pubmed_id
stringlengths 41
43
| abstract
stringlengths 3
18.8k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/33436406 | 1. BMJ Open Respir Res. 2021 Jan;8(1):e000845. doi: 10.1136/bmjresp-2020-000845.
Sleep apnoea is a risk factor for severe COVID-19.
Strausz S(1)(2)(3), Kiiskinen T(1)(4), Broberg M(1), Ruotsalainen S(1), Koskela
J(1)(5), Bachour A(6); FinnGen; Palotie A(1)(5)(7), Palotie T(2)(3), Ripatti
S(1)(5)(8), Ollila HM(9)(5)(10).
Collaborators: Palotie A, Daly M, Jacob H, Matakidou A, Runz H, John S, Plenge
R, McCarthy M, Hunkapiller J, Ehm M, Waterworth D, Fox C, Malarstig A, Klinger
K, Call K, Mäkelä T, Kaprio J, Virolainen P, Pulkki K, Kilpi T, Perola M,
Partanen J, Pitkäranta A, Kaarteenaho R, Vainio S, Savinainen K, Kosma VM,
Kujala U, Tuovila O, Hendolin M, Pakkanen R, Waring J, Riley-Gillis SB,
Matakidou A, Runz H, Liu J, Biswas S, Hunkapiller J, Waterworth D, Ehm M, Diogo
D, Fox C, Pfizer A, Marshall C, Hu X, Call K, Klinger K, Gossel M, Ripatti S,
Schleutker J, Perola M, Arvas M, Carpen O, Hinttala R, Kettunen J, Laaksonen R,
Mannermaa A, Paloneva J, Kujala U, Tuovila O, Hendolin M, Pakkanen R, Soininen
H, Julkunen V, Remes A, Kälviäinen R, Hiltunen M, Peltola J, Tienari P, Rinne J,
Ziemann A, Waring J, Esmaeeli S, Smaoui N, Lehtonen A, Eaton S, Runz H,
Lahdenperä S, Biswas S, Michon J, Kerchner G, Hunkapiller J, Bowers N, Teng E,
Merck J, Mehta V, Gormley P, Linden K, Whelan C, Xu F, Pulford D, Färkkilä M,
Pikkarainen S, Jussila A, Blomster T, Kiviniemi M, Voutilainen M, Georgantas B,
Heap G, Waring J, Smaoui N, Rahimov F, Lehtonen A, Usiskin K, Maranville J, Lu
T, Bowers N, Oh D, Michon J, Mehta V, Kalpala K, Miller M, Hu X, McCarthy L,
Eklund K, Palomäki A, Isomäki P, Pirilä L, Kaipiainen-Seppänen O, Huhtakangas J,
Georgantas B, Waring J, Rahimov F, Lertratanakul A, Smaoui N, Close D, Hochfeld
M, Bowers N, Michon J, Diogo D, Mehta V, Kalpala K, Bing N, Hu X, Gordillo JE,
Mars N, Laitinen T, Pelkonen M, Kauppi P, Kankaanranta H, Harju T, Smaoui N,
Close D, GreenbergCelgene S, Chen H, Bowers N, Michon J, Mehta V, Betts J, Ghosh
S, Salomaa V, Niiranen T, Juonala M, Metsärinne K, Kähönen M, Junttila J, Laakso
M, Pihlajamäki J, Sinisalo J, Taskinen MR, Tuomi T, Laukkanen J, Ben Challis AP,
Hunkapiller J, Bowers N, Michon J, Diogo D, Chu A, Mehta V, Parkkinen J, Miller
M, Muslin A, Waterworth D, Joensuu H, Meretoja T, Carpen O, Aaltonen L, Auranen
A, Karihtala P, Kauppila S, Auvinen P, Elenius K, Popovic R, Waring J,
Riley-Gillis B, Lehtonen A, Matakidou A, Schutzman J, Hunkapiller J, Bowers N,
Michon J, Mehta V, Loboda A, Chhibber A, Lehtonen H, McDonough S, Crohns M,
Kulkarni D, Kaarniranta K, Turunen J, Ollila T, Seitsonen S, Uusitalo H,
Aaltonen V, Uusitalo-Järvinen H, Luodonpää M, Hautala N, Runz H, Strauss E,
Bowers N, Chen H, Michon J, Podgornaia A, Mehta V, Diogo D, Hoffman J, Tasanen
K, Huilaja L, Hannula-Jouppi K, Salmi T, Peltonen S, Koulu L, Harvima I, Kalpala
