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http://www.ncbi.nlm.nih.gov/pubmed/35118122 | 1. Skin Appendage Disord. 2022 Jan;8(1):1-7. doi: 10.1159/000518191. Epub 2021
Sep 1.
Trichotillomania: What Do We Know So Far?
Melo DF(1), Lima CDS(2)(3), Piraccini BM(4)(5), Tosti A(6).
Author information:
(1)Dermatology Department, University of State of Rio de Janeiro (UERJ), Rio de
Janeiro, Brazil.
(2)Dermatology Department, University of State of Pará (UEPA), Belém, Brazil.
(3)Dermatology Department, University Center of Pará (CESUPA), Belém, Brazil.
(4)Department of Experimental, Diagnostic and Specialty Medicine (DIMES) Alma
Mater Studiorum University of Bologna, Bologna, Italy.
(5)IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
(6)Phillip Frost Department of Dermatology and Cutaneous Surgery, University of
Miami School of Medicine, Miami, Florida, USA.
Trichotillomania is defined as an obsessive-compulsive or related disorder in
which patients recurrently pull out hair from any region of their body. The
disease affects mainly female patients, who often deny the habit, and it usually
presents with a bizarre pattern nonscarring patchy alopecia with short hair and
a negative pull test. Trichoscopy can reveal the abnormalities resulting from
the stretching and fracture of hair shafts, and biopsy can be necessary if the
patient or parents have difficulties in accepting the self-inflicted nature of a
trichotillomania diagnosis. Trichotillomania requires a comprehensive treatment
plan and interdisciplinary approach. Physicians should always have a
nonjudgmental, empathic, and inviting attitude toward the patient. Behavioral
therapy has been used with success in the treatment of trichotillomania, but not
all patients are willing or able to comply with this treatment strategy.
Pharmacotherapy can be necessary, especially in adolescents and adult patients.
Options include tricyclic antidepressants, selective serotonin reuptake
inhibitors, and glutamate-modulating agents. Glutamate-modulating agents such as
N-acetylcysteine are a good first-line option due to significant benefits and
low risk of side effects. Physicians must emphasize that the role of
psychiatry-dermatology liaison is extremely necessary with concurrent support
services for the patient and parents, in case of pediatric patients. In
pediatric cases, parents should be advised and thoroughly educated that negative
feedback and punishment for hair pulling are not going to produce positive
results. Social support is a significant pillar to successful habit reversal
training; therefore, physicians must convey the importance of familial support
to achieving remission. This is a review article that aims to discuss the
literature on trichotillomania, addressing etiology, historical aspects,
clinical and trichoscopic features, main variants, differential diagnosis,
diagnostic clues, and psychological and pharmacological management.
Copyright © 2021 by S. Karger AG, Basel.
DOI: 10.1159/000518191
PMCID: PMC8787581
PMID: 35118122
Conflict of interest statement: Dr. Tosti reports being a consultant − DS
Laboratories, Monat Global, Almirall, Tirthy Madison, Eli Lilly, Bristol Myers
Squibb, and P&G. |
http://www.ncbi.nlm.nih.gov/pubmed/33805441 | 1. J Clin Med. 2021 Mar 29;10(7):1375. doi: 10.3390/jcm10071375.
Recent Progress in Oculopharyngeal Muscular Dystrophy.
Yamashita S(1).
Author information:
(1)Department of Neurology, Graduate School of Medical Sciences, Kumamoto
University, Kumamoto 860-8556, Japan.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy,
characterized by slowly progressive ptosis, dysphagia, and proximal limb
weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n
trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding
protein nuclear 1 gene (11-18 repeats in OPMD instead of the normal 10 repeats).
As the disease progresses, the patients gradually develop a feeling of
suffocation, regurgitation of food, and aspiration pneumonia, although the
initial symptoms and the progression patterns vary among the patients.
Autologous myoblast transplantation may provide therapeutic benefits by reducing
swallowing problems in these patients. Therefore, it is important to assemble
information on such patients for the introduction of effective treatments in
nonendemic areas. Herein, we present a concise review of recent progress in
clinical and pathological studies of OPMD and introduce an idea for setting up a
nation-wide OPMD disease registry in Japan. Since it is important to understand
patients' unmet medical needs, realize therapeutically targetable symptoms, and
identify indices of therapeutic efficacy, our attempt to establish a unique
patient registry of OPMD will be a helpful tool to address these urgent issues.
DOI: 10.3390/jcm10071375
PMCID: PMC8036457
PMID: 33805441
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript; or in the decision to
publish the results. |
http://www.ncbi.nlm.nih.gov/pubmed/35172056 | 1. N Engl J Med. 2022 Feb 17;386(7):655-666. doi: 10.1056/NEJMoa2108903.
EDP-938, a Respiratory Syncytial Virus Inhibitor, in a Human Virus Challenge.
Ahmad A(1), Eze K(1), Noulin N(1), Horvathova V(1), Murray B(1), Baillet M(1),
Grey L(1), Mori J(1), Adda N(1).
Author information:
(1)From Enanta Pharmaceuticals, Watertown, MA (A.A., N.A.); hVIVO, London (K.E.,
N.N., J.M.), Boyd Consultants, Crew (B.M.), BJM Pharma, St. Neots (B.M.), and
S-Cubed Biometrics, Abingdon (M.B., L.G.) - all in the United Kingdom; and
Linical, Frankfurt, Germany (V.H.).
Comment in
N Engl J Med. 2022 Feb 17;386(7):696-697. doi: 10.1056/NEJMe2118465.
J Pediatr. 2022 Aug;247:176-180. doi: 10.1016/j.jpeds.2022.04.053.
BACKGROUND: Respiratory syncytial virus (RSV) infection causes substantial
morbidity and mortality among infants, older adults, and immunocompromised
adults. EDP-938, a nonfusion replication inhibitor of RSV, acts by modulating
the viral nucleoprotein.
METHODS: In a two-part, phase 2a, randomized, double-blind, placebo-controlled
challenge trial, we assigned participants who had been inoculated with RSV-A
Memphis 37b to receive EDP-938 or placebo. Different doses of EDP-938 were
assessed. Nasal-wash samples were obtained from day 2 until day 12 for
assessments. Clinical symptoms were assessed by the participants, and
pharmacokinetic profiles were obtained. The primary end point was the area under
the curve (AUC) for the RSV viral load, as measured by
reverse-transcriptase-quantitative polymerase-chain-reaction assay. The key
secondary end point was the AUC for the total symptom score.
RESULTS: In part 1 of the trial, 115 participants were assigned to receive
EDP-938 (600 mg once daily [600-mg once-daily group] or 300 mg twice daily after
a 500-mg loading dose [300-mg twice-daily group]) or placebo. In part 2, a total
of 63 participants were assigned to receive EDP-938 (300 mg once daily after a
600-mg loading dose [300-mg once-daily group] or 200 mg twice daily after a
400-mg loading dose [200-mg twice-daily group]) or placebo. In part 1, the AUC
for the mean viral load (hours × log10 copies per milliliter) was 204.0 in the
600-mg once-daily group, 217.7 in the 300-mg twice-daily group, and 790.2 in the
placebo group. The AUC for the mean total symptom score (hours × score, with
higher values indicating greater severity) was 124.5 in the 600-mg once-daily
group, 181.8 in the 300-mg twice-daily group, and 478.8 in the placebo group.
The results in part 2 followed a pattern similar to that in part 1: the AUC for
the mean viral load was 173.9 in the 300-mg once-daily group, 196.2 in the
200-mg twice-daily group, and 879.0 in the placebo group, and the AUC for the
mean total symptom score was 99.3, 89.6, and 432.2, respectively. In both parts,
mucus production was more than 70% lower in each EDP-938 group than in the
placebo group. The four EDP-938 regimens had a safety profile similar to that of
placebo. Across all dosing regimens, the EDP-938 median time to maximum
concentration ranged from 4 to 5 hours, and the geometric mean half-life ranged
from 13.7 to 14.5 hours.
CONCLUSIONS: All EDP-938 regimens were superior to placebo with regard to
lowering of the viral load, total symptom scores, and mucus weight without
apparent safety concerns. (ClinicalTrials.gov number, NCT03691623.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2108903
PMID: 35172056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33720995 | 1. PLoS Pathog. 2021 Mar 15;17(3):e1009428. doi: 10.1371/journal.ppat.1009428.
eCollection 2021 Mar.
EDP-938, a novel nucleoprotein inhibitor of respiratory syncytial virus,
demonstrates potent antiviral activities in vitro and in a non-human primate
model.
Rhodin MHJ(1), McAllister NV(1), Castillo J(1), Noton SL(2), Fearns R(2), Kim
IJ(1), Yu J(1), Blaisdell TP(1), Panarese J(1), Shook BC(1), Or YS(1), Goodwin
B(1), Lin K(1).
Author information:
(1)Enanta Pharmaceuticals Inc., Watertown, Massachusetts, United States of
America.
(2)Department of Microbiology, Boston University School of Medicine, Boston,
Massachusetts, United States of America.
EDP-938 is a novel non-fusion replication inhibitor of respiratory syncytial
virus (RSV). It is highly active against all RSV-A and B laboratory strains and
clinical isolates tested in vitro in various cell lines and assays, with
half-maximal effective concentrations (EC50s) of 21, 23 and 64 nM against Long
(A), M37 (A) and VR-955 (B) strains, respectively, in the primary human
bronchial epithelial cells (HBECs). EDP-938 inhibits RSV at a post-entry
replication step of the viral life cycle as confirmed by time-of-addition study,
and the activity appears to be mediated by viral nucleoprotein (N). In vitro
resistance studies suggest that EDP-938 presents a higher barrier to resistance
compared to viral fusion or non-nucleoside L polymerase inhibitors with no
cross-resistance observed. Combinations of EDP-938 with other classes of RSV
inhibitors lead to synergistic antiviral activity in vitro. Finally, EDP-938 has
also been shown to be efficacious in vivo in a non-human primate model of RSV
infection.
DOI: 10.1371/journal.ppat.1009428
PMCID: PMC7993833
PMID: 33720995 [Indexed for MEDLINE]
Conflict of interest statement: I have read the journal’s policy and the authors
of this manuscript have the following competing interests: Authors’ MR, NM, JC,
IJK, JY, TB, JP, BS, YSO, BG, and KL were employees of Enanta Pharmaceuticals
and received salary, stock, and benefits compensation during the course of this
work. Authors SN and RF were paid by Enanta Pharmaceuticals for their work
performing assays whose data have been included in this manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/34225694 | 1. BMC Neurol. 2021 Jul 5;21(1):265. doi: 10.1186/s12883-021-02300-x.
A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1
c.35G > C; p.Gly12Ala point mutation.
Nishii YS(1), Noto YI(2), Yasuda R(1), Kitaoji T(1), Ashida S(1), Tanaka E(1),
Minami N(3), Nishino I(3), Mizuno T(1).
Author information:
(1)Department of Neurology, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841,
Japan.
(2)Department of Neurology, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841,
Japan. [email protected].
(3)Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira,
Tokyo, 187-8502, Japan.
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular
dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal
limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or
GCA trinucleotide repeat in PABPN1 gene.
CASE PRESENTATION: A 78-year-old woman presented with ptosis and gradually
progressive dysphagia. Her son had the same symptoms. A physical examination and
muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal
muscles of the upper limbs, and flexor muscles of the lower limbs.
Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic
pattern. Based on the characteristic muscle involvement pattern and needle-EMG
findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1
c.35G > C point mutation, which mimicked the effect of a common causative repeat
expansion mutation of OPMD.
CONCLUSION: We herein describe the first reported Japanese case of OPMD with
PABPN1 point mutation, suggesting that this mutation is causative in Asians as
well as in Europeans, in whom it was originally reported.
DOI: 10.1186/s12883-021-02300-x
PMCID: PMC8256512
PMID: 34225694 [Indexed for MEDLINE]
Conflict of interest statement: The authors report no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36401806 | 1. Rev Esp Quimioter. 2023 Feb;36(1):26-29. doi: 10.37201/req/096.2022. Epub 2022
Nov 21.
[EDP-938, a new antiviral with inhibitory activity against the nucleoprotein of
the respiratory syncytial virus].
[Article in Spanish]
Reina J(1), Iglesias C.
Author information:
(1)Jordi Reina, Unidad de Virología, Servicio de Microbiología, Hospital
Universitario Son Espases, Facultad de Medicina (UIB). Carretera Valldemossa 79,
07120 Palma de Mallorca, Spain. [email protected].
The absence of an effective vaccine against respiratory syncytial virus (RSV)
has led to the development of various drugs with the ability to inhibit or block
its replicative activity. The first generation, called fusion inhibitors, bind
to the protein on the viral surface and prevent the virus from binding and
entering the cell. However, its low efficacy has determined the start of studies
with second-generation compounds capable of binding or blocking the
nucleoprotein (N); most of these compounds are analogs of 1,4-benzodiazepines.
EDP-938 has shown high efficacy against RSV. The first trials in humans have
shown that this antiviral is rapidly absorbed after oral administration and has
a half-life of between 11-18 hours Administration for seven days of multiple
oral doses of up to 600 mg/day or 300 mg/day/twice a day, there were hardly any
significant adverse effects and the viral load in the lower respiratory tract
decreased significantly.
La ausencia de una vacuna eficaz frente al virus respiratorio sincitial (VRS) ha
determinado el desarrollo de diversos fármacos con capacidad para inhibir o
bloquear su actividad replicadora. Los de primera generación, denominados
inhibidores de la fusión, se fijan a la proteína F de la superficie viral y
evitan la unión y entrada del virus en la célula. Sin embargo su baja eficacia
ha determinado el inicio de los estudios con los compuestos de segunda
generación capaces de unirse o bloquear la nucleoproteína (N); la mayoría de
estos compuestos son análogos de las 1,4-benzodiacepinas. El EDP-938 ha mostrado
una elevada eficacia frente al VRS. Los primeros ensayos realizados en humanos
han mostrado que este antiviral se absorbe de forma rápida tras su
administración oral y presenta una vida media de entre 11-18 horas La
administración durante siete días de múltiples dosis orales de hasta 600 mg/día
o 300 mg/2 veces al día, no presentaban apenas efectos adversos significativos y
disminuía significativamente la carga viral a nivel del tracto respiratorio
inferior.
©The Author 2022. Published by Sociedad Española de Quimioterapia. This article
is distributed under the terms of the Creative Commons Attribution-NonCommercial
4.0 International (CC BY-NC
4.0)(https://creativecommons.org/licenses/by-nc/4.0/).
DOI: 10.37201/req/096.2022
PMCID: PMC9910671
PMID: 36401806 [Indexed for MEDLINE]
Conflict of interest statement: Los autores declaran no tener ningún conflicto
de intereses. |
http://www.ncbi.nlm.nih.gov/pubmed/28643244 | 1. Drugs. 2017 Aug;77(12):1369-1376. doi: 10.1007/s40265-017-0782-5.
Durvalumab: First Global Approval.
Syed YY(1).
Author information:
(1)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
[email protected].
Erratum in
Drugs. 2017 Oct;77(16):1817. doi: 10.1007/s40265-017-0826-x.
Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal
antibody that blocks programmed cell death ligand-1 binding to its receptors
(PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells.
The US FDA has granted durvalumab accelerated approval for the treatment of
patients with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing chemotherapy, or
within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Durvalumab ± tremelimumab is under phase III clinical trials in urothelial
carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck
squamous cell carcinoma. The drug is also being evaluated in phase I or II
clinical trials in a wide range of solid tumours and haematological
malignancies. This article summarizes the milestones in the development of
durvalumab leading to this first approval for urothelial carcinoma.
DOI: 10.1007/s40265-017-0782-5
PMCID: PMC5636860
PMID: 28643244 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29571563 | 1. Ann Pathol. 2018 Apr;38(2):110-125. doi: 10.1016/j.annpat.2018.01.007. Epub
2018 Mar 21.
[PD-L1 testing in non-small cell lung carcinoma: Guidelines from the PATTERN
group of thoracic pathologists].
[Article in French]
Lantuejoul S(1), Adam J(2), Girard N(3), Duruisseaux M(4), Mansuet-Lupo A(5),
Cazes A(6), Rouquette I(7), Gibault L(8), Garcia S(9), Antoine M(10), Vignaud
JM(11), Galateau-Sallé F(12), Sagan C(13), Badoual C(8), Penault-Llorca F(14),
Damotte D(5); pour le groupe pathologistes thoraciques de valorisation de
l’expertise, de la recherche et de l’innovation (PATTERN). Fondation Synergie
Lyon Cancer.
Author information:
(1)Département de biopathologie et département de recherche translationnelle et
d'innovations, centre Léon-Bérard UNICANCER, 28, rue Laennec, 69008 Lyon,
France; Inserm U1209/CNRS 5309, Grenoble-Alpes université, Institute for
Advanced Biosciences, 38700 La Tronche, France. Electronic address:
[email protected].
(2)Département de biologie et pathologie médicales, Gustave-Roussy, 114, rue
Edouard-Vaillant, 94805 Villejuif, France; Inserm U981, Gustave-Roussy, 94805
Villejuif, France.
(3)Institut du thorax Curie-Montsouris, institut Curie, 75005 Paris, France;
Université Claude-Bernard Lyon 1, université de Lyon, 69622 Villeurbanne,
France.
(4)Inserm 1052, CNRS 5286, centre de recherche en cancérologie de Lyon, institut
de cancérologie des Hospices Civiles de Lyon (IC-HCL), service de pneumologie,
hôpital Louis-Pradel, 69008 Lyon, France.
(5)Département de pathologie, hôpital Cochin, université Paris Descartes,
Assistance publique-hôpitaux de Paris, 74014 Paris, France.
(6)Inserm UMR1152, département de pathologie, hôpital Bichat, université Paris
Diderot, 75018 Paris, France.
(7)Département de pathologie, IUCT Oncopôle, CHU de Toulouse, 31059 Toulouse,
France.
(8)Département de pathologie, hôpital européen Georges-Pompidou, Assistance
publique-hôpitaux de Paris, 75015 Paris, France; Inserm UMR-S970, Paris centre
de recherche cardiovasculaire, Georges-Pompidou European Hospital, 75015 Paris,
France.
(9)Département de Pathologie, hôpital Nord, Assistance publique-hôpitaux de
Marseille, Aix-Marseille Université, CRCM, 13015 Marseille, France.
(10)Service d'anatomie pathologique, hôpital Tenon AP-HP, 75020 Paris, France;
UPMC université Paris 06, GRC n(o) 04, Theranoscan, 75252 Paris, France.
(11)Département de pathologie, CHRU de Nancy, 54035 Nancy, France; Inserm 1256,
université de Lorraine, 54505 Vandœuvre-lès-Nancy, France.
(12)Centre National Référent MESOPATH, Base Clinicobiologique nationale
MESOBANK, Registre multicentrique MESONAT centre Leon-Bérard, département de
biopathologie, 69008 Lyon, France.
(13)Inserm U1087, institut du Thorax, service d'anatomie et cytologique
pathologiques, hôpital Hotel-Dieu, CHU de Nantes, 44093 Nantes, France.
(14)UMR Inserm 1240 IMoST, Centre Jean-Perrin, département de pathologie,
université Clermont-Auvergne, 63011 Clermont-Ferrand, France.
Lung cancer is the leading cause of cancer death in France with low response
rates to conventional chemotherapy. Nevertheless, new therapies have emerged
recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab
(OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck & Co), or
PD-L1 ICI, such as atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®,
Astra-Zeneca), and avelumab (BAVENCIO®, EMD Serono). The prescription of
pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients
requires the demonstration of PD-L1 expression by tumor cells by
immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required
for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is
now considered as a companion diagnostic tool for this drug. Numerous
standardized PD-L1 assays performed on dedicated platforms have been validated
in clinical trials, each antibody being associated to one specific PD1 or PD-L1
inhibitor. However, not all pathologists have access to the dedicated platforms
and the high cost of these assays is still a limitation to their implementation;
in addition, the small size of the NSCLC tumor samples does not allow to perform
at the same time multiple assays for multiple drugs. The use of
laboratory-developed tests seems feasible but their validation must guarantee
the same sensitivities and specificities as standardized tests. In this context,
the French group of thoracic pathologists PATTERN has teamed up with thoracic
oncologists to provide recommendations on the indication, the critical technical
steps and the interpretation of the PD-L1 IHC test to help pathologists to
implement quickly and in the best conditions this new theranostic test.
Copyright © 2018 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.annpat.2018.01.007
PMID: 29571563 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30917623 | 1. Molecules. 2019 Mar 26;24(6):1190. doi: 10.3390/molecules24061190.
Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in
Immuno-Oncology.
Lee HT(1), Lee SH(2), Heo YS(3).
Author information:
(1)Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu,
Seoul 05029, Korea. [email protected].
(2)Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu,
Seoul 05029, Korea. [email protected].
(3)Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu,
Seoul 05029, Korea. [email protected].
Cancer cells can evade immune surveillance through the molecular interactions of
immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the
FDA-approved antibody drugs ipilimumab (Yervoy®), nivolumab (Opdivo®),
pembrolizumab (Keytruda®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®),
durvalumab (Imfinzi®), and avelumab (Bavencio®), which block the immune
checkpoint proteins, have brought about a significant breakthrough in the
treatment of a wide range of cancers, as they can induce durable therapeutic
responses. In recent years, crystal structures of the antibodies against PD-1,
PD-L1, and CTLA-4 have been reported. In this review, we describe the latest
structural studies of these monoclonal antibodies and their interactions with
the immune checkpoint proteins. A comprehensive analysis of the interactions of
these immune checkpoint blockers can provide a better understanding of their
therapeutic mechanisms of action. The accumulation of these structural studies
would provide a basis that is essential for the rational design of
next-generation therapies in immuno-oncology.
DOI: 10.3390/molecules24061190
PMCID: PMC6470598
PMID: 30917623 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34731446 | 1. Target Oncol. 2021 Nov;16(6):857-864. doi: 10.1007/s11523-021-00843-0. Epub
2021 Nov 3.
Durvalumab: A Review in Extensive-Stage SCLC.
Al-Salama ZT(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, 0754, Auckland, New
Zealand. [email protected].
Erratum in
Target Oncol. 2022 Jan;17(1):91. doi: 10.1007/s11523-021-00863-w.
