse transcriptase PCR) assay
("Lyra SARS-CoV-2") as the reference. The performance for flu A and flu B
detection was determined using 75 influenza-positive and 40 influenza-negative
retrospective specimens in comparison with the previously FDA-cleared BD Veritor
System for Rapid Detection of Flu A+B assay ("Veritor Flu") as the reference.
The Veritor SARS-CoV-2/Flu assay met the FDA EUA acceptance criteria (86.7%; 95%
confidence interval [95% CI]: 75.8 to 93.1) for SARS-CoV-2 testing compared to
Lyra SARS-CoV-2. The Veritor SARS-CoV-2/Flu assay also demonstrated 100%
agreement with the Veritor Flu for Flu A+B assay. For flu A detection, the lower
bound of the 95% CI was 91.2%; for flu B detection, the lower bound was 90.0%.
The dual detection capability of Veritor SARS-CoV-2/Flu for the etiologic agents
causing COVID-19 and flu will allow efficient differentiation between the two
illnesses, inform disease management, and facilitate optimal treatment.
IMPORTANCE COVID-19 and flu are two respiratory illnesses which share similar
clinical symptoms. The BD Veritor SARS-CoV-2/Flu assay has high sensitivity and
specificity for detecting the SARS-CoV-2 and influenza A/B, the two etiologic
agents causing COVID-19 and flu, respectively. This dual detection capability is
critical when overlap occurs between the COVID-19 pandemic and the flu season.
This triplex assay will allow efficient differentiation between the two
respiratory illnesses and support a point-of-care physician diagnosis to
facilitate the proper treatment and disease management for patients exhibiting
overlapping symptoms.
DOI: 10.1128/spectrum.01807-21
PMCID: PMC9045085
PMID: 35412847 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare a conflict of interest.
K.C., H.R., S.C., and C.K.C. are current and previous employees of Becton,
Dickinson and Company. The individuals acknowledged here have no additional
funding or additional compensation to disclose. Becton, Dickinson and Company;
BD Life Sciences-Integrated Diagnostic Solutions provided funding to both BD and
non-BD employee authors to support this study. K.C., H.R., S.C., and C.K.C. are
current and previous employees of Becton, Dickinson and Company. The individuals
acknowledged here have no additional funding or additional compensation to
disclose. S.Y. reports personal fees from Becton, Dickinson and Company; Quidel,
Inc.; and Safeguard Biosystems. |
http://www.ncbi.nlm.nih.gov/pubmed/35976445 | 1. J Cancer Res Clin Oncol. 2023 Jul;149(7):3701-3719. doi:
10.1007/s00432-022-04189-6. Epub 2022 Aug 17.
Triple negative breast cancer: approved treatment options and their mechanisms
of action.
Mandapati A(1), Lukong KE(2).
Author information:
(1)Biochemistry, Microbiology and Immunology, College of Medicine, University of
Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
(2)Biochemistry, Microbiology and Immunology, College of Medicine, University of
Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
kiven.lukong@usask.ca.
PURPOSE: Breast cancer, the most prevalent cancer worldwide, consists of 4 main
subtypes, namely, Luminal A, Luminal B, HER2-positive, and Triple-negative
breast cancer (TNBC). Triple-negative breast tumors, which do not express
estrogen, progesterone, and HER2 receptors, account for approximately 15-20% of
breast cancer cases. The lack of traditional receptor targets contributes to
the heterogenous, aggressive, and refractory nature of these tumors, resulting
in limited therapeutic strategies.
METHODS: Chemotherapeutics such as taxanes and anthracyclines have been the
traditional go to treatment regimens for TNBC patients. Paclitaxel, docetaxel,
doxorubicin, and epirubicin have been longstanding, Food and Drug Administration
(FDA)-approved therapies against TNBC. Additionally, the FDA approved PARP
inhibitors such as olaparib and atezolizumab to be used in combination with
chemotherapies, primarily to improve their efficiency and reduce adverse patient
outcomes. The immunotherapeutic Keytruda was the latest addition to the
FDA-approved list of drugs used to treat TNBC.
RESULTS: The following review aims to elucidate current FDA-approved
therapeutics and their mechanisms of action, shedding a light on the various
strategies currently used to circumvent the treatment-resistant nature of TNBC
cases.
CONCLUSION: The recent approval and use of therapies such as Trodelvy, olaparib
and Keytruda has its roots in the development of an understanding of signaling
pathways that drive tumour growth. In the future, the emergence of novel drug
delivery methods may help increase the efficiency of these therapies whiel
also reducing adverse side effects.
© 2022. The Author(s).
DOI: 10.1007/s00432-022-04189-6
PMCID: PMC10314854
PMID: 35976445 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. The
authors Aditya Mandapati and Kiven Erique report no other conflicts of interest
that are relevant to the contents of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/34484383 | 1. J Res Med Sci. 2021 Jul 31;26:51. doi: 10.4103/jrms.JRMS_820_20. eCollection
2021.
Co-infection between the severe acute respiratory syndrome coronavirus 2 and the
influenza Type B in Isfahan, Iran.
Heshmat-Ghahdarijani K(1), Vaseghi G(2), Nasirian M(3), Javanmard SH(4).
Author information:
(1)Heart Failure Research Center, Cardiovascular Research Institute, Isfahan
University of Medical Sciences, Isfahan, Iran.
(2)Isfahan Cardiovascular Research Center, Cardiovascular Research Institute,
Isfahan University of Medical Sciences, Isfahan, Iran.
(3)Department of Epidemiology and Biostatistics, Health School, Infectious
Diseases and Tropical Medicine Research Center, Isfahan University of Medical
Sciences, Isfahan, Iran.
(4)Applied Physiology Research Center, Cardiovascular Research Institute,
Isfahan University of Medical Sciences, Isfahan, Iran.
BACKGROUND: Some studies have been reported the rates of co-infection between
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus
in the different regions. In this study, we report the co-infection rates
between SARS-CoV-2 and influenza type B in Isfahan, Iran.
MATERIALS AND METHODS: All patients with a definite diagnosis of coronavirus
disease 2019 (COVID-19) from Isfahan COVID-19 registry (I-core) study were
enrolled from February 2020.
RESULTS: Of the 1639 laboratory COVID-19 confirmed in Isfahan province, only two
persons were positive for Influenza B from Isfahan COVID-19 registry (I-core).
Both patients were symptom-free after 3 months' follow-up.
CONCLUSION: During influenza season, differentiating other causes of respiratory
illness from COVID-19 is difficult, because common clinical manifestations of
COVID-19 mimic those of influenza. It seems that evaluating for co-infection
with different types of influenza viruses in patients with specific settings
should be considered.
Copyright: © 2021 Journal of Research in Medical Sciences.
DOI: 10.4103/jrms.JRMS_820_20
PMCID: PMC8384011
PMID: 34484383
Conflict of interest statement: There are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36006441 | 1. Blood Adv. 2023 Feb 28;7(4):644-648. doi: 10.1182/bloodadvances.2022007625.
Effects of teclistamab and talquetamab on soluble BCMA levels in patients with
relapsed/refractory multiple myeloma.
Girgis S(1), Wang Lin SX(1), Pillarisetti K(1), Verona R(1), Vieyra D(1),
Casneuf T(2), Fink D(1), Miao X(1), Chen Y(1), Stephenson T(1), Banerjee A(1),
Hilder BW(1), Russell J(1), Infante J(1), Elsayed Y(1), Smit J(1), Goldberg
JD(1).
Author information:
(1)Janssen Research & Development, LLC, Spring House, PA.
(2)Janssen Research & Development, LLC, Beerse, Belgium.
DOI: 10.1182/bloodadvances.2022007625
PMCID: PMC9979748
PMID: 36006441 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: D.F., Y.C., and
J.R. are former employees of Janssen Research & Development and may own
stock/stock options in Johnson & Johnson. The remaining authors are currently
employees of Janssen Research & Development and may own stock/stock options in
Johnson & Johnson. |
http://www.ncbi.nlm.nih.gov/pubmed/20660146 | 1. J Gen Virol. 2010 Nov;91(Pt 11):2874-83. doi: 10.1099/vir.0.022103-0. Epub
2010 Jul 21.
Biochemical and immunohistochemical characterization of feline spongiform
encephalopathy in a German captive cheetah.
Eiden M(1), Hoffmann C, Balkema-Buschmann A, Müller M, Baumgartner K, Groschup
MH.
Author information:
(1)Institute for Novel and Emerging Infectious Diseases at the Friedrich
Loeffler Institute (FLI), Federal Research Institute for Animal Health,
Greifswald-Insel Riems, Germany. martin.groschup@fli.bund.de
Feline spongiform encephalopathy (FSE) is a transmissible spongiform
encephalopathy that affects domestic cats (Felis catus) and captive wild members
of the family Felidae. In this report we describe a case of FSE in a captive
cheetah from the zoological garden of Nuremberg. The biochemical examination
revealed a BSE-like pattern. Disease-associated scrapie prion protein (PrP(Sc))
was widely distributed in the central and peripheral nervous system, as well as
in the lymphoreticular system and in other tissues of the affected animal, as
demonstrated by immunohistochemistry and/or immunoblotting. Moreover, we report
for the first time the use of the protein misfolding cyclic amplification
technique for highly sensitive detection of PrP(Sc) in the family Felidae. The
widespread PrP(Sc) deposition suggests a simultaneous lymphatic and neural
spread of the FSE agent. The detection of PrP(Sc) in the spleen indicates a
potential for prion infectivity of cheetah blood.
DOI: 10.1099/vir.0.022103-0
PMID: 20660146 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36352205 | 1. Drugs. 2022 Nov;82(16):1613-1619. doi: 10.1007/s40265-022-01793-1.
Teclistamab: First Approval.
Kang C(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
Teclistamab (TECVAYLI®), a bispecific antibody that targets CD3 and B cell
maturation antigen (BCMA), is being developed by Janssen Research and
Development for the treatment of relapsed or refractory multiple myeloma.
Teclistamab was recently granted conditional approval in the EU for the
treatment of adult patients with relapsed and refractory multiple myeloma who
have received three or more prior therapies (including an immunomodulatory
agent, a proteasome inhibitor and an anti-CD38 antibody) and have demonstrated
disease progression on the last therapy. Teclistamab was subsequently approved
in the US for the treatment of adult patients with relapsed or refractory
multiple myeloma who have received at least four prior lines of therapy
(including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38
antibody). This article summarizes the milestones in the development of
teclistamab leading to this first approval for relapsed or refractory multiple
myeloma.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01793-1
PMCID: PMC9646474
PMID: 36352205 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. Connie Kang is a salaried
employee of Adis International Ltd/Springer Nature, and declares no relevant
conflicts of interest. All authors contributed to the review and are responsible
for the article content. |
http://www.ncbi.nlm.nih.gov/pubmed/18725465 | 1. Vet Pathol. 2008 Sep;45(5):626-33. doi: 10.1354/vp.45-5-626.
Neuropathology of italian cats in feline spongiform encephalopathy surveillance.
Iulini B(1), Cantile C, Mandara MT, Maurella C, Loria GR, Castagnaro M,
Salvadori C, Porcario C, Corona C, Perazzini AZ, Maroni A, Caramelli M, Casalone
C.
Author information:
(1)CEA - Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle
d'Aosta, Via Bologna 148, 10154 Torino (Italy).
Feline spongiform encephalopathy (FSE) is a transmissible spongiform
encephalopathy associated with the consumption of feedstuffs contaminated with
tissue from bovine spongiform encephalopathy-affected cattle and characterized
by the accumulation in the central nervous system of an abnormal isoform of the
prion protein (PrP(sc)). Clinically, it presents as a progressive fatal
neurologic syndrome that is not easily distinguished from other feline
neurologic conditions. Most cases of FSE have been reported in England, where it
was first detected in 1990, but a few cases have been reported from other
European countries. To identify possible cases of FSE in Italy, the Italian
Ministry of Health funded a 2-year surveillance project during which the brains
from 110 domestic cats with neurologic signs were evaluated histologically for
spongiform encephalopathy and immunohistochemically to detect PrP(sc). Although
no cases of FSE were found, the study proved useful in monitoring the Italian
cat population for other neurologic diseases: neoplasia (21.8%), toxic-metabolic
encephalopathy (18.2%), granulomatous encephalitis (15.5%), suppurative
encephalitis (4.6%), trauma (3.6%), circulatory disorders (3.6%), degeneration
(2.7%), nonsuppurative encephalitis (2.7%), and neuromuscular diseases (1.8%).
No histologic lesions were found in 20% of the brains, and samples from 5.5% of
the cats were rejected as unsuitable.
DOI: 10.1354/vp.45-5-626
PMID: 18725465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11338713 | 1. Vet Rec. 2001 Apr 7;148(14):437-41. doi: 10.1136/vr.148.14.437.
Inconsistent detection of PrP in extraneural tissues of cats with feline
spongiform encephalopathy.
Ryder SJ(1), Wells GA, Bradshaw JM, Pearson GR.
Author information:
(1)Veterinary Laboratories Agency, Woodham Lane, New Haw, Addlestone, Surrey
KT15 3NB.
Feline spongiform encephalopathy (FSE), a transmissible spongiform
encephalopathy or prion disease of cats, first reported in Great Britain in
1990, is believed to result from the consumption of food contaminated by the
agent of bovine spongiform encephalopathy (BSE). The accumulation of PrP in
non-neural tissues of cats diagnosed as suffering from FSE was investigated by
immunohistochemistry. In the majority of the cats no disease-specific PrP was
detected in lymphoid tissues. Small amounts of PrP were detected in the spleen
of only two of 13 samples examined, in Peyer's patches of one of the two cases
for which suitable material was available, but in the myenteric plexus of all
four cats in which sections of intestine were examined. In addition PrP
immunostaining was found in the kidney of all the cats with FSE whose kidneys
were examined.
DOI: 10.1136/vr.148.14.437
PMID: 11338713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19738899 | 1. PLoS One. 2009 Sep 7;4(9):e6929. doi: 10.1371/journal.pone.0006929.
Possible case of maternal transmission of feline spongiform encephalopathy in a
captive cheetah.
Bencsik A(1), Debeer S, Petit T, Baron T.
Author information:
(1)Unité ATNC, Agence Française de Sécurité Sanitaire des Aliments (AFSSA),
Lyon, France. a.bencsik@afssa.fr
Feline spongiform encephalopathy (FSE) is considered to be related to bovine
spongiform encephalopathy (BSE) and has been reported in domestic cats as well
as in captive wild cats including cheetahs, first in the United Kingdom (UK) and
then in other European countries. In France, several cases were described in
cheetahs either imported from UK or born in France. Here we report details of
two other FSE cases in captive cheetah including a 2(nd) case of FSE in a
cheetah born in France, most likely due to maternal transmission. Complete prion
protein immunohistochemical study on both brains and peripheral organs showed
the close likeness between the two cases. In addition, transmission studies to
the TgOvPrP4 mouse line were also performed, for comparison with the
transmission of cattle BSE. The TgOvPrP4 mouse brains infected with cattle BSE
and cheetah FSE revealed similar vacuolar lesion profiles, PrP(d) brain mapping
with occurrence of typical florid plaques. Collectively, these data indicate
that they harbor the same strain of agent as the cattle BSE agent. This new
observation may have some impact on our knowledge of vertical transmission of
BSE agent-linked TSEs such as in housecat FSE, or vCJD.
DOI: 10.1371/journal.pone.0006929
PMCID: PMC2732902
PMID: 19738899 [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/12783238 | 1. Histochem Cell Biol. 2003 May;119(5):415-22. doi: 10.1007/s00418-003-0524-5.
Epub 2003 May 1.
First case of feline spongiform encephalopathy in a captive cheetah born in
France: PrP(sc) analysis in various tissues revealed unexpected targeting of
kidney and adrenal gland.
Lezmi S(1), Bencsik A, Monks E, Petit T, Baron T.
Author information:
(1)Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Unité de
Virologie - ATNC, 31 avenue Tony Garnier, 69364 Lyon cedex 07, France.
s.lezmi@lyon.afssa.fr
Feline spongiform encephalopathy (FSE), affecting domestic and captive feline
species, is a prion disease considered to be related to bovine spongiform
encephalopathy. Here we report an immunohistological analysis of the first
FSE-affected cheetah born in France. The duration of clinical signs, of which
ataxia was the main one, was about 8 weeks. The distribution of abnormal prion
protein (PrP(sc)) was studied by immunohistochemistry within 27 different
tissues. Different antibodies were used to visualise abnormal PrP deposits in
situ. PrP(sc )accumulation was detected in the central nervous system (cerebral
cortex, cerebellum, brain stem, spinal cord, retina), in peripheral nerves and
in lymphoid organs. PrP(sc) deposits were not observed within the enteric
nervous system nor in several other organs, such as pancreas, ovary, liver and
muscle. More interestingly, unusual PrP(sc )deposits were observed within the
zona fasciculata/reticularis of the adrenal gland and within some glomeruli of
the kidney raising the question of possible PrP(sc) excretion. The sympathetic
innervation of these two organs was visualised and compared to the distribution
of PrP(sc) deposits. Our results suggest the possibility that the infectious
agent is spread by both haematogenous and nervous pathways.
DOI: 10.1007/s00418-003-0524-5
PMID: 12783238 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22538991 | 1. Cell Mol Life Sci. 2012 Nov;69(21):3613-34. doi: 10.1007/s00018-012-0990-9.
Epub 2012 Apr 27.
Regulation of eukaryotic gene expression by the untranslated gene regions and
other non-coding elements.
Barrett LW(1), Fletcher S, Wilton SD.
Author information:
(1)Centre for Neuromuscular and Neurological Disorders (CNND), The University of
Western Australia (M518), 35 Stirling Highway, Crawley, WA 6009, Australia.
Barrel02@student.uwa.edu.au
There is now compelling evidence that the complexity of higher organisms
correlates with the relative amount of non-coding RNA rather than the number of
protein-coding genes. Previously dismissed as "junk DNA", it is the non-coding
regions of the genome that are responsible for regulation, facilitating complex
temporal and spatial gene expression through the combinatorial effect of
numerous mechanisms and interactions working together to fine-tune gene
expression. The major regions involved in regulation of a particular gene are
the 5' and 3' untranslated regions and introns. In addition, pervasive
transcription of complex genomes produces a variety of non-coding transcripts
that interact with these regions and contribute to regulation. This review
discusses recent insights into the regulatory roles of the untranslated gene
regions and non-coding RNAs in the control of complex gene expression, as well
as the implications of this in terms of organism complexity and evolution.
DOI: 10.1007/s00018-012-0990-9
PMCID: PMC3474909
PMID: 22538991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18631145 | 1. Biochem Soc Trans. 2008 Aug;36(Pt 4):708-11. doi: 10.1042/BST0360708.
Post-transcriptional regulation of gene expression by alternative
5'-untranslated regions in carcinogenesis.
Smith L(1).
Author information:
(1)Leeds Institute of Molecular Medicine, University of Leeds, St James's
University Hospital, Leeds, UK. medlsmi@leeds.ac.uk
Post-transcriptional regulation, via 5'-UTRs (5'-untranslated regions), plays an
important role in the control of eukaryotic gene expression. Recent analyses of
the mammalian transcriptome suggest that most of the genes express multiple
alternative 5'-UTRs and inappropriate expression of these regions has been shown
to contribute to the development of carcinogenesis. The present review will
focus on the complex post-transcriptional regulation of ERbeta (oestrogen
receptor beta) expression. In particular, results from our laboratory suggest
that the expression of alternative 5'-UTRs plays a key role in determining the
level of ERbeta protein expression. We have also shown that these alternative
ERbeta 5'-UTRs have a tissue-specific distribution and are differentially
expressed between various normal and tumour tissues. Our results also suggest
that alternative 5'-UTRs can influence downstream splicing events, thereby
perhaps affecting ERbeta function. These results suggest that alternative
5'-UTRs may have an overall influence on ER activity and this may have important
implications for our understanding of cancer biology and treatment.
DOI: 10.1042/BST0360708
PMID: 18631145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28287067 | 1. BMB Rep. 2017 Apr;50(4):194-200. doi: 10.5483/bmbrep.2017.50.4.040.
Translational control of mRNAs by 3'-Untranslated region binding proteins.
Yamashita A(1), Takeuchi O(2).
Author information:
(1)Department of Molecular Biology, Yokohama City University School of Medicine,
Yokohama 236-0004, Japan.
(2)Laboratory of Infection and Prevention, Institute for Frontier Life and
Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Eukaryotic gene expression is precisely regulated at all points between
transcription and translation. In this review, we focus on translational control
mediated by the 3'-untranslated regions (UTRs) of mRNAs. mRNA 3'-UTRs contain
cis-acting elements that function in the regulation of protein translation or
mRNA decay. Each RNA binding protein that binds to these cis-acting elements
regulates mRNA translation via various mechanisms targeting the mRNA cap
structure, the eukaryotic initiation factor 4E (eIF4E)-eIF4G complex, ribosomes,
and the poly (A) tail. We also discuss translation-mediated regulation of mRNA
fate. [BMB Reports 2017; 50(4): 194-200].
DOI: 10.5483/bmbrep.2017.50.4.040
PMCID: PMC5437963
PMID: 28287067 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICTS OF INTEREST The authors have no
conflicting financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/28985357 | 1. Nucleic Acids Res. 2017 Oct 13;45(18):10800-10810. doi: 10.1093/nar/gkx675.
CRISPR-Cas9-mediated functional dissection of 3'-UTRs.
Zhao W(1), Siegel D(1), Biton A(1)(2), Tonqueze OL(1), Zaitlen N(1), Ahituv
N(3), Erle DJ(1).
Author information:
(1)Lung Biology Center, Department of Medicine, University of California San
Francisco, 4th St, San Francisco, CA 94158, USA.
(2)Centre de Bioinformatique, Biostatistique et Biologie Intégrative, C3BI, USR
3756 Institut Pasteur et CNRS, 25-28 Rue du Dr Roux, Paris 75015, France.
(3)Department of Bioengineering and Therapeutic Sciences, Institute for Human
Genetics, University of California San Francisco, 4th St, San Francisco, CA
94158, USA.
Many studies using reporter assays have demonstrated that 3' untranslated
regions (3'-UTRs) regulate gene expression by controlling mRNA stability and
translation. Due to intrinsic limitations of heterologous reporter assays, we
sought to develop a gene editing approach to investigate the regulatory activity
of 3'-UTRs in their native context. We initially used dual-CRISPR (clustered,
regularly interspaced, short palindromic repeats)-Cas9 targeting to delete DNA
regions corresponding to nine chemokine 3'-UTRs that destabilized mRNA in a
reporter assay. Targeting six chemokine 3'-UTRs increased chemokine mRNA levels
as expected. However, targeting CXCL1, CXCL6 and CXCL8 3'-UTRs unexpectedly led
to substantial mRNA decreases. Metabolic labeling assays showed that targeting
these three 3'-UTRs increased mRNA stability, as predicted by the reporter
assay, while also markedly decreasing transcription, demonstrating an unexpected
role for 3'-UTR sequences in transcriptional regulation. We further show that
CRISPR-Cas9 targeting of specific 3'-UTR elements can be used for modulating
gene expression and for highly parallel localization of active 3'-UTR elements
in the native context. Our work demonstrates the duality and complexity of
3'-UTR sequences in regulation of gene expression and provides a useful approach
for modulating gene expression and for functional annotation of 3'-UTRs in the
native context.
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkx675
PMCID: PMC5737544
PMID: 28985357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27208003 | 1. J Mol Endocrinol. 2016 Aug;57(2):F29-34. doi: 10.1530/JME-16-0070. Epub 2016
May 20.
Alternative polyadenylation and RNA-binding proteins.
Erson-Bensan AE(1).
Author information:
(1)Department of Biological SciencesOrta Dogu Teknik Universitesi (ODTU) (METU),
Universiteler Mahallesi, Cankaya, Ankara, Turkey erson@metu.edu.tr.