K, Wu Y, Choy D, Michon J, Smaoui N, Rahimov F, Lehtonen A, Waterworth D,
Jalanko A, Kajanne R, Lyhs U, Kaunisto M, Davis J, Riley-Gillis B, Quarless D,
Petrovski S, Liu J, Chen CY, Bronson P, Yang R, Maranville J, Biswas S, Chang D,
Hunkapiller J, Bhangale T, Bowers N, Diogo D, Holzinger E, Gormley P, Wang X,
Chen X, Hedman Å, Auro K, Wang C, Xu E, Auge F, Chatelain C, Kurki M, Ripatti S,
Daly M, Karjalainen J, Havulinna A, Jalanko A, Palin K, Palta P, Della P, Zhou
W, Lemmelä S, Rivas M, Harju J, Palotie A, Lehisto A, Ganna A, Llorens V,
Karlsson A, Kristiansson K, Arvas M, Hyvärinen K, Ritari J, Wahlfors T, Koskinen
M, Carpen O, Kettunen J, Pylkäs K, Kalaoja M, Karjalainen M, Mantere T,
Kangasniemi E, Heikkinen S, Mannermaa A, Laakkonen E, Kononen J, Loukola A,
Laiho P, Sistonen T, Kaiharju E, Laukkanen M, Järvensivu E, Lähteenmäki S,
Männikkö L, Wong R, Kristiansson K, Mattsson H, Lemmelä S, Hiekkalinna T,
Jiménez M, Donner K, Palta P, Pärn K, Nunez-Fontarnau J, Harju J, Kilpeläinen E,
Sipilä T, Brein G, Dada A, Awaisa G, Shcherban A, Sipilä T, Laivuori H,
Havulinna A, Lemmelä S, Kiiskinen T, Laitinen T, Siirtola H, Tabuenca J, Kallio
L, Soini S, Partanen J, Pitkänen K, Vainio S, Savinainen K, Kosma VM, Kuopio T.
Author information:
(1)Institute for Molecular Medicine Finland (FIMM), University of Helsinki,
Helsinki, Finland.
(2)Orthodontics, Department of Oral and Maxillofacial Diseases, Clinicum,
Faculty of Medicine, University of Helsinki, Helsinki, Finland.
(3)Department of Oral and Maxillofacial Diseases, Helsinki University Hospital
(HUH), Helsinki, Finland.
(4)Finnish Institute for Health and Welfare, Helsinki, Finland.
(5)Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(6)Sleep Unit, Heart and Lung Center, Helsinki University Hospital (HUH),
Helsinki, Finland.
(7)Analytic and Translational Genetics Unit (ATGU), Department of Medicine,
Department of Neurology and Department of Psychiatry, Massachusetts General
Hospital, Boston, Massachusetts, USA.
(8)Department of Public Health, University of Helsinki, Helsinki, Finland.
(9)Institute for Molecular Medicine Finland (FIMM), University of Helsinki,
Helsinki, Finland [email protected].
(10)Stanford University School of Medicine, Palo Alto, CA, USA.
BACKGROUND: Obstructive sleep apnoea (OSA) is associated with higher body mass
index (BMI), diabetes, older age and male gender, which are all risk factors for
severe COVID-19.We aimed to study if OSA is an independent risk factor for
COVID-19 infection or for severe COVID-19.
METHODS: OSA diagnosis and COVID-19 infection were extracted from the hospital
discharge, causes of death and infectious diseases registries in individuals who
participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as
COVID-19 requiring hospitalisation. Multivariate logistic regression model was
used to examine association. Comorbidities for either COVID-19 or OSA were
selected as covariates. We performed a meta-analysis with previous studies.