Durvalumab (IMFINZI®), a fully human monoclonal antibody against programmed cell
death-ligand 1 (PD-L1), is approved for use in combination with etoposide and
either carboplatin or cisplatin for the first-line treatment of patients with
extensive-stage small cell lung cancer (ES-SCLC). In the pivotal phase III
CASPIAN trial in previously untreated adults with ES-SCLC, the addition of
durvalumab to chemotherapy for up to 4 cycles followed by maintenance durvalumab
was associated with a significantly longer overall survival and a favourable
hazard ratio for progression-free survival compared with chemotherapy alone for
up to 6 cycles. A higher proportion of patients in the durvalumab plus
chemotherapy group had an objective response compared with the chemotherapy
alone group. The efficacy of durvalumab was also sustained with longer
follow-up. Durvalumab in combination with etoposide and either carboplatin or
cisplatin had a manageable tolerability profile in patients with ES-SCLC. Given
the available evidence, durvalumab in combination with etoposide and either
carboplatin or cisplatin represents a valuable treatment option for the
first-line treatment of patients with ES-SCLC, and is an accepted standard of
care option in this setting.
Plain Language Summary: Small cell lung cancer (SCLC) is the most aggressive
form of lung cancer; extensive-stage (ES) disease, which accounts for about
two-thirds of all SCLC, is associated with high relapse rates and a poor
prognosis. Expression of programmed cell death-ligand 1 (PD-L1) on both tumour
cells and tumour-associated immune cells is an adaptive immune response that
helps tumour cells avoid detection and subsequent elimination by the immune
system. Durvalumab (IMFINZI®) is a fully human monoclonal antibody against
PD-L1, which blocks the interaction of PD-L1 with its receptors, thus enhancing
anti-tumour immune responses. When used in combination with chemotherapy
(etoposide and either carboplatin or cisplatin) in adults with untreated
ES-SCLC, durvalumab prolonged overall survival compared with chemotherapy alone;
the improvements in overall survival were also maintained with additional
follow-up. The tolerability profile of durvalumab in combination with
chemotherapy was manageable in patients with ES-SCLC. Durvalumab in combination
with chemotherapy is an effective and valuable treatment option for previously
untreated patients with ES-SCLC.
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s11523-021-00843-0
PMCID: PMC8648650
PMID: 34731446 [Indexed for MEDLINE]
Conflict of interest statement: Zaina T. Al-Salama 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/32727810 | 1. J Immunother Cancer. 2020 Jul;8(2):e000417. doi: 10.1136/jitc-2019-000417.
Small molecule AZD4635 inhibitor of A(2A)R signaling rescues immune cell
function including CD103(+) dendritic cells enhancing anti-tumor immunity.
Borodovsky A(#)(1), Barbon CM(#)(2), Wang Y(3), Ye M(3), Prickett L(3), Chandra
D(3), Shaw J(4), Deng N(3), Sachsenmeier K(5), Clarke JD(6), Linghu B(5), Brown
GA(7), Brown J(8), Congreve M(8), Cheng RK(9), Dore AS(8), Hurrell E(8), Shao
W(10), Woessner R(11), Reimer C(3), Drew L(3), Fawell S(3), Schuller AG(3), Mele
DA(12).
Author information:
(1)Discovery Biology, Nurix Inc, San Francisco, California, USA.
(2)Preclinical Biology, Bluefin Biomedicine, Beverly, Massachusetts, USA.
(3)Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
(4)Discovery Sciences, AstraZeneca PLC, Cambridge, Cambridgeshire, UK.
(5)Translational Medicine, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
(6)Drug Metabolism and Pharamcokinetics, AstraZeneca, Cambridge, Cambridgeshire,
UK.
(7)Discovery, Omass Technologies Ltd, Oxford, United Kingdom.
(8)Heptares Therapeutics, Welwyn Garden City, California, USA.
(9)X-ray Crystallography, LeadXPro, Villigen, Switzerland.
(10)Oncology, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
(11)Pharmacology, Blueprint Medicines, Cambridge, Massachusetts, USA.
(12)Bioscience, AstraZeneca R&D Boston, Waltham, Massachusetts, USA
[email protected].
(#)Contributed equally
Accumulation of extracellular adenosine within the microenvironment is a
strategy exploited by tumors to escape detection by the immune system. Adenosine
signaling through the adenosine 2A receptor (A2AR) on immune cells elicits a
range of immunosuppressive effects which promote tumor growth and limit the
efficacy of immune checkpoint inhibitors. Preclinical data with A2AR inhibitors
have demonstrated tumor regressions in mouse models by rescuing T cell function;
however, the mechanism and role on other immune cells has not been fully
elucidated.
METHODS: We report here the development of a small molecule A2AR inhibitor
including characterization of binding and inhibition of A2AR function with
varying amounts of a stable version of adenosine. Functional activity was tested
in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to
understand the intrinsic role on each cell type. The role of adenosine and A2AR
inhibition was tested in DC differentiation assays as well as co-culture assays
to access the cross-priming function of DCs. Syngeneic models were used to
assess tumor growth alone and in combination with alphaprogrammed death-ligand 1
(αPD-L1). Immunophenotyping by flow cytometry was performed to examine global
immune cell changes upon A2AR inhibition.
RESULTS: We provide the first report of AZD4635, a novel small molecule A2AR
antagonist which inhibits downstream signaling and increases T cell function as
well as a novel mechanism of enhancing antigen presentation by CD103+ DCs. The
role of antigen presentation by DCs, particularly CD103+ DCs, is critical to
drive antitumor immunity providing rational to combine a priming agent AZD4635
with check point blockade. We find adenosine impairs the maturation and antigen
presentation function of CD103+ DCs. We show in multiple syngeneic mouse tumor
models that treatment of AZD4635 alone and in combination with αPD-L1 led to
decreased tumor volume correlating with enhanced CD103+ function and T cell
response. We extend these studies into human DCs to show that adenosine promotes
a tolerogenic phenotype that can be reversed with AZD4635 restoring
antigen-specific T cell activation. Our results support the novel role of
adenosine signaling as an intrinsic negative regulator of CD103+ DCs maturation
and priming. We show that potent inhibition of A2AR with AZD4635 reduces tumor
burden and enhances antitumor immunity. This unique mechanism of action in
CD103+ DCs may contribute to clinical responses as AZD4635 is being evaluated in
clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid
malignancies.
CONCLUSION: We provide evidence implicating suppression of adaptive and innate
immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of
adenosine signaling through selective small molecule inhibition of A2AR using
AZD4635 restores T cell function via an internal mechanism as well as tumor
antigen cross-presentation by CD103+ DCs resulting in antitumor immunity.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/jitc-2019-000417
PMCID: PMC7394305
PMID: 32727810 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: A.B., C.M.B., Y.W., N.D.,
M.Y., J.S., K.S., D.C., L.P., J.D.C., B.L., W.S., R.W., C.R., L.D., S.F., A.G.S.
and D.A.M. are employees of AstraZeneca Pharmaceuticals. J.D.C., G.A.B., J.B.,
M.C., R.K.Y.C., A.S.D., E.H. are employees of Heptares Therapeutics. |
http://www.ncbi.nlm.nih.gov/pubmed/26110128 | 1. N Am J Med Sci. 2015 May;7(5):176-88. doi: 10.4103/1947-2714.157476.
Tumor-suppressor Genes, Cell Cycle Regulatory Checkpoints, and the Skin.
Abreu Velez AM(1), Howard MS(2).
Author information:
(1)Department of Immunodermatopathology, Georgia Dermatopathology Associates,
Atlanta, Georgia, USA.
(2)Department of Dermatopathology, Georgia Dermatopathology Associates, Atlanta,
Georgia, USA.
The cell cycle (or cell-division cycle) is a series of events that take place in
a cell, leading to its division and duplication. Cell division requires cell
cycle checkpoints (CPs) that are used by the cell to both monitor and regulate
the progress of the cell cycle. Tumor-suppressor genes (TSGs) or antioncogenes
are genes that protect the cell from a single event or multiple events leading
to cancer. When these genes mutate, the cell can progress to a cancerous state.
We aimed to perform a narrative review, based on evaluation of the manuscripts
published in MEDLINE-indexed journals using the Medical Subject Headings (MeSH)
terms "tumor suppressor's genes," "skin," and "cell cycle regulatory
checkpoints." We aimed to review the current concepts regarding TSGs, CPs, and
their association with selected cutaneous diseases. It is important to take into
account that in some cell cycle disorders, multiple genetic abnormalities may
occur simultaneously. These abnormalities may include intrachromosomal
insertions, unbalanced division products, recombinations, reciprocal deletions,
and/or duplication of the inserted segments or genes; thus, these presentations
usually involve several genes. Due to their complexity, these disorders require
specialized expertise for proper diagnosis, counseling, personal and family
support, and genetic studies. Alterations in the TSGs or CP regulators may occur
in many benign skin proliferative disorders, neoplastic processes, and
genodermatoses.
DOI: 10.4103/1947-2714.157476
PMCID: PMC4462812
PMID: 26110128
Conflict of interest statement: Conflict of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/21990031 | 1. J Pathol. 2012 Jan;226(2):352-64. doi: 10.1002/path.3022. Epub 2011 Oct 28.
The cell cycle and cancer.
Williams GH(1), Stoeber K.
Author information:
(1)Department of Pathology and Cancer Institute, University College London, UK.
[email protected]
Deregulation of the cell cycle underlies the aberrant cell proliferation that
characterizes cancer and loss of cell cycle checkpoint control promotes genetic
instability. During the past two decades, cancer genetics has shown that
hyperactivating mutations in growth signalling networks, coupled to loss of
function of tumour suppressor proteins, drives oncogenic proliferation. Gene
expression profiling of these complex and redundant mitogenic pathways to
identify prognostic and predictive signatures and their therapeutic targeting
has, however, proved challenging. The cell cycle machinery, which acts as an
integration point for information transduced through upstream signalling
networks, represents an alternative target for diagnostic and therapeutic
interventions. Analysis of the DNA replication initiation machinery and mitotic
engine proteins in human tissues is now leading to the identification of novel
biomarkers for cancer detection and prognostication, and is providing target
validation for cell cycle-directed therapies.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by
John Wiley & Sons, Ltd.
DOI: 10.1002/path.3022
PMID: 21990031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14744434 | 1. Cell. 2004 Jan 23;116(2):235-46. doi: 10.1016/s0092-8674(03)01075-4.
Principles of tumor suppression.
Sherr CJ(1).
Author information:
(1)Howard Hughes Medical Institute, Department of Genetics and Tumor Cell
Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis,
TN 38105, USA. [email protected]
Molecular genetic studies of familial cancer syndromes identified and defined
the recessive nature of tumor suppressor genes and resolved the paradox of why
tumors arising in such families exhibited an autosomally dominant pattern of
inheritance. Subsequent characterization of tumor suppressor proteins revealed
their widespread involvement in sporadic cancers and pinpointed key mechanisms
that protect animals against tumor development. We now recognize that tumor
suppressor genes regulate diverse cellular activities, including cell cycle
checkpoint responses, detection and repair of DNA damage, protein ubiquitination
and degradation, mitogenic signaling, cell specification, differentiation and
migration, and tumor angiogenesis. Their study has become a centerpiece of
contemporary cancer research.
DOI: 10.1016/s0092-8674(03)01075-4
PMID: 14744434 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33682629 | 1. J Biomol Struct Dyn. 2022 Oct;40(16):7256-7273. doi:
10.1080/07391102.2021.1896385. Epub 2021 Mar 8.
Implementation of computational approaches to explore the deleterious effects of
non-synonymous SNPs on pRB protein.
Rahaman MM(1), Islam R(1), Jewel GMNA(1), Hoque H(1).
Author information:
(1)Department of Genetic Engineering and Biotechnology, School of Life Sciences,
Shahjalal University of Science and Technology, Sylhet, Bangladesh.
Retinoblastoma 1 (RB1) is the first discovered tumor suppressor gene and
recognized as the simple model system whose encoded defective protein can cause
a pediatric cancer retinoblastoma. It functions as a negative regulator of the
cell cycle through the interactions with members of the E2F transcription
factors family. The protein of the RB1 gene (pRB) is engaged in various cell
cycle processes including apoptosis, cell cycle arrest and chromatin remodeling.
Recent studies on Retinoblastoma also exhibited multiple sets of point mutation
in the associated protein due to its large polymorphic information in the local
database. In this study, we identified the list of disease associated
non-synonymous single nucleotide polymorphisms (nsSNPs) in RB1 by incorporating
different computational algorithms, web servers, modeling of the mutants and
finally superimposing it. Out of 826 nsSNPs, W516G and W563G were predicted to
be highly deleterious variants in the conserved regions and found to have an
impact on protein structure and protein-protein interaction. Moreover, our study
concludes the effect of W516G variant was more detrimental in destabilizing
protein's nature as compared to W563G variant. We also found defective binding
of pRB having W516G mutation with E2F2 protein. Findings of this study will aid
in shortening of the expensive experimental cost of identifying disease
associated SNPs in retinoblastoma for which specialized personalized treatment
or therapy can be formulated.Communicated by Ramaswamy H. Sarma.
DOI: 10.1080/07391102.2021.1896385
PMID: 33682629 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2046748 | 1. Nature. 1991 Jun 6;351(6326):453-6. doi: 10.1038/351453a0.
The p53 tumour suppressor gene.
Levine AJ(1), Momand J, Finlay CA.
Author information:
(1)Department of Molecular Biology, Lewis Thomas Laboratory, Princeton
University, New Jersey 08544-1014.
The cell cycle is composed of a series of steps which can be negatively or
positively regulated by various factors. Chief among the negative regulators is
the p53 protein. Alteration or inactivation of p53 by mutation, or by its
interactions with oncogene products of DNA tumour viruses, can lead to cancer.
These mutations seem to be the most common genetic change in human cancers.
DOI: 10.1038/351453a0
PMID: 2046748 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12665054 | 1. Adv Cancer Res. 2003;88:101-44. doi: 10.1016/s0065-230x(03)88305-7.
Aberrant ubiquitin-mediated proteolysis of cell cycle regulatory proteins and
oncogenesis.
Bashir T(1), Pagano M.
Author information:
(1)Department of Pathology and NYU Cancer Institute, New York University School
of Medicine, New York, New York 10016, USA.
The ubiquitin pathway plays a central role in the regulation of cell growth and
cell proliferation by controlling the abundance of key cell cycle proteins.
Increasing evidence indicates that unscheduled proteolysis of many cell cycle
regulators contributes significantly to tumorigenesis and is indeed found in
many types of human cancers. Aberrant proteolysis with oncogenic potential is
elicited by two major mechanisms: defective degradation of positive cell cycle
regulators (i.e., proto-oncoproteins) and enhanced degradation of negative cell
cycle regulators (i.e., tumor suppressor proteins). In many cases, increased
protein stability is a result of mutations in the substrate that prevent the
recognition of the protein by the ubiquitin-mediated degradation machinery.
Alternatively, the specific recognition proteins mediating ubiquitination
(ubiquitin ligases) are not expressed or harbor mutations rendering them
inactive. In contrast, the overexpression of a ubiquitin ligase may result in
the enhanced degradation of a negative cell cycle regulator. This chapter aims
to review the involvement of the ubiquitin pathway in the scheduled destruction
of some important cell cycle regulators and to discuss the implications of their
aberrant degradation for the development of cancer.
DOI: 10.1016/s0065-230x(03)88305-7
PMID: 12665054 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20492666 | 1. Mol Cancer. 2010 May 21;9:116. doi: 10.1186/1476-4598-9-116.
Characterization of a naturally-occurring p27 mutation predisposing to multiple
endocrine tumors.
Molatore S(1), Kiermaier E, Jung CB, Lee M, Pulz E, Höfler H, Atkinson MJ,
Pellegata NS.
Author information:
(1)Institute of Pathology, Helmholtz Zentrum München, Ingolstaedter Landstrasse
1, 85764 Neuherberg, Germany.
BACKGROUND: p27Kip1 (p27) is an important negative regulator of the cell cycle
and a putative tumor suppressor. The finding that a spontaneous germline
frameshift mutation in Cdkn1b (encoding p27) causes the MENX multiple endocrine
neoplasia syndrome in the rat provided the first evidence that Cdkn1b is a tumor
susceptibility gene for endocrine tumors. Noteworthy, germline p27 mutations
were also identified in human patients presenting with endocrine tumors. At
present, it is not clear which features of p27 are crucial for this
tissue-specific tumor predisposition in both rats and humans. It was shown that
the MENX-associated Cdkn1b mutation causes reduced expression of the encoded
protein, but the molecular mechanisms are unknown. To better understand the role
of p27 in tumor predisposition and to characterize the MENX animal model at the
molecular level, a prerequisite for future preclinical studies, we set out to
assess the functional properties of the MENX-associated p27 mutant protein
(named p27fs177) in vitro and in vivo.
RESULTS: In vitro, p27fs177 retains some properties of the wild-type p27 (p27wt)
protein: it localizes to the nucleus; it interacts with cyclin-dependent kinases
and, to lower extent, with cyclins. In contrast to p27wt, p27fs177 is highly
unstable and rapidly degraded in every phase of the cell-cycle, including
quiescence. It is in part degraded by Skp2-dependent proteasomal proteolysis,
similarly to p27wt. Photobleaching studies showed reduced motility of p27fs177
in the nucleus compared to p27wt, suggesting that in this compartment p27fs177
is part of a multi-protein complex, likely together with the degradation
machinery. Studies of primary rat newborn fibroblasts (RNF) established from
normal and MENX-affected littermates confirmed the rapid degradation of p27fs177
in vivo which can be rescued by Bortezomib (proteasome inhibitor drug).
Overexpression of the negative regulators microRNA-221/222 plays no role in
regulating the amount of p27fs177 in RNFs and rat tissues.
CONCLUSION: Our findings show that reduced p27 levels, not newly acquired
properties, trigger tumor formation in rats, similarly to what has been observed
in mice. The molecular characteristics of p27fs177 establish MENX as a useful
preclinical model to evaluate compounds that inhibit p27 degradation for their
efficacy against endocrine tumors.
DOI: 10.1186/1476-4598-9-116
PMCID: PMC2881881
PMID: 20492666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10854145 | 1. World J Urol. 2000 Apr;18(2):111-20. doi: 10.1007/s003450050182.
Adenovirus p16 gene therapy for prostate cancer.
Allay JA(1), Steiner MS, Zhang Y, Reed CP, Cockroft J, Lu Y.
Author information:
(1)Genotherapeutics, Inc., Memphis, Tennessee, USA.
Surgery, radiation, or hormone deprivation alone does not adequately affect
local control of clinical or pathologic stage T3 prostate cancer. Lack of local
cancer control ultimately leads to a higher incidence of morbidity, distant
metastasis, and decreased survival, with patients having disease-specific
mortality exceeding 75%. Other novel therapies against this devastating and
common disease are needed for the achievement of long-term local cancer control.
For this purpose, therapeutic interventions should target prostate-cancer cells
at the molecular and cellular level in ways not possible by current modalities
of cancer treatment. Any strategy that can modify the biologic behavior of these
cells may potentially have the most significant clinical impact. As prostate
cancer represents an accumulation of genetic mutations that causes a prostate
cell to lose the ability to control its growth, one new approach against
prostate cancer may be gene therapy. Identification of key missing or mutated
tumor-suppressor genes that, when replaced, may inhibit or destroy
prostate-cancer cells may have the best chance of clinical success. One such
gene appears to be tumor-suppressor gene p16 (also known as MTS1, INK4A, and
CDKN2). Tumor-suppressor gene p16 is an important negative cell-cycle regulator
whose functional loss may significantly contribute to malignant transformation
and progression. Alterations in the p16 gene and its protein expression often
occur in prostate cancer. An adenoviral vector containing wild-type p16 (Adp16)
had a high transduction efficiency in prostate-cancer cells both in vitro and in
vivo. Moreover, prostate tumors injected with Adp16 expressed p16 and the
adenoviral vector expressed the transgene for up to 14 days. Wild-type p16
inhibited prostate-cancer proliferation in vitro and markedly suppressed tumors
in vivo. Pathologic evaluation of the Adp16-treated tumors showed dose-dependent
necrosis and fibrosis. Although the mechanism of p16 inhibition in cancer
remains to be elucidated, senescence and apoptosis may both be important;
however, the data suggest that p16-induced growth inhibition can function
independently of the retinoblastoma gene product.
DOI: 10.1007/s003450050182
PMID: 10854145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12542976 | 1. J Biochem Mol Biol. 2003 Jan 31;36(1):60-5. doi: 10.5483/bmbrep.2003.36.1.060.
Cell cycle and cancer.
Park MT(1), Lee SJ.
Author information:
(1)Laboratory of Radiation Effect, Radiological & Medical Research Center, Korea
Institute of Radiological & Medical Sciences, Seoul 139-706, Korea.
Cancer is frequently considered to be a disease of the cell cycle. As such, it
is not surprising that the deregulation of the cell cycle is one of the most
frequent alterations during tumor development. Cell cycle progression is a
highlyordered and tightly-regulated process that involves multiple checkpoints
that assess extracellular growth signals, cell size, and DNA integrity.
Cyclin-dependent kinases (CDKs) and their cyclin partners are positive
regulators or accelerators that induce cell cycle progression; whereas,
cyclindependent kinase inhibitors (CKIs) that act as brakes to stop cell cycle
progression in response to regulatory signals are important negative regulators.
Cancer originates from the abnormal expression or activation of positive
regulators and functional suppression of negative regulators. Therefore,
understanding the molecular mechanisms of the deregulation of cell cycle
progression in cancer can provide important insights into how normal cells
become tumorigenic, as well as how new cancer treatment strategies can be
designed.
DOI: 10.5483/bmbrep.2003.36.1.060
PMID: 12542976 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26573797 | 1. Cancer Res. 2015 Dec 1;75(23):5001-7. doi: 10.1158/0008-5472.CAN-15-0563. Epub
2015 Nov 16.
p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis.
Wang X(1), Simpson ER(2), Brown KA(3).
Author information:
(1)Metabolism and Cancer Laboratory, Centres for Cancer Research and
Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton,
Victoria, Australia. Department of Physiology, Monash University, Clayton,
Victoria, Australia.
(2)Metabolism and Cancer Laboratory, Centres for Cancer Research and
Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton,
Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash
University, Clayton, Victoria, Australia.
(3)Metabolism and Cancer Laboratory, Centres for Cancer Research and
Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton,
Victoria, Australia. Department of Physiology, Monash University, Clayton,
Victoria, Australia. [email protected].
Erratum in
Cancer Res. 2016 Mar 15;76(6):1668. doi: 10.1158/0008-5472.CAN-16-0231.