Our understanding of the extent of microRNA-based gene regulation has expanded
in an impressive pace over the past decade. Now, we are beginning to better
appreciate the role of 3'-UTR (untranslated region) cis-elements which harbor
not only microRNA but also RNA-binding protein (RBP) binding sites that have
significant effect on the stability and translational rate of mRNAs. To add
further complexity, alternative polyadenylation (APA) emerges as a widespread
mechanism to regulate gene expression by producing shorter or longer mRNA
isoforms that differ in the length of their 3'-UTRs or even coding sequences.
Resulting shorter mRNA isoforms generally lack cis-elements where trans-acting
factors bind, and hence are differentially regulated compared with the longer
isoforms. This review focuses on the RBPs involved in APA regulation and their
action mechanisms on APA-generated isoforms. A better understanding of the
complex interactions between APA and RBPs is promising for mechanistic and
clinical implications including biomarker discovery and new therapeutic
approaches.
© 2016 Society for Endocrinology.
DOI: 10.1530/JME-16-0070
PMID: 27208003 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16430990 | 1. Trends Genet. 2006 Mar;22(3):119-22. doi: 10.1016/j.tig.2006.01.001. Epub 2006
Jan 23.
Regulation of gene expression by alternative untranslated regions.
Hughes TA(1).
Author information:
(1)Leeds Institute for Molecular Medicine Level 4, JIF Building, St. James's
University Hospital, University of Leeds, Leeds, UK, LS9 7TF.
t.hughes@leeds.ac.uk
The untranslated regions of mRNAs can determine gene expression by influencing
mRNA stability and translational efficiency. Recent reports show that gene
expression can be regulated by the differential use of alternative untranslated
regions. Tissue-specific expression of transcripts that have different
untranslated regions (UTRs) can control protein expression enabling
developmental, physiological and pathological regulation. Several examples of
alternative UTRs have been characterized, including those found in AXIN2, FGF1
and BRCA1. Results from bioinformatics studies indicate that this mechanism is
more common than previously appreciated.
DOI: 10.1016/j.tig.2006.01.001
PMID: 16430990 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30961831 | 1. Trends Cancer. 2019 Apr;5(4):245-262. doi: 10.1016/j.trecan.2019.02.011. Epub
2019 Mar 22.
The Untranslated Regions of mRNAs in Cancer.
Schuster SL(1), Hsieh AC(2).
Author information:
(1)Molecular and Cellular Biology, University of Washington, Seattle, WA 98195,
USA; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle,
WA, 98109, USA.
(2)Molecular and Cellular Biology, University of Washington, Seattle, WA 98195,
USA; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle,
WA, 98109, USA; School of Medicine and Genome Sciences, University of
Washington, Seattle, WA 98195, USA. Electronic address: ahsieh@fredhutch.org.
The 5' and 3' untranslated regions (UTRs) regulate crucial aspects of
post-transcriptional gene regulation that are necessary for the maintenance of
cellular homeostasis. When these processes go awry through mutation or
misexpression of certain regulatory elements, the subsequent deregulation of
oncogenic gene expression can drive or enhance cancer pathogenesis. Although the
number of known cancer-related mutations in UTR regulatory elements has recently
increased markedly as a result of advances in whole-genome sequencing, little is
known about how the majority of these genetic aberrations contribute
functionally to disease. In this review we explore the regulatory functions of
UTRs, how they are co-opted in cancer, new technologies to interrogate cancerous
UTRs, and potential therapeutic opportunities stemming from these regions.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.trecan.2019.02.011
PMCID: PMC6465068
PMID: 30961831 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30120519 | 1. Curr Genet. 2019 Feb;65(1):127-131. doi: 10.1007/s00294-018-0877-x. Epub 2018
Aug 17.
3'untranslated regions: regulation at the end of the road.
El Mouali Y(1), Balsalobre C(2).
Author information:
(1)RNA Biology Group, Institute for Molecular Infection Biology, University of
Würzburg, Würzburg, Germany.
(2)Department of Genetics, Microbiology and Statistics, School of Biology,
University of Barcelona, Barcelona, Spain. cbalsalobre@ub.edu.
Post-transcriptional gene regulation in bacteria plays a major role in the
adaptation of bacterial cells to the changing conditions encountered in the
environment. In bacteria, most of the regulation at the level of mRNA seems to
be targeting the 5'untranslated regions where accessibility to the
ribosome-binding site can be modulated to alter gene expression. In recent
years, the role of 3'untranslated regions has gained attention also as a site
for post-transcriptional regulation. In addition to be a source of trans-encoded
small RNAs, the 3'untranslated regions can be targets to modulate gene
expression. Taking recent findings in the post-transcriptional regulation of the
hilD gene, encoding for the main regulator of virulence in Salmonella enterica
serovar Typhimurium, we highlight the role of 3'untranslated regions as targets
of post-transcriptional regulation mediated by small RNAs and discuss the
implications of transcriptional elongation in the 3'UTR-mediated regulation in
bacteria.
DOI: 10.1007/s00294-018-0877-x
PMID: 30120519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26386038 | 1. J Immunol. 2015 Oct 1;195(7):2963-71. doi: 10.4049/jimmunol.1500756.
Translating the Untranslated Region.
Schwerk J(1), Savan R(2).
Author information:
(1)Department of Immunology, University of Washington, Seattle, WA 98109.
(2)Department of Immunology, University of Washington, Seattle, WA 98109
savanram@uw.edu.
Gene expression programs undergo constant regulation to quickly adjust to
environmental stimuli that alter the physiological status of the cell, like
cellular stress or infection. Gene expression is tightly regulated by
multilayered regulatory elements acting in both cis and trans.
Posttranscriptional regulation of the 3' untranslated region (UTR) is a powerful
regulatory process that determines the rate of protein translation from mRNA.
Regulatory elements targeting the 3' UTR include microRNAs, RNA-binding
proteins, and long noncoding RNAs, which dramatically alter the immune response.
We provide an overview of our current understanding of posttranscriptional
regulation of immune gene expression. The focus of this review is on regulatory
elements that target the 3' UTR. We delineate how the synergistic or
antagonistic interactions of posttranscriptional regulators determine gene
expression levels and how dysregulation of 3' UTR-mediated posttranscriptional
control associates with human diseases.
Copyright © 2015 by The American Association of Immunologists, Inc.
DOI: 10.4049/jimmunol.1500756
PMCID: PMC4648541
PMID: 26386038 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21075793 | 1. Nucleic Acids Res. 2011 Mar;39(6):2393-403. doi: 10.1093/nar/gkq1158. Epub
2010 Nov 12.
Expression of distinct RNAs from 3' untranslated regions.
Mercer TR(1), Wilhelm D, Dinger ME, Soldà G, Korbie DJ, Glazov EA, Truong V,
Schwenke M, Simons C, Matthaei KI, Saint R, Koopman P, Mattick JS.
Author information:
(1)Institute for Molecular Biosciences, The University of Queensland, Brisbane,
QLD 4072, Australia.
The 3' untranslated regions (3'UTRs) of eukaryotic genes regulate mRNA
stability, localization and translation. Here, we present evidence that large
numbers of 3'UTRs in human, mouse and fly are also expressed separately from the
associated protein-coding sequences to which they are normally linked, likely by
post-transcriptional cleavage. Analysis of CAGE (capped analysis of gene
expression), SAGE (serial analysis of gene expression) and cDNA libraries, as
well as microarray expression profiles, demonstrate that the independent
expression of 3'UTRs is a regulated and conserved genome-wide phenomenon. We
characterize the expression of several 3'UTR-derived RNAs (uaRNAs) in detail in
mouse embryos, showing by in situ hybridization that these transcripts are
expressed in a cell- and subcellular-specific manner. Our results suggest that
3'UTR sequences can function not only in cis to regulate protein expression, but
also intrinsically and independently in trans, likely as noncoding RNAs, a
conclusion supported by a number of previous genetic studies. Our findings
suggest novel functions for 3'UTRs, as well as caution in the use of 3'UTR
sequence probes to analyze gene expression.
DOI: 10.1093/nar/gkq1158
PMCID: PMC3064787
PMID: 21075793 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19880380 | 1. Nucleic Acids Res. 2010 Jan;38(Database issue):D75-80. doi:
10.1093/nar/gkp902. Epub 2009 Oct 30.
UTRdb and UTRsite (RELEASE 2010): a collection of sequences and regulatory
motifs of the untranslated regions of eukaryotic mRNAs.
Grillo G(1), Turi A, Licciulli F, Mignone F, Liuni S, Banfi S, Gennarino VA,
Horner DS, Pavesi G, Picardi E, Pesole G.
Author information:
(1)Istituto Tecnologie Biomediche del Consiglio Nazionale delle Ricerche, via
Amendola 122/D, 70126 Bari, Italy.
The 5' and 3' untranslated regions of eukaryotic mRNAs (UTRs) play crucial roles
in the post-transcriptional regulation of gene expression through the modulation
of nucleo-cytoplasmic mRNA transport, translation efficiency, subcellular
localization and message stability. UTRdb is a curated database of 5' and 3'
untranslated sequences of eukaryotic mRNAs, derived from several sources of
primary data. Experimentally validated functional motifs are annotated and also
collated as the UTRsite database where more specific information on the
functional motifs and cross-links to interacting regulatory protein are
provided. In the current update, the UTR entries have been organized in a
gene-centric structure to better visualize and retrieve 5' and 3'UTR variants
generated by alternative initiation and termination of transcription and
alternative splicing. Experimentally validated miRNA targets and conserved
sequence elements are also annotated. The integration of UTRdb with genomic data
has allowed the implementation of an efficient annotation system and a powerful
retrieval resource for the selection and extraction of specific UTR subsets. All
internet resources implemented for retrieval and functional analysis of 5' and
3' untranslated regions of eukaryotic mRNAs are accessible at
http://utrdb.ba.itb.cnr.it/.
DOI: 10.1093/nar/gkp902
PMCID: PMC2808995
PMID: 19880380 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15608165 | 1. Nucleic Acids Res. 2005 Jan 1;33(Database issue):D141-6. doi:
10.1093/nar/gki021.
UTRdb and UTRsite: a collection of sequences and regulatory motifs of the
untranslated regions of eukaryotic mRNAs.
Mignone F(1), Grillo G, Licciulli F, Iacono M, Liuni S, Kersey PJ, Duarte J,
Saccone C, Pesole G.
Author information:
(1)Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano,
via Celoria 26, 20133 Milano, Italy.
The 5' and 3' untranslated regions of eukaryotic mRNAs play crucial roles in the
post-transcriptional regulation of gene expression through the modulation of
nucleo-cytoplasmic mRNA transport, translation efficiency, subcellular
localization and message stability. UTRdb is a curated database of 5' and 3'
untranslated sequences of eukaryotic mRNAs, derived from several sources of
primary data. Experimentally validated functional motifs are annotated (and also
collated as the UTRsite database) and cross-links to genomic and protein data
are provided. The integration of UTRdb with genomic and protein data has allowed
the implementation of a powerful retrieval resource for the selection and
extraction of UTR subsets based on their genomic coordinates and/or features of
the protein encoded by the relevant mRNA (e.g. GO term, PFAM domain, etc.). All
internet resources implemented for retrieval and functional analysis of 5' and
3' untranslated regions of eukaryotic mRNAs are accessible at
http://www.ba.itb.cnr.it/UTR/.
DOI: 10.1093/nar/gki021
PMCID: PMC539975
PMID: 15608165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36399486 | 1. Nucleic Acids Res. 2023 Jan 6;51(D1):D337-D344. doi: 10.1093/nar/gkac1016.
UTRdb 2.0: a comprehensive, expert curated catalog of eukaryotic mRNAs
untranslated regions.
Lo Giudice C(1), Zambelli F(2)(3), Chiara M(2)(3), Pavesi G(2)(3), Tangaro
MA(3), Picardi E(1)(3), Pesole G(1)(3).
Author information:
(1)Department of Biosciences, Biotechnology and Environment, University of Bari
A. Moro, 70126 Bari, Italy.
(2)Department of Biosciences, University of Milan, 20133 Milan, Italy.
(3)Institute of Biomembranes, Bioenergetics and Molecular Biotechnology,
Consiglio Nazionale delle Ricerche, 70126 Bari, Italy.
The 5' and 3' untranslated regions of eukaryotic mRNAs (UTRs) play crucial roles
in the post-transcriptional regulation of gene expression through the modulation
of nucleo-cytoplasmic mRNA transport, translation efficiency, subcellular
localization, and message stability. Since 1996, we have developed and
maintained UTRdb, a specialized database of UTR sequences. Here we present UTRdb
2.0, a major update of UTRdb featuring an extensive collection of eukaryotic 5'
and 3' UTR sequences, including over 26 million entries from over 6 million
genes and 573 species, enriched with a curated set of functional annotations.
Annotations include CAGE tags and polyA signals to label the completeness of 5'
and 3'UTRs, respectively. In addition, uORFs and IRES are annotated in 5'UTRs as
well as experimentally validated miRNA targets in 3'UTRs. Further annotations
include evolutionarily conserved blocks, Rfam motifs, ADAR-mediated RNA editing
events, and m6A modifications. A web interface allowing a flexible selection and
retrieval of specific subsets of UTRs, selected according to a combination of
criteria, has been implemented which also provides comprehensive download
facilities. UTRdb 2.0 is accessible at http://utrdb.cloud.ba.infn.it/utrdb/.
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkac1016
PMCID: PMC9825521
PMID: 36399486 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20037631 | 1. PLoS One. 2009 Dec 23;4(12):e8419. doi: 10.1371/journal.pone.0008419.
Reprogramming of 3' untranslated regions of mRNAs by alternative polyadenylation
in generation of pluripotent stem cells from different cell types.
Ji Z(1), Tian B.
Author information:
(1)Department of Biochemistry and Molecular Biology, Graduate School of
Biomedical Sciences and New Jersey Medical School, University of Medicine and
Dentistry of New Jersey, Newark, New Jersey, USA.
BACKGROUND: The 3' untranslated regions (3'UTRs) of mRNAs contain cis elements
involved in post-transcriptional regulation of gene expression. Over half of all
mammalian genes contain multiple polyadenylation sites that lead to different
3'UTRs for a gene. Studies have shown that the alternative polyadenylation (APA)
pattern varies across tissues, and is dynamically regulated in proliferating or
differentiating cells. Generation of induced pluripotent stem (iPS) cells, in
which differentiated cells are reprogrammed to an embryonic stem (ES) cell-like
state, has been intensively studied in recent years. However, it is not known
how 3'UTRs are regulated during cell reprogramming.
METHODS/MAIN FINDINGS: Using a computational method that robustly examines APA
across DNA microarray data sets, we analyzed 3'UTR dynamics in generation of iPS
cells from different cell types. We found that 3'UTRs shorten during
reprogramming of somatic cells, the extent of which depends on the type of
source cell. By contrast, reprogramming of spermatogonial cells involves 3'UTR
lengthening. The alternative polyadenylation sites that are highly responsive to
change of cell state in generation of iPS cells are also highly regulated during
embryonic development in opposite directions. Compared with other sites, they
are more conserved, can lead to longer alternative 3'UTRs, and are associated
with more cis elements for polyadenylation. Consistently, reprogramming of
somatic cells and germ cells involves significant upregulation and
downregulation, respectively, of mRNAs encoding polyadenylation factors, and RNA
processing is one of the most significantly regulated biological processes
during cell reprogramming. Furthermore, genes containing target sites of ES
cell-specific microRNAs (miRNAs) in different portions of 3'UTR are
distinctively regulated during cell reprogramming, suggesting impact of APA on
miRNA targeting.
CONCLUSIONS/SIGNIFICANCE: Taken together, these findings indicate that
reprogramming of 3'UTRs by APA, which result from regulation of both general
polyadenylation activity and cell type-specific factors and can reset
post-transcriptional gene regulatory programs in the cell, is an integral part
of iPS cell generation, and the APA pattern can be a good biomarker for cell
type and state, useful for sample classification. The results also suggest that
perturbation of the mRNA polyadenylation machinery or RNA processing activity
may facilitate generation of iPS cells.
DOI: 10.1371/journal.pone.0008419
PMCID: PMC2791866
PMID: 20037631 [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/24067953 | 1. J Virol. 2013 Dec;87(23):12838-49. doi: 10.1128/JVI.02374-13. Epub 2013 Sep
25.
Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3'
UTRs identify differential posttranscriptional control of gene expression in
lytic versus latent infection.
McClure LV(1), Kincaid RP, Burke JM, Grundhoff A, Sullivan CS.
Author information:
(1)Department of Molecular Genetics and Microbiology, University of Texas,
Austin, Texas, USA.
3' untranslated regions (UTRs) are known to play an important role in
posttranscriptional regulation of gene expression. Here we map the 3' UTRs of
Kaposi's sarcoma-associated herpesvirus (KSHV) using next-generation RNA
sequencing, 3' rapid amplification of cDNA ends (RACE), and tiled microarray
analyses. Chimeric reporters containing the KSHV 3' UTRs show a general trend
toward reduced gene expression under conditions of latent infection. Those 3'
UTRs with a higher GC content are more likely to be associated with reduced gene
expression. KSHV transcripts display an extensive use of shared polyadenylation
sites allowing for partially overlapping 3' UTRs and regulatory activities. In
addition, a subset of KSHV 3' UTRs is sufficient to convey increased gene
expression under conditions of lytic infection. These results suggest a role for
viral 3' UTRs in contributing to differential gene expression during latent
versus lytic infection.
DOI: 10.1128/JVI.02374-13
PMCID: PMC3838127
PMID: 24067953 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7662369 | 1. Curr Opin Cell Biol. 1995 Jun;7(3):386-92. doi: 10.1016/0955-0674(95)80094-8.
Diversity of cytoplasmic functions for the 3' untranslated region of eukaryotic
transcripts.
Decker CJ(1), Parker R.
Author information:
(1)Department of Molecular and Cellular Biology, University of Arizona, Tucson
85721, USA.
The 3' untranslated region (3' UTR) can control gene expression by affecting the
localization, stability and translation of mRNAs. The recent finding that 3'
UTRs can control the decapping rate of mRNAs, in combination with their ability
to influence the initiation of translation, suggests that 3' UTRs act through a
direct or indirect interaction between the 3' and 5' ends of mRNAs.
DOI: 10.1016/0955-0674(95)80094-8
PMID: 7662369 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10977083 | 1. Proc Int Conf Intell Syst Mol Biol. 2000;8:218-27.
UTR reconstruction and analysis using genomically aligned EST sequences.
Kan Z(1), Gish W, Rouchka E, Glasscock J, States D.
Author information:
(1)Institute for Biomedical Computing, Washington University, St. Louis, MO
63110, USA. zkan@ibc.wustl.edu
Untranslated regions (UTR) play important roles in the posttranscriptional
regulation of mRNA processing. There is a wealth of UTR-related information to
be mined from the rapidly accumulating EST collections. A computational tool,
UTR-extender, has been developed to infer UTR sequences from genomically aligned
ESTs. It can completely and accurately reconstruct 72% of the 3' UTRs and 15% of
the 5' UTRs when tested using 908 functionally cloned transcripts. In addition,
it predicts extensions for 11% of the 5' UTRs and 28% of the 3' UTRs. These
extension regions are validated by examining splicing frequencies and
conservation levels. We also developed a method called polyadenylation site scan
(PASS) to precisely map polyadenylation sites in human genomic sequences. A PASS
analysis of 908 genic regions estimates that 40-50% of human genes undergo
alternative polyadenylation. Using EST redundancy to assess expression levels,
we also find that genes with short 3' UTRs tend to be highly expressed.
PMID: 10977083 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22846368 | 1. Gene. 2012 Oct 10;507(2):106-11. doi: 10.1016/j.gene.2012.07.034. Epub 2012
Jul 27.
Characterization and evolution of 5' and 3' untranslated regions in eukaryotes.
Liu H(1), Yin J, Xiao M, Gao C, Mason AS, Zhao Z, Liu Y, Li J, Fu D.
Author information:
(1)Engineering Research Center of South Upland Agriculture of Ministry of
Education, PR China, College of Agronomy and Biotechnology, Southwest
University, Chongqing, China.
Untranslated regions (UTRs) in eukaryotes play a significant role in the
regulation of translation and mRNA half-life, as well as interacting with
specific RNA-binding proteins. However, UTRs receive less attention than more
crucial elements such as genes, and the basic structural and evolutionary
characteristics of UTRs of different species, and the relationship between these
UTRs and the genome size and species gene number is not well understood. To
address these questions, we performed a comparative analysis of 5' and 3'
untranslated regions of different species by analyzing the basic characteristics
of 244,976 UTRs from three eukaryote kingdoms (Plantae, Fungi, and Protista).
The results showed that the UTR lengths and SSR frequencies in UTRs increased
significantly with increasing species gene number while the length and G+C
content in 5' UTRs and different types of repetitive sequences in 3' UTRs
increased with the increase of genome size. We also found that the sequence
length of 5' UTRs was significantly positively correlated with the presence of
transposons and SSRs while the sequence length of 3' UTRs was significantly
positively correlated with the presence of tandem repeat sequences. These
results suggested that evolution of species complexity from lower organisms to
higher organisms is accompanied by an increase in the regulatory complexity of
UTRs, mediated by increasing UTR length, increasing G+C content of 5' UTRs, and
insertion and expansion of repetitive sequences.
Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2012.07.034
PMID: 22846368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28229978 | 1. J Biosci. 2017 Mar;42(1):189-207. doi: 10.1007/s12038-016-9660-7.
Untranslated regions of mRNA and their role in regulation of gene expression in
protozoan parasites.
Rao SJ(1), Chatterjee S, Pal JK.
Author information:
(1)Cell and Molecular Biology Laboratory, Department of Biotechnology,
Savitribai Phule Pune University, Pune 411 007, India.
Protozoan parasites are one of the oldest living entities in this world that
throughout their existence have shown excellent resilience to the odds of
survival and have adapted beautifully to ever changing rigors of the
environment. In view of the dynamic environment encountered by them throughout
their life cycle, and in establishing pathogenesis, it is unsurprising that
modulation of gene expression plays a fundamental role in their survival. In
higher eukaryotes, untranslated regions (UTRs) of transcripts are one of the
crucial regulators of gene expression (influencing mRNA stability and
translation efficiency). Parasitic protozoan genome studies have led to the
characterization (in silico, in vitro and in vivo) of a large number of their
genes. Comparison of higher eukaryotic UTRs with parasitic protozoan UTRs
reveals the existence of several similar and dissimilar facets of the UTRs. This
review focuses on the elements of UTRs of medically important protozoan
parasites and their regulatory role in gene expression. Such information may be
useful to researchers in designing gene targeting strategies linked with
perturbation of host-parasite relationships leading to control of specific
parasites.
DOI: 10.1007/s12038-016-9660-7
PMID: 28229978 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20720301 | 1. J Appl Genet. 2010;51(3):275-81. doi: 10.1007/BF03208856.
Use of chromosome walking in discovery of single-nucleotide polymorphism in
noncoding regions of a candidate actin gene in Pinus radiata.
Li W(1), Li H, Wu H, Chen XY.
Author information:
(1)Key Laboratory for Genetics and Breeding of Forest Trees and Ornamental
Plants, Ministry of Education, National Engineering Laboratory for Forest Tree
Breeding, Beijing Forestry University, Beijing, China.
Untranslated regions (UTRs) of eukaryotic mRNAs play crucial roles in
post-transcriptional regulation of gene expression via the modulation of
nucleocytoplasmic mRNA transport, translation efficiency, subcellular
localization, and message stability. Single-nucleotide polymorphisms (SNPs) in
UTRs of a candidate gene may also change the post-transcriptional regulation of
a gene or function by nucleotide mutation. For species that have not been
entirely sequenced genomically, new methods need to be devised to discover SNPs
in noncoding regions of candidate genes. In this study, based on the expressed
sequence tag (EST) of Pinus radiata (Monterey pine), we obtained all the
sequences of UTRs of the actin gene by using a chromosome walking method. We
also detected all the SNPs in and around the coding region of the actin gene. In
this way, the full genomic sequence (2154 bp) of the actin gene was identified,
including the 5’UTR, introns, the coding sequence, and the 3’UTR.