RESULTS: We identified 445 individuals with COVID-19, and 38 (8.5%) of them with
OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19
hospitalisation independent from age, sex, BMI and comorbidities
(p-unadjusted=5.13×10-5, OR-adjusted=2.93 (95% CI 1.02 to 8.39),
p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19
(p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across
15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe
COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021).
CONCLUSION: Risk for contracting COVID-19 was the same for patients with OSA and
those without OSA. In contrast, among COVID-19 positive patients, OSA was
associated with higher risk for hospitalisation. Our findings are in line with
earlier works and suggest OSA as an independent risk factor for severe COVID-19.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/bmjresp-2020-000845
PMCID: PMC7804843
PMID: 33436406 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/33150129 | 1. Glob Heart. 2020 Sep 22;15(1):64. doi: 10.5334/gh.814.
The Relationship of COVID-19 Severity with Cardiovascular Disease and Its
Traditional Risk Factors: A Systematic Review and Meta-Analysis.
Matsushita K(1)(2), Ding N(1)(2), Kou M(1)(2), Hu X(1)(2), Chen M(1)(2), Gao
Y(1)(2), Honda Y(1)(2), Zhao D(1)(2), Dowdy D(1), Mok Y(1)(2), Ishigami J(1)(2),
Appel LJ(1)(2).
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, US.
(2)Welch Center for Prevention, Epidemiology, and Clinical Research, US.
BACKGROUND: Whether cardiovascular disease (CVD) and its traditional risk
factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in
part, because of potential confounding by age and sex.
METHODS: We performed a systematic review of studies that explored pre-existing
CVD and its traditional risk factors as risk factors of severe COVID-19 (defined
as death, acute respiratory distress syndrome, mechanical ventilation, or
intensive care unit admission). We searched PubMed and Embase for papers in
English with original data (≥10 cases of severe COVID-19). Using random-effects
models, we pooled relative risk (RR) estimates and conducted meta-regression
analyses.
RESULTS: Of the 661 publications identified in our search, 25 papers met our
inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases.
Older age was consistently associated with severe COVID-19 in all eight eligible
studies, with RR >~5 in >60-65 versus <50 years. Three studies showed no change
in the RR of age after adjusting for covariate(s). In univariate analyses,
factors robustly associated with severe COVID-19 were male sex (10 studies;
pooled RR = 1.73, [95% CI 1.50-2.01]), hypertension (8 studies; 2.87
[2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97
[3.76-6.58]). RR for male sex was likely to be independent of age. For the other
three factors, meta-regression analyses suggested confounding by age. Only four
studies reported multivariable analysis, but most of them showed adjusted RR ~2
for hypertension, diabetes, and CVD. No study explored renin-angiotensin system
inhibitors as a risk factor for severe COVID-19.
CONCLUSIONS: Despite the potential for confounding, these results suggest that
hypertension, diabetes, and CVD are independently associated with severe
COVID-19 and, together with age and male sex, can be informative for predicting
the risk of severe COVID-19.
Copyright: © 2020 The Author(s).
DOI: 10.5334/gh.814
PMCID: PMC7546112
PMID: 33150129 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no competing interests to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/33368966 | 1. HIV Med. 2021 May;22(5):372-378. doi: 10.1111/hiv.13037. Epub 2020 Dec 27.
Immune deficiency is a risk factor for severe COVID-19 in people living with
HIV.
Hoffmann C(1)(2), Casado JL(3), Härter G(4), Vizcarra P(3), Moreno A(3),
Cattaneo D(5)(6), Meraviglia P(7), Spinner CD(8), Schabaz F(9), Grunwald S(10),
Gervasoni C(5)(7).
Author information:
(1)ICH Study Center Hamburg, Hamburg, Germany.
(2)University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
(3)Department of Infectious Diseases, Hospital Universitario Ramón y Cajal,
Madrid, Spain.
(4)Medicover Ulm MVZ, Ulm, Germany.