The tumor suppressor p53 has established functions in cancer. Specifically, it
has been shown to cause cell-cycle arrest and apoptosis in response to DNA
damage. It is also one of the most commonly mutated or silenced genes in cancer
and for this reason has been extensively studied. Recently, the role of p53 has
been shown to go beyond its effects on cell cycle and apoptosis, with effects on
metabolism emerging as a key contributor to cancer growth in situations where
p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is
poorly understood. The publication by Wang and colleagues demonstrates for the
first time that p53 is a key negative regulator of aromatase and, hence,
estrogen production in the breast tumor microenvironment. It goes further by
demonstrating that an important regulator of aromatase, the obesity-associated
and tumor-derived factor prostaglandin E2, inhibits p53 in the breast adipose
stroma. This review presents these findings in the context of established and
emerging roles of p53 and discusses possible implications for the treatment of
breast cancer.
©2015 American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-15-0563
PMID: 26573797 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1399577 | 1. Head Neck. 1992 Sep-Oct;14(5):407-14. doi: 10.1002/hed.2880140513.
Tumor suppressor genes.
Lee NK(1).
Author information:
(1)Department of Otolaryngology-Head and Neck Surgery, University of Texas
Southwestern Medical Center, Dallas 75235-9035.
Tumor suppressor genes are negative regulators of cell growth. When their normal
function is compromised, absence of their inhibitory effects can lead to
unrestrained cell cycling and growth. Strong evidence now confirms that loss of
proper function of these genes is a common occurrence leading to cancer. Their
failure can be caused by alterations in the gene DNA or malfunction of their
protein products. The recent extraordinary accumulation of knowledge about these
genes reveals that normal carcinogenesis represents breakdown of normal
regulatory processes.
DOI: 10.1002/hed.2880140513
PMID: 1399577 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32359398 | 1. Structure. 2020 Jul 7;28(7):847-857.e5. doi: 10.1016/j.str.2020.04.011. Epub
2020 Apr 30.
Identification of a Structural Determinant for Selective Targeting of HDMX.
Ben-Nun Y(1), Seo HS(2), Harvey EP(1), Hauseman ZJ(1), Wales TE(3), Newman
CE(1), Cathcart AM(1), Engen JR(3), Dhe-Paganon S(2), Walensky LD(4).
Author information:
(1)Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline
Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology,
Dana-Farber Cancer Institute, Boston, MA 02215, USA.
(2)Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215,
USA.
(3)Department of Chemistry and Chemical Biology, Northeastern University,
Boston, MA 02214, USA.
(4)Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline
Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology,
Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:
[email protected].
p53 is a critical tumor-suppressor protein that guards the human genome against
mutations by inducing cell-cycle arrest or apoptosis. Cancer cells subvert p53
by deletion, mutation, or overexpression of the negative regulators HDM2 and
HDMX. For tumors that retain wild-type p53, its reactivation by pharmacologic
targeting of HDM2 and/or HDMX represents a promising strategy, with a series of
selective small-molecule HDM2 inhibitors and a dual HDM2/HDMX stapled-peptide
inhibitor being evaluated in clinical trials. Because selective HDM2 targeting
can cause hematologic toxicity, selective HDMX inhibitors could provide an
alternative p53-reactivation strategy, but clinical candidates remain elusive.
Here, we applied a mutation-scanning approach to uncover p53-based stapled
peptides that are selective for HDMX. Crystal structures of stapled-peptide/HDMX
complexes revealed a molecular mechanism for the observed specificity, which was
validated by HDMX mutagenesis. Thus, we provide a blueprint for the development
of HDMX-selective inhibitors to dissect and target the p53/HDMX interaction.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.str.2020.04.011
PMCID: PMC7427690
PMID: 32359398 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Interests L.D.W. is a scientific
co-founder and shareholder in Aileron Therapeutics. The compositions of stapled
peptides used in the study have been patented by the Dana-Farber Cancer
Institute. |
http://www.ncbi.nlm.nih.gov/pubmed/9179973 | 1. Semin Diagn Pathol. 1997 May;14(2):123-32.
Alterations of tumor suppressor genes in bladder cancer.
Cordon-Cardo C(1), Reuter VE.
Author information:
(1)Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York
10021, USA.
The etiopathogenesis of neoplastic diseases is characterized by its multiple
nature. Multiple biological and physical agents have been identified as
initiating or promoting neoplastic mechanisms. However, they all appear to have
common molecular basis, granting genetic instability and causing somatic
derangements to preneoplastic and tumor cells. Target genes implicated in
cellular transformation and tumor progression have been divided into two
categories: proto-oncogenes (that when activated become dominant events
characterized by gain of function) and tumor suppressor genes (recessive events
characterized by the loss of function). Alteration in proto-oncogenes and tumor
suppressor genes seem equally prevalent among human cancers. Multiple mutations
appear to be required to conform the malignant phenotype. It is, therefore,
conceivable to view cancer as fundamentally a genetic disease entailing
inherited (also called "germline") or acquired (also termed "somatic") mutations
of genes in these two categories. The concept of tumor suppressor genes was
established in studies with somatic cell hybrids, revealing that when malignant
cells were fused with normal cells some of the hybrids were nontumorigenic.
Clinically, the existence and relevance of this category of genes was based on
epidemiological studies of the intraocular childhood tumor retinoblastoma, and
it was postulated that two independent events were needed to inactivate a given
gene. It was further shown that, in general, that was achieved by an allelic
loss followed by a point mutation of the remaining allele. A family of genes has
been characterized that follows this "two-hit" model including the two prototype
suppressors genes: the retinoblastoma (RB) and the TP53 (also known as p53)
genes. These genes encode a variety of molecules with distinct biological
properties, including cell cycle regulation and cellular differentiation.
Germline and somatic mutations of these genes appear to be the most common
abnormalities found in human cancer including bladder neoplasms. More recent
studies have shown that inactivation of some of these genes (i.e., TP53) occurs
in bladder tumors that have a more aggressive clinical outcome and poor
prognosis. In the following subheadings, the authors have reviewed the molecular
abnormalities associated with these recessive genes in bladder tumors and
discuss the potential clinical use of their detection. The implementation of
objective predictive assays to identify these alterations in clinical material
will enhance the ability to assess tumor biological activities and to design
effective treatment regimens. The need now is to translate this newly developed
scientific knowledge into diagnostic and therapeutic strategies, which, in turn,
will enhance quality of life and prolong patient survival.
PMID: 9179973 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9815577 | 1. Clin Cancer Res. 1997 Oct;3(10):1879-87.
Deregulated expression of p27(Kip1) in human breast cancers.
Sgambato A(1), Zhang YJ, Arber N, Hibshoosh H, Doki Y, Ciaparrone M, Santella
RM, Cittadini A, Weinstein IB.
Author information:
(1)Herbert Irving Comprehensive Cancer Center, Columbia University, College of
Physicians and Surgeons, New York, New York 10032, USA.
Protein complexes composed of cyclins and cyclin-dependent kinases control the
orderly progression of mammalian cells through the cell cycle. The p27(Kip1)
protein belongs to a family of cyclin-dependent kinase-inhibitory proteins that
are negative regulators of cell cycle progression and have been proposed as
candidate tumor suppressor genes. However, the p27(Kip1) gene is only rarely
mutated in human primary breast carcinomas and breast cancer cell lines. To
further address the role of p27(Kip1) in the development of human tumors, we
determined by Western blot analysis the levels of expression of the p27(Kip1)
protein in a series of human cancer cell lines and found that this protein is
expressed at high levels in many of these cell lines, even during exponential
growth. The levels of p27(Kip1) were significantly associated with the levels of
cyclins D1 and E. In contrast to the high level of p27(Kip1) in breast cancer
cell lines, three cell lines established from normal mammary epithelium
expressed low levels of this protein. Cell synchronization studies demonstrated
deregulation of the expression of p27(Kip1) throughout the cell cycle in two
breast cancer cell lines but normal regulation in a normal mammary epithelial
cell line. Immunohistochemical studies on p27(Kip1) expression in 52 primary
human breast cancers indicated that this protein was also expressed at
relatively high levels in 44% of the tumor samples, but it was barely detectable
or undetectable in the remaining 56% of the samples. Additional studies are
required to determine why some breast cancer cells express relatively high
levels of p27(Kip1) despite its known role as an inhibitor of cell cycle
progression.
PMID: 9815577 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11327114 | 1. Ann Med. 2001 Mar;33(2):113-22. doi: 10.3109/07853890109002066.
Checkpoint genes in cancer.
McDonald ER 3rd(1), El-Deiry WS.
Author information:
(1)Department of Medicine, Genetics and Pharmacology, University of Pennsylvania
School of Medicine, Philadelphia 19104, USA.
The mammalian cell cycle is exquisitely controlled by a 'machinery' composed of
cyclin-dependent kinases and their binding partners, the cyclins. These kinases
regulate transitions into DNA synthesis and mitosis, and their inactivity
contributes to cellular quiescence, differentiation and senescence. Cell cycle
transitions are, in turn, controlled by checkpoints that monitor ribonucleotide
pools, oxygen tension, the extracellular environment, growth signalling
programmes, the status of DNA replication, and the mitotic spindle apparatus.
Genes positively controlling cell cycle checkpoints can be targets for oncogenic
activation in cancer, whereas negative regulators, such as tumour suppressor
genes, are targeted for inactivation. Understanding the molecular details of
cell cycle regulation and checkpoint abnormalities in cancer offers insight into
potential therapeutic strategies.
DOI: 10.3109/07853890109002066
PMID: 11327114 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2140509 | 1. Bioessays. 1990 Feb;12(2):60-6. doi: 10.1002/bies.950120203.
Tumor suppressor genes.
Levine AJ(1).
Author information:
(1)Department of Biology, Lewis Thomas Laboratory, Princeton University, New
Jersey 08544-1014.
The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear
to function as negative regulators of cell division or abnormal cellular growth
in some differentiated cell types. Several types of cancers have been shown to
be derived from cells that have extensively mutated both alleles of one or both
of these genes, resulting in a loss-of-function mutation. In the case of the p53
gene, this mutational process appears to occur in two steps, with the first
mutation at the p53 locus resulting in a trans-dominant phenotype. The mutant
p53 gene product enters into an oligomeric protein complex with the wild-type
p53 protein derived from the other normal allele and such a complex is inactive
or less efficient in its negative regulation of growth control. This
intermediate stage of carcinogenesis selects for the proliferation of cells with
one mutant allele, enhancing the probability of obtaining a cancer cell with
both alleles damaged. The DNA tumor viruses have evolved mechanisms to interact
with the Rb and p53 negative regulators of cellular growth in order to enhance
their own replication in growing cells. SV40 and adenovirus type 5 produce viral
encoded proteins that also form oligomeric protein complexes with p53 and Rb,
presumably inactivating their functions. These viral proteins are also the
oncogene products of these viruses. Thus, the mechanisms by which cancer may
arise in a host, via mutations or virus infections, have fundamental common
pathways effecting the same cellular genes and gene products; Rb and p53.
DOI: 10.1002/bies.950120203
PMID: 2140509 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16150895 | 1. Carcinogenesis. 2005 Dec;26(12):2031-45. doi: 10.1093/carcin/bgi223. Epub 2005
Sep 8.
Tumor suppressor genetics.
Payne SR(1), Kemp CJ.
Author information:
(1)Fred Hutchinson Cancer Research Center, Seattle, WA 90109, USA.
The observation that mutations in tumor suppressor genes can have
haploinsufficient, as well as gain of function and dominant negative, phenotypes
has caused a reevaluation of the 'two-hit' model of tumor suppressor
inactivation. Here we examine the history of haploinsufficiency and tumor
suppressors in order to understand the origin of the 'two-hit' dogma. The
two-hit model of tumor suppressor gene inactivation was derived from
mathematical modeling of cancer incidence. Subsequent interpretations implied
that tumor suppressors were recessive, requiring mutations in both alleles. This
model has provided a useful conceptual framework for three decades of research
on the genetics and biology of tumor suppressor genes. Recently it has become
clear that mutations in tumor suppressor genes are not always completely
recessive. Haploinsufficiency occurs when one allele is insufficient to confer
the full functionality produced from two wild-type alleles. Haploinsufficiency,
however, is not an absolute property. It can be partial or complete and can vary
depending on tissue type, other epistatic interactions, and environmental
factors. In addition to simple quantitative differences (one allele versus two
alleles), gene mutations can have qualitative differences, creating gain of
function or dominant negative effects that can be difficult to distinguish from
dosage-dependence. Like mutations in many other genes, tumor suppressor gene
mutations can be haploinsufficient, dominant negative or gain of function in
addition to recessive. Thus, under certain circumstances, one hit may be
sufficient for inactivation. In addition, the phenotypic penetrance of these
mutations can vary depending on the nature of the mutation itself, the genetic
background, the tissue type, environmental factors and other variables.
Incorporating these new findings into existing models of the clonal evolution
will be a challenge for the future.
DOI: 10.1093/carcin/bgi223
PMID: 16150895 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8652807 | 1. Blood. 1996 Jun 15;87(12):4949-58.
Inactivation of multiple tumor-suppressor genes involved in negative regulation
of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in
primary lymphoid malignancies.
Hangaishi A(1), Ogawa S, Imamura N, Miyawaki S, Miura Y, Uike N, Shimazaki C,
Emi N, Takeyama K, Hirosawa S, Kamada N, Kobayashi Y, Takemoto Y, Kitani T,
Toyama K, Ohtake S, Yazaki Y, Ueda R, Hirai H.
Author information:
(1)Third Department of Internal Medicine, Faculty of Medicine, University of
Tokyo, Tokyo, Japan.
It is now evident that the cell cycle machinery has a variety of elements
negatively regulating cell cycle progression. However, among these negative
regulators in cell cycle control, only 4 have been shown to be consistently
involved in the development of human cancers as tumor suppressors: Rb
(Retinoblastoma susceptibility protein), p53, and two recently identified
cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because
there are functional interrelations among these negative regulators in the cell
cycle machinery, it is particularly interesting to investigate the multiplicity
of inactivations of these tumor suppressors in human cancers, including
leukemias/lymphomas. To address this point, we examined inactivations of these
four genes in primary lymphoid malignancies by Southern blot and polymerase
chain reaction-single-strand conformation polymorphism analyses. We also
analyzed Rb protein expression by Western blot analysis. The p16INK4A and
p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor
specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and
9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for
inactivations of all four tumor suppressors had one or more abnormalities of
these four tumor-suppressor genes, indicating that dysregulation of cell cycle
control is important for tumor development. Statistical analysis of
interrelations among impairments of these four genes indicated that
inactivations of the individual tumor-suppressor genes might occur almost
independently. In some patients, disruptions of multiple tumor-suppressor genes
occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with
p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53
inactivations. It is suggested that disruptions of multiple tumor suppressors in
a tumor cell confer an additional growth advantage on the tumor.
PMID: 8652807 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28235882 | 1. Clin Cancer Res. 2017 Oct 1;23(19):5666-5670. doi:
10.1158/1078-0432.CCR-16-0663. Epub 2017 Feb 24.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line
Treatment of Metastatic Melanoma.
Chuk MK(1), Chang JT(2), Theoret MR(2), Sampene E(3), He K(3), Weis SL(2), Helms
WS(2), Jin R(4), Li H(4), Yu J(4), Zhao H(4), Zhao L(5), Paciga M(6), Schmiel
D(6), Rawat R(6), Keegan P(2), Pazdur R(2).
Author information:
(1)Office of Hematology and Oncology Products (OHOP), Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
[email protected].
(2)Office of Hematology and Oncology Products (OHOP), Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
(3)Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food
and Drug Administration, Silver Spring, Maryland.
(4)Office of Clinical Pharmacology, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Silver Spring, Maryland.
(5)Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food
and Drug Administration, Silver Spring, Maryland.
(6)Office of Biotechnology Products, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Silver Spring, Maryland.
On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp &
Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous
infusion for the treatment of patients with unresectable or metastatic melanoma
who have progressed following treatment with ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor. Approval was based on demonstration of
objective tumor responses with prolonged response durations in 89 patients
enrolled in a randomized, multicenter, open-label, dose-finding, and
activity-estimating phase 1 trial. The overall response rate (ORR) by blinded
independent central review per RECIST v1.1 was 24% (95% confidence interval,
15-34); with 6 months of follow-up, 86% of responses were ongoing. The most
common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash,
decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated
adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and
thyroid disorders. The benefits of the observed ORR with prolonged duration of
responses outweighed the risks of immune-mediated adverse reactions in this
life-threatening disease and represented an improvement over available therapy.
Important regulatory issues in this application were role of durability of
response in the evaluation of ORR for accelerated approval, reliance on data
from a first-in-human trial, and strategies for dose selection. Clin Cancer Res;
23(19); 5666-70. ©2017 AACR.
©2017 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-16-0663
PMID: 28235882 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36401050 | 1. Methods Mol Biol. 2023;2587:557-568. doi: 10.1007/978-1-0716-2772-3_30.
Systemic Delivery of a Monoclonal Antibody to Immunologically Block Myostatin in
the A17 Mouse Model of OPMD.
Malerba A(1), Harish P(2), Popplewell L(3)(4).
Author information:
(1)Department of Biological Sciences, Royal Holloway University of London,
Egham, Surrey, UK.
(2)College of Health, Medicine and Life Science, Biosciences, Brunel University
London, Uxbridge, UK.
(3)Department of Biological Sciences, Royal Holloway University of London,
Egham, Surrey, UK. [email protected].
(4)National Horizons Centre, Teesside University, Darlington, UK.
[email protected].
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset rare muscle disease
affecting approximately 1 in 80,000 individuals worldwide. However, it can
affect as much as 1:600 individuals in some populations due to a strong founder
effect. The muscle pathology is characterized by progressive eyelid drooping
(ptosis), swallowing difficulties (dysphagia), and limb weakness at later stages
of disease progression. The genetic defect is associated with significant
fibrotic deposition and atrophy in affected muscles. No treatments are available
to cure the disease. Only surgical techniques to correct ptosis and swallowing
are currently possible, though they carry a risk of recurrence. Myostatin is a
negative regulator of muscle growth, and several strategies to downregulate its
expression have been developed with the aim of improving muscle mass and
strength in muscular pathologies. We recently showed that weekly systemic
treatment of the A17 murine model of OPMD with a monoclonal antibody for
myostatin improves body and muscle mass, increases muscle strength, and reduces
muscle fibrosis. Here, we describe the methodology for repeated intraperitoneal
delivery of myostatin antibody in the murine model. Furthermore, we detail the
most relevant analyses to assess histopathological and functional improvements
of this treatment in this mouse model.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_30
PMID: 36401050 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34932533 | 1. Cir Cir. 2021;89(S2):26-30. doi: 10.24875/CIRU.21000010.
Boerhaave syndrome. Case report and literature review.
[Article in English]
Salvador-Ibarra IJ(1), Pizaña-Davila A(1).
Author information:
(1)Departamento de Terapia Intensiva, Hospital Ángeles Mocel, Ciudad de México,
México.
Spontaneous lesions can affect only a part of the esophageal wall (Mallory-Weiss
syndrome) or constitute a full-thickness rupture of the organ, leading to
Boerhaave syndrome. Most commonly affecting males between 50 and 70 years of
age, Clinically, the Mackler triad is vomiting, severe chest pain, and
subcutaneous cervical emphysema. The delay in diagnosis explains the high
mortality rate of this pathology up to 40-60% in those treated at 48 hours. The
prognosis improves if treatment is established within the first 24 hours.
Publisher: Las lesiones espontáneas pueden afectar solo una parte de la pared
esofágica (síndrome de Mallory-Weiss) o constituir una rotura de espesor total
del órgano, dando lugar al síndrome de Boerhaave. Afecta con mayor frecuencia a
los varones entre 50 y 70 años de edad. Clínicamente conforma la tríada de
Mackler: vómito, dolor torácico intenso y enfisema subcutáneo cervical. El
retraso en el diagnóstico explica su alta tasa de mortalidad, de hasta el 40-60%
en los pacientes tratados a las 48 horas. El pronóstico mejora si se logra
instaurar el tratamiento dentro de las primeras 24 horas.
Copyright: © 2021 Permanyer.
DOI: 10.24875/CIRU.21000010
PMID: 34932533 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14633596 | 1. Am J Pathol. 2003 Dec;163(6):2211-9. doi: 10.1016/S0002-9440(10)63579-1.
Implantation-dependent expression of trophinin by maternal fallopian tube
epithelia during tubal pregnancies: possible role of human chorionic
gonadotrophin on ectopic pregnancy.
Nakayama J(1), Aoki D, Suga T, Akama TO, Ishizone S, Yamaguchi H, Imakawa K,
Nadano D, Fazleabas AT, Katsuyama T, Nozawa S, Fukuda MN.
Author information:
(1)Departments of Pathology, Internal Medicine, Surgery, and Laboratory
Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
[email protected]
Trophinin, tastin, and bystin have been identified as molecules potentially
involved in human embryo implantation. Both trophoblasts and endometrial
epithelial cells express trophinin, which mediates apical cell adhesion through
homophilic trophinin-trophinin binding. We hypothesized that trophinin's
function in embryo implantation is unique to humans and investigated the
expression of trophinin, tastin, and bystin in ectopic pregnancy, a condition
unique to humans. In tubal pregnancies, high levels of all three were found in
both trophoblasts and fallopian tubal epithelia. Trophinin expression in
maternal cells was particularly high in the area adjacent to the trophoblasts,
whereas trophinin was barely detectable in intact fallopian tubes from women
with in utero pregnancies or without pregnancies. When explants of intact
fallopian tube were incubated with the human chorionic gonadotrophin (hCG),
trophinin expression was enhanced in epithelial cells. Since the trophectoderm
of the human blastocyst secretes hCG before and after implantation, these
results suggest that hCG from the human embryo induces trophinin expression by
maternal cells. As both beta-subunit of hCG and trophinin genes have diverged in
mammals, the present study suggests a unique role of hCG and trophinin in human
embryo implantation, including the pathogenesis of ectopic pregnancy.
DOI: 10.1016/S0002-9440(10)63579-1
PMCID: PMC1892375
PMID: 14633596 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18218922 | 1. FASEB J. 2008 Jun;22(6):1960-72. doi: 10.1096/fj.07-081463. Epub 2008 Jan 24.
Tastin is required for bipolar spindle assembly and centrosome integrity during
mitosis.
Yang S(1), Liu X, Yin Y, Fukuda MN, Zhou J.
Author information:
(1)Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell
Biology, Chinese Academy of Sciences, Shanghai, China.