PCR amplification and DNA fragment sequencing from 200 unrelated P. radiata
trees revealed a total of 21 SNPs in the actin gene, of which 3 were located in
the 5’UTR, 3 in the introns, 10 in the coding sequence, and 5 in the
3’UTR. We show that chromosome walking can be used for obtaining the
sequence of UTRs, and then, based on this sequence, to discover SNPs in the
noncoding regions of candidate genes from this species without an entire genomic
sequence.
DOI: 10.1007/BF03208856
PMID: 20720301 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21543795 | 1. Proc Am Thorac Soc. 2011 May;8(2):163-6. doi: 10.1513/pats.201007-054MS.
Toward a systematic understanding of mRNA 3' untranslated regions.
Zhao W(1), Blagev D, Pollack JL, Erle DJ.
Author information:
(1)Department of Medicine, University of California, San Francisco, CA, USA.
Messenger RNAs (mRNAs) contain prominent untranslated regions (UTRs) that are
increasingly recognized to play roles in mRNA processing, transport, stability,
and translation. 3' UTRs are believed to harbor recognition sites for a diverse
set of RNA-binding proteins that regulate gene expression as well as most active
microRNA target sites. Although the roles of 3' UTRs in the normal and diseased
lung have not yet been studied extensively, available evidence suggests
important roles for 3' UTRs in lung development, inflammation, asthma, pulmonary
fibrosis, and cancer. Systematic, genome-wide approaches are beginning to
catalog functional elements within 3' UTRs and identify the proteins and
microRNAs that interact with these elements. Application of new data sets and
experimental approaches should provide powerful insights into how 3'
UTR-mediated regulatory events contribute to disease and may inspire novel
therapeutic approaches.
DOI: 10.1513/pats.201007-054MS
PMCID: PMC3131834
PMID: 21543795 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36375644 | 1. Metabolism. 2023 Jan;138:155344. doi: 10.1016/j.metabol.2022.155344. Epub 2022
Nov 12.
Isoform changes of action potential regulators in the ventricles of
arrhythmogenic phospholamban-R14del humanized mouse hearts.
Rogalska ME(1), Vafiadaki E(2), Erpapazoglou Z(3), Haghighi K(4), Green L(5),
Mantzoros CS(6), Hajjar RJ(7), Tranter M(5), Karakikes I(8), Kranias EG(4),
Stillitano F(9), Kafasla P(3), Sanoudou D(10).
Author information:
(1)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and
Technology, Barcelona 08003, Spain.
(2)Molecular Biology Division, Biomedical Research Foundation of the Academy of
Athens, 11527 Athens, Greece.
(3)Institute for Fundamental Biomedical Research, B.S.R.C. "Alexander Fleming",
16672 Athens, Greece.
(4)Department of Pharmacology and Systems Physiology, University of Cincinnati
College of Medicine, Cincinnati, OH 45267, USA.
(5)Department of Medicine, University of Cincinnati College of Medicine,
Cincinnati, OH 45267, USA.
(6)Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of
Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA
02215, USA.
(7)Flagship Pioneering, Cambridge, MA 02142, USA.
(8)Department of Cardiothoracic Surgery and Cardiovascular Institute, Stanford
University School of Medicine, 240 Pasteur Dr, Stanford, CA 94304, USA.
(9)Division Heart and Lung, Department of Cardiology, University Medical Center
Utrecht, 3584, CX, Utrecht, the Netherlands.
(10)Molecular Biology Division, Biomedical Research Foundation of the Academy of
Athens, 11527 Athens, Greece; Clinical Genomics and Pharmacogenomics Unit, 4(th)
Department of Internal Medicine, Attikon Hospital, Medical School, National and
Kapodistrian University of Athens, 11527 Athens, Greece; Center for New
Biotechnologies and Precision Medicine, Medical School, National and
Kapodistrian University of Athens, 11527 Athens, Greece. Electronic address:
dsanoudou@med.uoa.gr.
Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening
ventricular arrhythmias and sudden cardiac death and affects hundreds of
thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the
phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is
a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac
contractility. Despite global gene and protein expression studies, the molecular
mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized
PLN-R14del mouse model and human induced pluripotent stem cell derived
cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing
changes associated with the R14del mutation. We identified >200 significant
alternative splicing (AS) events and distinct AS profiles were observed in the
right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts.
Enrichment analysis of the AS events showed that the most affected biological
process was associated with "cardiac cell action potential", specifically in the
RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode
proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del
mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the
tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators
of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings
suggest that aberrant splicing may affect Ca2+-homeostasis in the heart,
contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.metabol.2022.155344
PMID: 36375644 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
have no conflicts of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/34287278 | 1. Curr Issues Mol Biol. 2021 Jul 6;43(2):605-617. doi: 10.3390/cimb43020044.
Evaluating the Effect of 3'-UTR Variants in DICER1 and DROSHA on Their
Tissue-Specific Expression by miRNA Target Prediction.
Bug DS(1), Tishkov AV(1), Moiseev IS(2), Petukhova NV(1).
Author information:
(1)Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State
University, 197022 St. Petersburg, Russia.
(2)R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and
Transplantation, Pavlov First Saint Petersburg State Medical University, 197022
St. Petersburg, Russia.
Untranslated gene regions (UTRs) play an important role in controlling gene
expression. 3'-UTRs are primarily targeted by microRNA (miRNA) molecules that
form complex gene regulatory networks. Cancer genomes are replete with
non-coding mutations, many of which are connected to changes in tumor gene
expression that accompany the development of cancer and are associated with
resistance to therapy. Therefore, variants that occurred in 3'-UTR under cancer
progression should be analysed to predict their phenotypic effect on gene
expression, e.g., by evaluating their impact on miRNA target sites. Here, we
analyze 3'-UTR variants in DICER1 and DROSHA genes in the context of
myelodysplastic syndrome (MDS) development. The key features of this analysis
include an assessment of both "canonical" and "non-canonical" types of
mRNA-miRNA binding and tissue-specific profiling of miRNA interactions with
wild-type and mutated genes. As a result, we obtained a list of DICER1 and
DROSHA variants likely altering the miRNA sites and, therefore, potentially
leading to the observed tissue-specific gene downregulation. All identified
variants have low population frequency consistent with their potential
association with pathology progression.
DOI: 10.3390/cimb43020044
PMCID: PMC8929110
PMID: 34287278 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29848076 | 1. Expert Opin Investig Drugs. 2018 Jun;27(6):523-533. doi:
10.1080/13543784.2018.1483334. Epub 2018 Jun 18.
The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.
Khoury R(1), Grysman N(1), Gold J(1), Patel K(1), Grossberg GT(1).
Author information:
(1)a Department of Psychiatry and Behavioral Neuroscience , Saint Louis
University School of Medicine , St. Louis , MO , USA.
INTRODUCTION: Despite recent advances in Alzheimer's disease (AD) research, no
breakthrough treatments have been discovered. Cholinesterase inhibitors and the
NMDA-receptor antagonist memantine are currently the two approved symptomatic
treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising
treatment strategy to improve cognition in AD, with a modest side-effect
profile.
AREAS COVERED: 5-HT6 receptors, exclusively found in the central nervous system,
modulate primarily GABA and glutamate levels, facilitating the secondary release
of other neurotransmitters including dopamine, noradrenaline, and acetylcholine,
all of which are compromised in AD. This review discusses findings of
preclinical and phase I-III clinical trials conducted with three major 5-HT6
receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of
AD.
EXPERT OPINION: Despite early positive findings, larger phase-III trials have
failed to demonstrate any statistically significant impact on cognition for both
idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors.
Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive
enhancing properties. Thus, a better understanding of the mechanism of action of
the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor
partial or inverse agonists may be promising in future AD trials.
DOI: 10.1080/13543784.2018.1483334
PMID: 29848076 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28867199 | 1. Semin Cell Dev Biol. 2018 Mar;75:61-69. doi: 10.1016/j.semcdb.2017.08.056.
Epub 2017 Sep 1.
Alternative polyadenylation in the regulation and dysregulation of gene
expression.
Turner RE(1), Pattison AD(1), Beilharz TH(2).
Author information:
(1)Development and stem cells Program, Monash Biomedicine Discovery Institute
and Department of Biochemistry and Molecular Biology, Monash University,
Melbourne, Victoria, 3800, Australia.
(2)Development and stem cells Program, Monash Biomedicine Discovery Institute
and Department of Biochemistry and Molecular Biology, Monash University,
Melbourne, Victoria, 3800, Australia. Electronic address:
traude.beilharz@monash.edu.
Transcriptional control shapes a cell's transcriptome composition, but it is RNA
processing that refines its expression. The untranslated regions (UTRs) of mRNA
are hotspots for regulatory control. Features in these can impact mRNA
stability, localisation and translation. Here we describe how alternative
cleavage and polyadenylation can change mRNA fate by changing the length of its
3'UTR.
Copyright © 2017 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2017.08.056
PMID: 28867199 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22614827 | 1. RNA Biol. 2012 May;9(5):563-76. doi: 10.4161/rna.20231. Epub 2012 May 1.
The role of the 3' untranslated region in post-transcriptional regulation of
protein expression in mammalian cells.
Matoulkova E(1), Michalova E, Vojtesek B, Hrstka R.
Author information:
(1)MMCI, RECAMO, Brno, Czech Republic.
The untranslated regions (UTRs) at the 3'end of mRNA transcripts contain
important sequences that influence the fate of mRNA and thus proteosynthesis. In
this review, we summarize the information known to date about 3'end processing,
sequence characteristics including related binding proteins and the role of
3'UTRs in several selected signaling pathways to delineate their importance in
the regulatory processes in mammalian cells. In addition to reviewing recent
advances in the more well known aspects, such as cleavage and polyadenylation
processes that influence mRNA stability and location, we concentrate on some
newly emerging concepts of the role of the 3'UTR, including alternative
polyadenylation sites in relation to proliferation and differentiation and the
recognition of the multi-functional properties of non-coding RNAs, including
miRNAs that commonly target the 3'UTR. The emerging picture is of a highly
complex set of regulatory systems that include autoregulation, cooperativity and
competition to fine tune proteosynthesis in context-dependent manners.
DOI: 10.4161/rna.20231
PMID: 22614827 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33928570 | 1. Methods Mol Biol. 2021;2282:57-75. doi: 10.1007/978-1-0716-1298-9_5.
Development of siRNA Therapeutics for the Treatment of Liver Diseases.
Holm A(1), Løvendorf MB(1), Kauppinen S(2).
Author information:
(1)Center for RNA Medicine, Department of Clinical Medicine, Aalborg University,
Copenhagen, Denmark.
(2)Center for RNA Medicine, Department of Clinical Medicine, Aalborg University,
Copenhagen, Denmark. ska@dcm.aau.dk.
Small interfering RNA (siRNA)-based therapeutics holds the promise to treat a
wide range of human diseases that are currently incurable using conventional
therapies. Most siRNA therapeutic efforts to date have focused on the treatment
of liver diseases due to major breakthroughs in the development of efficient
strategies for delivering siRNA drugs to the liver. Indeed, the development of
lipid nanoparticle-formulated and GalNAc-conjugated siRNA therapeutics has
resulted in recent FDA approvals of the first siRNA-based drugs, patisiran for
the treatment of hereditary transthyretin amyloidosis and givosiran for the
treatment of acute hepatic porphyria, respectively. Here, we describe the
current strategies for delivering siRNA drugs to the liver and summarize recent
advances in clinical development of siRNA therapeutics for the treatment of
liver diseases.
DOI: 10.1007/978-1-0716-1298-9_5
PMID: 33928570 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34095437 | 1. Alzheimers Dement (N Y). 2021 May 31;7(1):e12136. doi: 10.1002/trc2.12136.
eCollection 2021.
Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's
disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).
Lang FM(1)(2)(3), Mo Y(1), Sabbagh M(4), Solomon P(5), Boada M(6)(7), Jones
RW(8), Frisoni GB(9), Grimmer T(10), Dubois B(11), Harnett M(1), Friedhoff
SR(1)(2), Coslett S(1), Cummings JL(12).
Author information:
(1)Axovant Sciences New York New York USA.
(2)Roivant Sciences New York New York USA.
(3)Columbia University Vagelos College of Physicians & Surgeons New York New
York USA.
(4)Cleveland Clinic Lou Ruvo Center for Brain Health Las Vegas Nevada USA.
(5)Boston Center for Memory and Boston University Alzheimer's Disease Center
Boston Massachusetts USA.
(6)Research Center and Memory Clinic, Fundaciό ACE, Institut Català de
Neurociències Aplicades Universitat Internacional de Catalunya Barcelona Spain.
(7)Instituto de Salud Carlos III Networking Research Center on Neurodegenerative
Diseases (CIBERNED) Madrid Spain.
(8)RICE (The Research Institute for the Care of Older People) Bath UK.
(9)Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Istituto
Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Memory Clinic and
LANVIE - Laboratory of Neuroimaging of Aging University Hospitals and University
of Geneva Geneva Switzerland.
(10)School of Medicine, Klinikum rechts der Isar Technical University of Munich
Munich Germany.
(11)Department of Neurology and Institute for Alzheimer's Disease (IM2A),
Salpêtrière Hospital AP-HP, Sorbonne Université Paris France.
(12)Chambers-Grundy Center for Transformative Neuroscience Department of Brain
Health, School of Integrated Health Sciences University of Nevada Las Vegas
(UNLV) Las Vegas Nevada USA.
INTRODUCTION: A previous phase 2b study supported the use of the 5-HT6 receptor
antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's
disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this
hypothesis.
METHODS: MINDSET was a global, double-blind, randomized, placebo-controlled
trial in 1315 mild-to-moderate AD dementia patients on stable donepezil.
Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary
endpoints were change from baseline to week 24 on the Alzheimer's Disease
Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease
Cooperative Study-Activities of Daily Living (ADCS-ADL).
RESULTS: There were no statistically significant differences between intepirdine
and placebo groups (adjusted mean [95% confidence interval]) on the co-primary
endpoints ADAS-Cog (-0.36 [-0.95, 0.22], P = 0.2249) and ADCS-ADL (-0.09 [-0.90,
0.72], P = 0.8260). Intepirdine demonstrated a favorable safety profile similar
to placebo.
DISCUSSION: Intepirdine as adjunctive therapy to donepezil did not produce
statistical improvement over placebo on cognition or activities of daily living
in mild-to-moderate AD dementia patients.
© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical
Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's
Association.
DOI: 10.1002/trc2.12136
PMCID: PMC8165732
PMID: 34095437
Conflict of interest statement: Frederick M. Lang is a paid consultant and
former full‐time member of Axovant Sciences (Axovant) and is an employee and
shareholder of Roivant Sciences (Roivant). Shari Coslett is a former employee
and shareholder of Axovant. Sarah R. Friedhoff is a former employee of Axovant
and Roivant. Yi Mo is a former employee of Axovant. Mark Harnett was a former
paid consultant of Axovant and is a current paid consultant of Roivant. Jeffrey
L. Cummings has provided consultation to Acadia, Actinogen, Alkahest, Allergan,
Alzheon, Annovis, Avanir, Axsome, BiOasis, Biogen, Bracket, Cassava, Cerecin,
Cortexyme, Diadem, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green
Valley, GemVax, Grifols, Hisun, Merck, Otsuka, Resverlogix, Roche, Samumed,
Samus, Takeda, Third Rock, and United Neuroscience pharmaceutical and assessment
companies. Jeffrey L. Cummings has stock options in Prana, Neurokos, ADAMAS,
MedAvante, QR pharma, BiOasis. Jeffrey L. Cummings owns the copyright of the
Neuropsychiatric Inventory. Jeffrey L. Cummings is supported by KMA; NIGMS grant
P20GM109025; NINDS grant U01NS093334; and NIA grant R01AG053798. Timo Grimmer
certifies that there is no actual or potential conflict of interest in relation
to this article. Outside the submitted work, Timo Grimmer reported having
received consulting fees from Actelion, Biogen, Eli Lilly, Iqvia/Quintiles, MSD,
Novartis, Quintiles, Roche Pharma; lecture fees from Biogen, Lilly, Parexel,
Roche Pharma; and grants to his institution from Actelion and PreDemTech. Bruno
Dubois received fees for his participation in the scientific advisory board of
the study. The institutions of Paul Solomon, Merce Boada, Roy W. Jones, Giovanni
B. Frisoni, Timo Grimmer, and Bruno Dubois received funding for the conduct of
the study. |
http://www.ncbi.nlm.nih.gov/pubmed/35997897 | 1. BioDrugs. 2022 Sep;36(5):549-571. doi: 10.1007/s40259-022-00549-3. Epub 2022
Aug 23.
Therapeutic siRNA: State-of-the-Art and Future Perspectives.
Friedrich M(1)(2), Aigner A(3).
Author information:
(1)Faculty of Leipzig, Institute of Clinical Immunology,
Max-Bürger-Forschungszentrum (MBFZ), University of Leipzig, Leipzig, Germany.
(2)Department of Vaccines and Infection Models, Fraunhofer Institute for Cell
Therapy and Immunology IZI, Leipzig, Germany.
(3)Rudolf-Boehm Institute for Pharmacology and Toxicology, Clinical
Pharmacology, University of Leipzig, Haertelstrasse 16-18, 04107, Leipzig,
Germany. achim.aigner@medizin.uni-leipzig.de.
The highly specific induction of RNA interference-mediated gene knockdown, based
on the direct application of small interfering RNAs (siRNAs), opens novel
avenues towards innovative therapies. Two decades after the discovery of the RNA
interference mechanism, the first siRNA drugs received approval for clinical use
by the US Food and Drug Administration and the European Medicines Agency between
2018 and 2022. These are mainly based on an siRNA conjugation with a targeting
moiety for liver hepatocytes, N-acetylgalactosamine, and cover the treatment of
acute hepatic porphyria, transthyretin-mediated amyloidosis,
hypercholesterolemia, and primary hyperoxaluria type 1. Still, the development
of siRNA therapeutics faces several challenges and issues, including the
definition of optimal siRNAs in terms of target, sequence, and chemical
modifications, siRNA delivery to its intended site of action, and the absence of
unspecific off-target effects. Further siRNA drugs are in clinical studies,
based on different delivery systems and covering a wide range of different
pathologies including metabolic diseases, hematology, infectious diseases,
oncology, ocular diseases, and others. This article reviews the knowledge on
siRNA design and chemical modification, as well as issues related to siRNA
delivery that may be addressed using different delivery systems. Details on the
mode of action and clinical status of the various siRNA therapeutics are
provided, before giving an outlook on issues regarding the future of siRNA drugs
and on their potential as one emerging standard modality in pharmacotherapy.
Notably, this may also cover otherwise un-druggable diseases, the definition of
non-coding RNAs as targets, and novel concepts of personalized and combination
treatment regimens.
© 2022. The Author(s).
DOI: 10.1007/s40259-022-00549-3
PMCID: PMC9396607
PMID: 35997897 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interest to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/35819583 | 1. Pharm Res. 2022 Aug;39(8):1749-1759. doi: 10.1007/s11095-022-03333-8. Epub
2022 Jul 12.
Pharmacokinetic and Pharmacodynamic Modeling of siRNA Therapeutics - a
Minireview.
Jeon JY(1), Ayyar VS(1), Mitra A(2)(3).
Author information:
(1)Clinical Pharmacology and Pharmacometrics, Janssen Research & Development
LLC, Spring House, PA, USA.
(2)Clinical Pharmacology and Pharmacometrics, Janssen Research & Development
LLC, Spring House, PA, USA. amitra@kuraoncology.com.
(3)Clinical Pharmacology, Kura Oncology, San Diego, CA, USA.
amitra@kuraoncology.com.
The approval of four small interfering RNA (siRNA) products in the past few
years has demonstrated unequivocally the therapeutic potential of this novel
modality. Three such products (givosiran, lumasiran and inclisiran) are
liver-targeted, using tris N-acetylgalactosamine (GalNAc)3 as the targeting
ligand. Upon subcutaneous administration, GalNAc-conjugated siRNAs rapidly
distribute into the liver via asialoglycoprotein receptor (ASGPR) mediated
uptake in the hepatocytes, resulting in fast elimination from the systemic
circulation. Patisiran, on the other hand, has been formulated in a lipid
nanoparticle for optimal delivery to the liver. While several publications have
described preclinical and clinical pharmacokinetic (PK) and pharmacodynamic (PD)
results, including absorption, distribution, metabolism, and elimination (ADME)
profiles in selected species as well as limited modeling efforts for siRNA
therapeutics, there is no systematic review of the PK and PD models developed
for these agents or work summarizing the utility and application(s) of such
models in drug development and regulatory review. Here, we provide a mini-review
of the current state of modeling efforts for siRNA therapeutics within the early
preclinical, translational, and clinical stages of siRNA development. Diverse
modeling methods including simple compartmental, mechanistic and systems PK/PD,
physiologically-based PK (PBPK), population PK/PD, and dose-response-time models
are introduced and reviewed. The utility of such models in development and
regulatory review for siRNA therapeutics is also discussed with examples.
Finally, the current knowledge gaps in mechanism of action of siRNA and
resulting challenges in model development are summarized. The goal of this
minireview is to trigger cross-functional discussion amongst all key
stakeholders to generate key experimental datasets and align on current
assumptions, model structures, and approaches to facilitate development and
application of robust PK/PD models for siRNA therapeutics.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s11095-022-03333-8
PMID: 35819583 [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/26907624 | 1. J Pharmacol Exp Ther. 2016 May;357(2):320-30. doi: 10.1124/jpet.115.230300.
Epub 2016 Feb 23.
Comparative Characterization of Hepatic Distribution and mRNA Reduction of
Antisense Oligonucleotides Conjugated with Triantennary N-Acetyl Galactosamine
and Lipophilic Ligands Targeting Apolipoprotein B.
Watanabe A(1), Nakajima M(2), Kasuya T(2), Onishi R(2), Kitade N(2), Mayumi
K(2), Ikehara T(2), Kugimiya A(2).
Author information:
(1)Physicochemical and Preformulation (A.W.), Bioanalysis (R.O.), and Drug
Metabolism and Pharmacokinetics (N.K., K.M.), Research Laboratory for
Development, Exploratory Chemistry (M.N.) and Biotechnology-Based Medicine
(T.K., T.I, A.K.), Discovery Research Laboratory for Innovative Frontier
Medicines, Shionogi & Co., Ltd., Osaka, Japan ayahisa.watanabe@shionogi.co.jp.
(2)Physicochemical and Preformulation (A.W.), Bioanalysis (R.O.), and Drug
Metabolism and Pharmacokinetics (N.K., K.M.), Research Laboratory for
Development, Exploratory Chemistry (M.N.) and Biotechnology-Based Medicine
(T.K., T.I, A.K.), Discovery Research Laboratory for Innovative Frontier
Medicines, Shionogi & Co., Ltd., Osaka, Japan.
TriantennaryN-acetyl galactosamine (GalNAc, GN3) and lipophilic ligands such as
cholesterol andα-tocopherol conjugations dramatically improve the distribution
and efficacy of second-generation antisense oligonucleotides (ASOs) in the whole
liver. To characterize ligands for delivery to liver cells based on
pharmacokinetics and efficacy, we used a locked nucleic acid gapmer of ASO
targeting apolipoprotein B as a model compound and evaluated the amount of ASO
and apolipoprotein B mRNA in the whole liver, hepatocytes, and nonparenchymal
(NP) cells as well as plasma total cholesterol after administration of ASO
conjugated with these ligands to mice. Compared with unconjugated ASO, GN3
conjugation increased the amount (7-fold) and efficacy (more than 10-fold) of
ASO in hepatocytes only and showed higher efficacy than the increased rate of
the amount of ASO. On the other hand, lipophilic ligand conjugations led to
increased delivery (3- to 5-fold) and efficacy (5-fold) of ASO to both
hepatocytes and NP cells. GN3 and lipophilic ligand conjugations increased the
area under the curve of ASOs and the pharmacodynamic duration but did not change
the half-life in hepatocytes and NP cells compared with unconjugated ASO. In the
liver, the phosphodiester bond between ASO and these ligands was promptly
cleaved to liberate unconjugated ASO. These ligand conjugations reduced plasma
total cholesterol compared with unconjugated ASO, although these ASOs were well
tolerated with no elevation in plasma transaminases. These findings could
facilitate ligand selection tailored to liver cells expressed in disease-related
genes and could contribute to the discovery and development of RNA
interference-based therapy.