(5)Gestione Ambulatoriale Politerapie (GAP) Outpatient Clinic, ASST
Fatebenefratelli, Sacco University Hospital, Milan, Italy.
(6)Unit of Clinical Pharmacology, ASST Fatebenefratelli, Sacco University
Hospital, Milan, Italy.
(7)Department of Infectious Diseases, ASST Fatebenefratelli-Sacco University
Hospital, Milan, Italy.
(8)School of Medicine, Technical University of Munich, University Hospital
rechts der Isar, Munich, Germany.
(9)MVZ Karlsplatz München, Munich, Germany.
(10)Zentrum für Infektiologie Berlin/Prenzlauer Berg, Berlin, Germany.
OBJECTIVES: A prior T cell depletion induced by HIV infection may carry
deleterious consequences in the current COVID-19 pandemic. Clinical data on
patients co-infected with HIV and SARS-CoV-2 are still scarce.
METHODS: This multicentre cohort study evaluated risk factors for morbidity and
mortality of COVID-19 in people living with HIV (PLWH), infected with SARS-CoV-2
in three countries in different clinical settings. COVID-19 was clinically
classified as to be mild-to-moderate or severe.
RESULTS: Of 175 patients, 49 (28%) had severe COVID-19 and 7 (4%) patients died.
Almost all patients were on antiretroviral therapy (ART) and in 94%, HIV RNA was
below 50 copies/mL prior to COVID-19 diagnosis. In the univariate analysis, an
age 50 years or older, a CD4+ T cell nadir of < 200/µl, current CD4+ T cells <
350/µl and the presence of at least one comorbidity were significantly
associated with severity of COVID-19. No significant association was found for
gender, ethnicity, obesity, a detectable HIV RNA, a prior AIDS-defining illness,
or tenofovir (which was mainly given as alafenamide) or protease inhibitor use
in the current ART. In a multivariate analysis, the only factor associated with
risk for severe COVID-19 was a current CD4+ T cell count of < 350/µl (adjusted
odds ratio 2.85, 95% confidence interval 1.26-6.44, p=0.01). The only factor
associated with mortality was a low CD4 T cell nadir.
CONCLUSIONS: In PLWH, immune deficiency is a possible risk factor for severe
COVID-19, even in the setting of virological suppression. There is no evidence
for a protective effect of PIs or tenofovir alafenamide.
© 2020 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of
British HIV Association.
DOI: 10.1111/hiv.13037
PMID: 33368966 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33163160 | 1. F1000Res. 2020 Sep 9;9:1107. doi: 10.12688/f1000research.26186.2. eCollection
2020.
Predictors of COVID-19 severity: a systematic review and meta-analysis.
Mudatsir M(1), Fajar JK(1)(2), Wulandari L(3), Soegiarto G(4), Ilmawan M(5),
Purnamasari Y(5), Mahdi BA(4), Jayanto GD(2), Suhendra S(5), Setianingsih YA(6),
Hamdani R(7), Suseno DA(8), Agustina K(9), Naim HY(10), Muchlas M(11), Alluza
HHD(5), Rosida NA(5), Mayasari M(5), Mustofa M(5), Hartono A(12), Aditya R(5),
Prastiwi F(5), Meku FX(5), Sitio M(5), Azmy A(7), Santoso AS(13), Nugroho RA(5),
Gersom C(2), Rabaan AA(14), Masyeni S(15), Nainu F(16), Wagner AL(17), Dhama
K(18), Harapan H(1)(19).
Author information:
(1)Department of Microbiology, School of Medicine, Universitas Syiah Kuala,
Banda Aceh, Aceh, 23111, Indonesia.
(2)Brawijaya Internal Medicine Research Center, Department of Internal Medicine,
Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia.
(3)Department of Pulmonology and Respiratory Medicine, Faculty of Medicine,
Universitas Airlangga, Surabaya, East Java, 60286, Indonesia.
(4)Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga,
Surabaya, Easy Java, 60286, Indonesia.
(5)Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145,
Indonesia.