Tastin was previously characterized as an accessory protein for cell adhesion
that participates in early embryo implantation. Here, we report that tastin is
also required for spindle assembly during mitosis. Tastin protein levels peaked
in the G(2)/M phase and abruptly declined after cell division. Microscopy showed
that tastin is primarily localized on the microtubules, centrosomes, and the
mitotic spindle during the cell cycle. Tastin interacted with the dynein
intermediate chain, p150(Glued), and gamma-tubulin in addition to Tctex-1 (the
light chain of dynein). Overexpression of tastin led to monopolar spindle
formation, whereas loss of tastin expression caused profound mitotic block and
preferentially induced multipolar spindles. These multipolar spindles were
generated through a loss of cohesion in mitotic centrosomes; specifically,
tastin depletion caused the fragmentation of pericentrosomal material and the
splitting of the centrioles at the spindle poles. Tastin depletion induced
centrosome abnormalities exclusively during mitosis and required both
microtubule integrity and Eg5 activity. However, tastin depletion did not
disrupt the organization of spindle poles, as revealed by localization of
nuclear mitotic apparatus protein (NuMA) and the p150(Glued) component of
dynactin. These data indicate that the major function of tastin during mitosis
is to maintain the structural and dynamic features of centrosomes, thereby
contributing to spindle bipolarity.
DOI: 10.1096/fj.07-081463
PMID: 18218922 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12049630 | 1. Biochem J. 2002 Jun 15;364(Pt 3):669-77. doi: 10.1042/BJ20011836.
Human tastin, a proline-rich cytoplasmic protein, associates with the
microtubular cytoskeleton.
Nadano D(1), Nakayama J, Matsuzawa S, Sato TA, Matsuda T, Fukuda MN.
Author information:
(1)Department of Applied Molecular Biosciences, Graduate School of
Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
[email protected]
Tastin was originally identified as an accessory protein for trophinin, a cell
adhesion molecule that potentially mediates the initial attachment of the human
embryo to the uterine epithelium. However, no information regarding tastin's
function is available to date. The present study is aimed at understanding the
role of tastin in mammalian cells. Hence, we examined the intracellular
localization of tastin in human cell lines transfected with an expression vector
encoding influenza virus haemagglutinin (HA)-tagged tastin. Ectopically
expressed HA-tastin was seen as a pattern resembling the fibres that overlap the
microtubular cytoskeleton. When HA-tastin-expressing cells were cultured with
nocodazole to disrupt microtubule (MT) polymerization, tastin was dispersed to
the entire cytoplasm and an MT sedimentation assay showed tastin in the
supernatant; however, tastin was sedimented with polymeric MTs in cell lysates
not treated with nocodazole. Sedimentation assays using HA-tastin mutants
deleted at the N- or C-terminus revealed MT-binding activity associated with the
N-terminal basic region of tastin. A yeast two-hybrid screen for
tastin-interacting proteins identified Tctex-1, one of the light chains of
cytoplasmic dynein, as a tastin-binding protein. Immunoprecipitation and
Western-blot analysis confirmed binding of HA-tagged tastin and FLAG
(Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys epitope)-tagged Tctex-1 in human cells.
Furthermore, in vitro assays have demonstrated the binding between a fusion
protein, glutathione S-transferase-Tctex-1, and in vitro translated
(35)S-labelled tastin. As Tctex-1 is a component of a MT-based molecular motor,
these results suggest that tastin plays an important role in mammalian cells by
associating with the microtubular cytoskeleton.
DOI: 10.1042/BJ20011836
PMCID: PMC1222615
PMID: 12049630 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23194061 | 1. Reprod Biol Endocrinol. 2012 Nov 29;10:101. doi: 10.1186/1477-7827-10-101.
Enhancement of mouse sperm motility by trophinin-binding peptide.
Park SK(1), Yoon J, Wang L, Shibata TK, Motamedchaboki K, Shim KJ, Chang MS, Lee
SH, Tamura N, Hatakeyama S, Nadano D, Sugihara K, Fukuda MN.
Author information:
(1)Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical
Research Institute, La Jolla, CA 92037, USA.
BACKGROUND: Trophinin is an intrinsic membrane protein that forms a complex in
the cytoplasm with bystin and tastin, linking it microtubule-associated motor
dynein (ATPase) in some cell types. Previously, we found that human sperm tails
contain trophinin, bystin and tastin proteins, and that trophinin-binding GWRQ
(glycine, tryptophan, arginine, glutamine) peptide enhanced motility of human
sperm.
METHODS: Immunohistochemistry was employed to determine trophinin protein in
mouse spermatozoa from wild type mouse, by using spermatozoa from trophinin null
mutant mice as a negative control. Multivalent 8-branched GWRQ (glycine,
tryptophan, arginine, glutamine) peptide or GWRQ-MAPS, was chemically
synthesized, purified by HPLC and its structure was confirmed by MALDI-TOF mass
spectrometry. Effect of GWRQ-MAPS on mouse spermatozoa from wild type and
trophinin null mutant was assessed by a computer-assisted semen analyzer (CASA).
RESULTS: Anti-trophinin antibody stained the principal (central) piece of the
tail of wild type mouse sperm, whereas the antibody showed no staining on
trophinin null sperm. Phage particles displaying GWRQ bound to the principal
piece of sperm tail from wild type but not trophinin null mice. GWRQ-MAPS
enhanced motility of spermatozoa from wild type but not trophinin null mice.
CASA showed that GWRQ-MAPS enhanced both progressive motility and rapid motility
in wild type mouse sperm.
CONCLUSIONS: Present study established the expression of trophinin in the mouse
sperm tail and trophinin-dependent effect of GWRQ-MAPS on sperm motility. GWRQ
causes a significant increase in sperm motility.
DOI: 10.1186/1477-7827-10-101
PMCID: PMC3551822
PMID: 23194061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7758945 | 1. Genes Dev. 1995 May 15;9(10):1199-210. doi: 10.1101/gad.9.10.1199.
Trophinin and tastin, a novel cell adhesion molecule complex with potential
involvement in embryo implantation.
Fukuda MN(1), Sato T, Nakayama J, Klier G, Mikami M, Aoki D, Nozawa S.
Author information:
(1)La Jolla Cancer Research Foundation, California 92037, USA.
Two human epithelial cell lines, trophoblastic teratocarcinoma HT-H and
endometrial adenocarcinoma SNG-M cells, adhere to each other at their respective
apical cell surfaces in a divalent cation-independent manner. Two novel
molecules responsible for the adhesion between these two cell types were
identified by expression cDNA cloning. One, named trophinin, is an intrinsic
membrane protein and mediates homophilic self-binding. Another, named tastin, is
a cytoplasmic protein and is necessary for trophinin to function as a cell
adhesion molecule. Trophinin and tastin appear to be associated with the
cytoskeleton in HT-H and SNG-M cells. These molecules are normally not expressed
in various types of human cells in tissues, with the exception of macrophages.
Strong expression of these molecules was detected in the trophectoderm surface
of monkey blastocyst. These molecules are also expressed in human endometrial
surface epithelium on day 16/17 at the early secretory phase of human
endometrium, the time consistent with that expected for the "implantation
window."
DOI: 10.1101/gad.9.10.1199
PMID: 7758945 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11299965 | 1. Semin Reprod Med. 2000;18(3):265-71. doi: 10.1055/s-2000-12564.
Recent molecular approaches to elucidate the mechanism of embryo implantation:
trophinin, bystin, and tastin as molecules involved in the initial attachment of
blastocysts to the uterus in humans.
Aoki R(1), Fukuda MN.
Author information:
(1)Cancer Research Center, Burnham Institute, 10901 North Torrey, Pines Road, La
Jolla, CA 92037-1005, USA.
Elucidation of the implantation mechanism in humans at the molecular level has
been difficult because of methodological restrictions. Instead of using human
materials during the implantation period, two human tumor cell lines that
respectively mimic the biological behaviors of a blastocyst and uterine luminal
epithelial cells were utilized successfully to identify three novel adhesion
molecules named trophinin, bystin, and tastin. Trophinin is a membrane protein
strongly expressed both on the apical surface of the trophectoderm of a simian
blastocyst and at a putative implantation site of the human endometrium. Bystin
and tastin are cytoplasmic proteins that associate with trophinin by presumably
forming an active adhesion machinery. The expression patterns of these molecules
are suggestive of their involvement in the initial blastocyst attachment to the
uterus as well as in the subsequent placental development. Future perspectives
in molecular implantation research are also discussed in relation to
breakthroughs in assisted reproduction.
DOI: 10.1055/s-2000-12564
PMID: 11299965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16245277 | 1. Prostate. 2006 Feb 15;66(3):266-72. doi: 10.1002/pros.20323.
Bystin in perineural invasion of prostate cancer.
Ayala GE(1), Dai H, Li R, Ittmann M, Thompson TC, Rowley D, Wheeler TM.
Author information:
(1)Department of Pathology, Baylor College of Medicine, Houston, Texas 77030,
USA. [email protected]
BACKGROUND: Bystin, Trophinin, and Tastin are component proteins of an adhesion
molecule complex that plays a crucial role in the initial attachment of the
embryo to the uterus.
METHODS: Profiling of genes differentially expressed in the perineural invasion
(PNI) in vitro model by gene microarray analysis showed overexpression of bystin
in prostate cancer cells co-cultured with nerves. Validation was performed at
the RNA levels using quantitative PCR.
RESULTS: Bystin is overexpressed in cells co-cultured with nerves. Bystin is
also present in human prostatic carcinoma (PCa) cells in PNI location in
increasing gradient. Bystin is present in the supernatant of the PNI co-culture.
CONCLUSIONS: Their adhesive and invasive functions in the trophoblast suggest
that they might also play a role in perineural adhesion. Bystin is, therefore,
an important therapeutic target for neurotropic cancers.
Copyright (c) 2005 Wiley-Liss, Inc.
DOI: 10.1002/pros.20323
PMID: 16245277 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10797941 | 1. Semin Reprod Endocrinol. 1999;17(3):229-34. doi: 10.1055/s-2007-1016230.
Trophinin, tastin, and bystin: a complex mediating unique attachment between
trophoblastic and endometrial epithelial cells at their respective apical cell
membranes.
Fukuda MN(1), Nozawa S.
Author information:
(1)Cancer Research Center, Burnham Institute, La Jolla, CA 92037, USA.
Embryo implantation is a complex process consisting of multiple cross-talks
between maternal and embryonic cells. Defining the mechanisms underlying
implantation at molecular level is challenging task in reproductive biology. In
order to identify molecules involved in cellular interactions between
trophoblastic and endometrial epithelial cells, we have established two human
cell lines, trophoblastic HT-H and endometrial epithelial SNGM. These two cell
types exhibit cell adhesion at their respective apical cell membranes. Molecules
involved in this unique cell adhesion were identified by expression
complementary DNA cloning and were named trophinin, tastin, and bystin.
Trophinin is a membrane protein thought to have self-binding activity and thus
mediates homophilic cell adhesion. Tastin and bystin are cytoplasmic proteins
required for trophinin to exhibit cell adhesion activity. Trophinin is strongly
expressed in trophectoderm of monkey blastocysts. In human endometrium,
trophinin is expressed for a limited period in the luminal epithelium at the
time expected for implantation. In human placenta, trophinin, tastin, and bystin
are strongly expressed in trophoblast and endometrium at the uteroplacental
interface at an early stage in pregnancy. All these molecules disappear from the
human placenta in the second trimester. The unique expression pattern and cell
adhesion activity exhibited by trophinin, tastin, and bystin suggest strongly
the involvement of these molecules in the initial attachment of blastocyst to
uterus.
DOI: 10.1055/s-2007-1016230
PMID: 10797941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9560222 | 1. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5027-32. doi:
10.1073/pnas.95.9.5027.
A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin
and may be involved in trophinin-mediated cell adhesion between trophoblast and
endometrial epithelial cells.
Suzuki N(1), Zara J, Sato T, Ong E, Bakhiet N, Oshima RG, Watson KL, Fukuda MN.
Author information:
(1)The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037,
USA.
Trophinin and tastin form a cell adhesion molecule complex that potentially
mediates an initial attachment of the blastocyst to uterine epithelial cells at
the time of implantation. Trophinin and tastin, however, do not directly bind to
each other, suggesting the presence of an intermediary protein. The present
study identifies a cytoplasmic protein, named bystin, that directly binds
trophinin and tastin. Bystin consists of 306 amino acid residues and is
predicted to contain tyrosine, serine, and threonine residues in contexts
conforming to motifs for phosphorylation by protein kinases. Database searches
revealed a 53% identity of the predicted peptide sequence with the Drosophila
bys (mrr) gene. Direct protein-protein interactions of trophinin, tastin, and
bystin analyzed by yeast two-hybrid assays and by in vitro protein binding
assays indicated that binding between bystin and trophinin and between bystin
and tastin is enhanced when cytokeratin 8 and 18 are present as the third
molecule. Immunocytochemistry of bystin showed that bystin colocalizes with
trophinin, tastin, and cytokeratins in a human trophoblastic teratocarcinoma
cell, HT-H. It is therefore possible that these molecules form a complex and
thus are involved in the process of embryo implantation.
DOI: 10.1073/pnas.95.9.5027
PMCID: PMC20207
PMID: 9560222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21734376 | 1. Dig Dis. 2011;29(2):130-5. doi: 10.1159/000323874. Epub 2011 Jul 5.
Epigenetics: principles and practice.
Hamilton JP(1).
Author information:
(1)Division of Gastroenterology and Hepatology, The Johns Hopkins University
School of Medicine, Baltimore, MD 21205, USA. [email protected]
Epigenetics is defined as heritable changes in gene expression that are, unlike
mutations, not attributable to alterations in the sequence of DNA. The
predominant epigenetic mechanisms are DNA methylation, modifications to
chromatin, loss of imprinting and non-coding RNA. Epigenetic regulation of gene
expression appears to have long-term effects and wide-ranging effects on health.
Diet and environmental exposures may potentially alter the level and scope of
epigenetic regulation, thus interesting developments in the study of epigenetics
might explain correlations that researchers have found between lifestyle and
risk of disease. Aberrant epigenetic patterns have been linked to a number of
digestive diseases including Barrett's esophagus, cirrhosis, inflammatory bowel
disease, and numerous gastrointestinal malignancies. In fact, many exciting
discoveries about epigenetics in general have been made by studying diseases of
the gastrointestinal tract and hepatobiliary tree. Epigenetic modifications of
DNA in cancer and precancerous lesions offer hope and the promise of novel
biomarkers for early cancer detection, prediction, prognosis, and response to
treatment. Furthermore, reversal of epigenetic changes represents a potential
target of novel therapeutic strategies and medication design. In the future, it
is anticipated that innovative diagnostic tests, treatment regimens, and even
lifestyle modifications will be based on epigenetic mechanisms and be
incorporated into the practice of medicine.
Copyright © 2011 S. Karger AG, Basel.
DOI: 10.1159/000323874
PMCID: PMC3134032
PMID: 21734376 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26216216 | 1. Hum Genomics. 2015 Jul 28;9(1):17. doi: 10.1186/s40246-015-0041-3.
Epigenetic inheritance and the missing heritability.
Trerotola M(1), Relli V(2), Simeone P(3), Alberti S(4)(5).
Author information:
(1)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(2)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(3)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(4)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(5)Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology
and Physiopathology, 'G. d'Annunzio' University, Chieti, Italy.
[email protected].
Genome-wide association studies of complex physiological traits and diseases
consistently found that associated genetic factors, such as allelic
polymorphisms or DNA mutations, only explained a minority of the expected
heritable fraction. This discrepancy is known as "missing heritability", and its
underlying factors and molecular mechanisms are not established. Epigenetic
programs may account for a significant fraction of the "missing heritability."
Epigenetic modifications, such as DNA methylation and chromatin assembly states,
reflect the high plasticity of the genome and contribute to stably alter gene
expression without modifying genomic DNA sequences. Consistent components of
complex traits, such as those linked to human stature/height, fertility, and
food metabolism or to hereditary defects, have been shown to respond to
environmental or nutritional condition and to be epigenetically inherited. The
knowledge acquired from epigenetic genome reprogramming during development, stem
cell differentiation/de-differentiation, and model organisms is today shedding
light on the mechanisms of (a) mitotic inheritance of epigenetic traits from
cell to cell, (b) meiotic epigenetic inheritance from generation to generation,
and (c) true transgenerational inheritance. Such mechanisms have been shown to
include incomplete erasure of DNA methylation, parental effects, transmission of
distinct RNA types (mRNA, non-coding RNA, miRNA, siRNA, piRNA), and persistence
of subsets of histone marks.
DOI: 10.1186/s40246-015-0041-3
PMCID: PMC4517414
PMID: 26216216 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33781317 | 1. Clin Epigenetics. 2021 Mar 29;13(1):65. doi: 10.1186/s13148-021-01049-x.
A review of epigenetic changes in asthma: methylation and acetylation.
Sheikhpour M(1)(2), Maleki M(3), Ebrahimi Vargoorani M(3)(4), Amiri V(3).
Author information:
(1)Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of
Iran, Tehran, Iran. [email protected].
(2)Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran.
[email protected].
(3)Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of
Iran, Tehran, Iran.
(4)Department of Microbiology, College of Basic Sciences, Tehran North Branch,
Islamic Azad University, Tehran, Iran.
Several studies show that childhood and adulthood asthma and its symptoms can be
modulated through epigenetic modifications. Epigenetic changes are inheritable
modifications that can modify the gene expression without changing the DNA
sequence. The most common epigenetic alternations consist of DNA methylation and
histone modifications. How these changes lead to asthmatic phenotype or promote
the asthma features, in particular by immune pathways regulation, is an
understudied topic. Since external effects, like exposure to tobacco smoke, air
pollution, and drugs, influence both asthma development and the epigenome,
elucidating the role of epigenetic changes in asthma is of great importance.
This review presents available evidence on the epigenetic process that drives
asthma genes and pathways, with a particular focus on DNA methylation, histone
methylation, and acetylation. We gathered and assessed studies conducted in this
field over the past two decades. Our study examined asthma in different aspects
and also shed light on the limitations and the important factors involved in the
outcomes of the studies. To date, most of the studies in this area have been
carried out on DNA methylation. Therefore, the need for diagnostic and
therapeutic applications through this molecular process calls for more research
on the histone modifications in this disease.
DOI: 10.1186/s13148-021-01049-x
PMCID: PMC8008616
PMID: 33781317 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/23448446 | 1. Curr Pharm Des. 2013;19(34):6156-85. doi: 10.2174/1381612811319340010.
Epigenetic and disease targets by polyphenols.
Pan MH(1), Lai CS, Wu JC, Ho CT.
Author information:
(1)Department of Food Science, Rutgers University, 65 Dudley Road, New
Brunswick, NJ 08901, USA. [email protected].
An epigenetic change is defined as an alteration in gene expression that does
not involve a change in the DNA sequence. Epigenetic modifications, including
DNA methylation, histone modification (acetylation, methylation and
phosphorylation) and miRNA, are critical for regulating developmental events.
However, aberrant epigenetic mechanisms may lead to pathological consequences
such as cardiovascular disease (CAD), neurodegenerative disease, obesity,
metabolic disorder, bone and skeletal diseases and various cancers. Given that
epigenetic modifications are heritable and reversible, in contrast to genetic
changes, they have been identified as promising targets for disease prevention
strategies. Over the past few decades, polyphenols, which are widely present in
foods such as fruits and vegetables, have been shown to exhibit a broad spectrum
of biological activities for human health. Polyphenols reverse adverse
epigenetic regulation by altering DNA methylation and histone modification, and
they modulate microRNA expression or directly interact with enzymes that result
in the reactivation of silenced tumor suppressor genes or the inactivation of
oncogenes. Therefore, dietary polyphenol- targeted epigenetics becomes an
attractive approach for disease prevention and intervention. In this review, we
summarize the current knowledge and underlying mechanisms of the most common
dietary polyphenols and their influence on major epigenetic mechanisms
associated with disease intervention.
DOI: 10.2174/1381612811319340010
PMID: 23448446 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23165337 | 1. Nat Rev Neurol. 2013 Jan;9(1):35-43. doi: 10.1038/nrneurol.2012.226. Epub 2012
Nov 20.
Epigenetic changes in patients with multiple sclerosis.
Koch MW(1), Metz LM, Kovalchuk O.
Author information:
(1)Department of Clinical Neurosciences, University of Calgary, Foothills
Hospital, 1403-29th Street N. W., Calgary, AB T2N 2T9, Canada.
[email protected]
Epigenetic changes influence gene expression without altering the DNA sequence.
DNA methylation, histone modification and microRNA-associated
post-transcriptional gene silencing are three key epigenetic mechanisms.
Multiple sclerosis (MS) is a disease of the CNS with both inflammatory and
neurodegenerative features. Although studies on epigenetic changes in MS only
began in the past decade, a growing body of literature suggests that epigenetic
changes may be involved in the development of MS, possibly by mediating the
effects of environmental risk factors, such as smoking, vitamin D deficiency and
Epstein-Barr virus infection. Such studies are also beginning to deliver
important insights into the pathophysiology of MS. For example, inflammation and
demyelination in relapsing-remitting MS may be related to the increased
differentiation of T cells toward a T-helper 17 phenotype, which is an important
epigenetically regulated pathophysiological mechanism. In progressive MS, other
epigenetically regulated mechanisms, such as increased histone acetylation and
citrullination of myelin basic protein, might exacerbate the disease course. In
this Review, we summarize current knowledge on the role of epigenetic changes in
the pathophysiology of MS.
DOI: 10.1038/nrneurol.2012.226
PMID: 23165337 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36057300 | 1. Int J Biol Macromol. 2022 Oct 31;219:1261-1271. doi:
10.1016/j.ijbiomac.2022.08.182. Epub 2022 Aug 31.
A review on CRISPR/Cas-based epigenetic regulation in plants.
Jogam P(1), Sandhya D(2), Alok A(3), Peddaboina V(4), Allini VR(2), Zhang B(5).
Author information:
(1)Department of Biotechnology, Kakatiya University, Warangal, Telangana 506009,
India. Electronic address: [email protected].
(2)Department of Biotechnology, Kakatiya University, Warangal, Telangana 506009,
India.
(3)Department of Plant Pathology, University of Minnesota, Saint Paul, MN 55108,
USA.
(4)Department of Microbiology, Kakatiya University, Warangal, Telangana 506009,
India.
(5)Department of Biology, East Carolina University, Greenville, NC 27858, USA.
Electronic address: [email protected].
Epigenetic changes are the heritable modifications in genes without altering DNA
sequences. The epigenetic changes occur in the plant genomes to regulate gene
expression patterns, which were used to regulate different biological processes,
including coping various environmental stresses. These changes, including DNA
methylation, non-coding RNA regulation, and histone modification, play a vital
role in the transcription and translation processes to regulate gene expression.