Copyright © 2016 by The American Society for Pharmacology and Experimental
Therapeutics.
DOI: 10.1124/jpet.115.230300
PMID: 26907624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35251767 | 1. Mol Ther Nucleic Acids. 2022 Feb 10;27:1116-1126. doi:
10.1016/j.omtn.2022.02.004. eCollection 2022 Mar 8.
Engineering miRNA features into siRNAs: Guide-strand bulges are compatible with
gene repression.
Hauptmann J(1), Hehne V(1), Balzer M(1), Bethge L(1), Wikstrom Lindholm M(1).
Author information:
(1)Silence Therapeutics GmbH, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Synthetic siRNA guide strands are typically designed with perfect
complementarity to the passenger strand and the target mRNA. We examined whether
siRNAs with intentional guide-strand bulges are functional in vitro and in vivo.
Importantly, this was done by systematic shortening of the passenger strand,
evaluating identical 19-mer guide-strand sequences but forcing them into
conformations with 1- to 4-nt bulges after annealing. We demonstrate that
guide-strand bulges can be well tolerated at several positions of unmodified and
modified siRNAs. Beyond that, we show that GalNAc-conjugated siRNAs with bulges
at certain positions of the guide strand repress transthyretin in murine primary
hepatocytes and in vivo in mice. In vivo, a GalNAc-conjugated siRNA with a 1-nt
bulge at position 14 of the guide strand was as active as the perfectly
complementary siRNA. Finally, in a luciferase reporter system, mRNA target
sequences were systematically shortened so that RNA-induced silencing complex
activity could only occur with a guide-strand bulge. Here, luciferase reporters
were repressed when 1- and 2-nt deletions of the reporter were applied to the
edges of the sequence. We conclude that some guide-strand bulges versus target
transcript can result in target repression and therefore should be evaluated as
off-target risks.
© 2022 The Author(s).
DOI: 10.1016/j.omtn.2022.02.004
PMCID: PMC8881630
PMID: 35251767
Conflict of interest statement: All authors are employees of and have stock
options in Silence Therapeutics GmbH. |
http://www.ncbi.nlm.nih.gov/pubmed/24992960 | 1. Nucleic Acids Res. 2014 Jul;42(13):8796-807. doi: 10.1093/nar/gku531. Epub
2014 Jul 3.
Targeted delivery of antisense oligonucleotides to hepatocytes using
triantennary N-acetyl galactosamine improves potency 10-fold in mice.
Prakash TP(1), Graham MJ(1), Yu J(1), Carty R(1), Low A(1), Chappell A(1),
Schmidt K(1), Zhao C(1), Aghajan M(1), Murray HF(1), Riney S(1), Booten SL(1),
Murray SF(1), Gaus H(1), Crosby J(1), Lima WF(1), Guo S(1), Monia BP(1), Swayze
EE(1), Seth PP(2).
Author information:
(1)Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
(2)Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
pseth@isisph.com.
Triantennary N-acetyl galactosamine (GalNAc, GN3: ), a high-affinity ligand for
the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the
potency of second-generation gapmer antisense oligonucleotides (ASOs) 6-10-fold
in mouse liver. When combined with next-generation ASO designs comprised of
short S-cEt (S-2'-O-Et-2',4'-bridged nucleic acid) gapmer ASOs, ∼ 60-fold
enhancement in potency relative to the parent MOE (2'-O-methoxyethyl RNA) ASO
was observed. GN3: -conjugated ASOs showed high affinity for mouse ASGPR, which
results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells.
After internalization into cells, the GN3: -ASO conjugate is metabolized to
liberate the parent ASO in the liver. No metabolism of the GN3: -ASO conjugate
was detected in plasma suggesting that GN3: acts as a hepatocyte targeting
prodrug that is detached from the ASO by metabolism after internalization into
the liver. GalNAc conjugation also enhanced potency and duration of the effect
of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR)
in transgenic mice. The unconjugated ASOs are currently in late stage clinical
trials for the treatment of familial chylomicronemia and TTR-mediated
polyneuropathy. The ability to translate these observations in humans offers the
potential to improve therapeutic index, reduce cost of therapy and support a
monthly dosing schedule for therapeutic suppression of gene expression in the
liver using ASOs.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gku531
PMCID: PMC4117763
PMID: 24992960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30576769 | 1. Cell Mol Gastroenterol Hepatol. 2019;7(3):597-618. doi:
10.1016/j.jcmgh.2018.12.004. Epub 2018 Dec 19.
Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects
Mice Against Nonalcoholic Fatty Liver Disease.
Cansby E(1), Nuñez-Durán E(1), Magnusson E(1), Amrutkar M(2), Booten SL(3),
Kulkarni NM(1), Svensson LT(4), Borén J(5), Marschall HU(5), Aghajan M(3),
Mahlapuu M(6).
Author information:
(1)Lundberg Laboratory for Diabetes Research, Department of Molecular and
Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska
University Hospital, Gothenburg, Sweden.
(2)Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical
Medicine, University of Oslo, Oslo, Norway.
(3)Ionis Pharmaceuticals, Carlsbad, California.
(4)Department of Biology and Biological Engineering, National Bioinformatics
Infrastructure Sweden, Science for Life Laboratory, Chalmers University of
Technology, Gothenburg, Sweden.
(5)Wallenberg Laboratory, Department of Molecular and Clinical Medicine,
Institute of Medicine, University of Gothenburg, Sahlgrenska University
Hospital, Gothenburg, Sweden.
(6)Lundberg Laboratory for Diabetes Research, Department of Molecular and
Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska
University Hospital, Gothenburg, Sweden. Electronic address:
Margit.Mahlapuu@gu.se.
Comment in
Cell Mol Gastroenterol Hepatol. 2019;7(3):682-683. doi:
10.1016/j.jcmgh.2018.12.008.
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic
steatohepatitis (NASH) are emerging as leading causes of liver disease
worldwide. Currently, no specific pharmacologic therapy is available for
NAFLD/NASH, which has been recognized as one of the major unmet medical needs of
the 21st century. Our recent studies in genetic mouse models, human cell lines,
and well-characterized patient cohorts have identified serine/threonine protein
kinase (STK)25 as a critical regulator of hepatic lipid partitioning and
NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25
inhibitors on NAFLD development and progression in a mouse model of diet-induced
obesity.
METHODS: We developed a hepatocyte-specific triantennary N-acetylgalactosamine
(GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and
evaluated its effect on NAFLD features in mice after chronic exposure to dietary
lipids.
RESULTS: We found that systemic administration of hepatocyte-targeting
GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory
infiltration, hepatic stellate cell activation, nutritional fibrosis, and
hepatocellular damage in the liver compared with mice treated with
GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local
tolerability concerns. We also observed protection against high-fat-diet-induced
hepatic oxidative stress and improved mitochondrial function with Stk25 ASO
treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene
expression and acetyl-CoA carboxylase protein abundance in the liver, providing
insight into the molecular mechanisms underlying repression of hepatic
steatosis.
CONCLUSIONS: This study provides in vivo nonclinical proof-of-principle for the
metabolic benefit of liver-specific inhibition of STK25 in the context of
obesity and warrants future investigations to address the therapeutic potential
of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jcmgh.2018.12.004
PMCID: PMC6411916
PMID: 30576769 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36181334 | 1. Med Sci Monit. 2022 Oct 1;28:e938532. doi: 10.12659/MSM.938532.
Editorial: Rebound COVID-19 and Cessation of Antiviral Treatment for SARS-CoV-2
with Paxlovid and Molnupiravir.
Parums DV(1).
Author information:
(1)Science Editor, Medical Science Monitor, International Scientific
Information, Inc., Melville, NY, USA.
One of the most recently described clinical associations with SARS-CoV-2
infection is rebound COVID-19, which occurs between five and eight days
following the cessation of antiviral treatment. Most case reports of rebound
COVID-19 have been associated with cessation of treatment with the combined oral
antiviral agent nirmatrelvir/ritonavir (Paxlovid). On 24 May 2022, the US
Centers for Disease Control and Prevention (CDC) issued a Health Alert Network
(HAN) Health Advisory update for patients, healthcare providers, and public
health departments on COVID-19 rebound or recurrence of COVID-19. However,
population data from the US showed no significant differences in the risk of
developing rebound COVID-19 between patients treated with Paxlovid and
Molnupiravir. The mechanisms of rebound COVID-19 remain unclear but may involve
the development of resistance to the antiviral drug, impaired immunity to the
virus, or insufficient drug dosing. A further explanation may be the persistence
of a high viral load of SARS-CoV-2 in individuals who are no longer symptomatic.
This Editorial aims to provide an update on what is known about rebound COVID-19
and the current public health implications.
DOI: 10.12659/MSM.938532
PMCID: PMC9536144
PMID: 36181334 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None declared |
http://www.ncbi.nlm.nih.gov/pubmed/36200701 | 1. Clin Infect Dis. 2023 Feb 18;76(4):573-581. doi: 10.1093/cid/ciac663.
Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus
Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment.
Epling BP(1), Rocco JM(1), Boswell KL(2), Laidlaw E(1), Galindo F(1), Kellogg
A(3), Das S(4), Roder A(5), Ghedin E(5), Kreitman A(5), Dewar RL(6), Kelly
SEM(7), Kalish H(7), Rehman T(6), Highbarger J(6), Rupert A(8), Kocher G(9),
Holbrook MR(9), Lisco A(1), Manion M(1), Koup RA(2), Sereti I(1).
Author information:
(1)Laboratory of Immunoregulation, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland, USA.
(2)Immunology Laboratory, Vaccine Research Center, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
(3)Clinical Research Directorate, Frederick National Laboratory for Cancer
Research, Leidos Biomedical Research, Frederick, Maryland, USA.
(4)Department of Laboratory Medicine, Clinical Center, National Institutes of
Health, Bethesda, Maryland, USA.
(5)Systems Genomics Section, Laboratory of Parasitic Diseases, Division of
Intramural Research, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland, USA.
(6)Virus Isolation and Serology Laboratory, Frederick National Laboratory,
Frederick, Maryland, USA.
(7)Trans-NIH Shared Resource on Biomedical Engineering and Physical Science,
National Institute of Biomedical Imaging and Bioengineering, National Institutes
of Health, Bethesda, Maryland, USA.
(8)AIDS Monitoring Laboratory, Frederick National Laboratory, Frederick,
Maryland, USA.
(9)Integrated Research Facility at Fort Detrick, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Frederick, Maryland,
USA.
Update of
medRxiv. 2022 Jun 17:2022.06.16.22276392. doi: 10.1101/2022.06.16.22276392.
BACKGROUND: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of
hospitalization and death by coronavirus disease 2019 (COVID-19) but has been
associated with symptomatic rebound after therapy completion.
METHODS: Six individuals with relapse of COVID-19 symptoms after treatment with
nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior
antiviral therapy and 7 patients with acute Omicron infection (controls) were
studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were
measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and
targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain,
and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization
tests against wild-type and Omicron spike protein, as well as T-cell stimulation
assays, were performed.
RESULTS: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies
were found in all participants. Anti-nucleocapsid IgG and Omicron-specific
neutralizing antibodies increased in patients with rebound. Robust
SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared
with early acute COVID-19 patients. Inflammatory markers mostly decreased during
rebound. Two patients sampled longitudinally demonstrated an increase in
activated cytokine-producing CD4+ T cells against viral proteins. No
characteristic resistance mutations were identified. SARS-CoV-2 was isolated by
culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of
8.
CONCLUSIONS: Nirmatrelvir/ritonavir treatment does not impede adaptive immune
responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust
antibody and T-cell immune response, arguing against a high risk of disease
progression. The presence of infectious virus supports the need for isolation
and assessment of longer treatment courses.
CLINICAL TRIALS REGISTRATION: NCT04401436.
Published by Oxford University Press on behalf of Infectious Diseases Society of
America 2022.
DOI: 10.1093/cid/ciac663
PMCID: PMC9619622
PMID: 36200701 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflicts of interest. E. G. reports
grants or contracts from the National Science Foundation and NIH and a
leadership or fiduciary role in other board, society, committee, or advocacy
group for American Society for Microbiology (ASM, unpaid). All other authors
report no potential conflicts. All authors have submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Conflicts that the editors
consider relevant to the content of the manuscript have been disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/35982660 | 1. medRxiv [Preprint]. 2022 Aug 2:2022.08.01.22278278. doi:
10.1101/2022.08.01.22278278.
Viral and Symptom Rebound in Untreated COVID-19 Infection.
Deo R(1), Choudhary MC(1), Moser C(2), Ritz J(2), Daar ES(3), Wohl DA(4),
Greninger AL(5), Eron JJ(4), Currier JS(6), Hughes MD(2), Smith DM(7), Chew
KW(6), Li JZ(1); ACTIV-2/A5401 Study Team.
Author information:
(1)Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
(2)Harvard T.H. Chan School of Public Health, Boston, MA.
(3)Lundquist Institute at Harbor-University of California, Los Angeles Medical
Center, Torrance, CA.
(4)University of North Carolina, Chapel Hill, NC.
(5)University of Washington Medical Center, Seattle, WA.
(6)David Geffen School of Medicine at University of California, Los Angeles, Los
Angeles, CA.
(7)University of California, San Diego, San Diego, CA.
BACKGROUND: There are reports of viral RNA and symptom rebound in people with
COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral
and symptom trajectories of COVID-19 has not been well described, we evaluated
the incidence of viral and symptom rebound in untreated outpatients with
mild-moderate COVID-19.
METHODS: The study population included 568 participants enrolled in the
ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were
collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants
recorded the severity of 13 targeted symptoms daily from day 0 to 28. Viral
rebound was defined as ≥0.5 log10 viral RNA copies/mL increase and symptom
rebound was defined as a 4-point total symptom score increase from baseline.
Baseline was defined as study day 4 (primary analysis) or 8 days from symptom
onset (secondary analysis).
FINDINGS: In both the primary and secondary analyses, 12% of participants had
viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47
years, P=0.04). Symptom rebound occurred in 27% of participants after initial
symptom improvement and in 10% of participants after initial symptom resolution.
The combination of high-level viral rebound to ≥5.0 log10 RNA copies/mL and
symptom rebound after initial improvement was observed in 1-2% of participants.
INTERPRETATION: Viral RNA rebound or symptom relapse in the absence of antiviral
treatment is common, but the combination of high-level viral and symptom rebound
is rare.
DOI: 10.1101/2022.08.01.22278278
PMCID: PMC9387151
PMID: 35982660
Conflict of interest statement: Declaration of interests KWC has received
research funding to the institution from Merck Sharp & Dohme and is a consultant
for Pardes Bioscences. ESD has consulted for Gilead, Merck and ViiV and received
research support from Gilead and ViiV. JZL has consulted for Abbvie and received
research funding from Merck. JSC has consulted for Merck & Company. ALG reports
contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen and Hologic and
research support from Gilead and Merck, outside of the described work. JJE has
consulted for GSK, and Merck. DAW has consulted for Gilead and ViiV and received
research support from Gilead, ViiV, and Lilly. |
http://www.ncbi.nlm.nih.gov/pubmed/36472873 | 1. JAMA Netw Open. 2022 Dec 1;5(12):e2245086. doi:
10.1001/jamanetworkopen.2022.45086.
Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and
Molnupiravir.
Wong GL(1)(2)(3), Yip TC(1)(2)(3), Lai MS(1)(2)(3), Wong VW(1)(2)(3), Hui
DS(1)(2)(4), Lui GC(1)(2)(4).
Author information:
(1)Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Hong Kong Special Administrative Region, China.
(2)Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong
Special Administrative Region, China.
(3)Institute of Digestive Disease, The Chinese University of Hong Kong, Hong
Kong Special Administrative Region, China.
(4)Stanley Ho Centre for Emerging Infectious Diseases, Jockey Club School of
Public Health & Primary Care, The Chinese University of Hong Kong, Hong Kong
Special Administrative Region, China.
IMPORTANCE: Some patients treated with nirmatrelvir-ritonavir have experienced
rebound of COVID-19 infections and symptoms; however, data are scarce on whether
viral rebound also occurs in patients with COVID-19 receiving or not receiving
molnupiravir.
OBJECTIVE: To examine the incidence of viral rebound in patients with COVID-19
who were treated with the oral antiviral agents nirmatrelvir-ritonavir and
molnupiravir.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study identified 41 255 patients
with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in
Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values
measured. Patients were followed up until the occurrence of the clinical end
point of interest, death, date of data retrieval (July 31, 2022), or up to 30
days of follow-up, whichever came first.
EXPOSURES: Molnupiravir or nirmatrelvir-ritonavir treatment.
MAIN OUTCOMES AND MEASURES: Viral rebound, defined as a Ct value greater than 40
that decreased to 40 or less.
RESULTS: Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%]
male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir
users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers,
oral antiviral users were older, had more comorbidities, and had lower complete
vaccination rates. The mean (SD) baseline Ct value was slightly higher in
nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and
molnupiravir users (20.9 [5.4]) (P = .04). Viral rebound occurred in 68 nonusers
(0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%).
Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir
users, and neither of the nirmatrelvir-ritonavir users died of COVID-19.
CONCLUSIONS AND RELEVANCE: In this cohort study, viral rebound was uncommon in
patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated
with increased risk of mortality. Given these findings, novel oral antivirals
should be considered as a treatment for more patients with COVID-19 in the early
phase of the infection.
DOI: 10.1001/jamanetworkopen.2022.45086
PMCID: PMC9856258
PMID: 36472873 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: Dr G.L.-H.
Wong reported receiving grants from Gilead Sciences and personal fees from
Abbott, AbbVie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen,
and Roche outside the submitted work. Dr Yip reported serving as a speaker and
consultant for Gilead Sciences outside the submitted work. Dr V.W.-S. Wong
reported receiving personal fees from Abbott, AbbVie, Boehringer Ingelheim,
Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, and
TARGET PharmaSolutions and grants from Gilead Sciences outside the submitted
work. Dr Lui reported receiving grants from Gilead Sciences, MSD, and ViiV
outside the submitted work. No other disclosures were reported. |
http://www.ncbi.nlm.nih.gov/pubmed/35794889 | 1. medRxiv [Preprint]. 2022 Jun 22:2022.06.21.22276724. doi:
10.1101/2022.06.21.22276724.
COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022.
Wang L(1), Berger NA(1), Davis PB(2), Kaelber DC(3), Volkow ND(4), Xu R(5).
Author information:
(1)Center for Science, Health, and Society, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(2)Center for Community Health Integration, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(3)The Center for Clinical Informatics Research and Education, The MetroHealth
System, Cleveland, OH, USA.
(4)National Institute on Drug Abuse, National Institutes of Health, Bethesda,
MD, USA.
(5)Center for Artificial Intelligence in Drug Discovery, Case Western Reserve
University School of Medicine, Cleveland, OH, USA.
IMPORTANCE: Recent case reports document that some patients who were treated
with Paxlovid experienced rebound COVID-19 infections and symptoms 2 to 8 days
after completing a 5-day course of Paxlovid. The Centers for Disease Control and
Prevention (CDC) has recently issued a Health Alert Network Health Advisory to
update the public on the potential for COVID-19 rebound after Paxlovid
treatments. However, the rates of COVID-19 rebound in a real-world population or
whether rebound is unique to Paxlovid remains unknown.
OBJECTIVES: To examine the rates and relative risks of COVID-19 rebound in
patients treated with Paxlovid or with Molnupiravir and to compare
characteristics of patients who experienced COVID-19 rebound to those who did
not.
DESIGN SETTING AND PARTICIPANTS: Retrospective cohort study of electronic health
records (EHRs) of 92 million patients from a multicenter and nationwide database
in the US. The study population comprised 13,644 patients age ≥ 18 years who
contracted COVID-19 between 1/1/2022-6/8/2022 and were treated with Paxlovid (n
=11,270) or with Molnupiravir (n =2,374) within 5 days of their COVID-19
infection.
EXPOSURES: Paxlovid or Molnupiravir.
MAIN OUTCOMES AND MEASURES: Three types of COVID-19 rebound outcomes (COVID-19
infections, COVID-19 related symptoms, and hospitalizations) were examined.
Hazard ratios and 95% confidence interval (CI) of 7-day and 30-day risk for
COVID-19 rebound between patients treated with Paxlovid and patients treated
with Molnupiravir were calculated before and after propensity-score matching.
RESULTS: The 7-day and 30-day COVID-19 rebound rates after Paxlovid treatment
were 3.53% and 5.40% for COVID-19 infection, 2.31% and 5.87% for COVID-19
symptoms, and 0.44% and 0.77% for hospitalizations. The 7-day and 30-day
COVID-19 rebound rates after Molnupiravir treatment were 5.86% and 8.59% for
COVID-19 infection, 3.75% and 8.21% for COVID-19 symptoms, and 0.84% and 1.39%
for hospitalizations. After propensity-score matching, there were no significant
differences in COVID-19 rebound risks between Paxlovid and Molnupiravir:
infection (HR 0.90, 95% CI: 0.73-1.11), COVID-19 symptoms (HR: 1.03, 95% CI:
0.83-1.27), or hospitalizations (HR: 0.92, 95% CI: 0.56-1.55). Patients with
COVID-19 rebound had significantly higher prevalence of underlying medical
conditions than those without.
CONCLUSIONS AND RELEVANCE: COVID-19 rebound occurred both after Paxlovid and
Molnupiravir, especially in patients with underlying medical conditions. This
indicates that COVID-19 rebound is not unique to Paxlovid and the risks were
similar for Paxlovid and Molnupiravir. For both drugs the rates of COVID-19
rebound increased with time after treatments. Our results call for continuous
surveillance of COVID-19 rebound after Paxlovid and Molnupiravir treatments.
Studies are necessary to determine the mechanisms underlying COVID-19 rebounds
and to test dosing and duration regimes that might prevent such rebounds in
vulnerable patients.
DOI: 10.1101/2022.06.21.22276724
PMCID: PMC9258292
PMID: 35794889
Conflict of interest statement: Declaration of interests LW, NAB, PBD, DCK, NDV,
RX have no financial interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/32619697 | 1. J Infect. 2020 Nov;81(5):816-846. doi: 10.1016/j.jinf.2020.06.073. Epub 2020
Jun 30.
Clinical recurrences of COVID-19 symptoms after recovery: Viral relapse,
reinfection or inflammatory rebound?
Gousseff M(1), Penot P(2), Gallay L(3), Batisse D(4), Benech N(5), Bouiller
K(6), Collarino R(7), Conrad A(8), Slama D(9), Joseph C(10), Lemaignen A(11),
Lescure FX(12), Levy B(13), Mahevas M(14), Pozzetto B(15), Vignier N(16),
Wyplosz B(17), Salmon D(18), Goehringer F(19), Botelho-Nevers E(20); in behalf
of the COCOREC study group.
Author information:
(1)Service de Medecine interne, Maladies Infectieuses, hematologie, Centre
Hospitalier Bretagne Atlantique, 20, boulevard Maurice Guillaudot, 56000 Vannes,
France. Electronic address: marie.gousseff@ch-bretagne-atlantique.fr.
(2)Hôpital intercommunal André Grégoire, groupement hospitalier Grand Paris Nord
Est, 56, boulevard de la Boissière, 93100 Montreuil, France. Electronic address:
pauline.penot@ght-gpne.fr.
(3)Service Médecine Interne, Pr Hot, INMG CNRS UMR5310 INSERM U1217, Place
d'arsonvaal, 69003 Lyon, France. Electronic address: laure.gallay@chu-lyon.fr.
(4)Department of Infectious Diseases and Immunology, Cochin-Hôtel-Dieu Hospital,
Publique -Hôpitaux de Paris (APHP), University of Paris. 1, place parvis Notre
Dame, 75014 Paris, France.