(6)Department of Urology, Faculty of Medicine, Universitas Airlangga, Surabaya,
East Java, 60285, Indonesia.
(7)Department of Orthopedic Surgery, Faculty of Medicine, Universitas Brawijaya,
Malang, East Java, 65145, Indonesia.
(8)Department of Obstetry and Gynecology, Faculty of Medicine, Universitas
Brawijaya, Malang, East Java, 65145, Indonesia.
(9)Department of Neurology, Faculty of Medicine, Universitas Brawijaya, Malang,
East Java, 65145, Indonesia.
(10)Department of Urology, Faculty of Medicine, Universitas Brawijaya, Malang,
East Java, 65145, Indonesia.
(11)Faculty of Animal Science, Universitas Brawijaya, Malang, East Java, 65145,
Indonesia.
(12)Faculty of Medicine, Universitas Negeri Sebelas Maret, Surakarta, Surakarta,
57126, Indonesia.
(13)Department of Cardiology and Vascular Medicine, Faculty of Medicine,
Universitas Brawijaya, Malang, East Java, 65145, Indonesia.
(14)Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran,
Dhahran, 31311, Saudi Arabia.
(15)Department of Internal Medicine, Faculty of Medicine and Health Science,
Universitas Warmadewa, Denpasar, Bali, 80235, Indonesia.
(16)Faculty of Pharmacy, Hasanuddin University, Makassar, Makassar, 90245,
Indonesia.
(17)Department of Epidemiology, University of Michigan, Ann Arbor, MI, 48109,
USA.
(18)Division of Pathology, Indian Veterinary Research Institute, Izatnagar,
Uttar Pradesh, 243 122, India.
(19)Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda
Aceh, Aceh, 23111, Indonesia.
Background: The unpredictability of the progression of coronavirus disease 2019
(COVID-19) may be attributed to the low precision of the tools used to predict
the prognosis of this disease. Objective: To identify the predictors associated
with poor clinical outcomes in patients with COVID-19. Methods: Relevant
articles from PubMed, Embase, Cochrane, and Web of Science were searched as of
April 5, 2020. The quality of the included papers was appraised using the
Newcastle-Ottawa scale (NOS). Data of interest were collected and evaluated for
their compatibility for the meta-analysis. Cumulative calculations to determine
the correlation and effect estimates were performed using the Z test. Results:
In total, 19 papers recording 1,934 mild and 1,644 severe cases of COVID-19 were
included. Based on the initial evaluation, 62 potential risk factors were
identified for the meta-analysis. Several comorbidities, including chronic
respiratory disease, cardiovascular disease, diabetes mellitus, and hypertension
were observed more frequent among patients with severe COVID-19 than with the
mild ones. Compared to the mild form, severe COVID-19 was associated with
symptoms such as dyspnea, anorexia, fatigue, increased respiratory rate, and
high systolic blood pressure. Lower levels of lymphocytes and hemoglobin;
elevated levels of leukocytes, aspartate aminotransferase, alanine
aminotransferase, blood creatinine, blood urea nitrogen, high-sensitivity
troponin, creatine kinase, high-sensitivity C-reactive protein, interleukin 6,
D-dimer, ferritin, lactate dehydrogenase, and procalcitonin; and a high
erythrocyte sedimentation rate were also associated with severe COVID-19.
Conclusion: More than 30 risk factors are associated with a higher risk of
severe COVID-19. These may serve as useful baseline parameters in the
development of prediction tools for COVID-19 prognosis.
Copyright: © 2021 Mudatsir M et al.
DOI: 10.12688/f1000research.26186.2
PMCID: PMC7607482
PMID: 33163160 [Indexed for MEDLINE]
Conflict of interest statement: No competing interests were disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/35137371 | 1. Adv Exp Med Biol. 2021;1353:115-129. doi: 10.1007/978-3-030-85113-2_7.
Risk Factors for COVID-19: Diabetes, Hypertension, and Obesity.
Buscemi S(1), Corleo D(2), Randazzo C(2).