Gene engineering for the development of stress-tolerant crops via the DNA
methylation pathway initially needs a proper selection of genes and its
promoter. Manipulating epigenetics requires genetic engineering tools such as
Zinc finger nucleases (ZFN), transcription activator-like effector nucleases
(TALENs), and clustered regularly interspaced short palindromic repeats
(CRISPR)/CRISPR-associated protein (Cas). However, CRISPR/Cas9 mediated
epigenetic editing refers to transcriptional reprogramming at the targeted sites
using epigenetic enzymes fused with decatalytical Cas9 (dCas9). This review
focused on the different epigenetic mechanisms in plants and their potential
contribution to developing epigenetic tools. The dCas9 endonuclease tethered
with transcriptional repressor or activator domain leads to CRISPR inhibitor
(CRISPRi) or activator (CRISPRa) for regulating gene expression. The dCas9 has
been successfully fused with other various effector domains for constructing
epigenetic tools, including the DNA methyltransferase 3A (DNMT3A), or the DNA
demethylase TET. Multiple efforts have been made to improve epigenome editing in
plants. Initially, incorporating SunTag into the dCas9-EpiEffector complex was
used as an epigenetic tool; demethylation of target loci with dCas9-SunTag-TET1
futher increased its efficiency. Additionally, SunTag could also be fused with
the dCas9-DNMT3A complex to augment CpG methylation at a targeted loci.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ijbiomac.2022.08.182
PMID: 36057300 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23273101 | 1. Pain. 2013 Jan;154(1):15-23. doi: 10.1016/j.pain.2012.06.011.
Chronic opioid use is associated with increased DNA methylation correlating with
increased clinical pain.
Doehring A(1), Oertel BG, Sittl R, Lötsch J.
Author information:
(1)Institute of Clinical Pharmacology, Goethe-University, Theodor Stern Kai 7,
60590 Frankfurt am Main, Germany Fraunhofer Project Group Translational Medicine
and Pharmacology (IME-TMP), Theodor Stern Kai 7, D-60590 Frankfurt am Main,
Germany Department of Anesthesiology, Universitätsklinikum Erlangen,
Krankenhausstraße 12, D-91054 Erlangen, Germany.
Comment in
Pain. 2013 Jan;154(1):1-2. doi: 10.1016/j.pain.2012.10.016.
Environmentally caused changes in chromosomes that do not alter the DNA sequence
but cause phenotypic changes by altering gene transcription are summarized as
epigenetics. A major epigenetic mechanism is methylation or demethylation at
CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored
therapeutic consequences. Here we report increased methylation at a CpG rich
island in the OPRM1 gene coding for μ-opioid receptors and at a global
methylation site (LINE-1) in leukocytes of methadone-substituted former opiate
addicts compared with matched healthy controls. Higher DNA methylation
associated with chronic opioid exposure was reproduced in an independent cohort
of opioid-treated as compared to non-opioid-treated pain patients. This suggests
that opioids may stimulate DNA methylation. The OPRM1 methylation had no
immediate effect on μ-opioid receptor transcription and was not associated with
opioid dosing requirements. However, the global DNA methylation at LINE-1 was
significantly correlated with increased chronic pain. This suggests inhibitory
effects on the transcription of still unspecified nocifensive gene products. It
further implies that opioids may be causally associated with increased
genome-wide DNA methylation, although currently there is no direct evidence of
this. This has phenotypic consequences for pain and may provide a new,
epigenetics-associated mechanism of opioid-induced hyperalgesia. The results
indicate a potential influence of opioid analgesics on the patients' epigenome.
They emphasize the need for reliable and cost-effective screening tools and may
imply that high-throughput screening for lead compounds in artificial expression
systems may not provide the best tools for identifying new pain medications.
Copyright © 2012 International Association for the Study of Pain. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.pain.2012.06.011
PMID: 23273101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22359295 | 1. Methods Mol Biol. 2012;863:207-19. doi: 10.1007/978-1-61779-612-8_12.
Epigenome and DNA methylation in oral squamous cell carcinoma.
García MP(1), García-García A.
Author information:
(1)Oral Medicine, Oral Surgery and Implantology Unit, Entrerríos s/n, Santiago
de Compostela, Spain. [email protected]
Epigenetics studies and defines inherited changes in gene expression that are
not encoded in the DNA sequence. The most studied epigenetic change in mammalian
DNA is cytosine methylation in CpG dinucleotide areas. The other main group in
epigenetic changes includes the posttranslational modifications of histones,
mainly phosphorylation, deacetylation changes, and in the ubiquitinylation
status. Oral squamous cell carcinoma is the most common malignancy of the oral
cavity, and epigenetic changes are very common, as described in this chapter.
Alterations in the DNA methylation status resulting from exposure to
environmental stress agents have been documented even before birth. Although
many epigenetic markers are potentially reversible, the mechanism still remains
unclear and many epigenetic changes persist across cell lines and the life of
the organism.
DOI: 10.1007/978-1-61779-612-8_12
PMID: 22359295 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34728591 | 1. J Biosci. 2021;46(4):94. doi: 10.1007/s12038-021-00215-w.
Epigenetic interaction of microbes with their mammalian hosts.
Rajeev R(1), Dwivedi AP, Sinha A, Agarwaal V, Dev RR, Kar A, Khosla S.
Author information:
(1)Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
The interaction of microbiota with its host has the ability to alter the
cellular functions of both, through several mechanisms. Recent work, from many
laboratories including our own, has shown that epigenetic mechanisms play an
important role in the alteration of these cellular functions. Epigenetics
broadly refers to change in the phenotype without a corresponding change in the
DNA sequence. This change is usually brought by epigenetic modifications of the
DNA itself, the histone proteins associated with the DNA in the chromatin,
non-coding RNA or the modifications of the transcribed RNA. These modifications,
also known as epigenetic code, do not change the DNA sequence but alter the
expression level of specific genes. Microorganisms seem to have learned how to
modify the host epigenetic code and modulate the host transcriptome in their
favour. In this review, we explore the literature that describes the epigenetic
interaction of bacteria, fungi and viruses, with their mammalian hosts.
DOI: 10.1007/s12038-021-00215-w
PMCID: PMC8550911
PMID: 34728591 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16341272 | 1. Cell Mol Biol Lett. 2005;10(4):631-47.
The role of mammalian DNA methyltransferases in the regulation of gene
expression.
Turek-Plewa J(1), Jagodziński PP.
Author information:
(1)Department of Biochemistry and Molecular Biology, Karol Marcinkowski
University of Medical Sciences, Poznań, Poland.
The term epigenetic modification denotes reversible traits of gene expression
that do not include alterations to the DNA sequence. These epigenetic
alterations are responsible for chromatin structure stability, genome integrity,
modulation of tissue-specific gene expression, embryonic development, genomic
imprinting and X-chromosome inactivation in females. Epigenetic changes include
reversible DNA methylation and histone acetylation or methylation. The
modification of mammalian genomic DNA includes the methylation at the 5-position
of the cytosine (C) residue within cytosine-guanine dinucleotides (CpG),
resulting in the formation of 5-methylcytosine (m5C). Regulatory DNA sequences
in vertebrates often have little or no methylation. The methylation of mammalian
genomic DNA is catalyzed by DNA methyltransferases (DNMTs), which play a special
role in the initiation of chromatin remodeling and gene expression regulation.
The mammalian DNMTs are DNMT1, DNMT3A and DNMT3B, which together with accessory
proteins, like DNMT3L, are responsible for methylation pattern acquisition
during gametogenesis, embryogenesis and somatic tissue development. Reversible
epigenetic alterations lead to selective utilization of genome information
through the activation or inactivation of transcription of functional genes
during gametogenesis, embryogenesis and cell differentiation. Recently, several
disparate isoforms of DNMT1 were identified in human somatic and female and male
germ cells. Recent advances in the investigation of DNMT function in epigenetic
DNA changes have formed the basis of the understanding of various disorder
etiopathogeneses, and as a result, have facilitated and enabled new therapies
with respect to these diseases.
PMID: 16341272 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20620207 | 1. Genomics. 2010 Oct;96(4):191-8. doi: 10.1016/j.ygeno.2010.07.001. Epub 2010
Jul 8.
Redefining regulation of DNA methylation by RNA interference.
Muthusamy V(1), Bosenberg M, Wajapeyee N.
Author information:
(1)Department of Dermatology, Yale University School of Medicine, New Haven, CT
06510, USA.
Epigenetic changes refer to heritable changes that may modulate gene expression
without affecting DNA sequence. DNA methylation is one such heritable epigenetic
change, which is causally associated with the transcription regulation of many
genes in the mammalian genome. Altered DNA methylation has been implicated in a
wide variety of human diseases including cancer. Understanding the regulation of
DNA methylation is likely to improve the ability to diagnose and treat these
diseases. With the advent of high-throughput RNA interference (RNAi) screens,
answering epigenetic questions on a genomic scale is now possible. Two recent
genome-wide RNAi screens have addressed the regulation of DNA methylation in
cancer, leading to the identification of the regulators of epigenetic silencing
by oncogenic RAS and how epigenetic silencing of the tumor suppressor RASSF1A is
maintained. These RNAi screens have much wider applications, since similar
screens can now be adapted to identify the mechanism of silencing of any human
disease-associated gene that is epigenetically regulated. In this review, we
discuss two recent genome-wide RNAi screens for epigenetic regulators and
explore potential applications in understanding DNA methylation and gene
expression regulation in mammalian cells. We also discuss some of the key
unanswered questions in the field of DNA methylation and suggest genome-wide
RNAi screens designed to answer them.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygeno.2010.07.001
PMCID: PMC3726036
PMID: 20620207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20728889 | 1. J Biomech. 2010 Nov 16;43(15):2881-6. doi: 10.1016/j.jbiomech.2010.07.033.
Epub 2010 Aug 21.
The epigenetic mechanism of mechanically induced osteogenic differentiation.
Arnsdorf EJ(1), Tummala P, Castillo AB, Zhang F, Jacobs CR.
Author information:
(1)Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo
Alto, CA, United States.
Epigenetic regulation of gene expression occurs due to alterations in chromatin
proteins that do not change DNA sequence, but alter the chromatin architecture
and the accessibility of genes, resulting in changes to gene expression that are
preserved during cell division. Through this process genes are switched on or
off in a more durable fashion than other transient mechanisms of gene
regulation, such as transcription factors. Thus, epigenetics is central to
cellular differentiation and stem cell linage commitment. One such mechanism is
DNA methylation, which is associated with gene silencing and is involved in a
cell's progression towards a specific fate. Mechanical signals are a crucial
regulator of stem cell behavior and important in tissue differentiation;
however, there has been no demonstration of a mechanism whereby mechanics can
affect gene regulation at the epigenetic level. In this study, we identified
candidate DNA methylation sites in the promoter regions of three osteogenic
genes from bone marrow derived mesenchymal stem cells (MSCs). We demonstrate
that mechanical stimulation alters their epigenetic state by reducing DNA
methylation and show an associated increase in expression. We contrast these
results with biochemically induced differentiation and distinguish expression
changes associated with durable epigenetic regulation from those likely to be
due to transient changes in regulation. This is an important advance in stem
cell mechanobiology as it is the first demonstration of a mechanism by which the
mechanical micro-environment is able to induce epigenetic changes that control
osteogenic cell fate, and that can be passed to daughter cells. This is a first
step to understanding that will be vital to successful bone tissue engineering
and regenerative medicine, where continued expression of a desired long-term
phenotype is crucial.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jbiomech.2010.07.033
PMCID: PMC2975768
PMID: 20728889 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35735917 | 1. J Dev Biol. 2022 Jun 16;10(2):26. doi: 10.3390/jdb10020026.
Epigenetics and Early Development.
Gopinathan G(1), Diekwisch TGH(1).
Author information:
(1)TAMU Center for Craniofacial Research and Diagnosis, Texas A&M College of
Dentistry, Dallas, TX 75246, USA.
The epigenome controls all aspect of eukaryotic development as the packaging of
DNA greatly affects gene expression. Epigenetic changes are reversible and do
not affect the DNA sequence itself but rather control levels of gene expression.
As a result, the science of epigenetics focuses on the physical configuration of
chromatin in the proximity of gene promoters rather than on the mechanistic
effects of gene sequences on transcription and translation. In the present
review we discuss three prominent epigenetic modifications, DNA methylation,
histone methylation/acetylation, and the effects of chromatin remodeling
complexes. Specifically, we introduce changes to the methylated state of DNA
through DNA methyltransferases and DNA demethylases, discuss the effects of
histone tail modifications such as histone acetylation and methylation on gene
expression and present the functions of major ATPase subunit containing
chromatin remodeling complexes. We also introduce examples of how changes in
these epigenetic factors affect early development in humans and mice. In
summary, this review provides an overview over the most important epigenetic
mechanisms and provides examples of the dramatic effects of epigenetic changes
in early mammalian development.
DOI: 10.3390/jdb10020026
PMCID: PMC9225096
PMID: 35735917
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to
publish the results. |
http://www.ncbi.nlm.nih.gov/pubmed/20309920 | 1. Mt Sinai J Med. 2010 Mar-Apr;77(2):225-35. doi: 10.1002/msj.20176.
Epigenetics in women's health care.
Pozharny Y(1), Lambertini L, Clunie G, Ferrara L, Lee MJ.
Author information:
(1)Mount Sinai School of Medicine, New York, NY, USA.
Epigenetics refers to structural modifications to genes that do not change the
nucleotide sequence itself but instead control and regulate gene expression. DNA
methylation, histone modification, and RNA regulation are some of the mechanisms
involved in epigenetic modification. Epigenetic changes are believed to be a
result of changes in an organism's environment that result in fixed and
permanent changes in most differentiated cells. Some environmental changes that
have been linked to epigenetic changes include starvation, folic acid, and
various chemical exposures. There are periods in an organism's life cycle in
which the organism is particularly susceptible to epigenetic influences; these
include fertilization, gametogenesis, and early embryo development. These are
also windows of opportunity for interventions during the reproductive life cycle
of women to improve maternal-child health. New data suggest that epigenetic
influences might be involved in the regulation of fetal development and the
pathophysiology of adult diseases such as cancer, diabetes, obesity, and
neurodevelopmental disorders. Various epigenetic mechanisms may also be involved
in the pathogenesis of preeclampsia and intrauterine growth restriction.
Additionally, environmental exposures are being held responsible for causing
epigenetic changes that lead to a disease process. Exposure to heavy metals,
bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has
been shown to affect the epigenetic memory of an organism. Their long-term
effects are unclear at this point, but many ongoing studies are attempting to
elucidate the pathophysiological effects of such gene-environment interactions.
(c) 2010 Mount Sinai School of Medicine.
DOI: 10.1002/msj.20176
PMID: 20309920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23529258 | 1. Gen Thorac Cardiovasc Surg. 2013 May;61(5):262-9. doi:
10.1007/s11748-013-0235-3. Epub 2013 Mar 26.
Epigenetic alterations and their clinical implications in esophageal squamous
cell carcinoma.
Toh Y(1), Egashira A, Yamamoto M.
Author information:
(1)Department of Gastroenterological Surgery, National Kyushu Cancer Center,
3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. [email protected]
Alterations in the regulation of gene expression that do not involve a change in
the DNA sequence have been increasingly recognized as an important key event of
carcinogenesis, referred to as "epigenetic" changes. Major epigenetic mechanisms
include the methylation of cytosines in DNA, changes of histone and chromatin
structure by covalent posttranslational modifications of histone proteins and
alterations in the expression of microRNAs. These epigenetic alterations have
also been identified in esophageal squamous cell carcinoma (ESCC). In this brief
review, we will discuss DNA hypermethylation of the tumor suppressor gene
promoters, histone modifications including histone acetylation/deacetylation and
histone methylation and microRNAs in ESCC. Clinical implications of these
epigenetic alterations in ESCC will be also discussed.
DOI: 10.1007/s11748-013-0235-3
PMID: 23529258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25694547 | 1. J Exp Bot. 2015 Jun;66(12):3541-8. doi: 10.1093/jxb/eru502. Epub 2015 Feb 17.
Epigenetic variation and environmental change.
Meyer P(1).
Author information:
(1)Centre for Plant Sciences, University of Leeds, Leeds, UK
[email protected].
Environmental conditions can change the activity of plant genes via epigenetic
effects that alter the competence of genetic information to be expressed. This
may provide a powerful strategy for plants to adapt to environmental change.
However, as epigenetic changes do not modify DNA sequences and are therefore
reversible, only those epi-mutations that are transmitted through the germline
can be expected to contribute to a long-term adaptive response. The major
challenge for the investigation of epigenetic adaptation theories is therefore
to identify genomic loci that undergo epigenetic changes in response to
environmental conditions, which alter their expression in a heritable way and
which improve the plant's ability to adapt to the inducing conditions. This
review focuses on the role of DNA methylation as a prominent epigenetic mark
that controls chromatin conformation, and on its potential in mediating
expression changes in response to environmental signals.
© The Author 2015. Published by Oxford University Press on behalf of the Society
for Experimental Biology. All rights reserved. For permissions, please email:
[email protected].
DOI: 10.1093/jxb/eru502
PMID: 25694547 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17413852 | 1. Pediatr Res. 2007 May;61(5 Pt 2):24R-29R. doi: 10.1203/pdr.0b013e3180457684.
Epigenetics and microRNAs.
Chuang JC(1), Jones PA.
Author information:
(1)Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive
Cancer Center, University of Southern California, Los Angeles 90089, USA.
Epigenetics is defined as mitotically and meiotically heritable changes in gene
expression that do not involve a change in the DNA sequence. Two major areas of
epigenetics-DNA methylation and histone modifications-are known to have profound
effects on controlling gene expression. DNA methylation is involved in normal
cellular control of expression, and aberrant hypermethylation can lead to
silencing of tumor-suppressor genes in carcinogenesis. Histone modifications
control the accessibility of the chromatin and transcriptional activities inside
a cell. MicroRNAs (miRNAs) are small RNA molecules, approximately 22 nucleotides
long that can negatively control their target gene expression
posttranscriptionally. There are currently more than 460 human miRNAs known, and
the total number is predicted to be much larger. Recently, the expression of
miRNAs has been definitively linked to cancer development, and miRNA profiles
can be used to classify human cancers. miRNAs are encoded in our genome and are
generally transcribed by RNA polymerase II. Despite the growing evidence for
their importance in normal physiology, little is known about the regulation of
miRNA expression. In this review, we will examine the relationship between
miRNAs and epigenetics. We examine the effects of miRNAs on epigenetic
machinery, and the control of miRNA expression by epigenetic mechanisms.
Epigenetics is defined as heritable changes in gene expression that do not
involve a change in DNA sequence.
DOI: 10.1203/pdr.0b013e3180457684
PMID: 17413852 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35664328 | 1. Front Genet. 2022 May 18;13:819941. doi: 10.3389/fgene.2022.819941.
eCollection 2022.
Unravelling the Role of Epigenetic Modifications in Development and Reproduction
of Angiosperms: A Critical Appraisal.
Kumari P(1), Khan S(1), Wani IA(1), Gupta R(2), Verma S(3), Alam P(4), Alaklabi
A(5).
Author information:
(1)Conservation and Molecular Biology Lab., Department of Botany, Baba Ghulam
Shah Badshah University, Rajouri, India.
(2)Division of Soil Sciences & Agricultural Chemistry, Faculty of Agriculture
Sher e Kashmir University of Agricultural Sciences and Technology, Chatha,
India.
(3)Department of Botany, University of Jammu, Jammu, India.
(4)Department of Biology, College of Science and Humanities, Prince Sattam bin
Abdulaziz University (PSAU), Alkharj, Saudi Arabia.
(5)Department of Biology, College of Science, University of Bisha, Bisha, Saudi
Arabia.
Epigenetics are the heritable changes in gene expression patterns which occur
without altering DNA sequence. These changes are reversible and do not change
the sequence of the DNA but can alter the way in which the DNA sequences are
read. Epigenetic modifications are induced by DNA methylation, histone
modification, and RNA-mediated mechanisms which alter the gene expression,
primarily at the transcriptional level. Such alterations do control genome
activity through transcriptional silencing of transposable elements thereby
contributing toward genome stability. Plants being sessile in nature are highly
susceptible to the extremes of changing environmental conditions. This increases
the likelihood of epigenetic modifications within the composite network of genes
that affect the developmental changes of a plant species. Genetic and epigenetic
reprogramming enhances the growth and development, imparts phenotypic
plasticity, and also ensures flowering under stress conditions without changing
the genotype for several generations. Epigenetic modifications hold an immense
significance during the development of male and female gametophytes,
fertilization, embryogenesis, fruit formation, and seed germination. In this
review, we focus on the mechanism of epigenetic modifications and their dynamic
role in maintaining the genomic integrity during plant development and
reproduction.
Copyright © 2022 Kumari, Khan, Wani, Gupta, Verma, Alam and Alaklabi.
DOI: 10.3389/fgene.2022.819941
PMCID: PMC9157814
PMID: 35664328
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/21416922 | 1. Sheng Li Ke Xue Jin Zhan. 2010 Oct;41(5):335-40.
[The physiological and pathological significance of epigenetic regulation in
neural development].
[Article in Chinese]
Li P(1), Sun FY.
Author information:
(1)Department of Neurobiology and State Key Laboratory of Medical Neurobiology,
Shanghai Medical College of Fudan University, Shanghai 200032, China.
Epigenetics refers to changes in gene expression that do not entail a change in
DNA sequence, namely phenotype changed, other than the genotype. These changes
may remain through cell division for the remainder of the cell's life and may
also last for multiple generations. It contains DNA methylation, histone
modification, chromatin remodeling, gene imprinting and so on. Methylation is
one of the chief epigenetic modify patterns in genomic DNA. DNA methylation via
the interaction of methylation-CpG-binding proteins will affect the gene
expression. Furthermore, the dysfuction of epigenetic mechanisms may lead to
multiple genetic neurodevelopmental disorders and degenerative diseases. Here we
mainly rewiewed the physiological and pathological significance of epigenetics
regulations in neural development and neurodegeneration.
PMID: 21416922 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25797698 | 1. Pharmacol Ther. 2015 Jul;151:72-86. doi: 10.1016/j.pharmthera.2015.03.003.
Epub 2015 Mar 20.
Epigenomes as therapeutic targets.
Hamm CA(1), Costa FF(2).
Author information:
(1)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's
Hospital of Chicago Research Center and Department of Pediatrics, Northwestern
University's Feinberg School of Medicine, 225 E. Chicago Avenue, Box 220,
Chicago, IL 60611-2605, USA. Electronic address: [email protected].