(5)Service des Maladies Infectieuses et Tropicales, Hôpital de La Croix-Rousse,
Hospices Civils de Lyon, 103, Grande Rue de La Croix-Rousse, 69004 Lyon, France.
Electronic address: nicolas.benech@chu-lyon.fr.
(6)Department of infectious disease, University Hospital of Besançon, F-25000
Besançon, France; UMR-CNRS 6249 Chrono-environnement, Université Bourgogne
Franche-Comté, 25000 Besançon, France. Electronic address:
kbouiller@chu-besancon.fr.
(7)Service des Maladies infectieuses et tropicales, Assistance publique-
hôpitaux de Paris, Centre hospitalier universitaire Bicêtre, 78 rue du général
Leclerc, 94270 Le Kremlin-Bicêtre, France. Electronic address:
rocco.collarino@aphp.fr.
(8)Service des Maladies Infectieuses et Tropicales, Hôpital de La Croix-Rousse,
Hospices Civils de Lyon, 103, Grande Rue de La Croix-Rousse, 69004 Lyon, France.
Electronic address: anne.conrad@chu-lyon.fr.
(9)Department of Infectious Diseases and Immunology, Cochin-Hôtel-Dieu Hospital,
Assistance, Publique -Hôpitaux de Paris (APHP), University of Paris. 1, place
parvis Notre Dame, 75014 Paris, France.
(10)Service des Maladies Infectieuses et Tropicales, CHU Amiens-Picardie, Place
Victor Pauchet 80054 Amiens, France. Electronic address:
joseph.cedric@chu-amiens.fr.
(11)Service de Médecine Interne et Maladies Infectieuses, CHRU de Tours, Hôpital
Bretonneau, Université de Tours, 2, Boulevard Tonnellé, 37000 Tours, France.
Electronic address: adrien.lemaignen@univ-tours.fr.
(12)AP-HP, Infectious and Tropical Diseases Department, Bichat-Claude Bernard
University, Hospital, Paris, France; University of Paris, French Institute for
Health and Medical Research (INSERM), IAME, U1137, Team DesCID, Paris, France.
46 rue Henri Huchard, 75018 Paris, France. Electronic address:
xavier.lescure@aphp.fr.
(13)Service de Médecine Intensive et Reanimation Brabois, CHRU Nancy, Pôle
Cardio-Médico-Chirurgical, Vandoeuvre-les-Nancy, INSERM U1116, Faculté de
Médecine, Vandoeuvre-les-Nancy, and Université de Lorraine, France.
(14)Service de Médecine Interne, Centre Hospitalier Universitaire Henri-Mondor,
Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil,
France. IMRB - U955 - INSERM Equipe n°2 "Transfusion et maladies du globule
rouge" EFS Île-de-France, Hôpital Henri-Mondor, AP-HP, 51, avenue du
Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France. Electronic address:
matthieu.mahevas@aphp.fr.
(15)GIMAP (EA 3064), University of Saint-Etienne, University of Lyon, Faculty of
Medicine of Saint-Etienne, 42023 cedex 02 Saint-Etienne, France. Electronic
address: bruno.pozzetto@chu-st-etienne.fr.
(16)Groupe hospitalier Sud Ile de France & INSERM, Institut Pierre Louis
d'Épidémiologie et de, Santé Publique (IPLESP), Sorbonne Université, Paris,
France, 270 avenue Marc Jacquet, 77 000 Melun, France.
(17)Service des Maladies infectieuses et tropicales, Assistance publique-
hôpitaux de Paris, Centre hospitalier universitaire Bicêtre, 78 rue du général
Leclerc, 94270 Le Kremlin-Bicêtre, France. Electronic address:
Benjamin.wyplosz@aphp.fr.
(18)Department of Infectious Diseases and Immunology, Cochin-Hôtel-Dieu
Hospital, Assistance, Publique -Hôpitaux de Paris (APHP), University of Paris.
1, place parvis Notre Dame, 75014 Paris, France. Electronic address:
Dominique.salmon@aphp.fr.
(19)Service de Maladies Infectieuses et Tropicales, Centre Régional
Universitaire de Nancy, Hôpitaux de Brabois, Rue du Morvan, 54511 Vandoeuvre Lés
Nancy, France. Electronic address: f.goehringer@chru-nancy.fr.
(20)Infectious Diseases Department, University Hospital of Saint-Etienne, 42055
cedex 02 Saint-Etienne, GIMAP (EA 3064), France; University of Saint-Etienne,
University of Lyon, Faculty of Medicine of Saint-Etienne, 42023 cedex 02
Saint-Etienne, France. Electronic address:
elisabeth.botelho-nevers@chu-st-etienne.fr.
Comment in
J Infect. 2021 Feb;82(2):282-327. doi: 10.1016/j.jinf.2020.08.011.
J Infect. 2020 Dec;81(6):979-997. doi: 10.1016/j.jinf.2020.08.019.
J Infect. 2021 Mar;82(3):414-451. doi: 10.1016/j.jinf.2020.10.019.
J Infect. 2021 Apr;82(4):84-123. doi: 10.1016/j.jinf.2020.10.029.
J Infect. 2021 Aug;83(2):e6-e8. doi: 10.1016/j.jinf.2021.06.015.
For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an
immunizing non-relapsing disease. We report a national case series of 11
virologically-confirmed COVID-19 patients having experienced a second
clinically- and virologically-confirmed acute COVID-19 episode. According to the
clinical history, we discuss either re-infection or reactivation hypothesis.
Larger studies including further virological, immunological and epidemiologic
data are needed to understand the mechanisms of these recurrences.
Copyright © 2020 The British Infection Association. Published by Elsevier Ltd.
All rights reserved.
DOI: 10.1016/j.jinf.2020.06.073
PMCID: PMC7326402
PMID: 32619697 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest None of the
authors has any conflict of interest to declare regarding this subject. This
work had no financial support. |
http://www.ncbi.nlm.nih.gov/pubmed/35898366 | 1. Cureus. 2022 Jun 23;14(6):e26239. doi: 10.7759/cureus.26239. eCollection 2022
Jun.
COVID-19 Rebound After Paxlovid Treatment: A Case Series and Review of
Literature.
Alshanqeeti S(1)(2), Bhargava A(1).
Author information:
(1)Internal Medicine, Ascension St. John Hospital, Detroit, USA.
(2)Infectious Disease, King Saud University, Riyadh, SAU.
Since the declaration of COVID-19 as a pandemic in 2020, several therapies have
been developed to reduce symptoms of COVID-19 infection and prevent progression.
Paxlovid is an antiviral that was authorized for emergency use in December 2021
for non-hospitalized symptomatic patients with COVID-19 to prevent progression
to severe disease. Relapse of symptoms following a period of improvement after
treatment with Paxlovid has been described recently. Data are limited, but the
disease course in available case reports is usually mild and requires no
additional antiviral treatment. We present the cases of COVID-19 relapse
(COVID-19 rebound) in two patients following treatment with Paxlovid.
Copyright © 2022, Alshanqeeti et al.
DOI: 10.7759/cureus.26239
PMCID: PMC9308388
PMID: 35898366
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/35982673 | 1. medRxiv [Preprint]. 2022 Aug 6:2022.08.04.22278450. doi:
10.1101/2022.08.04.22278450.
COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1
subvariant predominance period.
Wang L(1), Volkow ND(2), Davis PB(3), Berger NA(1), Kaelber DC(4), Xu R(5).
Author information:
(1)Center for Science, Health, and Society, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(2)National Institute on Drug Abuse, National Institutes of Health, Bethesda,
MD, USA.
(3)Center for Community Health Integration, Case Western Reserve University
School of Medicine, Cleveland, OH, USA.
(4)The Center for Clinical Informatics Research and Education, The MetroHealth
System, Cleveland, OH, USA.
(5)Center for Artificial Intelligence in Drug Discovery, Case Western Reserve
University School of Medicine, Cleveland, OH, USA.
Paxlovid was authorized by FDA to treat mild-to-moderate COVID-19. In May 2022,
the Centers for Disease Control and Prevention (CDC) issued a Health Alert
Network Health Advisory on potential COVID-19 rebound after Paxlovid treatment.
Since June 2022, Omicron BA.5 has become the dominant subvariant in the US,
which is more resistant to neutralizing antibodies than the previous subvariant
BA.2.12.1. Questions remain as to how COVID-19 rebound after Paxlovid treatment
differs between the BA.5 and BA.2.12.1 subvariants. This is a retrospective
cohort study of 15,913 patients who contracted COVID-19 between
5/8/2022-7/18/2022 and were prescribed Paxlovid within 5 days of their COVID-19
infection. The study population was divided into 2 cohorts: (1) BA.5 cohort
(n=5,161) - contracted COVID-19 during 6/19/22-7/18/22 when BA.5 was the
predominant subvariant2. (2) BA.2.12.1 cohort (n=10,752) - contracted COVID-19
during 5/8/22-6/18/22 when the BA.2.12.1 was the predominant subvariant. The
risks of both COVID-19 rebound infections and symptoms 2-8 days after Paxlovid
treatment were higher in the BA.5 cohort than in the propensity-score matched
BA.2.12.1 cohort: rebound infections (Hazard Ratio or HR: 1.32, 95% CI:
1.06-1.66), rebound symptoms (HR: 1.32, 95% CI: 1.04-1.68). As SARS-CoV-2
evolves with successive subvariants more evasive to antibodies, continuous
vigilant monitoring is necessary for COVID-19 rebounds after Paxlovid treatment
and longer time duration of Paxlovid treatment warrants evaluation.
DOI: 10.1101/2022.08.04.22278450
PMCID: PMC9387159
PMID: 35982673
Conflict of interest statement: Declaration of interests LW, NAB, PBD, DCK, NDV,
RX have no financial interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/35734093 | 1. medRxiv [Preprint]. 2022 Jun 17:2022.06.16.22276392. doi:
10.1101/2022.06.16.22276392.
COVID-19 redux: clinical, virologic, and immunologic evaluation of clinical
rebound after nirmatrelvir/ritonavir.
Epling BP(1), Rocco JM(1), Boswell KL(2), Laidlaw E(1), Galindo F(1), Kellogg
A(3), Das S(4), Roder A(5), Ghedin E(5), Kreitman A(5), Dewar RL(6), Kelly
SEM(7), Kalish H(7), Rehman T(6), Highbarger J(6), Rupert A(8), Kocher G(9),
Holbrook MR(9), Lisco A(1), Manion M(1), Koup RA(2), Sereti I(1).
Author information:
(1)Laboratory of Immunoregulation, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD, USA.
(2)Immunology Laboratory, Vaccine Research Center, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
(3)Clinical Research Directorate (CRD), Frederick National Laboratory for Cancer
Research, Leidos Biomedical Research, Frederick, MD, USA.
(4)Department of Laboratory Medicine, Clinical Center, National Institutes of
Health, Bethesda, MD, USA.
(5)Systems Genomics Section, Laboratory of Parasitic Diseases, Division of
Intramural Research, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, MD, USA.
(6)Virus Isolation and Serology Laboratory, Frederick National Laboratory,
Frederick, MD, USA.
(7)Trans-NIH Shared Resource on Biomedical Engineering and Physical Science,
National Institute of Biomedical Imaging and Bioengineering, National Institutes
of Health, Bethesda, MD, USA.
(8)AIDS Monitoring Laboratory, Frederick National Laboratory, Frederick, MD,
USA.
(9)Integrated Research Facility at Fort Detrick, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
Update in
Clin Infect Dis. 2023 Feb 18;76(4):573-581. doi: 10.1093/cid/ciac663.
Clinical rebound of COVID-19 after nirmatrelvir/ritonavir treatment has been
reported. We performed clinical, virologic, and immune measurements in seven
patients with symptomatic rebound, six after nirmatrelvir/ritonavir treatment
and one without previous treatment. There was no evidence of severe disease or
impaired antibody and T-cell responses in people with rebound symptoms.
DOI: 10.1101/2022.06.16.22276392
PMCID: PMC9216730
PMID: 35734093
Conflict of interest statement: All authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35651781 | 1. Ther Adv Hematol. 2022 May 27;13:20406207221093980. doi:
10.1177/20406207221093980. eCollection 2022.
Zanubrutinib in lymphoproliferative disorders: a comprehensive review.
Muñoz J(1), Wang Y(2), Jain P(3), Wang M(3).
Author information:
(1)Program Director, Lymphoma, Mayo Clinic, 5881 E. Mayo Boulevard, Phoenix, AZ
85054, USA.
(2)Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
(3)The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a
paradigm shift in the treatment of patients with B-cell lymphomas and chronic
lymphocytic leukemia. BTK was clinically validated as a target by the efficacy
of the first-in-class inhibitor ibrutinib. The extended survival conferred by
BTK inhibitors has brought long-term tolerability to the foreground. To minimize
toxicities thought to be attributable to off-target kinase inhibition, a next
generation of BTK inhibitors with greater selectivity was developed. In the
United States, zanubrutinib, a next-generation BTK inhibitor, has been approved
for treating adults with mantle cell lymphoma who have received at least one
prior therapy, for adults with Waldenström macroglobulinemia, and for adults
with relapsed or refractory marginal zone lymphoma who have received at least
one anti-CD20-based therapy. Because few head-to-head comparative trials of BTK
inhibitors have so far been reported, no BTK 'inhibitor of choice' can be
identified. Zanubrutinib has promising efficacy in its approved indications and
appears to have reduced cardiac toxicities, particularly atrial fibrillation,
which may influence the choice of BTK inhibitor treatment by prescribers.
Further studies are needed to inform on optimal treatment sequencing of
zanubrutinib and its combination with other agents. Here, we summarize existing
clinical evidence for its efficacy and safety in mantle cell lymphoma,
Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic
leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative
indications.
PLAIN LANGUAGE SUMMARY: Zanubrutinib is a drug that was shown to effectively
treat cancer of B cells without causing excessive serious side effects Patients
with certain B-cell malignancies (cancers of white blood cells) benefit from
treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK
protein and keep cancer from growing and spreading. Patients experience extended
survival with ibrutinib, the first-generation BTK inhibitor approved by US Food
and Drug Administration (FDA); however, one in five patients quit treatment
because of harmful side effects. Ibrutinib-related side effects such as
increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and
high blood pressure are thought to be caused by ibrutinib blocking other
proteins besides the intended target protein BTK. To reduce these side effects,
zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more
specifically than ibrutinib. Results of clinical studies on zanubrutinib
treatment appear promising in patients with several types of B-cell
malignancies, including mantle cell lymphoma (MCL), Waldenström
macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic
leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data
to determine which BTK inhibitor is most effective in treating B-cell
malignancies without causing harmful side effects. Early data from the phase 3
ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and
fewer patients experience side effects and quit treatment. Zanubrutinib is
currently approved for use for treatment of adult patients with MCL who have
received at least one prior therapy, for adults with WM, and for adults with MZL
who have received at least one anti-CD20-based therapy.
© The Author(s), 2022.
DOI: 10.1177/20406207221093980
PMCID: PMC9150264
PMID: 35651781
Conflict of interest statement: Conflict of interest statement: The authors
declared the following potential conflicts of interest with respect to the
research, authorship, and/or publication of this article: JM reports consultancy
role with, research funding from, and speakers’ bureau for Pharmacyclics, Bayer,
Gilead/Kite Pharma, Janssen, and Celgene; consultancy role with Pfizer, Alexion,
Fosunkite, Innovent, Debiopharm, Epizyme, Karyopharm, and Genmab; consultancy
role with Juno/Celgene; consultancy role with and speakers’ bureau for Bristol
Myers Squibb, BeiGene; consultancy role with, honoraria from, and speakers’
bureau for Kyowa; consultancy role with, research funding from, honoraria from,
and speakers’ bureau for Seattle Genetics; research funding from Merck, Portola,
Incyte, and Millennium; research funding from and speakers’ bureau for
Genentech; speakers’ bureau for Acrotech/Aurobindo, Verastem, AstraZeneca,
Roche, and AbbVie. YW reports research funding from, and advisory role with
Incyte and Loxo Oncology; research funding from InnoCare, Novartis, and
Genentech; advisory role with Eli Lilly and TG therapeutics. PJ reports
consultancy role with Eli Lilly, Incyte, Kite, research funding from
AstraZeneca. MW reports research funding and honoraria from Acerta Pharma;
consultancy role with, research funding, and honoraria from AstraZeneca,
BeiGene, Janssen, and Kite Pharma; honoraria from Anticancer Association, CAHON,
Chinese Medical Association, Clinical Care Options, Dava Oncology, Hebei Cancer
Prevention Federation, Imbruvica, Imedex, Moffit Cancer Center, Mumbai
Hematology Group, Newbridge Pharmaceuticals, OMI, Physicians Education Resources
(PER), Scripps, and The First Affiliated Hospital of Zhejiang University;
consultancy role with Bayer Healthcare, CSTone, DTRM Biopharma (Cayman) Limited,
and Genentech; research funding from BioInvent, Celgene, and Molecular
Templates; consultancy role with and honoraria from Epizyme and Miltenyi
Biomedicine GmbH; consultancy role with and research funding from InnoCare,
Juno, Loxo Oncology, Oncternal, Pharmacyclics, and VelosBio. |
http://www.ncbi.nlm.nih.gov/pubmed/34599390 | 1. Curr Cardiol Rep. 2021 Oct 1;23(11):157. doi: 10.1007/s11886-021-01589-x.
Interleukin-1 and the NLRP3 Inflammasome in Pericardial Disease.
Vecchié A(1), Del Buono MG(2), Chiabrando GJ(3), Dentali F(4), Abbate A(2),
Bonaventura A(5).
Author information:
(1)Department of Internal Medicine, ASST Sette Laghi, Viale Luigi Borri, 57,
21100, Varese, Italy. alessandra.vecchie@asst-settelaghi.it.
(2)Division of Cardiology, Department of Internal Medicine, Pauley Heart Center,
Virginia Commonwealth University, Richmond, VA, USA.
(3)Cardiology Service, Hospital Italiano of Buenos Aires, Buenos Aires,
Argentina.
(4)Department of Medicine and Surgery, Insubria University, Varese, Italy.
(5)Department of Internal Medicine, ASST Sette Laghi, Viale Luigi Borri, 57,
21100, Varese, Italy.
PURPOSE OF REVIEW: Pericarditis is a generally benign disease, although
complications and/or recurrences may occur in up to 30% of cases. New evidence
on the pathophysiology of the disease has accumulated in recent years.
RECENT FINDINGS: Recently, it has been shown that the activation of the NLRP3
(NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome
is central in the pathophysiology of pericarditis. These findings derive from
clinical data, an experimental animal model of acute pericarditis supporting a
role for the NLRP3 inflammasome in pericarditis, and from indirect evidence of
inhibitors of NLRP3 inflammasome in clinical trials. Pericarditis is regarded as
a stereotypical response to an acute damage of the mesothelial cells of the
pericardial layers. NLRP3 inflammasome, a macromolecular structure sensing
damage and releasing pro-inflammatory cytokines, is centrally involved as it
releases interleukin (IL)-1β, whose auto-induction feeds an autoinflammatory
disease, mostly responsible for recurrences. Colchicine, an inhibitor of NLRP3
inflammasome formation, and IL-1-targeted therapies, such as anakinra and
rilonacept, were found to effectively blunt the acute inflammation and reduce
the risk for recurrences.
© 2021. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s11886-021-01589-x
PMCID: PMC8485973
PMID: 34599390 [Indexed for MEDLINE]
Conflict of interest statement: Dr. Bonaventura received a travel grant from
Kiniksa Pharmaceuticals Ltd. and honoraria from Effetti s.r.l. (Milan, Italy).
Dr. Vecchié received a travel grant from Kiniksa Pharmaceuticals Ltd. and
honoraria from Effetti s.r.l. (Milan, Italy). Dr. Abbate has served as a
consultant for Applied Clinical Intel, AstraZeneca, Cromos Pharma, Effetti
s.r.l, Janssen, Kiniksa Pharmaceuticals Ltd., Eli Lilly, Merck, Olatec, Swedish
Orphan Biovitrum, Novo Nordisk, and Serpin Pharma. He has also has received
research support from Janssen, Olatec, Novartis, R-Pharm, and Serpin Pharma. In
addition, Dr. Abbate has a patent Novel cryopyrin inhibitor issued, and a patent
Alpha-1 antitripsin to treat cardiovascular conditions pending. All other
authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34556390 | 1. Eur J Intern Med. 2022 Jan;95:24-31. doi: 10.1016/j.ejim.2021.09.002. Epub
2021 Sep 20.
Recent advances in pericarditis.
Bizzi E(1), Picchi C(2), Mastrangelo G(3), Imazio M(4), Brucato A(5).
Author information:
(1)Internal Medicine Department, Fatebenefratelli Hospital, Piazzale Principessa
Clotilde 3, 20121, Milano, Italy. Electronic address:
emanuele.bizzi@asst-fbf-sacco.it.
(2)Internal Medicine Department, Fatebenefratelli Hospital, Piazzale Principessa
Clotilde 3, 20121, Milano, Italy. Electronic address:
Chiara.picchi@asst-fbf-sacco.it.
(3)Department of Pediatrics, Fatebenefratelli Hospital, Piazzale Principessa
Clotilde 3, 20121, Milano, Italy. Electronic address:
Greta.mastrangelo@asst-fbf-saccco.it.
(4)Cardiology, Cardiothoracic Department, University Hospital Santa Maria della
Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100, Udine, Italy.
(5)University of Milano, Department of biomedical and clinical sciences "Luigi
Sacco", Fatebenefratelli Hospital, Piazzale Principessa Clotilde 3, 20121,
Milano, Italy. Electronic address: Antonio.brucato@asst-fbf-sacco.it.
Comment in
Eur J Intern Med. 2023 Jun;112:133-135. doi: 10.1016/j.ejim.2023.02.007.
Pericardial diseases are an heterogeneous group of entities, ranging from acute
pericarditis to asymptomatic pericardial effusions. New advances in
understanding the processes underlying them have been made. In 2020 a
prospective study defined the reference intervals of the component of normal
pericardial fluid, that was found to be rich in nucleated cells, proteins,
albumin and LDH, at levels compatible with the inflammatory exudates of other
biological fluids such as pleural or peritoneal fluid; Light's criteria should
not be used to evaluate it. Recently we also analyzed systematically large
chronic idiopathic non-inflammatory pericardial effusions, observing that a
non-invasive wait-and-see approach may be the best choice in clinical practice
in oligosymptomatic cases. Concerning acute recurrent pericarditis (RP), an
innovative interaction between cardiologists, internists and pediatric
rheumatologists led to the intuition of a pivotal role of IL-1 in recurrent
pericarditis characterized by an evident inflammatory recurrent phenotype, and
recent data have shown the striking efficacy of anakinra and rilonacept in these
patients. The proper selection of the patient is important; the ideal candidate
for anti-IL-1 therapy is the patient with RP with high levels of serum
C-reactive protein, high fever, neutrophil leukocitosis, pleuropulmonary
involvement, frequent exacerbations and resistant to conventional therapy. On
the contrary, anti-IL-1 drugs are not indicated in patients with pericardial
effusion whose cause is not attributable to inflammatory phenomena. Finally,
many patients with RP are women of childbearing age, and the possibility for
these women to become pregnant must be addressed by multidisciplinary teams.
Copyright © 2021. Published by Elsevier B.V.
DOI: 10.1016/j.ejim.2021.09.002
PMID: 34556390 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34569270 | 1. J Am Heart Assoc. 2021 Oct 5;10(19):e021685. doi: 10.1161/JAHA.121.021685.
Epub 2021 Sep 25.
Emerging Therapies for Recurrent Pericarditis: Interleukin-1 inhibitors.
Lo Presti S(1), Elajami TK(2), Reyaldeen R(1), Anthony C(1), Imazio M(3), Klein
AL(1).
Author information:
(1)Center for the Diagnosis and Treatment of Pericardial Diseases Section of
Cardiovascular Imaging Department of Cardiovascular Medicine Heart, Vascular,
and Thoracic InstituteCleveland Clinic Cleveland OH.
(2)Columbia University Division of CardiologyMount Sinai Heart Institute Miami
Beach FL.