Author information:
(1)Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna
e Specialistica di Eccellenza (PROMISE), University of Palermo (Italy), Palermo,
Italy. [email protected].
(2)Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna
e Specialistica di Eccellenza (PROMISE), University of Palermo (Italy), Palermo,
Italy.
INTRODUCTION: The recent global pandemic of coronavirus disease 2019 (COVID-19),
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has
involved more than 7 million people worldwide and been associated with more than
400,000 deaths. No clear information is known about all the potential risk
factors for COVID-19 or what factors adversely influence its clinical course and
mortality. Therefore, we analyzed the role of obesity, type 2 diabetes, and
hypertension as risk factors for COVID-19.
METHODS: We identified articles for inclusion by searching PubMed and Google
Scholar (last accessed 15 June 2020). Retrospective review of literature.
Analysis of epidemiological data concerning obesity prevalence and COVID-19
incidence, particularly in Italy and the USA.
RESULTS: Data from several retrospective studies of prevalence showed that
patients with hypertension, type 2 diabetes, and obesity may have more severe
COVID-19, intensive care unit admission, and higher mortality rates, but it is
not definitively clear if this is an independent association. In general, the
prevalence of obesity in patients with COVID-19 seems to be the same as that of
the general population throughout the world; however, obesity seems to be
associated with more severe disease and mortality in younger (< 60 years)
patients. Similar effects seem to occur in patients with diabetes and/or
hypertension but at older ages (> 60 years). In strict connection, it has been
proposed that the use of drugs inhibiting angiotensin-converting enzyme 2
(ACE-2) or dipeptidyl dipeptidase 4 (DPP-4) might influence viral activity and
disease severity since ACE-2 and DPP-4 receptors mediate SARS-CoV-2 entry into
the host cells; however, no evidence exists to date that shows that this may be
the case.
CONCLUSION: Overall, diabetes, hypertension, and obesity seem to negatively
affect the clinical course and disease outcome in patients with COVID-19.
However, these data need further confirmation by studies with more accurate data
registration.
© 2021. The Author(s), under exclusive license to Springer Nature Switzerland
AG.
DOI: 10.1007/978-3-030-85113-2_7
PMID: 35137371 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32612666 | 1. Immun Ageing. 2020 Jun 30;17:21. doi: 10.1186/s12979-020-00192-y. eCollection
2020.
SARS-CoV-2 disease severity and diabetes: why the connection and what is to be
done?
Mazucanti CH(1), Egan JM(1).
Author information:
(1)National Institute on Aging, Intramural Research Program, 251 Bayview
Boulevard, Baltimore, MD 21224 USA.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus
responsible for the current coronavirus disease 2019 (COVID-19) pandemic, has
infected over 3.5 million people all over the world since the first case was
reported from Wuhan, China 5 months ago. As more epidemiological data regarding
COVID-19 patients is acquired, factors that increase the severity of the
infection are being identified and reported. One of the most consistent
co-morbidities associated with worse outcome in COVID-19 patients is diabetes,
along with age and cardiovascular disease. Studies on the association of
diabetes with other acute respiratory infections, namely SARS, MERS, and
Influenza, outline what seems to be an underlying factor in diabetic patients
that makes them more susceptible to complications. In this review we summarize
what we think may be the factors driving this pattern between diabetes, aging
and poor outcomes in respiratory infections. We also review therapeutic
considerations and strategies for treatment of COVID-19 in diabetic patients,
and how the additional challenge of this co-morbidity requires attention to
glucose homeostasis so as to achieve the best outcomes possible for patients.
© The Author(s) 2020.
DOI: 10.1186/s12979-020-00192-y
PMCID: PMC7325192
PMID: 32612666
Conflict of interest statement: Competing interestsThe authors declare no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35124268 | 1. Clin Gastroenterol Hepatol. 2022 Jul;20(7):1553-1560.e78. doi:
10.1016/j.cgh.2022.01.045. Epub 2022 Feb 3.
Mendelian Randomization Analysis Reveals No Causal Relationship Between
Nonalcoholic Fatty Liver Disease and Severe COVID-19.