(2)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's
Hospital of Chicago Research Center and Department of Pediatrics, Northwestern
University's Feinberg School of Medicine, 225 E. Chicago Avenue, Box 220,
Chicago, IL 60611-2605, USA; StartUp Health Academy, 2000 Broadway St, 18th
Floor, New York, NY 10.023, USA; Genomic Enterprise, 2405 N. Sheffield Av., #
14088, Chicago, IL 60.614, USA; Genomic Sciences and Biotechnology Program, UCB
- Brasilia, SGAN 916 Modulo B, Bloco C, 70.790-160 Brasilia, Brazil. Electronic
address: [email protected].
Epigenetics is a molecular phenomenon that pertains to heritable changes in gene
expression that do not involve changes in the DNA sequence. Epigenetic
modifications in a whole genome, known as the epigenome, play an essential role
in the regulation of gene expression in both normal development and disease.
Traditional epigenetic changes include DNA methylation and histone
modifications. Recent evidence reveals that other players, such as non-coding
RNAs, may have an epigenetic regulatory role. Aberrant epigenetic signaling is
becoming to be known as a central component of human disease, and the reversible
nature of the epigenetic modifications provides an exciting opportunity for the
development of clinically relevant therapeutics. Current epigenetic therapies
provide a clinical benefit through disrupting DNA methyltransferases or histone
deacetylases. However, the emergence of next-generation epigenetic therapies
provides an opportunity to more effectively disrupt epigenetic disease states.
Novel epigenetic therapies may improve drug targeting and drug delivery,
optimize dosing schedules, and improve the efficacy of preexisting treatment
modalities (chemotherapy, radiation, and immunotherapy). This review discusses
the epigenetic mechanisms that contribute to the disease, available epigenetic
therapies, epigenetic therapies currently in development, and the potential
future use of epigenetic therapeutics in a clinical setting.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pharmthera.2015.03.003
PMID: 25797698 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30580428 | 1. Methods Mol Biol. 2019;1909:129-135. doi: 10.1007/978-1-4939-8973-7_10.
Epigenetic Characterization of Cell-Free DNA.
Gurioli G(1).
Author information:
(1)Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la
Cura dei Tumori (IRST) IRCCS, Meldola, Italy. [email protected].
Cell-free DNA can be evaluated for the epigenetic component. Epigenetic
alterations consist of changes in gene functions that do not involve changes in
DNA sequence. The mainly studied epigenetic alteration is DNA methylation
occurring at CpG islands in the promoter regions for which several literature
data showed clinical relevance. This chapter is an overview of the epigenetic
alterations detected in cell-free DNA.
DOI: 10.1007/978-1-4939-8973-7_10
PMID: 30580428 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33866814 | 1. Philos Trans R Soc Lond B Biol Sci. 2021 Jun 7;376(1826):20200111. doi:
10.1098/rstb.2020.0111. Epub 2021 Apr 19.
How does epigenetics influence the course of evolution?
Ashe A(1), Colot V(2), Oldroyd BP(3).
Author information:
(1)School of Life and Environmental Sciences, University of Sydney, Sydney, New
South Wales 2006, Australia.
(2)Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Centre National
de la Recherche Scientifique (CNRS), Institut National de la Santé et de la
Recherche Médicale (INSERM), Ecole Normale Supérieure, PSL Research University,
75005 Paris, France.
(3)Wissenschaftskolleg zu Berlin, Wallotstrasse 19, 14193 Berlin, Germany.
Epigenetics is the study of changes in gene activity that can be transmitted
through cell divisions but cannot be explained by changes in the DNA sequence.
Epigenetic mechanisms are central to gene regulation, phenotypic plasticity,
development and the preservation of genome integrity. Epigenetic mechanisms are
often held to make a minor contribution to evolutionary change because
epigenetic states are typically erased and reset at every generation, and are
therefore, not heritable. Nonetheless, there is growing appreciation that
epigenetic variation makes direct and indirect contributions to evolutionary
processes. First, some epigenetic states are transmitted intergenerationally and
affect the phenotype of offspring. Moreover, bona fide heritable 'epialleles'
exist and are quite common in plants. Such epialleles could, therefore, be
subject to natural selection in the same way as conventional DNA sequence-based
alleles. Second, epigenetic variation enhances phenotypic plasticity and
phenotypic variance and thus can modulate the effect of natural selection on
sequence-based genetic variation. Third, given that phenotypic plasticity is
central to the adaptability of organisms, epigenetic mechanisms that generate
plasticity and acclimation are important to consider in evolutionary theory.
Fourth, some genes are under selection to be 'imprinted' identifying the sex of
the parent from which they were derived, leading to parent-of-origin-dependent
gene expression and effects. These effects can generate hybrid disfunction and
contribute to speciation. Finally, epigenetic processes, particularly DNA
methylation, contribute directly to DNA sequence evolution, because they act as
mutagens on the one hand and modulate genome stability on the other by keeping
transposable elements in check. This article is part of the theme issue 'How
does epigenetics influence the course of evolution?'
DOI: 10.1098/rstb.2020.0111
PMCID: PMC8059608
PMID: 33866814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20627830 | 1. Mol Oncol. 2010 Jun;4(3):242-54. doi: 10.1016/j.molonc.2010.04.002. Epub 2010
Apr 29.
The epigenetics of breast cancer.
Jovanovic J(1), Rønneberg JA, Tost J, Kristensen V.
Author information:
(1)Department for Clinical Molecular Biology (EpiGen), Institute for Clinical
Medicine, Akershus University Hospital, University of Oslo, Norway.
Epigenetic changes can be defined as stable molecular alterations of a cellular
phenotype such as the gene expression profile of a cell that are heritable
during somatic cell divisions (and sometimes germ line transmissions) but do not
involve changes of the DNA sequence itself. Epigenetic phenomena are mediated by
several molecular mechanisms comprising histone modifications,
polycomb/trithorax protein complexes, small non-coding or antisense RNAs and DNA
methylation. These different modifications are closely interconnected.
Epigenetic regulation is critical in normal growth and development and closely
conditions the transcriptional potential of genes. Epigenetic mechanisms convey
genomic adaption to an environment thereby ultimately contributing towards given
phenotype. In this review we will describe the various aspects of epigenetics
and in particular DNA methylation in breast carcinogenesis and their potential
application for diagnosis, prognosis and treatment decision.
(c) 2010. Published by Elsevier B.V.
DOI: 10.1016/j.molonc.2010.04.002
PMCID: PMC5527941
PMID: 20627830 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12473517 | 1. Lancet Oncol. 2002 Dec;3(12):755-63. doi: 10.1016/s1470-2045(02)00932-4.
Epigenetics in cancer: implications for early detection and prevention.
Verma M(1), Srivastava S.
Author information:
(1)Cancer Biomarker Research Group, Division of Cancer Prevention, National
Cancer Institute, MD 20892-7346, USA. [email protected]
Knowledge of the molecular events that occur during the early stages of cancer
has advanced rapidly. The initiation and development of cancer involves several
molecular changes, which include epigenetic alterations. Epigenetics is the
study of modifications in gene expression that do not involve changes in DNA
nucleotide sequences. Modifications in gene expression through methylation of
DNA and remodelling of chromatin via histone proteins are believed to be the
most important of the epigenetic changes. The study of epigenetics offers great
potential for the identification of biomarkers that can be used to detect and
diagnose cancer in its earliest stages and to accurately assess individual risk.
There has been a recent surge of interest among researchers as variations in the
methylation of DNA have been shown to be the most consistent molecular changes
in many neoplasms. An important distinction between a genetic and an epigenetic
change in cancer is that epigenetic changes can be reversed more easily by use
of therapeutic interventions. The discovery of these basic premises should
stimulate much future research on epigenetics.
DOI: 10.1016/s1470-2045(02)00932-4
PMID: 12473517 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33866804 | 1. Philos Trans R Soc Lond B Biol Sci. 2021 Jun 7;376(1826):20200114. doi:
10.1098/rstb.2020.0114. Epub 2021 Apr 19.
The impact of epigenetic information on genome evolution.
Yi SV(1), Goodisman MAD(1).
Author information:
(1)School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA
30332, USA.
Epigenetic information affects gene function by interacting with chromatin,
while not changing the DNA sequence itself. However, it has become apparent that
the interactions between epigenetic information and chromatin can, in fact,
indirectly lead to DNA mutations and ultimately influence genome evolution. This
review evaluates the ways in which epigenetic information affects genome
sequence and evolution. We discuss how DNA methylation has strong and pervasive
effects on DNA sequence evolution in eukaryotic organisms. We also review how
the physical interactions arising from the connections between histone proteins
and DNA affect DNA mutation and repair. We then discuss how a variety of
epigenetic mechanisms exert substantial effects on genome evolution by
suppressing the movement of transposable elements. Finally, we examine how
genome expansion through gene duplication is also partially controlled by
epigenetic information. Overall, we conclude that epigenetic information has
widespread indirect effects on DNA sequences in eukaryotes and represents a
potent cause and constraint of genome evolution. This article is part of the
theme issue 'How does epigenetics influence the course of evolution?'
DOI: 10.1098/rstb.2020.0114
PMCID: PMC8059978
PMID: 33866804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31609563 | 1. Ned Tijdschr Geneeskd. 2019 Oct 10;163:D4123.
[Clinical implications of epigenetic changes].
[Article in Dutch]
Mannens MMAM(1)(2).
Author information:
(1)Amsterdam UMC, afd. Klinische Genetica, Amsterdam.
(2)Contact: M.M.A.M. Mannens ([email protected]).
Inherited and acquired changes in DNA can influence the coding for gene products
(proteins). When the function of a protein is disturbed, this may lead to
disease. DNA in chromatin can be condensed or be arranged in an open structure.
The activity of genes is significantly affected by the accessibility to DNA by
transcription factors and other proteins involved in the transcription of genes.
The accessibility of DNA is regulated by epigenetic processes, including
methylation of cytosine. In these circumstances the nucleic sequence of the DNA
does not change. Nevertheless, disturbances of these processes can also
culminate in disease. Epigenetic changes to DNA are reversible. This offers
opportunities for treatment and recovery in conditions that are a result of
disturbed epigenetic processes.
PMID: 31609563 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19183791 | 1. J Biomol Tech. 2008 Dec;19(5):281-4.
DNA methylation signature analysis: how easy is it to perform?
Piperi C(1), Farmaki E, Vlastos F, Papavassiliou AG, Martinet N.
Author information:
(1)Department of Biological Chemistry, Medical School, University of Athens,
Athens, Greece.
Epigenetic changes, or heritable alterations in gene function that do not affect
DNA sequence, are rapidly gaining acceptance as co-conspirators in
carcinogenesis. Although DNA methylation signature analysis by
methylation-specific polymerase chain reaction has been a breakthrough method in
speed and sensitivity for gene methylation studies, several factors still limit
its application as a routine diagnostic and prognostic test.
PMCID: PMC2628070
PMID: 19183791 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22949838 | 1. Int J Mol Sci. 2012;13(8):9900-9922. doi: 10.3390/ijms13089900. Epub 2012 Aug
8.
Molecular mechanisms of epigenetic variation in plants.
Fujimoto R(1), Sasaki T(2), Ishikawa R(3)(4), Osabe K(5), Kawanabe T(6), Dennis
ES(5).
Author information:
(1)Graduate School of Science and Technology, Niigata University, Nishi-ku,
Niigata 950-2181, Japan.
(2)Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of
Sciences, Dr. Bohrgasse 3, Vienna 1030, Austria.
(3)Laboratory of Plant Breeding, Graduate School of Agricultural Science, Kobe
University, Nada, Kobe 657-8510, Japan.
(4)Cell and Developmental Biology, John Innes Centre, Norwich Research Park,
Colney, Norwich NR4 7UH, UK.
(5)Commonwealth Scientific and Industrial Research Organisation (CSIRO) Plant
Industry, Canberra ACT 2601, Australia.
(6)Watanabe Seed Co., Ltd, Machiyashiki, Misato-cho, Miyagi 987-8607, Japan.
Natural variation is defined as the phenotypic variation caused by spontaneous
mutations. In general, mutations are associated with changes of nucleotide
sequence, and many mutations in genes that can cause changes in plant
development have been identified. Epigenetic change, which does not involve
alteration to the nucleotide sequence, can also cause changes in gene activity
by changing the structure of chromatin through DNA methylation or histone
modifications. Now there is evidence based on induced or spontaneous mutants
that epigenetic changes can cause altering plant phenotypes. Epigenetic changes
have occurred frequently in plants, and some are heritable or metastable causing
variation in epigenetic status within or between species. Therefore, heritable
epigenetic variation as well as genetic variation has the potential to drive
natural variation.
DOI: 10.3390/ijms13089900
PMCID: PMC3431836
PMID: 22949838 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21941617 | 1. Genes Cancer. 2011 Jun;2(6):607-17. doi: 10.1177/1947601910393957.
DNA methylation: superior or subordinate in the epigenetic hierarchy?
Jin B(1), Li Y, Robertson KD.
Author information:
(1)Department of Biochemistry & Molecular Biology, Medical College of Georgia
Cancer Center, Augusta, GA, USA.
Epigenetic modifications are heritable changes in gene expression not encoded by
the DNA sequence. In the past decade, great strides have been made in
characterizing epigenetic changes during normal development and in disease
states like cancer. However, the epigenetic landscape has grown increasingly
complicated, encompassing DNA methylation, the histone code, noncoding RNA, and
nucleosome positioning, along with DNA sequence. As a stable repressive mark,
DNA methylation, catalyzed by the DNA methyltransferases (DNMTs), is regarded as
a key player in epigenetic silencing of transcription. DNA methylation may
coordinately regulate the chromatin status via the interaction of DNMTs with
other modifications and with components of the machinery mediating those marks.
In this review, we will comprehensively examine the current understanding of the
connections between DNA methylation and other epigenetic marks and discuss
molecular mechanisms of transcriptional repression in development and in
carcinogenesis.
DOI: 10.1177/1947601910393957
PMCID: PMC3174260
PMID: 21941617
Conflict of interest statement: The author(s) declared no potential conflicts of
interest with respect to the authorship and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/30079076 | 1. Front Plant Sci. 2018 Jul 17;9:1048. doi: 10.3389/fpls.2018.01048. eCollection
2018.
Epigenetic Regulation of Juvenile-to-Adult Transition in Plants.
Xu Y(1), Zhang L(1), Wu G(1).
Author information:
(1)State Key Laboratory of Subtropical Silviculture, School of Agriculture and
Food Sciences, Zhejiang Agriculture and Forestry University, Hangzhou, China.
Epigenetic regulation is referred to as changes in gene function that do not
involve changes in the DNA sequence, it is usually accomplished by DNA
methylation, histone modifications (repressive marks such as H3K9me, H3K27me,
H2Aub, or active marks such as H3K4me, H3K36me, H3Ac), and chromatin remodeling
(nucleosome composition, occupancy, and location). In plants, the shoot apex
produces different lateral organs during development to give rise to
distinguishable phases of a juvenile, an adult and a reproductive phase after
embryogenesis. The juvenile-to-adult transition is a key developmental event in
plant life cycle, and it is regulated by a decrease in the expression of a
conserved microRNA-miR156/157, and a corresponding increase in the expression of
its target genes encoding a set of plant specific SQUAMOSA PROMOTER BINDING
PROTEIN-LIKE (SPL) proteins. Recent work has revealed that the miR156/157-SPL
pathway is the master regulator of juvenile-to-adult transition in plants, and
genes in this pathway are subjected to epigenetic regulation, such as DNA
methylation, histone modifications, and chromatin remodeling. In this review, we
summarized the recent progress in understanding the epigenetic regulation of the
miR156/157-SPL pathway during juvenile-to-adult transition and bring forward
some perspectives of future research in this field.
DOI: 10.3389/fpls.2018.01048
PMCID: PMC6063087
PMID: 30079076 |
http://www.ncbi.nlm.nih.gov/pubmed/23895656 | 1. Epigenomics. 2013 Aug;5(4):439-52. doi: 10.2217/epi.13.37.
Combining genomic and proteomic approaches for epigenetics research.
Han Y(1), Garcia BA.
Author information:
(1)Epigenetics Program, Department of Biochemistry & Biophysics, Perelman School
of Medicine, University of Pennsylvania, 1009C Stellar-Chance Laboratories, 422
Curie Boulevard, Philadelphia, PA 19104, USA.
Epigenetics is the study of changes in gene expression or cellular phenotype
that do not change the DNA sequence. In this review, current methods, both
genomic and proteomic, associated with epigenetics research are discussed. Among
them, chromatin immunoprecipitation (ChIP) followed by sequencing and other
ChIP-based techniques are powerful techniques for genome-wide profiling of
DNA-binding proteins, histone post-translational modifications or nucleosome
positions. However, mass spectrometry-based proteomics is increasingly being
used in functional biological studies and has proved to be an indispensable tool
to characterize histone modifications, as well as DNA-protein and
protein-protein interactions. With the development of genomic and proteomic
approaches, combination of ChIP and mass spectrometry has the potential to
expand our knowledge of epigenetics research to a higher level.
DOI: 10.2217/epi.13.37
PMCID: PMC4055025
PMID: 23895656 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28815391 | 1. Curr Diab Rep. 2017 Aug 16;17(10):89. doi: 10.1007/s11892-017-0916-x.
The Role of Epigenetics in Type 1 Diabetes.
Jerram ST(1), Dang MN(1), Leslie RD(2)(3).
Author information:
(1)Queen Mary University of London, Mile End Rd, London, E1 4NS, UK.
(2)Queen Mary University of London, Mile End Rd, London, E1 4NS, UK.
[email protected].
(3)The Blizard Institute, London, UK. [email protected].
PURPOSE OF REVIEW: Epigenetics is defined as mitotically heritable changes in
gene expression that do not directly alter the DNA sequence. By implication,
such epigenetic changes are non-genetically determined, although they can be
affected by inherited genetic variation. Extensive evidence indicates that
autoimmune diseases including type 1 diabetes are determined by the interaction
of genetic and non-genetic factors. Much is known of the genetic causes of these
diseases, but the non-genetic effects are less clear-cut. Further, it remains
unclear how they interact to cause the destructive autoimmune process. This
review identifies the key issues in the genetic/non-genetic interaction,
examining the most recent evidence of the role of non-genetic effects in the
disease process, including the impact of epigenetic effects on key pathways.
RECENT FINDINGS: Recent research indicates that these pathways likely involve
immune effector cells both of the innate and adaptive immune response.
Specifically, there is evidence of cell type-specific enrichment in altered DNA
methylation, changes which were temporally stable and enriched at gene
regulatory elements. Epigenomics remains in its infancy, and we anticipate
further studies will define how the interaction of genetic and non-genetic
effects induces tissue-specific destruction and enhances our ability to predict,
and possibly even modify that process.
DOI: 10.1007/s11892-017-0916-x
PMCID: PMC5559569
PMID: 28815391 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST: Samuel T. Jerram, Mary N.
Dang and R. David Leslie declare that they have no conflict of interest. HUMAN
AND ANIMAL RIGHTS AND INFORMED CONSENT: This article does not contain any
studies with human or animal subjects performed by any of the authors. |
http://www.ncbi.nlm.nih.gov/pubmed/32133274 | 1. World J Clin Oncol. 2020 Feb 24;11(2):43-52. doi: 10.5306/wjco.v11.i2.43.
Can epigenetic and inflammatory biomarkers identify clinically aggressive
prostate cancer?
Santos PB(1), Patel H(2), Henrique R(3), Félix A(4).
Author information:
(1)Department of Urology, Prof. Doutor Fernando Fonseca Hospital, Amadora
2720-276, Portugal. [email protected].
(2)Department of Urology, University Hospital North Norway, Tromsø 9019, Norway.
(3)Departments of Pathology and Cancer Biology and Epigenetics Group-Research
Center, Portuguese Oncology Institute of Porto, Porto 4200-072, Portugal.
(4)Department of Pathology, Portuguese Oncology Institute of Lisbon, Lisbon
1099-023, Portugal.
Prostate cancer (PCa) is a highly prevalent malignancy and constitutes a major
cause of cancer-related morbidity and mortality. It emerges through the
acquisition of genetic and epigenetic alterations. Epigenetic modifications
include DNA methylation, histone modifications and microRNA deregulation. These
generate heritable transformations in the expression of genes but do not change
the DNA sequence. Alterations in DNA methylation (hypo and hypermethylation) are
the most characterized in PCa. They lead to genomic instability and inadequate
gene expression. Major and minor-specific modifications in chromatin recasting
are involved in PCa, with signs suggesting a dysfunction of enzymes modified by
histones. MicroRNA deregulation also contributes to the initiation of PCa,
including involvement in androgen receptor signalization and apoptosis. The
influence of inflammation on prostate tumor carcinogenesis is currently much
better known. Recent discoveries about microbial species resident in the urinary
tract suggest that these are the initiators of chronic inflammation, promoting
prostate inflammatory atrophy and eventually leading to PCa. Complete
characterization of the relationship between the urinary microbiome and
prostatic chronic inflammation will be crucial to develop plans for the
prevention of PCa. The prevalent nature of epigenetic and inflammatory
alterations may provide potential biomarkers for PCa diagnosis, treatment
decisions, evaluation of prognosis and posttreatment surveillance.
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights
reserved.
DOI: 10.5306/wjco.v11.i2.43
PMCID: PMC7046922
PMID: 32133274
Conflict of interest statement: Conflict-of-interest statement: The authors have
no conflicts of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/27730435 | 1. Adv Exp Med Biol. 2016;933:59-68. doi: 10.1007/978-981-10-2041-4_6.
Epigenetic Regulation in Cystogenesis.
Woo YM(1).
Author information:
(1)Molecular Medicine Laboratory, Department of Life systems, Sookmyung Women's
University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, South Korea.
[email protected].
Epigenetic regulation refers to heritable changes in gene expression that do not
involve any alteration of the DNA sequence. DNA methylation, histone
modification, and gene regulation by microRNAs are well-known epigenetic
modulations that are closely associated with several cellular processes and
diverse disease states, such as cancers, even under precancerous conditions.
More recently, several studies have indicated that epigenetic changes may be
associated with renal cystic diseases, including autosomal dominant polycystic
kidney disease, and the restoration of altered epigenetic factors may become a
therapeutic target of renal cystic disease and would be expected to have minimal
side effects. This review focuses on recently reported findings on epigenetic
and considers the potential of targeting epigenetic regulation as a novel
therapeutic approach to control cystogenesis.