(3)University CardiologyA.O.U. Città della Salute e della Scienza di Torino
Turin Italy.
Recurrent pericarditis (RP) is a complex inflammatory disorder associated with
adverse outcomes and poor quality of life. After the first episode of acute
pericarditis, a non-negligible group of patients will fail to achieve complete
remission despite treatment and will be challenged by side effects from the
chronic use of medications like corticosteroids. The cause of RP remains unknown
in the majority of cases, mainly due to a gap in knowledge of its complex
pathophysiology. Over the past 2 decades, the interleukin-1 (IL-1) pathway has
been uncovered as a key element in the inflammatory cascade, allowing the
development of pharmacological targets known as IL-1 inhibitors. This group of
medications has emerged as a treatment option for patients with RP
colchicine-resistance and steroid dependents. Currently, anakinra and
rilonacept, have demonstrated beneficial impact in clinical outcomes with a
reasonable safety profile in randomized clinical trials. There is still paucity
of data regarding the use of canakinumab in the treatment of patients with RP.
Although further studies are needed to refine therapeutic protocols and taper of
concomitant therapies, IL-1 inhibitors, continue to consolidate as part of the
pharmacological armamentarium to manage this complex condition with potential
use as monotherapy. The aim of this review is to highlight the role of IL-1
pathway in RP and discuss the efficacy, safety, and clinical applicability of
IL-1 inhibitors in the treatment of RP based on current evidence.
DOI: 10.1161/JAHA.121.021685
PMCID: PMC8649126
PMID: 34569270 [Indexed for MEDLINE]
Conflict of interest statement: Dr Massimo Imazio discloses that he serves as
scientific advisory board for Kiniksa and SOBI. Dr Allan Klein discloses that he
received a research grant from Kiniksa and serves as scientific advisory board
for Kiniksa, Sobi, and Pfizer. The remaining authors have no disclosures to
report. |
http://www.ncbi.nlm.nih.gov/pubmed/34459270 | 1. Ann Pharmacother. 2022 May;56(5):572-581. doi: 10.1177/10600280211036499. Epub
2021 Aug 28.
Rilonacept: A Newly Approved Treatment for Recurrent Pericarditis.
Schwier NC(1).
Author information:
(1)University of Oklahoma Health Sciences Center College of Pharmacy, Oklahoma
City, OK, USA.
OBJECTIVE: To review the pharmacology, efficacy, and safety of rilonacept for
the prevention and treatment of recurrent pericarditis (RP).
DATA SOURCES: A MEDLINE search was conducted between January 2006 and April 2021
using the following terms: rilonacept, pharmacology, pericarditis, recurrent
pericarditis, interleukin (IL) antagonist, and pharmacology; prescribing
information was also used.
STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing
pharmacology, efficacy, and safety of IL antagonists were reviewed.
DATA SYNTHESIS: Rilonacept traps IL-1α and IL-1β. In the Phase III trial,
rilonacept was associated with a lower risk of recurrence, more persistent
clinical response, and higher amount of days with no or minimal pericarditis
symptoms, compared with placebo. The median time to pain response was 5 days,
and median time to normalization of C-reactive protein was 7 days with
rilonacept. All patients receiving rilonacept during the run-in period were able
to be weaned off of standard background therapy, leading to transition to
rilonacept monotherapy. The most common adverse effects were upper respiratory
tract infections and injection site reactions.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Rilonacept may be used for the
prevention and treatment of multiple recurrences in patients receiving
background therapy for RP, and reduction in risk of recurrence in adults and
adolescents ≥12 years with elevated C-reactive protein. Rilonacept may be
considered to wean patients from standard background therapy.
CONCLUSION: Rilonacept is a safe, once weekly, subcutaneously administered IL-1
"trap," indicated for the treatment of RP, and reduction in risk of recurrent
pericarditis in adults and children ≥12 years of age.
DOI: 10.1177/10600280211036499
PMID: 34459270 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34528670 | 1. Eur Heart J. 2022 Aug 14;43(31):2946-2957. doi: 10.1093/eurheartj/ehab452.
Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.
Imazio M(1), Lazaros G(2), Gattorno M(3), LeWinter M(4), Abbate A(5), Brucato
A(6), Klein A(7).
Author information:
(1)Head of Cardiology, Cardiothoracic Department, University Hospital "Santa
Maria della Misericordia", ASUFC, Piazzale Santa Maria della Misericordia 15,
Udine 33100, Italy.
(2)1st Cardiology Clinic, National and Kapodistrian University of Athens, School
of Medicine, Hippokration General Hospital, Athens, Greece.
(3)Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS G.
Gaslini, Genova, Italy.
(4)Cardiology Unit, University of Vermont Medical Center, Burlington, VT, USA.
(5)VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, USA.
(6)Department of Biomedical and Clinical Sciences "Sacco", Fatebenefratelli
Hospital, Università di Milano, Milan, Italy.
(7)Center for the Diagnosis and Treatment of Pericardial Diseases, Section of
Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular,
and Thoracic Institute, Cleveland Clinic, USA.
Anti-interleukin (IL)-1 agents have been developed for the treatment of
autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an
important pathophysiologic process. IL-1α and IL-1β are the most studied members
of the IL-1 family of cytokines and have the strongest proinflammatory effects.
A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory
effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial
cells) and IL-1β (released by inflammatory cells) is now a well-recognized
therapeutic target in patients with recurrent idiopathic pericarditis.
Currently, there are three available anti-IL-1 agents: anakinra (recombinant
human IL-1Ra), rilonacept (a soluble decoy receptor 'trap', binding both IL-1α
and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients
with corticosteroid-dependent and colchicine-resistant recurrent pericarditis
with evidence of systemic inflammation, as evidenced by elevated C-reactive
protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day
subcutaneously usually for at least 6 months, then tapered) and rilonacept
(320 mg subcutaneously for the first day followed by 160 mg subcutaneously
weekly) have been clearly demonstrated in observational studies and randomized
controlled clinical trials. Severe side effects are rare and discontinuation
rates are very low (<4%). The most common reported side effect is injection site
reactions (>50% of patients). In this article, we describe the historical and
pathophysiological background and provide a comprehensive review of these
agents, which appear to be the most significant advance in medical therapy of
recurrent pericarditis in the last 5 years.
© The Author(s) 2021. Published by Oxford University Press on behalf of the
European Society of Cardiology.
DOI: 10.1093/eurheartj/ehab452
PMCID: PMC9375710
PMID: 34528670 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: M.I., G.L., M.G., M.L.W.,
A.A., A.B., and A.K. have been Advisory Board members for SOBI and KINIKSA. This
study was not funded. |
http://www.ncbi.nlm.nih.gov/pubmed/34268651 | 1. Brain Tumor Pathol. 2021 Jul;38(3):210-217. doi: 10.1007/s10014-021-00409-y.
Epub 2021 Jul 15.
Clinical implications of molecular analysis in diffuse glioma stratification.
Mizoguchi M(1), Hata N(2), Kuga D(2), Hatae R(2), Akagi Y(2), Sangatsuda Y(2),
Fujioka Y(2), Takigawa K(2), Funakoshi Y(2), Suzuki SO(3), Iwaki T(3).
Author information:
(1)Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
mmizoguc@ns.med.kyushu-u.ac.jp.
(2)Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
(3)Department of Neuropathology, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan.
The revised 4th edition of the 2016 World Health Organization Classification of
Tumors of the Central Nervous System (2016 CNS WHO) has introduced the
integrated diagnostic classification that combines molecular and histological
diagnoses for diffuse gliomas. In this study, we evaluated the molecular
alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62;
grade 4, 182) based on this classification. Mutations in the isocitrate
dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and
when combined with 1p/19q status, LGGs could be stratified into three groups
except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma,
IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33).
1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup
even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a
relatively worse prognosis; however, this subgroup was more heterogeneous. Of
this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall
survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis
indicated pTERT mutation as early molecular event for gliomagenesis. Therefore,
pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO
grade 4), regardless of histological findings, and future treatment strategy
should be considered based on the precise molecular analysis.
© 2021. The Japan Society of Brain Tumor Pathology.
DOI: 10.1007/s10014-021-00409-y
PMID: 34268651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34667950 | 1. Neurooncol Adv. 2021 Oct 1;3(1):vdab127. doi: 10.1093/noajnl/vdab127.
eCollection 2021 Jan-Dec.
Prognostic implications of epidermal and platelet-derived growth factor receptor
alterations in 2 cohorts of IDHwt glioblastoma.
Alnahhas I(1), Rayi A(1), Guillermo Prieto Eibl MDP(1), Ong S(1), Giglio P(1),
Puduvalli V(1).
Author information:
(1)Division of Neuro-Oncology, Department of Neurology, the Ohio State
University Wexner Medical Center, Columbus, Ohio, USA.
BACKGROUND: Glioblastoma remains a deadly brain cancer with dismal prognosis.
Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT
promoter methylation have been proven to be prognostic and predictive to
response to treatment in gliomas. In this manuscript, we aimed to correlate
other mutations and genetic alterations with various clinical endpoints in
patients with IDH-wild-type (IDHwt) glioblastoma.
METHODS: We compiled a comprehensive clinically annotated database of IDHwt GBM
patients treated at the Ohio State University Wexner Medical Center for whom we
had mutational data through a CLIA-certified genomic laboratory. We then added
data that is publicly available from Memorial Sloan Kettering Cancer Center
through cBioPortal. Each of the genetic alterations (mutations, deletions, and
amplifications) served as a variable in univariate and multivariate Cox
proportional hazard models.
RESULTS: A total of 175 IDHwt GBM patients with available MGMT promoter
methylation data from both cohorts were included in the analysis. As expected,
MGMT promoter methylation was significantly associated with improved overall
survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was
26.5 and 18 months, respectively (HR 0.45; P = .003). Moreover, EGFR/ERBB
alterations were associated with favorable outcome (HR of 0.37 (P = .003), but
only in MGMT promoter unmethylated GBM. We further found that patients with
EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly
worse outcome (HR 7.89; P = .025).
CONCLUSIONS: Our data provide further insight into the impact of genetic
alterations on various clinical outcomes in IDHwt GBM in 2 cohorts of patients
with detailed clinical information and inspire new therapeutic strategies for
IDHwt GBM.
© The Author(s) 2021. Published by Oxford University Press, the Society for
Neuro-Oncology and the European Association of Neuro-Oncology.
DOI: 10.1093/noajnl/vdab127
PMCID: PMC8519397
PMID: 34667950 |
http://www.ncbi.nlm.nih.gov/pubmed/32305004 | 1. Ann Diagn Pathol. 2020 Jun;46:151519. doi: 10.1016/j.anndiagpath.2020.151519.
Epub 2020 Apr 8.
1p/19q co-deleted fibrillary astrocytomas: Not everything that is co-deleted is
an oligodendroglioma.
Andrews C(1), Prayson RA(2).
Author information:
(1)University School and Cleveland Clinic Department of Anatomic Pathology, USA.
(2)University School and Cleveland Clinic Department of Anatomic Pathology, USA.
Electronic address: praysor@ccf.org.
The presence of chromosome 1p/19q co-deletion is one of the hallmark required
criteria for the diagnosis of oligodendroglioma, using the 2016 World Health
Organization (WHO) Classification of Tumours of the Central Nervous System.
Descriptions in the literature of astrocytomas, primarily glioblastomas,
demonstrating partial losses on one or the other chromosome have been described.
The significance of these small deletions is uncertain. Only rarely have cases
of fibrillary astrocytoma been described as having co-deletion, which may
potentially cause diagnostic confusion with oligodendroglioma. The goal of this
study is to examine a large number of fibrillary astrocytomas to document how
often 1p/19q co-deletions are present by Fluorescent In Situ Hybridization
(FISH) testing (the testing method of choice in many institutions) and to
evaluate what other markers may be helpful in avoiding misdiagnosis. This study
is a retrospective evaluation of 359 fibrillary astrocytomas (55 grade II, 62
grade III and 242 grade IV) encountered between June 2016 and June 2019, we
identified 11 tumors (3.1%) that had 1p/19q co-deletion by FISH testing. The
clinical and pathologic features of these cases were reviewed. The 11 cases with
co-deletion included 5 females who ranged in age from 37 to 86 years (median
63 years). Tumors arose in the temporal lobe in 5 patients, frontal lobe in 2,
parietal lobe in 2, occipital lobe in 1, and cerebellum in 1. Final diagnoses
included glioblastoma in 8 patients, anaplastic astrocytoma in 2, and diffuse
astrocytoma in 1. Only 1 case (anaplastic astrocytoma) demonstrated evidence of
IDH-1 immunoreactivity; none of the other 10 tumors showed evidence of an IDH1/2
mutation by PCR testing. Four tumors demonstrated p53 immunostaining of 30% or
more. ATRX mutation as evidenced by loss of staining was observed in only 2
cases. Evidence of EGFR amplification by FISH testing was noted in 5 cases. Of
particular note in the one case that demonstrated both 1p/19q co-deletion and an
IDH-1 mutation, LOH testing was done and showed only partial losses on both
chromosomes. Additionally, this tumor also demonstrated evidence of ATRX and p53
mutations by immunohistochemistry. In conclusion, co-deletions were noted in a
minority of astrocytomas (3.1% of cases in the current study). Only 1 of 11 of
these cases also demonstrated evidence of an IDH mutation, potentially raising
differential diagnostic confusion with oligodendroglioma. Use of LOH 1p/19q
testing, if available, or other markers such as ATRX, p53 and EGFR may be
helpful in avoiding misclassification of such tumors as oligodendroglioma.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.anndiagpath.2020.151519
PMID: 32305004 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest Both authors
declare no potential conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32894375 | 1. Cell Mol Neurobiol. 2022 Apr;42(3):709-722. doi: 10.1007/s10571-020-00959-3.
Epub 2020 Sep 7.
A 1p/19q Codeletion-Associated Immune Signature for Predicting Lower Grade
Glioma Prognosis.
Xu J(1), Liu F(2), Li Y(1), Shen L(3).
Author information:
(1)Department of Neurosurgery, Huzhou Cent Hospital, Affiliated Cent Hospital
Huzhou University, 198 Hongqi Road, Huzhou, 313000, Zhejiang, China.
(2)Department of Neurosurgery, The Affiliated Changzhou No. 2 People's Hospital
of Nanjing Medical University, 68 Gehu Road, Changzhou, 213000, Jiangsu, China.
(3)Department of Neurosurgery, The Affiliated Changzhou No. 2 People's Hospital
of Nanjing Medical University, 68 Gehu Road, Changzhou, 213000, Jiangsu, China.
soochowneuro@163.com.
Lower grade gliomas (LGGs) with codeletion of chromosomal arms 1p and 19q (1p/19
codeletion) have a favorable outcome. However, its overall survival (OS) varies.
Here, we established an immune signature associated with 1p/19q codeletion for
accurate prediction of prognosis of LGGs. The Chinese Glioma Genome Atlas (CGGA)
and The Cancer Genome Atlas (TCGA) databases with RNA sequencing and
corresponding clinical data were dichotomized into training group and testing
group. The immune-related differentially expressed genes (DEGs) associated with
1p/19q codeletion were screened using Cox proportional hazards regression
analyses. A prognostic signature was established using dataset from CGGA and
tested in TCGA database. Subsequently, we explored the correlation between the
prognostic signature and immune response. Thirteen immune genes associated with
1p/19q codeletion were used to construct a prognostic signature. The 1-, 3-,
5-year survival rates of the low-risk group were approximately 97%, 89%, and
79%, while those of the high-risk group were 81%, 50% and 34%, respectively, in
the training group. The nomogram which comprised age, WHO grade, primary or
recurrent types, 1p/19q codeletion status and risk score provided accurate
prediction for the survival rate of glioma. DEGs that were highly expressed in
the high-risk group clustered with many immune-related pathways. Immune
checkpoints including TIM3, PD1, PDL1, CTLA4, TIGIT, MIR155HG, and CD48 were
correlated with the risk score. VAV3 and TNFRFSF11B were found to be candidate
immune checkpoints associated with prognosis. The 1p/19q codeletion-associated
immune signature provides accurate prediction of OS. VAV3 and TNFRFSF11B are
novel immune checkpoints.
© 2020. Springer Science+Business Media, LLC, part of Springer Nature.
DOI: 10.1007/s10571-020-00959-3
PMID: 32894375 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31370384 | 1. J Pathol Transl Med. 2019 Sep;53(5):298-307. doi: 10.4132/jptm.2019.07.15.
Epub 2019 Aug 2.
Reclassification of Mongolian Diffuse Gliomas According to the Revised 2016
World Health Organization Central Nervous System Tumor Classification.
Ochirjav E(1), Enkhbat B(1), Baldandorj T(1), Choe G(2).
Author information:
(1)Department of Pathology, School of Biomedicine, Mongolian National University
of Medical Sciences, Ulaanbaatar, Mongolia.
(2)Department of Pathology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine, Seongnam, Korea.
BACKGROUND: The 2016 World Health Organization (WHO) classification of central
nervous system (CNS) tumors has been modified to incorporate the IDH mutation
and 1p/19q co-deletion in the diagnosis of diffuse gliomas. In this study, we
aimed to evaluate the feasibility and prognostic significance of the revised
2016 WHO classification of CNS tumors in Mongolian patients with diffuse
gliomas.
METHODS: A total of 124 cases of diffuse gliomas were collected, and tissue
microarray blocks were made. IDH1 mutation was tested using
immunohistochemistry, and 1p/19q co-deletion status was examined using
fluorescence in situ hybridization analysis.
RESULTS: According to the 2016 WHO classification, 124 cases of diffuse brain
glioma were reclassified as follows: 10 oligodendroglioma, IDHmut and 1p/19q
co-deleted; three anaplastic oligodendroglioma, IDHmut and 1p/19q co-deleted; 35
diffuse astrocytoma, IDHmut, 11 diffuse astrocytoma, IDHwt, not otherwise
specified (NOS); 22 anaplastic astrocytoma, IDHmut, eight anaplastic
astrocytoma, IDHwt, NOS; and 35 glioblastoma, IDHwt, NOS, respectively. The 2016
WHO classification presented better prognostic value for overall survival in
patients with grade II tumors than traditional histological classification.
Among patients with grade II tumors, those with oligodendroglioma IDHmut and
1p/19q co-deleted and diffuse astrocytoma IDHmut showed significantly higher
survival than those with diffuse astrocytoma IDHwt, NOS (p<.01).
CONCLUSIONS: Mongolian diffuse gliomas could be reclassified according to the
new 2016 WHO classification. Reclassification revealed substantial changes in
diagnosis of both oligodendroglial and astrocytic entities. We have confirmed
that the revised 2016 WHO CNS tumor classification has prognostic significance
in Mongolian patients with diffuse gliomas, especially those with grade II
tumors.
DOI: 10.4132/jptm.2019.07.15
PMCID: PMC6755654
PMID: 31370384
Conflict of interest statement: Conflicts of Interest The authors declare that
they have no potential conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27090007 | 1. Nat Commun. 2016 Apr 19;7:11263. doi: 10.1038/ncomms11263.
Integrated multi-omics analysis of oligodendroglial tumours identifies three
subgroups of 1p/19q co-deleted gliomas.
Kamoun A(1), Idbaih A(2)(3)(4)(5), Dehais C(5), Elarouci N(1), Carpentier
C(2)(3)(4), Letouzé E(1), Colin C(6), Mokhtari K(2)(3)(4)(7), Jouvet A(8),
Uro-Coste E(9), Martin-Duverneuil N(10), Sanson M(2)(3)(4)(5), Delattre
JY(2)(3)(4)(5)(11), Figarella-Branger D(6)(12), de Reyniès A(1), Ducray
F(13)(14)(15); POLA network.
Collaborators: Adam C, Andraud M, Aubriot-Lorton MH, Bauchet L, Beauchesne P,
Bielle F, Blechet C, Campone M, Carpentier AF, Carpiuc I, Cazals-Hatem D,
Chenard MP, Chiforeanu D, Chinot O, Cohen-Moyal E, Colin P, Dam-Hieu P,
Desenclos C, Desse N, Dhermain F, Diebold MD, Eimer S, Faillot T, Fesneau M,
Fontaine D, Gaillard S, Gauchotte G, Gaultier C, Ghiringhelli F, Godard J, Gueye
EM, Guillamo JS, Hamdi-Elouadhani S, Honnorat J, Kemeny JL, Khallil T, Labrousse
F, Langlois O, Laquerriere A, Larrieu-Ciron D, Lechapt-Zalcman E, Guérinel CL,
Levillain PM, Loiseau H, Loussouarn D, Maurage CA, Menei P, Motsuo Fotso MJ,
Noel G, Parker F, Peoc'h M, Polivka M, Quintin-Roué I, Ramirez C, Ricard D,
Richard P, Rigau V, Rousseau A, Runavot G, Sevestre H, Tortel MC, Vandenbos F,
Vauleon E, Viennet G, Villa C.
Author information:
(1)Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le
Cancer, 75013 Paris, France.
(2)Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut
de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.
(3)INSERM U975, 75013 Paris, France.
(4)CNRS, UMR 7225, 75013 Paris, France.
(5)AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin,
75013 Paris, France.
(6)Université de la Méditerranée, Aix-Marseille, Faculté de Médecine La Timone,
CRO2, UMR 911, 13885 Marseille, France.
(7)AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Laboratoire de Neuropathologie
R. Escourolle, 75013 Paris, France.
(8)Département de Pathologie et Neuropathologie, Hôpital Neurologique, Hospices
Civils de Lyon, 69374 Lyon, France.
(9)CHU Toulouse, Hôpital de Rangueil, Service d'Anatomie et Cytologie
Pathologique, 31400 Toulouse, France.
(10)AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neuroradiologie,
75013 Paris, France.
(11)Onconeurotek, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
(12)AP-HM, Hôpital de la Timone, Service d'Anatomie Pathologique et de
Neuropathologie, 13885 Marseille, France.
(13)Hospices Civils de Lyon, Hôpital Neurologique, Service de Neuro-Oncologie,
69374 Lyon, France.
(14)Department of Cancer Cell Plasticity, Cancer Research Centre of Lyon, INSERM
U1052, CNRS UMR5286, 69008 Lyon, France.
(15)Université Claude Bernard Lyon 1, 69000 Lyon, France.
Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three
molecular subgroups are currently distinguished on the basis of the IDH mutation
and 1p/19q co-deletion. Here we present an integrated analysis of the
transcriptome, genome and methylome of 156 OT. Not only does our multi-omics
classification match the current classification but also reveals three subgroups
within 1p/19q co-deleted tumours, associated with specific expression patterns
of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell
(OPC) and neuronal lineage. We confirm the validity of these three subgroups
using public datasets. Importantly, the OPC-like group is associated with more
aggressive clinical and molecular patterns, including MYC activation. We show
that the MYC activation occurs through various alterations, including MYC
genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c
down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is
associated with a poorer outcome independently of histological grade. Our study
reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
DOI: 10.1038/ncomms11263
PMCID: PMC4838899
PMID: 27090007 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/29218432 | 1. J Neurooncol. 2018 Mar;137(1):181-189. doi: 10.1007/s11060-017-2710-7. Epub
2017 Dec 7.
The 2016 revision of the WHO Classification of Central Nervous System Tumours:
retrospective application to a cohort of diffuse gliomas.
Rogers TW(1), Toor G(2), Drummond K(2)(3), Love C(2), Field K(4)(5), Asher R(6),
Tsui A(1), Buckland M(7), Gonzales M(8).
Author information:
(1)Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, VIC,
3050, Australia.
(2)Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, 3050,
Australia.
(3)Department of Surgery, University of Melbourne, Parkville, VIC, 3050,
Australia.
(4)Department of Medical Oncology, Peter MacCallum Cancer Centre, Parkville,
VIC, 3050, Australia.
(5)Department of Medicine, University of Melbourne, Parkville, VIC, 3050,
Australia.
(6)Co-operative Trials Group for Neuro Oncology, NHMRC Trials Centre,
Camperdown, NSW, 2050, Australia.
(7)Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW,
2050, Australia.
(8)Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, VIC,
3050, Australia. michael.gonzales@mh.org.au.