Li J(1), Tian A(1), Zhu H(2), Chen L(3), Wen J(4), Liu W(5), Chen P(6).
Author information:
(1)Department of Pathology, College of Basic Medical Sciences, Jilin University,
Changchun, China.
(2)Teaching Department, First Affiliated Hospital of Jilin University,
Changchun, China.
(3)School of Clinical Medicine, Jilin University, Changchun, China.
(4)Department of Genetics, College of Basic Medical Sciences, Jilin University,
Changchun, China.
(5)Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy
and Health Sciences, Wayne State University, Detroit, Michigan; Department of
Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan.
Electronic address: [email protected].
(6)Department of Pathology, College of Basic Medical Sciences, Jilin University,
Changchun, China; Department of Genetics, College of Basic Medical Sciences,
Jilin University, Changchun, China. Electronic address: [email protected].
Comment in
Clin Gastroenterol Hepatol. 2022 Oct;20(10):2416-2417. doi:
10.1016/j.cgh.2022.03.037.
BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has
witnessed more than 4.5 million deaths as of the time of writing. Whether
nonalcoholic fatty liver disease (NAFLD) increases the risk for severe COVID-19
remains unclear. We sought to address this question using 2-sample Mendelian
randomization (TSMR) analysis approaches in large cohorts.
METHODS: We performed large-scale TSMR analyses to examine whether there is a
causal relationship between NAFLD, serum alanine aminotransferase, grade of
steatosis, NAFLD Activity Score, or fibrosis stage and severe COVID-19. To
maximize the power of this analysis, we performed a genome-wide meta-analysis to
identify single nucleotide polymorphisms associated with NAFLD. We also examined
the impact of 20 major comorbid factors of NAFLD on severe COVID-19.
RESULTS: Univariate analysis of the UK Biobank data demonstrated a significant
association between NAFLD and severe COVID-19 (odds ratio [OR], 3.06; P = 1.07 ×
10-6). However, this association disappeared after demographic and comorbid
factors were adjusted (OR, 1.57; P = .09). TSMR study indicated that NAFLD (OR,
0.97; P = .61), alanine aminotransferase level (OR, 1.03; P = .47), grade of
steatosis (OR, 1.08; P = .41), NAFLD Activity Score (OR, 1.02; P = .39), and
fibrosis stage (OR, 1.01; P = .87) were not associated with severe COVID-19.
Among all NAFLD-related comorbid factors, body mass index (OR, 1.73; P = 7.65 ×
10-9), waist circumference (OR, 1.76; P = 2.58 × 10-5), and hip circumference
(OR, 1.33; P = 7.26 × 10-3) were the only ones demonstrated a causal impact on
severe COVID-19.
CONCLUSIONS: There is no evidence supporting that NAFLD is a causal risk factor
for severe COVID-19. Previous observational associations between NAFLD and
COVID-19 are likely attributed to the correlation between NAFLD and obesity.
Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cgh.2022.01.045
PMCID: PMC8812093
PMID: 35124268 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33340043 | 1. Nephrol Dial Transplant. 2021 Jan 1;36(1):87-94. doi: 10.1093/ndt/gfaa314.
Chronic kidney disease is a key risk factor for severe COVID-19: a call to
action by the ERA-EDTA.
ERA-EDTA Council; ERACODA Working Group.
Collaborators: Ortiz A, Cozzolino M, Fliser D, Fouque D, Goumenos D, Massy ZA,
Rosenkranz AR, Rychlık I, Soler MJ, Stevens K, Torra R, Tuglular S, Wanner C,
Gansevoort RT, Duivenvoorden R, Franssen CFM, Hemmelder MH, Hilbrands LB, Jager
KJ, Noordzij M, Vart P, Gansevoort RT.
Comment in
Nephrol Dial Transplant. 2021 Jan 1;36(1):8-11. doi: 10.1093/ndt/gfaa339.