DOI: 10.1007/978-981-10-2041-4_6
PMID: 27730435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29541423 | 1. Oncotarget. 2017 Dec 17;9(13):11414-11426. doi: 10.18632/oncotarget.23356.
eCollection 2018 Feb 16.
Role of novel histone modifications in cancer.
Shanmugam MK(1), Arfuso F(2), Arumugam S(3), Chinnathambi A(4), Jinsong B(1),
Warrier S(5), Wang LZ(1)(6), Kumar AP(1)(6)(7)(8)(9), Ahn KS(10), Sethi G(1),
Lakshmanan M(3)(11).
Author information:
(1)Department of Pharmacology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore, Singapore.
(2)Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences,
Curtin Health Innovation Research Institute, Curtin University, Perth, WA,
Australia.
(3)Institute of Molecular and Cell Biology, ASTAR, Biopolis Drive, Proteos,
Singapore, Singapore.
(4)Department of Botany and Microbiology, College of Science, King Saud
University, Riyadh, Kingdom of Saudi Arabia.
(5)Division of Cancer Stem Cells and Cardiovascular Regeneration, School of
Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore,
India.
(6)Cancer Science Institute of Singapore, National University of Singapore,
Singapore, Singapore.
(7)Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth,
WA, Australia.
(8)National University Cancer Institute, National University Health System,
Singapore, Singapore.
(9)Department of Biological Sciences, University of North Texas, Denton, Texas,
USA.
(10)College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul,
Korea.
(11)Department of Pathology, National University Hospital Singapore, Singapore,
Singapore.
Erratum in
Oncotarget. 2018 Apr 10;9(27):19460. doi: 10.18632/oncotarget.25152.
Oncogenesis is a multistep process mediated by a variety of factors including
epigenetic modifications. Global epigenetic post-translational modifications
have been detected in almost all cancers types. Epigenetic changes appear
briefly and do not involve permanent changes to the primary DNA sequence. These
epigenetic modifications occur in key oncogenes, tumor suppressor genes, and
transcription factors, leading to cancer initiation and progression. The most
commonly observed epigenetic changes include DNA methylation, histone lysine
methylation and demethylation, histone lysine acetylation and deacetylation.
However, there are several other novel post-translational modifications that
have been observed in recent times such as neddylation, sumoylation,
glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as
transcriptional regulation and these have been briefly discussed in this
article. We have also highlighted the diverse epigenetic changes that occur
during the process of tumorigenesis and described the role of histone
modifications that can occur on tumor suppressor genes as well as oncogenes,
which regulate tumorigenesis and can thus form the basis of novel strategies for
cancer therapy.
DOI: 10.18632/oncotarget.23356
PMCID: PMC5834259
PMID: 29541423
Conflict of interest statement: CONFLICTS OF INTEREST There is no conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18042143 | 1. APMIS. 2007 Oct;115(10):1039-59. doi: 10.1111/j.1600-0463.2007.apm_636.xml.x.
Epigenetic changes in cancer.
Grønbaek K(1), Hother C, Jones PA.
Author information:
(1)Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
[email protected]
A cancer develops when a cell acquires specific growth advantages through the
stepwise accumulation of heritable changes in gene function. Basically, this
process is directed by changes in two different classes of genes: Tumor
suppressor genes that inhibit cell growth and survival and oncogenes that
promote cell growth and survival. Since several alterations are usually required
for a cancer to fully develop, the malignant phenotype is determined by the
compound status of tumor suppressor genes and oncogenes. Cancer genes may be
changed by several mechanisms, which potentially alter the protein encoding
nucleotide template, change the copy number of genes, or lead to increased gene
transcription. Epigenetic alterations, which, by definition, comprise
mitotically and meiotically heritable changes in gene expression that are not
caused by changes in the primary DNA sequence, are increasingly being recognized
for their roles in carcinogenesis. These epigenetic alterations may involve
covalent modifications of amino acid residues in the histones around which the
DNA is wrapped, and changes in the methylation status of cytosine bases (C) in
the context of CpG dinucleotides within the DNA itself. Methylation of clusters
of CpGs called "CpG-islands" in the promoters of genes has been associated with
heritable gene silencing. The present review will focus on how disruption of the
epigenome can contribute to cancer. In contrast to genetic alterations, gene
silencing by epigenetic modifications is potentially reversible. Treatment by
agents that inhibit cytosine methylation and histone deacetylation can initiate
chromatin decondensation, demethylation and reestablishment of gene
transcription. Accordingly, in the clinical setting, DNA methylation and histone
modifications are very attractive targets for the development and implementation
of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic
therapy has recently been approved by the United States Food and Drug
Administration (US FDA) for use in the treatment of myelodysplastic syndrome
(MDS) and primary cutaneous T-cell lymphoma (CTCL).
DOI: 10.1111/j.1600-0463.2007.apm_636.xml.x
PMID: 18042143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33482325 | 1. Genomics. 2021 Mar;113(2):540-551. doi: 10.1016/j.ygeno.2020.12.042. Epub 2021
Jan 20.
Epigenetics and microRNAs in cardiovascular diseases.
Colpaert RMW(1), Calore M(2).
Author information:
(1)Department of Molecular Genetics, Faculty of Health, Medicine and Life
Sciences, Faculty of Science and Engineering, Maastricht University, the
Netherlands.
(2)Department of Molecular Genetics, Faculty of Health, Medicine and Life
Sciences, Faculty of Science and Engineering, Maastricht University, the
Netherlands. Electronic address: [email protected].
Cardiovascular diseases are among the leading causes of mortality worldwide.
Besides environmental and genetic changes, these disorders can be influenced by
processes which do not affect DNA sequence yet still play an important role in
gene expression and which can be inherited. These so-called 'epigenetic' changes
include DNA methylation, histone modifications, and ATP-dependent chromatin
remodeling enzymes, which influence chromatin remodeling and gene expression.
Next to these, microRNAs are non-coding RNA molecules that silence genes
post-transcriptionally. Both epigenetic factors and microRNAs are known to
influence cardiac development and homeostasis, in an individual fashion but also
in a complex regulatory network. In this review, we will discuss how epigenetic
factors and microRNAs interact with each other and how together they can
influence cardiovascular diseases.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygeno.2020.12.042
PMID: 33482325 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31696298 | 1. Arch Dermatol Res. 2020 Sep;312(7):461-466. doi: 10.1007/s00403-019-02005-9.
Epub 2019 Nov 6.
DNA methylation and inflammatory skin diseases.
Mervis JS(1), McGee JS(2).
Author information:
(1)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, J-505, Boston, MA, 02118, USA.
(2)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, J-505, Boston, MA, 02118, USA. [email protected].
Epigenetics is the study of heritable changes in gene expression that do not
originate from alternations in the DNA sequence. Epigenetic modifications
include DNA methylation, histone modification, and gene silencing via the action
of microRNAs. Epigenetic dysregulation has been implicated in many disease
processes. In the field of dermatology, epigenetic regulation has been
extensively explored as a pathologic mechanism in cutaneous T-cell lymphoma
(CTCL), which has led to the successful development of epigenetic therapies for
CTCL. In recent years, the potential role of epigenetic regulation in the
pathogeneses of inflammatory skin diseases has gained greater appreciation. In
particular, epigenetic changes in psoriasis and atopic dermatitis have been
increasingly studied, with DNA methylation the most rigorously investigated to
date. In this review, we provide an overview of DNA methylation in inflammatory
skin diseases with an emphasis on psoriasis and atopic dermatitis.
DOI: 10.1007/s00403-019-02005-9
PMID: 31696298 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17317097 | 1. Reprod Toxicol. 2007 Apr-May;23(3):267-82. doi:
10.1016/j.reprotox.2007.01.004. Epub 2007 Jan 19.
Techniques used in studies of epigenome dysregulation due to aberrant DNA
methylation: an emphasis on fetal-based adult diseases.
Ho SM(1), Tang WY.
Author information:
(1)Department of Environmental Health, College of Medicine, University of
Cincinnati, Cincinnati, OH, USA. [email protected]
Epigenetic changes are heritable modifications that do not involve alterations
in the primary DNA sequence. They regulate crucial cellular functions such as
genome stability, X-chromosome inactivation, and gene imprinting.
Epidemiological and experimental observations now suggest that such changes may
also explain the fetal basis of adult diseases such as cancer, obesity,
diabetes, cardiovascular disorders, neurological diseases, and behavioral
modifications. The main molecular events known to initiate and sustain
epigenetic modifications are histone modification and DNA methylation. This
review specifically focuses on existing and emerging technologies used in
studying DNA methylation, which occurs primarily at CpG dinucleotides in the
genome. These include standard exploratory tools used for global profiling of
DNA methylation and targeted gene investigation: methylation sensitive
restriction fingerprinting (MSRF), restriction landmark genomic scanning (RLGS),
methylation CpG island amplification-representational difference analysis
(MCA-RDA), differential methylation hybridization (DMH), and cDNA microarrays
combined with treatment with demethylating agents and inhibitors of histone
deacetylase. The basic operating principals, resource requirements,
applications, and benefits and limitations of each methodology are discussed.
Validation methodologies and functional assays needed to establish the role of a
CpG-rich sequence in regulating the expression of a target or candidate gene are
outlined. These include in silico database searches, methylation status studies
(bisulfite genomic sequencing, COBRA, MS-PCR, MS-SSCP), gene expression studies,
and promoter activity analyses. Our intention is to give readers a starting
point for choosing methodologies and to suggest a workflow to follow during
their investigations. We believe studies of epigenetic changes such as DNA
methylation hold great promise in understanding the early origins of adult
diseases and in advancing their diagnosis, prevention, and treatment.
DOI: 10.1016/j.reprotox.2007.01.004
PMCID: PMC2055548
PMID: 17317097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16567863 | 1. Indian J Med Res. 2006 Jan;123(1):17-24.
Epigenetic therapy--a new development in pharmacology.
Peedicayil J(1).
Author information:
(1)Department of Pharmacology & Clinical Pharmacology, Christian Medical
College, Vellore, India. [email protected]
Epigenetics, heritable changes in gene expression that do not involve changes in
DNA sequence, is known to be involved in disease. Two important epigenetic
changes that are known to contribute to disease are abnormal methylation
patterns of DNA and modifications of histones in chromatin. This review
describes a new development in pharmacology, epigenetic therapy, which attempts
to correct these changes. At present two groups of drugs are being developed.
One inhibits DNA methyltransferases (DNMTs) resulting in the inhibition of DNA
methylation. This group of drugs may prove to be useful in the treatment of
cancer where hypermethylation of tumour suppressor genes is known to lead to
silencing of these genes. The other group of drugs inhibits histone deacetylases
(HDACs) resulting in the accumulation of acetylated histones which are thought
to mediate the anticancer effects of these drugs. Both these drug groups have
shown promising results in drug trials for the treatment of cancer. Since
epigenetic changes are thought to underlie a wide range of diseases, the scope
of epigenetic therapy is likely to expand.
PMID: 16567863 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24295192 | 1. Nurs Clin North Am. 2013 Dec;48(4):649-59. doi: 10.1016/j.cnur.2013.08.004.
Epub 2013 Nov 1.
An overview of epigenetics in nursing.
Clark AE(1), Adamian M, Taylor JY.
Author information:
(1)Yale University, School of Nursing, 400 West Campus Drive, Orange, CT 06477,
USA.
Epigenetic changes to the genome are biochemical alterations to the DNA that do
not change an individual's genome but do change and influence gene expression.
The nursing profession is qualified to conduct and integrate epigenetic-focused
nursing research into practice. This article discusses current epigenetic
nursing research, provides an overview of how epigenetic research relates to
nursing practice, makes recommendations, and provides epigenetic online
resources for nursing research. An overview of major epigenetic studies in
nursing (specific to childbirth studies, preeclampsia, metabolic syndrome,
immunotherapy cancer, and pain) is provided, with recommendations on next steps.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cnur.2013.08.004
PMCID: PMC3873714
PMID: 24295192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30455036 | 1. J Genet Genomics. 2018 Nov 20;45(11):621-638. doi: 10.1016/j.jgg.2018.09.004.
Epub 2018 Nov 6.
Retrospective and perspective of plant epigenetics in China.
Duan CG(1), Zhu JK(2), Cao X(3).
Author information:
(1)Shanghai Center for Plant Stress Biology and Center of Excellence for
Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
Electronic address: [email protected].
(2)Shanghai Center for Plant Stress Biology and Center of Excellence for
Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China;
Department of Horticulture and Landscape Architecture, Purdue University, West
Lafayette, IN 47907, USA. Electronic address: [email protected].
(3)State Key Laboratory of Plant Genomics and National Center for Plant Gene
Research, Institute of Genetics and Developmental Biology, Chinese Academy of
Sciences, Beijing 100101, China. Electronic address: [email protected].
Epigenetics refers to the study of heritable changes in gene function that do
not involve changes in the DNA sequence. Such effects on cellular and
physiological phenotypic traits may result from external or environmental
factors or be part of normal developmental program. In eukaryotes, DNA wraps on
a histone octamer (two copies of H2A, H2B, H3 and H4) to form nucleosome, the
fundamental unit of chromatin. The structure of chromatin is subjected to a
dynamic regulation through multiple epigenetic mechanisms, including DNA
methylation, histone posttranslational modifications (PTMs), chromatin
remodeling and noncoding RNAs. As conserved regulatory mechanisms in gene
expression, epigenetic mechanisms participate in almost all the important
biological processes ranging from basal development to environmental response.
Importantly, all of the major epigenetic mechanisms in mammalians also occur in
plants. Plant studies have provided numerous important contributions to the
epigenetic research. For example, gene imprinting, a mechanism of parental
allele-specific gene expression, was firstly observed in maize; evidence of
paramutation, an epigenetic phenomenon that one allele acts in a single locus to
induce a heritable change in the other allele, was firstly reported in maize and
tomato. Moreover, some unique epigenetic mechanisms have been evolved in plants.
For example, the 24-nt siRNA-involved RNA-directed DNA methylation (RdDM)
pathway is plant-specific because of the involvements of two plant-specific
DNA-dependent RNA polymerases, Pol IV and Pol V. A thorough study of epigenetic
mechanisms is of great significance to improve crop agronomic traits and
environmental adaptability. In this review, we make a brief summary of important
progress achieved in plant epigenetics field in China over the past several
decades and give a brief outlook on future research prospects. We focus our
review on DNA methylation and histone PTMs, the two most important aspects of
epigenetic mechanisms.
Copyright © 2018 Institute of Genetics and Developmental Biology, Chinese
Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd.
All rights reserved.
DOI: 10.1016/j.jgg.2018.09.004
PMID: 30455036 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32445090 | 1. Adv Exp Med Biol. 2020;1253:3-55. doi: 10.1007/978-981-15-3449-2_1.
Epigenetics in Health and Disease.
Zhang L(1), Lu Q(1), Chang C(2)(3).
Author information:
(1)Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics,
Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
(2)Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's
Hospital, Hollywood, FL, 33021, USA. [email protected].
(3)Division of Rheumatology, Allergy and Clinical Immunology, University of
California Davis, Davis, CA, 95616, USA. [email protected].
Epigenetic mechanisms, which include DNA methylation, histone modification, and
microRNA (miRNA), can produce heritable phenotypic changes without a change in
DNA sequence. Disruption of gene expression patterns which are governed by
epigenetics can result in autoimmune diseases, cancers, and various other
maladies. Mechanisms of epigenetics include DNA methylation (and demethylation),
histone modifications, and non-coding RNAs such as microRNAs. Compared to
numerous studies that have focused on the field of genetics, research on
epigenetics is fairly recent. In contrast to genetic changes, which are
difficult to reverse, epigenetic aberrations can be pharmaceutically reversible.
The emerging tools of epigenetics can be used as preventive, diagnostic, and
therapeutic markers. With the development of drugs that target the specific
epigenetic mechanisms involved in the regulation of gene expression, development
and utilization of epigenetic tools are an appropriate and effective approach
that can be clinically applied to the treatment of various diseases.
DOI: 10.1007/978-981-15-3449-2_1
PMID: 32445090 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24298130 | 1. Pediatrics. 2013 Dec;132(Suppl 3):S216-23. doi: 10.1542/peds.2013-1032F.
Epigenetics and primary care.
Wright R(1), Saul RA.
Author information:
(1)FAAP, Departments of Preventive Medicine and Pediatrics, Icahn School of
Medicine at Mount Sinai, One Gustave L. Levy Pl, Box 1057, New York, NY 10029.
[email protected].
Epigenetics, the study of functionally relevant chemical modifications to DNA
that do not involve a change in the DNA nucleotide sequence, is at the interface
between research and clinical medicine. Research on epigenetic marks, which
regulate gene expression independently of the underlying genetic code, has
dramatically changed our understanding of the interplay between genes and the
environment. This interplay alters human biology and developmental trajectories,
and can lead to programmed human disease years after the environmental exposure.
In addition, epigenetic marks are potentially heritable. In this article, we
discuss the underlying concepts of epigenetics and address its current and
potential applicability for primary care providers.
DOI: 10.1542/peds.2013-1032F
PMID: 24298130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15485357 | 1. Annu Rev Genomics Hum Genet. 2004;5:479-510. doi:
10.1146/annurev.genom.5.061903.180014.
Epigenetics and human disease.
Jiang YH(1), Bressler J, Beaudet AL.
Author information:
(1)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, Texas 77030, USA. [email protected]
Epigenetics is comprised of the stable and heritable (or potentially heritable)
changes in gene expression that do not entail a change in DNA sequence. The role
of epigenetics in the etiology of human disease is increasingly recognized with
the most obvious evidence found for genes subject to genomic imprinting.
Mutations and epimutations in imprinted genes can give rise to genetic and
epigenetic phenotypes, respectively; uniparental disomy and imprinting defects
represent epigenetic disease phenotypes. There are also genetic disorders that
affect chromatin structure and remodeling. These disorders can affect chromatin
in trans or in cis, as well as expression of both imprinted and nonimprinted
genes. Data from Angelman and Beckwith-Wiedemann syndromes and other disorders
indicate that a monogenic or oligogenic phenotype can be caused by a mixed
epigenetic and genetic and mixed de novo and inherited (MEGDI) model. The MEGDI
model may apply to some complex disease traits and could explain negative
results in genome-wide genetic scans.
DOI: 10.1146/annurev.genom.5.061903.180014
PMID: 15485357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34182142 | 1. Semin Cancer Biol. 2022 Aug;83:377-383. doi: 10.1016/j.semcancer.2021.06.022.
Epub 2021 Jun 26.
Epigenetic Regulation of Cancer Immune Cells.
Avella Patino DM(1), Radhakrishnan V(2), Suvilesh KN(2), Manjunath Y(3), Li
G(3), Kimchi ET(4), Staveley-O'Carroll KF(4), Warren WC(5), Kaifi JT(6), Mitchem
JB(7).
Author information:
(1)Department of Surgery, Ellis Fischel Cancer Center, USA; Harry S. Truman
Memorial Veterans' Hospital, Columbia, MO, USA. Electronic address:
[email protected].
(2)Department of Surgery, Ellis Fischel Cancer Center, USA.
(3)Department of Surgery, Ellis Fischel Cancer Center, USA; Harry S. Truman
Memorial Veterans' Hospital, Columbia, MO, USA.
(4)Department of Surgery, Ellis Fischel Cancer Center, USA; Harry S. Truman
Memorial Veterans' Hospital, Columbia, MO, USA; Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA.
(5)Department of Surgery, Ellis Fischel Cancer Center, USA; Bond Life Sciences
Center, University of Missouri, Columbia, MO, USA; Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA.
(6)Department of Surgery, Ellis Fischel Cancer Center, USA; Harry S. Truman
Memorial Veterans' Hospital, Columbia, MO, USA; Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA. Electronic
address: [email protected].
(7)Department of Surgery, Ellis Fischel Cancer Center, USA; Harry S. Truman
Memorial Veterans' Hospital, Columbia, MO, USA; Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA. Electronic
address: [email protected].
The epigenetic regulation of immune response involves reversible and heritable
changes that do not alter the DNA sequence. Though there have been extensive
studies accomplished relating to epigenetic changes in cancer cells, recent
focus has been shifted on epigenetic-mediated changes in the immune cells
including T cells, Macrophages, Natural Killer cells and anti-tumor immune
responses. This review compiles the most relevant and recent literature related
to the role of epigenetic mechanisms including DNA methylation and histone
modifications in immune cells of wide range of cancers. We also include recent
research with respect to role of the most relevant transcription factors that
epigenetically control the anti-tumor immune response. Finally, a statement of
future direction that promises to look forward for strategies to improve
immunotherapy in cancer.
Copyright © 2021. Published by Elsevier Ltd.
DOI: 10.1016/j.semcancer.2021.06.022
PMID: 34182142 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24455281 | 1. Genet Res Int. 2013;2013:317569. doi: 10.1155/2013/317569. Epub 2013 Dec 23.
DNA methylation pattern as important epigenetic criterion in cancer.
Ghavifekr Fakhr M(1), Farshdousti Hagh M(1), Shanehbandi D(1), Baradaran B(1).
Author information:
(1)Immunology Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran.
Epigenetic modifications can affect the long-term gene expression without any
change in nucleotide sequence of the DNA. Epigenetic processes intervene in the
cell differentiation, chromatin structure, and activity of genes since the
embryonic period. However, disorders in genes' epigenetic pattern can affect the
mechanisms such as cell division, apoptosis, and response to the environmental
stimuli which may lead to the incidence of different diseases and cancers. Since
epigenetic changes may return to their natural state, they could be used as
important targets in the treatment of cancer and similar malignancies. The aim
of this review is to assess the epigenetic changes in normal and cancerous
cells, the causative factors, and epigenetic therapies and treatments.
DOI: 10.1155/2013/317569
PMCID: PMC3884803
PMID: 24455281 |
http://www.ncbi.nlm.nih.gov/pubmed/34058565 | 1. Poult Sci. 2021 Jul;100(7):101164. doi: 10.1016/j.psj.2021.101164. Epub 2021
Mar 26.
Chicken embryo as a model in epigenetic research.
Bednarczyk M(1), Dunislawska A(2), Stadnicka K(2), Grochowska E(2).
Author information:
(1)Department of Animal Biotechnology and Genetics, UTP University of Science
and Technology, 85-084 Bydgoszcz, Poland. Electronic address: [email protected].
(2)Department of Animal Biotechnology and Genetics, UTP University of Science
and Technology, 85-084 Bydgoszcz, Poland.