The classification of central nervous system tumours has more recently been
shaped by a focus on molecular pathology rather than histopathology. We
re-classified 82 glial tumours according to the molecular-genetic criteria of
the 2016 revision of the World Health Organization (WHO) Classification of
Tumours of the Central Nervous System. Initial diagnoses and grading were based
on the morphological criteria of the 2007 WHO scheme. Because of the impression
of an oligodendroglial component on initial histological assessment, each tumour
was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate
dehydrogenase (IDH-1 and 2) genes. Additionally, expression of proteins encoded
by alpha-thalassemia X-linked mental retardation (ATRX) and TP53 genes was
assessed by immunohistochemistry. We found that all but two tumours could be
assigned to a specific category in the 2016 revision. The most common change in
diagnosis was from oligoastrocytoma to specifically astrocytoma or
oligodendroglioma. Analysis of progression free survival (PFS) for WHO grade II
and III tumours showed that the objective criteria of the 2016 revision
separated diffuse gliomas into three distinct molecular categories: chromosome
1p/19q co-deleted/IDH mutant, intact 1p/19q/IDH mutant and IDH wild type. No
significant difference in PFS was found when comparing IDH mutant grade II and
III tumours suggesting that IDH status is more informative than tumour grade.
The segregation into distinct molecular sub-types that is achieved by the 2016
revision provides an objective evidence base for managing patients with grade II
and III diffuse gliomas based on prognosis.
DOI: 10.1007/s11060-017-2710-7
PMID: 29218432 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32020379 | 1. Int J Clin Oncol. 2020 Jun;25(6):1004-1009. doi: 10.1007/s10147-020-01628-7.
Epub 2020 Feb 4.
Clinical impact of revisions to the WHO classification of diffuse gliomas and
associated future problems.
Sonoda Y(1).
Author information:
(1)Department of Neurosurgery, Faculty of Medicine, Yamagata University,
Iida-Nishi, 2-2-2, Yamagata, 990-9585, Japan. ysonoda@med.id.yamagata-u.ac.jp.
The publication of the 2016 World Health Organization Classification of Tumors
of the Central Nervous System (2016 WHO CNS) represented a major change in the
classification of brain tumors. It is essential to determine the IDH and 1p/19q
statuses of diffuse gliomas to ensure that the final diagnosis is accurate. The
integrated diagnostic method outlined in the 2016 WHO CNS has enabled more
precise prediction of the prognoses of diffuse gliomas. However, there are
further two points that need to be addressed when planning future clinical
trials. The first is the problems with the WHO grading system for diffuse
gliomas. The second is that examinations for IDH mutations and 1p/19q
co-deletion are not sufficient on their own to accurately predict the prognosis
of diffuse glioma patients. Risk of an IDH-mut diffuse glioma should be
evaluated based on a combination of clinical factors (age and the resection
rate), molecular factors (the presence/absence of CDKN2A deletion), and
histological factors (morphology and the mitotic index). Glioblastoma (GBM) have
also been classified according to their IDH status; however, the frequency of
IDH gene mutations is only 5-10% in GBM. Other molecular markers such as MGMT
methylation, pTERT mutations and EGFR amplification could be more important to
predict clinical outcome. Therefore, the next revision of the classification of
diffuse gliomas will propose a detailed classification based on additional
markers. In the near future, treatments for diffuse gliomas will be chosen
according to the molecular profile of each tumor.
DOI: 10.1007/s10147-020-01628-7
PMID: 32020379 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18710393 | 1. Brain Pathol. 2009 Oct;19(4):623-9. doi: 10.1111/j.1750-3639.2008.00206.x.
Epub 2008 Aug 15.
Interphase cytogenetics for 1p19q and t(1;19)(q10;p10) may distinguish
prognostically relevant subgroups in extraventricular neurocytoma.
Rodriguez FJ(1), Mota RA, Scheithauer BW, Giannini C, Blair H, New KC, Wu KJ,
Dickson DW, Jenkins RB.
Author information:
(1)Department of Laboratory Medicine, Mayo Clinic, Rochester, MN 55905, USA.
rodriguez.fausto@mayo.edu
Co-deletion of chromosome arms 1p and 19q, characteristic of oligodendroglial
tumors, was recently found to be mediated by t(1;19)(q10;p10). To evaluate the
prevalence of 1p19q co-deletion and t(1;19) in extraventricular neurocytomas
(EVN), we studied tumors from 23 patients, including 13 females and 10 males
(median age at diagnosis 34 years, range 2-76 years). Fluorescence in situ
hybridization (FISH) studies were performed with probes targeting 1p36/1q25 and
19q13/19p13 to assess for 1p19q co-deletion, as well as chromosome 1
alpha-satellite and 19p12 to detect t(1;19)(q10;p10). FISH was successful in 21
(91%) cases and demonstrated 1p19q co-deletion in five cases (24%) or isolated
1p loss in two cases (10%). Evidence for t(1;19) was found in four (of five)
cases with 1p19q co-deletion. Three tumors with 1p19q loss and t(1;19)
demonstrated atypical histologic features, compared with one (of 17) tumors
without 1p19q co-deletion (P = 0.01, Fisher exact test). In addition, tumors
with t(1;19) showed increased mitotic activity compared with tumors without
t(1;19) (P = 0.045; Wilcoxon rank sum test). The four patients with t(1;19)
developed tumor recurrence (n = 3), or expired (n = 2) 3.5 to 5.5 years after
first resection. These results suggest that 1p19q loss and t(1;19) occur in a
subset of EVN, and may be associated with aggressive histology in these tumors.
DOI: 10.1111/j.1750-3639.2008.00206.x
PMCID: PMC2742575
PMID: 18710393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32681084 | 1. Sci Rep. 2020 Jul 17;10(1):11922. doi: 10.1038/s41598-020-68733-5.
Human IDH mutant 1p/19q co-deleted gliomas have low tumor acidity as evidenced
by molecular MRI and PET: a retrospective study.
Yao J(1)(2)(3), Hagiwara A(1)(2), Raymond C(1)(2), Shabani S(1), Pope WB(2),
Salamon N(2), Lai A(4)(5), Ji M(4)(5), Nghiemphu PL(4)(5), Liau LM(6), Cloughesy
TF(4)(5), Ellingson BM(7)(8)(9)(10).
Author information:
(1)UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and
Imaging Biomarkers, University of California, Los Angeles, 924 Westwood Blvd.,
Suite 615, Los Angeles, CA, 90024, USA.
(2)Department of Radiological Sciences, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA, USA.
(3)Department of Bioengineering, Henry Samueli School of Engineering and Applied
Science, University of California, Los Angeles, Los Angeles, CA, USA.
(4)UCLA Neuro-Oncology Program, University of California, Los Angeles, Los
Angeles, CA, USA.
(5)Department of Neurology, David Geffen School of Medicine, University of
California, Los Angeles, Los Angeles, CA, USA.
(6)Department of Neurosurgery, David Geffen School of Medicine, University of
California, Los Angeles, Los Angeles, CA, USA.
(7)UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and
Imaging Biomarkers, University of California, Los Angeles, 924 Westwood Blvd.,
Suite 615, Los Angeles, CA, 90024, USA. bellingson@mednet.ucla.edu.
(8)Department of Radiological Sciences, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA, USA.
bellingson@mednet.ucla.edu.
(9)Department of Bioengineering, Henry Samueli School of Engineering and Applied
Science, University of California, Los Angeles, Los Angeles, CA, USA.
bellingson@mednet.ucla.edu.
(10)UCLA Neuro-Oncology Program, University of California, Los Angeles, Los
Angeles, CA, USA. bellingson@mednet.ucla.edu.
Co-deletion of 1p/19q is a hallmark of oligodendroglioma and predicts better
survival. However, little is understood about its metabolic characteristics. In
this study, we aimed to explore the extracellular acidity of WHO grade II and
III gliomas associated with 1p/19q co-deletion. We included 76 glioma patients
who received amine chemical exchange saturation transfer (CEST) imaging at 3 T.
Magnetic transfer ratio asymmetry (MTRasym) at 3.0 ppm was used as the
pH-sensitive CEST biomarker, with higher MTRasym indicating lower pH. To control
for the confounder factors, T2 relaxometry and
L-6-18F-fluoro-3,4-dihydroxyphenylalnine (18F-FDOPA) PET data were collected in
a subset of patients. We found a significantly lower MTRasym in 1p/19q
co-deleted gliomas (co-deleted, 1.17% ± 0.32%; non-co-deleted, 1.72% ± 0.41%,
P = 1.13 × 10-7), while FDOPA (P = 0.92) and T2 (P = 0.61) were not
significantly affected. Receiver operating characteristic analysis confirmed
that MTRasym could discriminate co-deletion status with an area under the curve
of 0.85. In analysis of covariance, 1p/19q co-deletion status was the only
significant contributor to the variability in MTRasym when controlling for age
and FDOPA (P = 2.91 × 10-3) or T2 (P = 8.03 × 10-6). In conclusion, 1p/19q
co-deleted gliomas were less acidic, which may be related to better prognosis.
Amine CEST-MRI may serve as a non-invasive biomarker for identifying 1p/19q
co-deletion status.
DOI: 10.1038/s41598-020-68733-5
PMCID: PMC7367867
PMID: 32681084 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/26257825 | 1. Mol Cytogenet. 2015 Aug 7;8:60. doi: 10.1186/s13039-015-0156-1. eCollection
2015.
Observations of the genomic landscape beyond 1p19q deletions and EGFR
amplification in glioma.
Paxton CN(1), Rowe LR(1), South ST(2).
Author information:
(1)ARUP Institute for Clinical and Experimental Pathology® ARUP Laboratories,
500 Chipeta Way, Salt Lake City, UT 84108 USA.
(2)ARUP Institute for Clinical and Experimental Pathology® ARUP Laboratories,
500 Chipeta Way, Salt Lake City, UT 84108 USA ; Departments of Pathology and
Pediatrics, University of Utah, Salt Lake City, UT USA.
BACKGROUND: With recent advancements in molecular techniques, the opportunities
to gather whole genome information have increased, even in degraded samples such
as FFPE tissues. As a result, a broader view of the genomic landscape of solid
tumors may be explored. Whole genome copy number and loss of heterozygosity
patterns can advance our understanding of mechanisms and complexity of various
tumors.
RESULTS: Genome-wide alterations involving copy number changes and loss of
heterozygosity were identified in 17 glioma samples with positive FISH results
for 1p19q co-deletions (n = 9) or EGFR amplification (n = 8). Gliomas positive
for 1p19q co-deletions did not have other frequently recurrent genomic
alterations. Additional copy-number alterations were observed in individual
cases, and consisted primarily of large-scale changes, including gains or losses
of entire chromosomes. The genomic architecture of EGFR amplified gliomas was
much more complex, with a high number of gains and losses across the genome.
Recurrent alterations in EGFR amplified gliomas were both focal, such as CDKN2A
homozygous deletions, and large, such as chromosome 10 loss.
CONCLUSIONS: Microarray enabled a broader picture of the genomic alterations
occurring in glioma cases. Gliomas with 1p19q co-deletion had a relatively quiet
genome, apart from the selected co-deletion. Additional alterations in isolated
cases, involved primarily larger aberrations. On the other hand, EGFR amplified
cases tended to be more complex and have specific abnormalities associated with
the EGFR amplification. Furthermore, 1p19q co-deletions and EGFR amplification
associated copy number changes appeared to often be mutually exclusive.
DOI: 10.1186/s13039-015-0156-1
PMCID: PMC4528708
PMID: 26257825 |
http://www.ncbi.nlm.nih.gov/pubmed/31157866 | 1. Carcinogenesis. 2019 Oct 16;40(10):1229-1239. doi: 10.1093/carcin/bgz102.
Systematically characterize the clinical and biological significances of 1p19q
genes in 1p/19q non-codeletion glioma.
Chai RC(1)(2)(3), Zhang KN(1)(2), Chang YZ(4), Wu F(1)(2), Liu YQ(1)(2), Zhao
Z(1)(2), Wang KY(1)(2), Chang YH(1)(2), Jiang T(1)(2)(3)(4), Wang
YZ(1)(2)(3)(4).
Author information:
(1)Department of Molecular Neuropathology, Beijing Neurosurgical Institute,
Capital Medical University, Beijing, China.
(2)Chinese Glioma Genome Atlas Network (CGGA), Beijing, China.
(3)China National Clinical Research Center for Neurological Diseases.
(4)Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical
University, Beijing, China.
1p/19q codeletion, which leads to the abnormal expression of 1p19q genes in
oligodendroglioma, is associated with chemosensitivity and favorable prognosis.
Here, we aimed to explore the clinical implications of 1p19q gene expression in
1p/19q non-codel gliomas. We analyzed expression of 1p19q genes in 668 1p/19q
non-codel gliomas obtained from The Cancer Genome Atlas (n = 447) and the
Chinese Glioma Genome Atlas (n = 221) for training and validation, respectively.
The expression of 1p19q genes was significantly correlated with the
clinicopathological features and overall survival of 1p/19q non-codel gliomas.
Then, we derived a risk signature of 25 selected 1p19q genes that not only had
prognosis value in total 1p/19q non-codel gliomas but also had prognosis value
in stratified gliomas. The prognosis value of the risk signature was superior
than known clinicopathological features in 1p/19q non-codel gliomas and was also
highly associated with the following features: loss of CDKN2A/B copy number in
mutant-IDH-astrocytoma; telomerase reverse transcriptase (TERT) promoter
mutation, combined chromosome 7 gain/chromosome 10 loss and epidermal growth
factor receptor amplification in wild-type-IDH-astrocytoma; classical and
mesenchymal subtypes in glioblastoma. Furthermore, genes enriched in the
biological processes of cell division, extracellular matrix, angiogenesis
significantly correlated to the signature risk score, and this is also supported
by the immunohistochemistry and cell biology experiments. In conclusion, the
expression profile of 1p19q genes is highly associated with the malignancy and
prognosis of 1p/19q non-codel gliomas. A 25-1p19q-gene signature has powerfully
predictive value for both malignant molecular pathological features and
prognosis across distinct subgroups of 1p/19q non-codel gliomas.
© The Author(s) 2019. Published by Oxford University Press. All rights reserved.
For Permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/carcin/bgz102
PMID: 31157866 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33361717 | 1. Malays J Pathol. 2020 Dec;42(3):369-376.
FISHing for 1p19q codel in oligodendroglioma.
Kong PL(1), Cheah PL, Mun KS, Chiew SF, Lau TP, Koh CC, Teoh KH, Nazarina AR,
Looi LM.
Author information:
(1)Genomic Medical Science, University Malaya, Faculty of Medicine and Health
Sciences, Department of Pathology, Kuala Lumpur, Malaysia.
po_lian88@siswa.um.edu.my.
Together with isocitrate dehydrogenase (IDH) mutation, co-deletion of 1p19q
(1p19q codel) is a prerequisite for diagnosis of oligodendroglioma, making it
imperative that histopathology laboratories introduce testing for 1p19q codel.
To date there is still no consensus reference range and cut-offs that confirm
deletion of 1p or 19q. We embarked on determining our reference range in 11
formalinfixed, paraffin-embedded non-neoplastic brain tissue using fluorescence
in situ hybridisation (FISH) with the Vysis 1p36/1q25 and 19q13/19p13 FISH Probe
Kit (Abbott Molecular Inc., USA). At same time we attempted to validate our
methodology in 13 histologically-confirmed IDH-mutant oligodendrogliomas. For
1p, percentage cells with deletion (range=8-23%; mean±SD = 15.73±5.50%) and
target: control (1p36:1q25) ratio (range = 0.89-0.96; mean±SD = 0.92±0.03) in
non-neoplastic brain, differed significantly (p<0.000) from oligodendroglioma
(percentage cells with deletion: range = 49-100%; mean±SD = 82.46±15.21%;
target:control ratio range:0.50-0.76; mean±SD = 0.59±0.08). For 19q, percentage
cells with deletion (range = 7-20%; mean±SD = 12.00±3.49%) and target:control
(19q13/19p13) ratio (range:0.90-0.97; mean±SD = 0.94±0.02) in non-neoplastic
brain also differed significantly from oligodendroglioma (percentage cells with
deletion: range = 45-100%; mean±SD = 82.62±18.13%; target:control ratio
range:0.50-0.78; mean±SD = 0.59±0.09). Using recommended calculation method, for
diagnosis of 1p deletion, percentage of cells showing deletion should be >32-33%
and/or target:control ratio <0.83. For 19q, percentage of cells showing deletion
should be >22% and target:control ratio <0.88. Using these cut-offs all 13
oligodendroglioma demonstrated 1p19q codel.
PMID: 33361717 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25971646 | 1. Clin Oncol (R Coll Radiol). 2015 Aug;27(8):445-53. doi:
10.1016/j.clon.2015.04.008. Epub 2015 May 10.
FISHing Tips: What Every Clinician Should Know About 1p19q Analysis in Gliomas
Using Fluorescence in situ Hybridisation.
Pinkham MB(1), Telford N(2), Whitfield GA(3), Colaco RJ(4), O'Neill F(2), McBain
CA(4).
Author information:
(1)Clinical Oncology, Christie NHS Foundation Trust, Manchester, UK; School of
Medicine, University of Queensland, Brisbane, Australia. Electronic address:
Mark.pinkham@trinity.oxon.org.
(2)Oncology Cytogenetics, Christie NHS Foundation Trust, Manchester, UK.
(3)Clinical Oncology, Christie NHS Foundation Trust, Manchester, UK; The
University of Manchester, Manchester Academic Health Science Centre, Christie
NHS Foundation Trust, Manchester, UK.
(4)Clinical Oncology, Christie NHS Foundation Trust, Manchester, UK.
1p19q co-deletion is a chromosomal alteration associated with primary brain
tumours of oligodendroglial histology. It is an established predictive and
prognostic biomarker that informs whether patients are offered radiotherapy,
chemotherapy or both. In the near future, 1p19q co-deletion status may also be
incorporated into the reclassification of gliomas. Analysis is commonly carried
out using fluorescence in situ hybridisation (FISH) because it is a reliable and
validated laboratory technique. The result is generally considered to be
dichotomous (1p19q co-deletion present or absent), but there are subtleties in
interpretation that are of clinical relevance. Separate centres may interpret
certain chromosome deletion patterns differently. Pivotal trials in mixed and
pure anaplastic oligodendrogliomas have used slightly different FISH probe
ratios as the cut-off for chromosome deletion. Here we review the clinical
implications of this variability and review the process of 1p19q co-deletion
assessment using FISH in gliomas from a clinician's perspective. We also
consider common alternative methods of analysis.
Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd.
All rights reserved.
DOI: 10.1016/j.clon.2015.04.008
PMID: 25971646 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33482430 | 1. Comput Med Imaging Graph. 2021 Mar;88:101831. doi:
10.1016/j.compmedimag.2020.101831. Epub 2020 Nov 27.
Automated MRI based pipeline for segmentation and prediction of grade, IDH
mutation and 1p19q co-deletion in glioma.
Decuyper M(1), Bonte S(2), Deblaere K(3), Van Holen R(2).
Author information:
(1)Medical Image and Signal Processing (MEDISIP), Ghent University, Ghent,
Belgium. Electronic address: milan.decuyper@ugent.be.
(2)Medical Image and Signal Processing (MEDISIP), Ghent University, Ghent,
Belgium.
(3)Department of Radiology, Ghent University Hospital, Ghent, Belgium.
In the WHO glioma classification guidelines grade (glioblastoma versus
lower-grade glioma), IDH mutation and 1p/19q co-deletion status play a central
role as they are important markers for prognosis and optimal therapy planning.
Currently, diagnosis requires invasive surgical procedures. Therefore, we
propose an automatic segmentation and classification pipeline based on routinely
acquired pre-operative MRI (T1, T1 postcontrast, T2 and/or FLAIR). A 3D U-Net
was designed for segmentation and trained on the BraTS 2019 training dataset.
After segmentation, the 3D tumor region of interest is extracted from the MRI
and fed into a CNN to simultaneously predict grade, IDH mutation and 1p19q
co-deletion. Multi-task learning allowed to handle missing labels and train one
network on a large dataset of 628 patients, collected from The Cancer Imaging
Archive and BraTS databases. Additionally, the network was validated on an
independent dataset of 110 patients retrospectively acquired at the Ghent
University Hospital (GUH). Segmentation performance calculated on the BraTS
validation set shows an average whole tumor dice score of 90% and increased
robustness to missing image modalities by randomly excluding input MRI during
training. Classification area under the curve scores are 93%, 94% and 82% on the
TCIA test data and 94%, 86% and 87% on the GUH data for grade, IDH and 1p19q
status respectively. We developed a fast, automatic pipeline to segment glioma
and accurately predict important (molecular) markers based on pre-therapy MRI.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.compmedimag.2020.101831
PMID: 33482430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29550880 | 1. Brain Tumor Pathol. 2018 Apr;35(2):106-113. doi: 10.1007/s10014-018-0312-5.
Epub 2018 Mar 17.
Immunohistochemical ATRX expression is not a surrogate for 1p19q codeletion.
Yamamichi A(1), Ohka F(1), Aoki K(1), Suzuki H(1), Kato A(1), Hirano M(1),
Motomura K(1), Tanahashi K(1), Chalise L(1), Maeda S(1), Wakabayashi T(1), Kato
Y(2), Natsume A(3).
Author information:
(1)Department of Neurosurgery, Nagoya University School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
(2)Department of Antibody Drug Development, Graduate School of Medicine, New
Industry Creation Hatchery Center, Tohoku University, Sendai, Miyagi, Japan.
(3)Department of Neurosurgery, Nagoya University School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. anatsume@med.nagoya-u.ac.jp.
The IDH-mutant and 1p/19q co-deletion (1p19q codel) provides significant
diagnostic and prognostic value in lower-grade gliomas. As ATRX mutation and
1p19q codel are mutually exclusive, ATRX immunohistochemistry (IHC) may
substitute for 1p19q codel, but this has not been comprehensively examined. In
the current study, we performed ATRX-IHC in 78 gliomas whose ATRX statuses were
comprehensively determined by whole exome sequencing. Among the 60 IHC-positive
and 18 IHC-negative cases, 86.7 and 77.8% were ATRX-wildtype and ATRX-mutant,
respectively. ATRX mutational patterns were not consistent with ATRX-IHC. If our
cohort had only used IDH status and IHC-based ATRX expression for diagnosis, 78
tumors would have been subtyped as 48 oligodendroglial tumors, 16 IDH-mutant
astrocytic tumors, and 14 IDH-wildtype astrocytic tumors. However, when the
1p19q codel test was performed following ATRX-IHC, 8 of 48 ATRX-IHC-positive
tumors were classified as "1p19q non-codel" and 3 of 16 ATRX-IHC-negative tumors
were classified as "1p19q codel"; a total of 11 tumors (14%) were incorrectly
classified. In summary, we observed dissociation between ATRX-IHC and actual
1p19q codel in 11 of 64 IDH-mutant LGGs. In describing the complex IHC
expression of ATRX somatic mutations, our results indicate the need for caution
when using ATRX-IHC as a surrogate of 1p19q status.
DOI: 10.1007/s10014-018-0312-5
PMID: 29550880 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28340142 | 1. Neuro Oncol. 2017 Jun 1;19(6):786-795. doi: 10.1093/neuonc/now285.
Multigene signature for predicting prognosis of patients with 1p19q co-deletion
diffuse glioma.
Hu X(1)(2), Martinez-Ledesma E(1), Zheng S(1), Kim H(1)(3), Barthel F(1)(3),
Jiang T(4), Hess KR(5), Verhaak RGW(1)(6)(3).
Author information:
(1)Department of Genomic Medicine, The University of Texas MD Anderson Cancer
Center, Houston, Texas
(2)Program of Bioinformatics and Biostatistics, The University of Texas-Houston
Graduate School of Biomedical Sciences, Houston, Texas
(3)Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
(4)Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical
University, Beijing, China
(5)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, Texas
(6)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, Texas
BACKGROUND: Co-deletion of 1p and 19q marks a diffuse glioma subtype associated
with relatively favorable overall survival; however, heterogeneous clinical
outcomes are observed within this category.
METHODS: We assembled gene expression profiles and sample annotation of 374
glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status
using gene expression when annotation was missing. A first cohort was randomly
split into training (n = 170) and a validation dataset (n = 163). A second
validation set consisted of 41 expression profiles. An elastic-net penalized Cox
proportional hazards model was applied to build a classifier model through
cross-validation within the training dataset.
RESULTS: The selected 35-gene signature was used to identify high-risk and
low-risk groups in the validation set, which showed significantly different
overall survival (P = .00058, log-rank test). For time-to-death events, the
high-risk group predicted by the gene signature yielded a hazard ratio of 1.78
(95% confidence interval, 1.02-3.11). The signature was also significantly
associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDH-mutant
1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested
that high risk was associated with increased acetylation activity and
inflammatory response. Tumor purity was found to be significantly decreased in
high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type
glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted
gliomas.
CONCLUSION: We identified a 35-gene signature that identifies high-risk and
low-risk categories of 1p/19q positive glioma patients. We have demonstrated
heterogeneity amongst a relatively new glioma subtype and provided a stepping
stone towards risk stratification.
© The Author(s) 2017. Published by Oxford University Press on behalf of the
Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/neuonc/now285
PMCID: PMC5464432
PMID: 28340142 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24197863 | 1. Brain Tumor Pathol. 2014 Oct;31(4):257-64. doi: 10.1007/s10014-013-0168-7.
Epub 2013 Nov 7.
Alpha-internexin and altered CIC expression as a supportive diagnostic marker
for oligodendroglial tumors with the 1p/19q co-deletion.
Nagaishi M(1), Suzuki A, Nobusawa S, Yokoo H, Nakazato Y.
Author information:
(1)Department of Human Pathology, Gunma University Graduate School of Medicine,
3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan,
masaya.nagaishi@gmail.com.
α-Internexin (INA) has been proposed as a biomarker of oligodendroglial tumors
with the 1p/19q co-deletion. On the other hand, sequence studies have recently
linked the CIC mutation and subsequent altered CIC expression to the 1p/19q
co-deletion in oligodendroglial tumors. We assessed the usability of combination
immunohistochemical analysis using CIC and INA as a surrogate tool for the
1p/19q status in 39 cases of oligodendroglial tumors. The positive expression of
INA was observed in 10 cases (52 %) of oligodendroglial tumors with the 1p/19q
co-deletion, and in only 3 cases of oligodendroglial tumors without the 1p/19q
co-deletion (15 %, P = 0.012). The lack of CIC expression was detected in 13
cases (68 %) of oligodendroglial tumors with the 1p/19q co-deletion, and in only
1 case of oligodendroglial tumors without the 1p/19q co-deletion (5 %,
P < 0.0001). Combined immunohistochemical analysis assessed by INA expression
and/or the lack of CIC expression was strongly associated with the 1p/19q
co-deletion in oligodendroglial tumors, indicating a potential surrogate marker
of the 1p/19q state. Although combined immunohistochemical analysis cannot be
totally replaced by molecular genetic analysis as a definitive diagnostic
technique, it may contribute to a steady morphological diagnosis by predicting
the 1p/19q state in oligodendroglial tumors.
DOI: 10.1007/s10014-013-0168-7
PMID: 24197863 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25277207 | 1. Oncotarget. 2014 Sep 15;5(17):7960-79. doi: 10.18632/oncotarget.2401.
Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and
cell clonogenicity.
Chittaranjan S(1), Chan S(1), Yang C(1), Yang KC(1), Chen V(1), Moradian A(2),
Firme M(1), Song J(1), Go NE(3), Blough MD(4), Chan JA(5), Cairncross JG(4),
Gorski SM(3), Morin GB(6), Yip S(7), Marra MA(6).
Author information:
(1)Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
BC, Canada.
(2)Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
BC, Canada. California Institute of Technology, Beckman Institute, Pasadena, CA,
USA.
(3)Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
BC, Canada. Department of Molecular Biology and Biochemistry, Simon Fraser
University, Burnaby, BC, Canada.
(4)Department of Clinical Neurosciences, University of Calgary, Calgary, AB,
Canada. Southern Alberta Cancer Research Institute, University of Calgary,
Calgary, AB, Canada. Clark H. Smith Brain Tumour Centre, University of Calgary,
Calgary, AB, Canada.
(5)Southern Alberta Cancer Research Institute, University of Calgary, Calgary,
AB, Canada. Department of Pathology and Laboratory Medicine, University of
Calgary, Calgary, AB, Canada. Clark H. Smith Brain Tumour Centre, University of
Calgary, Calgary, AB, Canada.
(6)Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
BC, Canada. Department of Medical Genetics, University of British Columbia,
Vancouver, BC, Canada.
(7)Department of Pathology and Laboratory Medicine Vancouver General Hospital,
Vancouver, BC, Canada.
The majority of oligodendrogliomas (ODGs) exhibit combined losses of chromosomes
1p and 19q and mutations of isocitrate dehydrogenase (IDH1-R132H or IDH2-R172K).
Approximately 70% of ODGs with 1p19q co-deletions harbor somatic mutations in
the Capicua Transcriptional Repressor (CIC) gene on chromosome 19q13.2. Here we
show that endogenous long (CIC-L) and short (CIC-S) CIC proteins are
predominantly localized to the nucleus or cytoplasm, respectively. Cytoplasmic
CIC-S is found in close proximity to the mitochondria. To study wild type and
mutant CIC function and motivated by the paucity of 1p19q co-deleted ODG lines,
we created HEK293 and HOG stable cell lines ectopically co-expressing CIC and
IDH1. Non-mutant lines displayed increased clonogenicity, but cells
co-expressing the mutant IDH1-R132H with either CIC-S-R201W or -R1515H showed
reduced clonogenicity in an additive manner, demonstrating cooperative effects
in our assays. Expression of mutant CIC-R1515H increased cellular
2-Hydroxyglutarate (2HG) levels compared to wild type CIC in IDH1-R132H
background. Levels of phosphorylated ATP-citrate Lyase (ACLY) were lower in cell
lines expressing mutant CIC-S proteins compared to cells expressing wild type
CIC-S, supporting a cytosolic citrate metabolism-related mechanism bof reduced
clonogenicity in our in vitro model systems. ACLY or phospho-ACLY were similarly
reduced in CIC-mutant 1p19q co-deleted oligodendroglioma patient samples.
DOI: 10.18632/oncotarget.2401
PMCID: PMC4202173
PMID: 25277207 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interests The authors declare that
they have no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35114775 | 1. Folia Neuropathol. 2021;59(4):350-358. doi: 10.5114/fn.2021.112562.
Can oligodendrocyte transcriptional factor-2 (Olig2) be used as an alternative
for 1p/19q co-deletions to distinguish oligodendrogliomas from other glial
neoplasms?
Kurdi M(1), Alkhatabi H(2), Butt N(3), Albayjani H(4), Aljhdali H(5), Mohamed
F(1), Alsinani T(6), Baeesa S(7), Almuhaini E(8), Al-Ghafari A(9), Hakamy S(4),
Faizo E(10), Bahakeem B(11).
Author information:
(1)Department of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz
University, Saudi Arabia.
(2)Department of Medical Laboratory Technology, Faculty of Applied Medical
Science, King Abdulaziz University, Jeddah, Saudi Arabia.
(3)Department of Family and Community Medicine, Faculty of Medicine in Rabigh,
King Abdulaziz University, Saudi Arabia.
(4)Center of Excellence in Genomic Research, King Abdulaziz University, Jeddah,
Saudi Arabia.
(5)Department of Pathology, Faculty of Medicine, King Abdulaziz University,
Jeddah, Saudi Arabia.
(6)Department of Surgery, King Fahad General Hospital, Jeddah, Saudi Arabia.
(7)Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University,
Jeddah, Saudi Arabia.
(8)Department of Biochemistry, Faculty of Science, King Abdulaziz University,
Jeddah, Saudi Arabia.
(9)Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King
Abdulaziz University, Jeddah, Saudi Arabia.
(10)Department of Neurosurgery, Tabuk University, Tabuk, Saudi Arabia.
(11)Faculty of Medicine, Umm-Alqura University, Makkah, Saudi Arabia.
AIM OF THE STUDY: Oligodendrocyte transcriptional factor-2 (Olig2) is an
essential marker for oligodendrocytes expression. We aimed to explore the
expression of Olig2 in different glial neoplasms and to investigate if diffuse
Olig2 expression can replace 1p19q co-deletion for the diagnosis of
oligodendroglioma.
MATERIAL AND METHODS: Olig2 was performed on 53 samples of different glial
neoplasms using immunohistochemistry (IHC). 1p/19q deletions were investigated
using fluorescence in situ hybridization (FISH).
RESULTS: Olig2 labelling of different glial neoplasms revealed various
expressions, in which 26 tumours showed diffuse expression (≥ 60%) and 23
tumours showed partial focal expression (< 50%). Four tumours showed no
expression. Of the 26 tumours, 6 oligodendrogliomas had 1p19q co-deletion and
the remaining 3 oligodendrogliomas showed no co-deletion. Three
non-oligodendroglial tumours were found to have 19q deletion. The FISH of the
remaining tumours (14/26) showed no aberrations. There was no significant
difference in the final diagnosis by using 1p19q co-deletion test among glial
neoplasms with diffuse Olig2 expression (p = 0.248).
CONCLUSIONS: Olig2 marker cannot be used as an alternative diagnostic method for
1p19q co-deletion to distinguish oligodendrogliomas from other glial neoplasms.
Although some glial tumours showed diffuse Olig2 expression, 1p19q co-deletion
testing is the best diagnostic method.
DOI: 10.5114/fn.2021.112562
PMID: 35114775 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29890994 | 1. Acta Neuropathol Commun. 2018 Jun 11;6(1):49. doi: 10.1186/s40478-018-0544-y.
Network-based analysis of oligodendrogliomas predicts novel cancer gene
candidates within the region of the 1p/19q co-deletion.
Gladitz J(1), Klink B(2)(3), Seifert M(4)(5).
Author information:
(1)Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of
Medicine, Technische Universität Dresden, Dresden, Germany.
(2)Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine,
Technische Universität Dresden, Dresden, Germany.
(3)National Center for Tumor Diseases, Dresden, Germany.
(4)Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of
Medicine, Technische Universität Dresden, Dresden, Germany.
michael.seifert@tu-dresden.de.
(5)National Center for Tumor Diseases, Dresden, Germany.
michael.seifert@tu-dresden.de.
Oligodendrogliomas are primary human brain tumors with a characteristic 1p/19q
co-deletion of important prognostic relevance, but little is known about the
pathology of this chromosomal mutation. We developed a network-based approach to
identify novel cancer gene candidates in the region of the 1p/19q co-deletion.
Gene regulatory networks were learned from gene expression and copy number data
of 178 oligodendrogliomas and further used to quantify putative impacts of
differentially expressed genes of the 1p/19q region on cancer-relevant pathways.
We predicted 8 genes with strong impact on signaling pathways and 14 genes with
strong impact on metabolic pathways widespread across the region of the 1p/19
co-deletion. Many of these candidates (e.g. ELTD1, SDHB, SEPW1, SLC17A7, SZRD1,
THAP3, ZBTB17) are likely to push, whereas others (e.g. CAP1, HBXIP, KLK6,
PARK7, PTAFR) might counteract oligodendroglioma development. For example,
ELTD1, a functionally validated glioblastoma oncogene located on 1p, was
overexpressed. Further, the known glioblastoma tumor suppressor SLC17A7 located
on 19q was underexpressed. Moreover, known epigenetic alterations triggered by
mutated SDHB in paragangliomas suggest that underexpressed SDHB in
oligodendrogliomas may support and possibly enhance the epigenetic reprogramming
induced by the IDH-mutation. We further analyzed rarely observed deletions and
duplications of chromosomal arms within oligodendroglioma subcohorts identifying
putative oncogenes and tumor suppressors that possibly influence the development
of oligodendroglioma subgroups. Our in-depth computational study contributes to
a better understanding of the pathology of the 1p/19q co-deletion and other
chromosomal arm mutations. This might open opportunities for functional
validations and new therapeutic strategies.
DOI: 10.1186/s40478-018-0544-y
PMCID: PMC5996550
PMID: 29890994 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: No
ethical approval was required for this study. All utilized public omics data
sets were generated by others who obtained ethical approval. COMPETING
INTERESTS: The authors declare that they have no competing interests.
PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/26206478 | 1. Brain Pathol. 2016 Mar;26(2):206-14. doi: 10.1111/bpa.12291. Epub 2015 Aug 14.
Molecular Analysis of Pediatric Oligodendrogliomas Highlights Genetic
Differences with Adult Counterparts and Other Pediatric Gliomas.
Nauen D(1), Haley L(1), Lin MT(1), Perry A(2), Giannini C(3), Burger PC(1),
Rodriguez FJ(1).
Author information:
(1)Department of Pathology, Division of Neuropathology, Johns Hopkins University
School of Medicine, Baltimore, MD.
(2)Department of Pathology, Division of Neuropathology, University of California
San Francisco School of Medicine, San Francisco, CA.
(3)Laboratory of Medicine and Pathology, Mayo Clinic College of Medicine,
Rochester, MN.
Oligodendroglioma represents a distinctive neoplasm in adults but similar
neoplasms occur rarely in children. We studied 20 cases of pediatric
oligodendroglioma by SNP array (median age 9 years, range 1-19; 15 grade II and
5 grade III). Cytogenetic abnormalities were present in 8 (53%) grade II and all
five anaplastic oligodendrogliomas. Most changes were in the form of deletion
and copy neutral loss of heterozygosity (LOH). The most common abnormality was
1p deletion (n = 5). Whole arm 1p19q co-deletion was present in three cases from
adolescent patients and 9p loss in 3, including one low-grade oligodendroglioma
with CDKN2A homozygous deletion. Common losses were largely limited to the
anaplastic subset (n = 5) and included 3q29 (n = 3), 11p (n = 3), 17q (n = 3),
4q (n = 2), 6p (n = 2), 13q (n = 2), 14q (n = 2), 17p (n = 2) and whole Ch 18
loss (n = 2). Gains were non-recurrent except for whole Ch 7 (n = 2) and gain on
12q (n = 2) including the MDM2 locus. Possible germ line LOH (or uniparental
disomy) was present in seven cases (35%), with one focal abnormality
(22q13.1-13.2) in two. BRAF-KIAA1549 fusions and BRAF p.V600E mutations were
absent (n = 13 and 8). In summary, cytogenetic alterations in pediatric
oligodendrogliomas are characterized mostly by genomic losses, particularly in
anaplastic tumors.
© 2015 International Society of Neuropathology.
DOI: 10.1111/bpa.12291
PMCID: PMC4724334
PMID: 26206478 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20035368 | 1. J Neurooncol. 2010 Aug;99(1):57-64. doi: 10.1007/s11060-009-0100-5. Epub 2009
Dec 25.
High rate of deletion of chromosomes 1p and 19q in insular oligodendroglial
tumors.
Wu A(1), Aldape K, Lang FF.
Author information:
(1)The Department of Neurosurgery, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Boulevard, Box 442, Houston, TX 77030, USA.
It has been reported recently that oligodendroglial tumors arising in the insula
rarely harbor co-deletions of chromosomes 1p and 19q, a molecular signature
which is associated with a good prognosis and increased responsiveness to
radiation and chemotherapy compared with tumors in which 1p and/or 19q is
intact. In the context of this claim, we analyzed a series of insular
oligodendroglial tumors in order to determine the frequency of 1p/19q
co-deletion in tumors arising in this region. We identified 14 insular cases
operated on after 2003 in which testing for losses of 1p and 19q was performed.
Of these cases, co-deletion of 1p and 19q occurred in eight (57%). Four (50%) of
eight oligodendrogliomas and four (67%) of six oligoastrocytomas demonstrated
1p/19q co-deletions. Seven of the eight tumors with co-deletion of 1p/19q were
WHO grade II gliomas. There were no statistical differences between tumors with
1p/19q co-deletion compared to those with 1p and/or 19q intact in terms of age,
preoperative KPS, presenting symptoms, left versus right lateralization, tumor
location (purely insular versus extension into frontal or temporal lobe),
preoperative tumor size. There was a preponderance of females in the co-deletion
group, and a greater average extent of resection. In contradistinction to
previous reports, loss of 1p/19q occurs commonly in insular oligodendroglial
tumors. With respect to 1p/19q, insular gliomas do not appear to be distinct
from gliomas arising elsewhere in the brain.
DOI: 10.1007/s11060-009-0100-5
PMCID: PMC2891585
PMID: 20035368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26542540 | 1. Genes Chromosomes Cancer. 2016 Feb;55(2):169-76. doi: 10.1002/gcc.22323. Epub
2015 Nov 6.
Integrated analysis identified genes associated with a favorable prognosis in
oligodendrogliomas.
Liu Y(1)(2), Hu H(1)(2), Zhang C(1)(2), Wang Z(1)(2), Li M(2)(3), Jiang
T(1)(2)(3)(4).
Author information:
(1)Department of Molecular Neuropathology, Beijing Neurosurgical Institute,
Capital Medical University, Beijing, China.
(2)Chinese Glioma Cooperative Group (CGCG), China.
(3)Department of Neurosurgery, Capital Medical University, Beijing Tiantan
Hospital, Beijing, China.
(4)Brain Tumor Center, Beijing Institute for Brain Disorders, Beijing, China.
Oligodendrogliomas (ODs) are the second most common malignant brain tumor and
exhibit characteristic co-deletion of chromosomal arms 1p and 19q (co-deletion
1p/19q), which is associated with down-regulation of tumor suppressors. However,
co-deletion 1p/19q indicates a favorable prognosis that cannot be explained by
the down-regulation of tumor suppressors. In the present study, we determined
that co-deletion 1p/19q was associated with reduced Ki-67 protein level based on
analysis of 354 ODs. To identify genes associated with reduced Ki-67 and a
favorable prognosis of codeletion 1p/19q, we analyzed 96 ODs with RNA-sequencing
and 136 ODs and 4 normal brain tissue samples with RNA microarrays. We thus
identified seven genes within chromosomal arms 1p/19q with significantly reduced
expression in samples with co-deletion of 1p/19q compared to samples with intact
1p/19q. A significant positive correlation was observed between these candidate
genes and Ki-67 expression based on analysis of mRNA expression in 305 gliomas
and 5 normal brain tissue samples. Survival analysis confirmed the prognostic
value of these candidate genes. This finding suggests that these genes within
chromosomal arms 1p/19q are associated with low Ki-67 and a favorable prognosis
in ODs with co-deletion 1p/19q and provides novel therapeutic targets.
© 2015 Wiley Periodicals, Inc.
DOI: 10.1002/gcc.22323
PMID: 26542540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18565359 | 1. Rev Neurol (Paris). 2008 Jun-Jul;164(6-7):595-604. doi:
10.1016/j.neurol.2008.04.002. Epub 2008 May 21.
[Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas:
critical review of the literature and implications in daily clinical practice].
[Article in French]
Fontaine D(1), Vandenbos F, Lebrun C, Paquis V, Frenay M.
Author information:
(1)Service de neurochirurgie, hôpital Pasteur, CHU de Nice, UNSA, 30, avenue de
la Voie-Romaine, 06000 Nice, France. fontaine.d@chu-nice.fr
Losses of chromosomes 1p and 19q are deemed correlated with diagnosis of
oligodendroglioma, higher chemosensitivity and better prognosis. We reviewed the
literature to evaluate the usefulness of these correlations in daily clinical
practice. The rates of deletions relative to histology (WHO classifications)
were extracted from 33 studies, including 2666 patients. The 1p deletions and
1p19q codeletion mean rates were respectively 65.4 and 63.3% in
oligodendrogliomas, 28.7 and 21.6% in oligoastrocytomas, 13.2 and 7.5% in
astrocytomas, 11.6 and 2.9% in glioblastomas. The presence of 1p deletion and
1p19q codeletion were strongly correlated with the histological diagnosis
corresponding to oligodendroglioma. Calculation of specificity, sensitivity,
predictive positive values and false negative rates suggests that presence of
deletion 1p or codeletion represents a strong argument in favor of the diagnosis
of oligodendroglioma. However, considering the high false negative rate, absence
of such deletions does not rule out the diagnosis. In grade 3 oligodendroglial
tumors, the probability of responding to chemotherapy, and the duration of
response, were higher when codeletions were present. This suggests that, in
these tumors, the presence of codeletion is a strong argument in favor of
adjuvant chemotherapy. However, chemotherapy should not be systematically
excluded when codeletions are absent, as the chances of response are about 33%
in this situation. Data concerning low-grade gliomas were more controversial.
Oligodendroglial tumors with 1p deletion or 1p19q codeletion seemed to have a
better prognosis, as five-year survival rates were 50% higher than in tumors
without deletion. This might be explained by the correlation between 1p deletion
and other identified prognosis factors: (1) higher chemosensitivity, (2) tumor
location more frequently in the frontal lobe, leading to better resection and
lower risk of neurological deficit, (3) slower growth rate, (4) higher risk of
epilepsy, leading to an early detection.
DOI: 10.1016/j.neurol.2008.04.002
PMID: 18565359 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34125374 | 1. J Neurooncol. 2021 Jul;153(3):447-454. doi: 10.1007/s11060-021-03781-z. Epub
2021 Jun 14.
A single institution retrospective analysis on survival based on treatment
paradigms for patients with anaplastic oligodendroglioma.
Bush NAO(#)(1)(2), Young JS(#)(3), Zhang Y(3), Dalle Ore CL(3), Molinaro AM(3),
Taylor J(1)(2), Clarke J(1)(2), Prados M(1), Braunstein SE(4), Raleigh DR(3)(4),
Chang SM(2), Berger MS(3), Butowski NA(5).
Author information:
(1)Division of Neuro-Oncology, Department of Neurological Surgery, University of
California, San Francisco, CA, USA.
(2)Department of Neurology, University of California, San Francisco, CA, USA.
(3)Department of Neurological Surgery, University of California, San Francisco,
CA, USA.
(4)Department of Radiation Oncology, University of California, San Francisco,
CA, USA.
(5)Division of Neuro-Oncology, Department of Neurological Surgery, University of
California, San Francisco, CA, USA. butowski@neurosurg.ucsf.edu.
(#)Contributed equally
INTRODUCTION: Anaplastic oligodendrogliomas are high-grade gliomas defined
molecularly by 1p19q co-deletion. There is no curative therapy, and standard of
care includes surgical resection followed by radiation and chemotherapy.
However, the benefit of up-front radiation with chemotherapy compared to
chemotherapy alone has not been demonstrated in a randomized control trial.
Given the potential long-term consequences of radiation therapy, such as
cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual
impairment, there is an effort to balance longevity with radiation toxicity.
METHODS: We performed a retrospective single institution analysis of survival of
patients with anaplastic oligodendroglioma over 20 years.
RESULTS: 159 patients were identified as diagnosed with an anaplastic
oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to
have AO at original diagnosis and had documented 1p19q co-deletion with a median
of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of
patients were treated with radiation and chemotherapy at diagnosis, and 50 %
were treated with adjuvant chemotherapy alone. The group treated with
chemotherapy alone had a trend of receiving more cycles of chemotherapy than
patients treated with radiation and chemotherapy upfront (p = 0.051). Median
overall survival has not yet been reached. The related risk of progression in
the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the
patients who received radiation and chemotherapy (hazard ratio = 4.85
(1.74-13.49), p = 0.002). However, there was no significant difference in
overall survival in patients treated with upfront chemotherapy compared to
patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate
analysis of age, KPS, extent of resection, or upfront versus delayed radiation
was not associated with improved survival.
CONCLUSIONS: Initial treatment with adjuvant chemotherapy alone, rather than
radiation and chemotherapy, may be an option for some patients with anaplastic
oligodendroglioma, as it is associated with similar overall survival despite
shorter progression free survival.
© 2021. The Author(s).
DOI: 10.1007/s11060-021-03781-z
PMCID: PMC8279971
PMID: 34125374 [Indexed for MEDLINE] |