Epigenetics is defined as the study of changes in gene function that are
mitotically or meiotically heritable and do not lead to a change in DNA
sequence. Epigenetic modifications are important mechanisms that fine tune the
expression of genes in response to extracellular signals and environmental
changes. In vertebrates, crucial epigenetic reprogramming events occur during
early embryogenesis and germ cell development. Chicken embryo, which develops
external to the mother's body, can be easily manipulated in vivo and in vitro,
and hence, it is an excellent model for performing epigenetic studies.
Environmental factors such as temperature can affect the development of an
embryo into the phenotype of an adult. A better understanding of the
environmental impact on embryo development can be achieved by analyzing the
direct effects of epigenetic modifications as well as their molecular background
and their intergenerational and transgenerational inheritance. In this overview,
the current possibility of epigenetic changes during chicken embryonic
development and their effects on long-term postembryonic development are
discussed.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.psj.2021.101164
PMCID: PMC8170499
PMID: 34058565 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36346551 | 1. Clin Rev Allergy Immunol. 2022 Dec;63(3):447-471. doi:
10.1007/s12016-022-08956-8. Epub 2022 Nov 8.
Epigenetic Dysregulation in Autoimmune and Inflammatory Skin Diseases.
Gibson F(1), Hanly A(1), Grbic N(1), Grunberg N(1), Wu M(1), Collard M(2), Alani
RM(3).
Author information:
(1)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, Boston, MA, 02118, USA.
(2)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, Boston, MA, 02118, USA. [email protected].
(3)Department of Dermatology, Boston University School of Medicine, 609 Albany
Street, Boston, MA, 02118, USA. [email protected].
Epigenetics is the study of heritable, reversible gene expression patterns that
do not originate from alterations in the DNA sequence. Epigenetic modifications
influence gene expression patterns and include DNA methylation, histone
modifications, and gene regulation via non-coding RNAs. While the study of
epigenetics has been most broadly applied to neoplastic diseases, the role of
the epigenome in a wide range of disease processes including autoimmune,
allergic, and inflammatory processes is increasingly being recognized. Recent
advances in the study of the epigenome have led to novel insights into the
pathogenesis and potential therapeutic targets of various pathologic entities
including inflammatory diseases. In this review, we examine the nature of
epigenetic modifications in several well-studied autoimmune, allergic, and/or
inflammatory disorders of the skin including systemic lupus erythematosus,
vitiligo, systemic sclerosis, alopecia areata, pemphigus, psoriasis, atopic
dermatitis, keloidal scarring, and hidradenitis suppurativa with the aim to
determine how such epigenetic changes may be targeted for therapeutic benefit.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s12016-022-08956-8
PMID: 36346551 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32235270 | 1. Curr Opin Nephrol Hypertens. 2020 May;29(3):280-285. doi:
10.1097/MNH.0000000000000602.
Epigenomics and the kidney.
Wilson PC(1), Ledru N, Humphreys BD.
Author information:
(1)Department of Pathology and Immunology Division of Nephrology, Department of
Medicine Department of Developmental Biology, Washington University in St.
Louis, St. Louis, Missouri, USA.
PURPOSE OF REVIEW: Epigenetic modifications are reversible changes to a cell's
DNA or histones that alter gene expression but not DNA sequence. The present
review will explore epigenomic profiling and bioinformatics techniques for the
study of kidney development and disease.
RECENT FINDINGS: Reversible DNA and histone modifications influence chromatin
accessibility and can be measured by a variety of recent techniques including
DNase-seq, ATAC-seq, and single cell ATAC-seq. These approaches have been used
to demonstrate that DNA methylation is critical for nephron progenitor
maturation, for example. New bioinformatics techniques allow the prediction of
chromatin loops that connect regulatory elements to target genes. Recent studies
have demonstrated that DNA elements regulate transcription in the kidney via
long-range physical interactions and create a new framework for understanding
how genome wide association studies risk loci contribute to kidney disease.
Increasingly, epigenomic approaches are being combined with transcriptomic
analyses to generate multimodal datasets.
SUMMARY: Epigenomics has expanded our knowledge of gene architecture and
regulation. Novel tools and techniques have led to the emergence of 'multiomics'
in which epigenomic profiling, transcriptomics, and additional methods
complement each other to improve our understanding of kidney disease and
development.
DOI: 10.1097/MNH.0000000000000602
PMCID: PMC7730478
PMID: 32235270 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest Dr. Humphreys reports
receiving grants from Chinook Therapeutics and Janssen; receiving consulting
fees from Celgene, Chinook Therapeutics, Indalo Therapeutics, Janssen,
Medimmune, and Merck; receiving honoraria from Genentech; and equity ownership
in Chinook Therapeutics, all outside of this work. Drs. Wilson and Ledru have
nothing to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/30522005 | 1. Curr Opin Psychol. 2019 Aug;28:76-80. doi: 10.1016/j.copsyc.2018.11.010. Epub
2018 Nov 22.
Epigenetics and meditation.
Kaliman P(1).
Author information:
(1)Faculty of Health Sciences, Universitat Oberta de Catalunya, Av. Tibidabo,
39-43, 08035, Barcelona, Spain; Honorary Fellow, Center for Healthy Minds,
University of Wisconsin-Madison, United States. Electronic address:
[email protected].
In the last decade, epigenetics has taken center stage to explain the
relationships between stress exposure, health and behavior. Acquired or
inherited epigenetic changes modulate gene expression states without modifying
the DNA sequence itself, they can be long-lasting, yet, they are potentially
reversible. Several studies have explored whether meditation-based interventions
can influence gene expression profiles towards healthier directions, identifying
candidate genes and biological pathways that seem to be sensitive to
contemplative practices. However, to date, the clinical implications of these
molecular outcomes and their potential long-lasting epigenetic bases remain
mostly unknown. The present article addresses these topics from a broad
perspective and analyzes future research questions and perspectives at the
crossroads of contemplative sciences and epigenetics.
Copyright © 2018 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.copsyc.2018.11.010
PMID: 30522005 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31374565 | 1. Hum Reprod Update. 2019 Sep 11;25(5):518-540. doi: 10.1093/humupd/dmz017.
Transgenerational inheritance: how impacts to the epigenetic and genetic
information of parents affect offspring health.
Xavier MJ(1)(2), Roman SD(1)(2)(3), Aitken RJ(1)(2)(4), Nixon B(1)(2).
Author information:
(1)Reproductive Science Group, Faculty of Science, The University of Newcastle,
Callaghan, NSW 2308, Australia.
(2)Priority Research Centre for Reproductive Science, The University of
Newcastle, Callaghan, NSW 2308, Australia.
(3)Priority Research Centre for Chemical Biology and Clinical Pharmacology, The
University of Newcastle, Callaghan, NSW 2308, Australia.
(4)Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW
2308, Australia.
BACKGROUND: A defining feature of sexual reproduction is the transmission of
genomic information from both parents to the offspring. There is now compelling
evidence that the inheritance of such genetic information is accompanied by
additional epigenetic marks, or stable heritable information that is not
accounted for by variations in DNA sequence. The reversible nature of epigenetic
marks coupled with multiple rounds of epigenetic reprogramming that erase the
majority of existing patterns have made the investigation of this phenomenon
challenging. However, continual advances in molecular methods are allowing
closer examination of the dynamic alterations to histone composition and DNA
methylation patterns that accompany development and, in particular, how these
modifications can occur in an individual's germline and be transmitted to the
following generation. While the underlying mechanisms that permit this form of
transgenerational inheritance remain unclear, it is increasingly apparent that a
combination of genetic and epigenetic modifications plays major roles in
determining the phenotypes of individuals and their offspring.
OBJECTIVE AND RATIONALE: Information pertaining to transgenerational inheritance
was systematically reviewed focusing primarily on mammalian cells to the
exclusion of inheritance in plants, due to inherent differences in the means by
which information is transmitted between generations. The effects of
environmental factors and biological processes on both epigenetic and genetic
information were reviewed to determine their contribution to modulating
inheritable phenotypes.
SEARCH METHODS: Articles indexed in PubMed were searched using keywords related
to transgenerational inheritance, epigenetic modifications, paternal and
maternal inheritable traits and environmental and biological factors influencing
transgenerational modifications. We sought to clarify the role of epigenetic
reprogramming events during the life cycle of mammals and provide a
comprehensive review of how the genomic and epigenomic make-up of progenitors
may determine the phenotype of its descendants.
OUTCOMES: We found strong evidence supporting the role of DNA methylation
patterns, histone modifications and even non-protein-coding RNA in altering the
epigenetic composition of individuals and producing stable epigenetic effects
that were transmitted from parents to offspring, in both humans and rodent
species. Multiple genomic domains and several histone modification sites were
found to resist demethylation and endure genome-wide reprogramming events.
Epigenetic modifications integrated into the genome of individuals were shown to
modulate gene expression and activity at enhancer and promoter domains, while
genetic mutations were shown to alter sequence availability for methylation and
histone binding. Fundamentally, alterations to the nuclear composition of the
germline in response to environmental factors, ageing, diet and toxicant
exposure have the potential to become hereditably transmitted.
WIDER IMPLICATIONS: The environment influences the health and well-being of
progeny by working through the germline to introduce spontaneous genetic
mutations as well as a variety of epigenetic changes, including alterations in
DNA methylation status and the post-translational modification of histones. In
evolutionary terms, these changes create the phenotypic diversity that fuels the
fires of natural selection. However, rather than being adaptive, such variation
may also generate a plethora of pathological disease states ranging from
dominant genetic disorders to neurological conditions, including spontaneous
schizophrenia and autism.
© The Author(s) 2019. Published by Oxford University Press on behalf of the
European Society of Human Reproduction and Embryology. All rights reserved. For
permissions, please e-mail: [email protected].
DOI: 10.1093/humupd/dmz017
PMID: 31374565 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26639162 | 1. Medwave. 2015 Nov 26;15(10):e6324. doi: 10.5867/medwave.2015.10.6324.
Statins and atherosclerosis: the role of epigenetics.
[Article in English, Spanish; Abstract available in Spanish from the publisher]
Storino Farina M(1), Rojano Rada J(2), Molina Garrido A(2), Martínez X(2),
Pulgar A(2), Paniagua R(2), Garrido J(2).
Author information:
(1)SServicio de Medicina Interna, Hospital Dr. Miguel Pérez Carreño, IVSS,
Caracas, Venezuela. Clínica Fénix Salud, Caracas, Venezuela. Address: Edificio
Loma Escondida, Piso 8, Apartamento 87, Urbanización Lomas del Ávila, Palo
Verde, Municipio Sucre, Estado Miranda CP 1070, Venezuela. Email:
[email protected].
(2)Servicio de Medicina Interna, Hospital Dr. Miguel Pérez Carreño, IVSS,
Caracas, Venezuela.
Atherosclerosis is an immune-inflammatory disease, in which pathophysiological
mechanisms include inflammation patterns and epigenetic changes that alter gene
expression of several inflammatory and non-inflammatory mediators. Epigenetics
is offering explanations on how diet, environmental factors and lifestyle can
influence the onset and progression of the disease, and how these alterations
can be transmitted to the following generations without any changes in DNA
sequences. Statins, through their pleiotropic effects, provide a useful tool in
controlling the progression of plaques and their subsequent impact.
Publisher: La aterosclerosis es una enfermedad de tipo inmunoinflamatoria, en la
cual los mecanismos fisiopatológicos incluyen patrones de inflamación y cambios
epignéticos que alteran la expresión genética de varios mediadores inflamatorios
y no inflamatorios. La epigenética está ofreciendo explicaciones sobre cómo la
dieta, los factores ambientales y el estilo de vida pueden influir en la
aparición y progresión de la enfermedad, y cómo las alteraciones pueden ser
transmitidas a las siguientes generaciones sin que haya modificaciones en las
secuencias de ADN. Las estatinas, a través de los efectos pleiotrópicos, ofrecen
una herramienta de gran ayuda en el control de la progresión de las placas y sus
subsiguientes repercusiones.
DOI: 10.5867/medwave.2015.10.6324
PMID: 26639162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36143200 | 1. J Pers Med. 2022 Aug 30;12(9):1418. doi: 10.3390/jpm12091418.
The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.
McCluskey G(1)(2)(3), Donaghy C(2), Morrison KE(3)(4), McConville J(3)(5), Duddy
W(1), Duguez S(1).
Author information:
(1)Personalised Medicine Center, School of Medicine, Ulster University, Derry
BT47 6SB, UK.
(2)Department of Neurology, Altnagelvin Hospital, Derry, BT47 6SB, UK.
(3)Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
(4)Faculty of Medicine, Health & Life Sciences, Queen's University, Belfast BT9
6AG, UK.
(5)Department of Neurology, Ulster Hospital, Dundonald, Belfast BT16 1RH, UK.
Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and
Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by
progressive motor neuron degeneration, weakness and muscular atrophy. Lipid
dysregulation is well recognised in each of these conditions and occurs prior to
neurodegeneration. Several lipid markers have been shown to predict prognosis in
ALS. Sphingolipids are complex lipids enriched in the central nervous system and
are integral to key cellular functions including membrane stability and
signalling pathways, as well as being mediators of neuroinflammation and
neurodegeneration. This review highlights the metabolism of sphingomyelin (SM),
the most abundant sphingolipid, and of its metabolite ceramide, and its role in
the pathophysiology of neurodegeneration, focusing on MNDs. We also review
published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12
demonstrated upregulation of multiple SM species and 6 demonstrated upregulation
of ceramides. SM species also correlated with markers of clinical progression in
five of six studies. These data highlight the potential use of SM and ceramide
as biomarkers in ALS. Finally, we review potential therapeutic strategies for
targeting sphingolipid metabolism in neurodegeneration.
DOI: 10.3390/jpm12091418
PMCID: PMC9501626
PMID: 36143200
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/21626001 | 1. Nervenarzt. 2011 Jun;82(6):697-706. doi: 10.1007/s00115-010-2967-y.
[Motor neuron diseases].
[Article in German]
Petri S(1), Meyer T.
Author information:
(1)Klinik für Neurologie-OE 7210, Medizinische Hochschule Hannover, Hannover.
[email protected]
Motor neuron diseases (MND) are a group of neurodegenerative disorders which are
present in clinical, prognostic and genetic diversity. The most common MND are
amyotrophic lateral sclerosis (ALS), proximal spinal muscular atrophy (SMA) and
various forms of hereditary and sporadic lower motor neuron syndromes including
hereditary motor neuropathies (HMN). Familial and "sporadic" forms of ALS and
lower motor neuron syndromes are known. The essential pathogenic findings in MND
have emerged from molecular biological examinations of the hereditary forms of
MND. In ALS, one consistent neuropathological feature is intraneuronal protein
inclusions which arise from TDP-43, FUS, SOD1 or ataxin-2 aggregations. TDP-43,
FUS, SOD1 and ataxin-2 are multifunctional DNA/RNA-binding proteins which are
involved in transcription regulation. SMA and HMN are associated with different
genes whose gene products may also be involved in RNA processing. A disturbance
in the regulation of RNA possibly represents an overlapping pathophysiological
characteristic in MND. The elucidation of common pathways in the cascade of
motor neuron degeneration is an essential point of departure for molecular
genetically defined treatment strategies both in ALS and in hereditary and
sporadic lower motor neuron syndromes.
DOI: 10.1007/s00115-010-2967-y
PMID: 21626001 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34603008 | 1. Front Aging Neurosci. 2021 Sep 17;13:723871. doi: 10.3389/fnagi.2021.723871.
eCollection 2021.
Motor Neuron Diseases and Neuroprotective Peptides: A Closer Look to Neurons.
Zuccaro E(1)(2)(3), Piol D(1), Basso M(4), Pennuto M(1)(2)(3).
Author information:
(1)Department of Biomedical Sciences, University of Padua, Padua, Italy.
(2)Veneto Institute of Molecular Medicine, Padua, Italy.
(3)Padova Neuroscience Center, Padua, Italy.
(4)Department of Cellular, Computational and Integrative Biology - CIBIO,
University of Trento, Trento, Italy.
Motor neurons (MNs) are specialized neurons responsible for muscle contraction
that specifically degenerate in motor neuron diseases (MNDs), such as
amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA),
and spinal muscular atrophy (SMA). Distinct classes of MNs degenerate at
different rates in disease, with a particular class named fast-fatigable MNs
(FF-MNs) degenerating first. The etiology behind the selective vulnerability of
FF-MNs is still largely under investigation. Among the different strategies to
target MNs, the administration of protective neuropeptides is one of the
potential therapeutic interventions. Pituitary adenylate cyclase-activating
polypeptide (PACAP) is a neuropeptide with beneficial effects in many
neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease,
and more recently SBMA. Another neuropeptide that has a neurotrophic effect on
MNs is insulin-like growth factor 1 (IGF-1), also known as somatomedin C. These
two peptides are implicated in the activation of neuroprotective pathways
exploitable in the amelioration of pathological outcomes related to MNDs.
Copyright © 2021 Zuccaro, Piol, Basso and Pennuto.
DOI: 10.3389/fnagi.2021.723871
PMCID: PMC8484953
PMID: 34603008
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/32671738 | 1. Adv Exp Med Biol. 2020;1207:53-74. doi: 10.1007/978-981-15-4272-5_3.
Autophagy and Motor Neuron Diseases.
Zhang X(1), Yang K(2), Le W(3).
Author information:
(1)Department of Neurology, Shanghai Jiaotong University Affiliated Sixth
People's Hospital, Shanghai, China.
(2)Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical
University, Dalian, China.
(3)Liaoning Provincial Center for Clinical Research on Neurological Diseases,
The First Affiliated Hospital, Dalian Medical University, Dalian, China.
[email protected].
Motor neuron diseases (MND) are a group of fatal progressive neurodegenerative
diseases, which selectively affect the motor system in the anterior horn of
spinal cord, brainstem, cortex and pyramidal tract. Motor neurons could be
divided into two groups, which are upper groups in the motor cortex and lower
groups in the brain stem and spinal cord. Loss of lower motor neurons leads to
muscle weakness, wasting and cramps. Loss of upper motor neurons leads to brisk
reflexes and functional limits. There are several types of motor neuron disease:
amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), progressive
muscular atrophy (PMA), primary lateral sclerosis (PLS). Now, the studies of
autophagy in MND focus on the type of ALS, so this chapter will summarize the
alteration of autophagy in motor neurons, and how that knowledge contributes to
our understanding of the pathogenesis of ALS.
DOI: 10.1007/978-981-15-4272-5_3
PMID: 32671738 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17569066 | 1. Acta Neuropathol. 2007 Jul;114(1):71-9. doi: 10.1007/s00401-007-0234-5. Epub
2007 Jun 14.
TDP-43 in differential diagnosis of motor neuron disorders.
Dickson DW(1), Josephs KA, Amador-Ortiz C.
Author information:
(1)Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo
Road, Jacksonville, FL, 32224, USA. [email protected]
Motor neuron disorders are clinically and pathologically heterogeneous. They can
be classified into those that affect primarily upper motor neurons, lower motor
neurons or both. The most common disorder to affect both upper and lower motor
neurons is amyotrophic lateral sclerosis (ALS). Some forms of motor neuron
disease (MND) affect primarily motor neurons in the spinal cord or brainstem,
while others affect motor neurons at all levels of the neuraxis. A number of
genetic loci have been identified for the various motor neuron disorders.
Several of the MND genes encode for proteins important for cytoskeletal
stability and axoplasmic transport. Despite these genetic advances, the
relationship of the various motor neuron disorders to each other is unclear.
Except for rare familial forms of ALS associated with mutations in superoxide
dismutase type 1 (SOD1), which are associated with neuronal inclusions that
contain SOD1, specific molecular or cellular markers that differentiate ALS from
other motor neuron disorders have not been available. Recently, the TAR DNA
binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions
in ALS, and it has been suggested that TDP-43 may be a specific marker for ALS.
This pilot study aimed to determine the value of TDP-43 in the differential
diagnosis of MND. Immunohistochemistry for TDP-43 was used to detect neuronal
inclusions in the medulla of disorders affecting upper motor neurons, lower
motor neurons or both. Medullary motor neuron pathology also was assessed in
frontotemporal lobar degeneration (FTLD) that had no evidence of MND. TDP-43
immunoreactivity was detected in the hypoglossal nucleus in all cases of ALS,
all cases of FTLD-MND and some of cases of primary lateral sclerosis (PLS). It
was not detected in FTLD-PLS. Surprisingly, sparse TDP-43 immunoreactivity was
detected in motor neurons in about 10% of FTLD that did not have clinical or
pathologic features of MND. The results suggest that TDP-43 immunoreactivity is
useful in differentiating FTLD-MND and ALS from other disorders associated with
upper or lower motor neuron pathology. It also reveals subclinical MND in a
subset of cases of FTLD without clinical or pathologic evidence of MND.
DOI: 10.1007/s00401-007-0234-5
PMID: 17569066 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21426252 | 1. Expert Rev Clin Immunol. 2011 Mar;7(2):143-53. doi: 10.1586/eci.11.5.
rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused
by C1-inhibitor deficiency.
Varga L(1), Farkas H.
Author information:
(1)3rd Department of Internal Medicine, Semmelweis University Budapest, H-1125
Kútvölgyi street 4, Budapest, Hungary. [email protected]
Recombinant human C1 esterase inhibitor (rhC1INH) (Ruconest(®), Pharming) is a
new drug developed for the relief of symptoms occurring in patients with
angioedema due to C1-inhibitor deficiency. Pertinent results have already been
published elsewhere; this article summarizes the progress made since then.
Similar to the purified C1-inhibitor derived from human plasma, the therapeutic
efficacy of rhC1INH results from its ability to block the actions of enzymes
belonging to the overactivated bradykinin-forming pathway, at multiple
locations. During clinical trials into the management of acute edema, a total of
190 subjects received recombinant C1-inhibitor by intravenous infusion on 714
occasions altogether. Dose-ranging efficacy studies established 50 U/kg as the
recommended dose, and demonstrated the effectiveness of this agent in all
localizations of hereditary angioedema attacks. Studies into the safety of
rhC1INH based on 300 administrations to healthy subjects or hereditary
angioedema patients followed-up for 90 days have not detected the formation of
autoantibodies against rhC1INH or IgE antibodies directed against rabbit
proteins, even after repeated administration on multiple occasions. These
findings met favorable appraisal by the EMA, which granted European marketing
authorization for rhC1INH. Pharming is expected to file a biological licence
with the US FDA by the end of 2010 to obtain marketing approval in the USA. The
launch of rhC1INH onto the pharmaceutical market may represent an important
progress in the management of hereditary angioedema patients.
DOI: 10.1586/eci.11.5
PMID: 21426252 [Indexed for MEDLINE] |