Diabetes, hypertension and cardiovascular disease have been listed as risk
factors for severe coronavirus disease 2019 (COVID-19) since the first report of
the disease in January 2020. However, this report did not mention chronic kidney
disease (CKD) nor did it provide information on the relevance of estimated
glomerular filtration rate (eGFR) or albuminuria. As the disease spread across
the globe, information on larger populations with greater granularity on risk
factors emerged. The recently published OpenSAFELY project analysed factors
associated with COVID-19 death in 17 million patients. The picture that arose
differs significantly from initial reports. For example, hypertension is not an
independent risk factor for COVID-19 death [adjusted hazard ratio (aHR) 0.89],
but renal disease very much is. Dialysis (aHR 3.69), organ transplantation (aHR
3.53) and CKD (aHR 2.52 for patients with eGFR <30 mL/min/1.73 m2) represent
three of the four comorbidities associated with the highest mortality risk from
COVID-19. The risk associated with CKD Stages 4 and 5 is higher than the risk
associated with diabetes mellitus (aHR range 1.31-1.95, depending upon glycaemic
control) or chronic heart disease (aHR 1.17). In another recent publication, the
Global Burden of Disease collaboration identified that worldwide, CKD is the
most prevalent risk factor for severe COVID-19. Moreover, the distribution of
risk factors for COVID-19 mortality appears to be different in patients with CKD
when compared with the general population. The high prevalence of CKD in
combination with the elevated risk of mortality from COVID-19 in CKD
necessitates urgent action for this group of patients. This article defines
essential action points (summarized in Box 1), among which is advocating the
inclusion of CKD patients in clinical trials testing the efficacy of drugs and
vaccines to prevent severe COVID-19.
© The Author(s) 2020. Published by Oxford University Press on behalf of
ERA-EDTA.
DOI: 10.1093/ndt/gfaa314
PMCID: PMC7771976
PMID: 33340043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36431276 | 1. J Clin Med. 2022 Nov 17;11(22):6799. doi: 10.3390/jcm11226799.
Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children
and Adults with and without COVID-19.
Wissing SI(1), Obeid R(2), Rädle-Hurst T(1), Rohrer T(3), Herr C(4), Schöpe
J(5), Geisel J(2), Bals R(4)(6), Abdul-Khaliq H(1).
Author information:
(1)Department of Pediatric Cardiology, Saarland University Hospital, 66421
Homburg, Germany.
(2)Department of Clinical Chemistry and Laboratory Medicine, Saarland University
Hospital, 66421 Homburg, Germany.
(3)Department of Pediatric Endocrinology, Saarland University Hospital, 66421
Homburg, Germany.
(4)Department of Internal Medicine V-Pulmonology, Allergology and Critical Care
Medicine, Saarland University Hospital, 66421 Homburg, Germany.
(5)Institute for Medical Biometry, Epidemiology and Medical Informatics,
Saarland University Medical Center, 66421 Homburg, Germany.
(6)Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz
Centre for Infection Research (HZI), Saarland University Campus, 66123
Saarbrücken, Germany.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the
coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death.
Various risk factors for a severe course, such as higher age, male gender and
pre-existing illnesses are known. However, pathophysiological risk factors are
largely unclear. Notably, the mild course of disease in children is conspicuous.
Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and
is a key enzyme in infection. Differences in the distribution of ACE2 can
provide insights into different courses of COVID-19. Our aim was to elucidate
the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2
(sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367
individuals including children and adults with and without COVID-19.
sACE2-levels were compared between the groups according to age and sex. In
adults and children with COVID-19, sACE2-concentrations are significantly higher
compared to healthy individuals. sACE2-levels increase with age and are lower in
children compared to adults with COVID-19. Sex doesn't significantly influence
sACE2-concentration. It remains unclear whether sACE2 concentrations increase
because of the infection and what factors could influence this response. In
conclusion, the increase of sACE2-concentration with age could indicate that
ACE2 concentrations mirror increased COVID-19 severity.
DOI: 10.3390/jcm11226799
PMCID: PMC9698605
PMID: 36431276
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36260598 | 1. PLoS One. 2022 Oct 19;17(10):e0275101. doi: 10.1371/journal.pone.0275101.
eCollection 2022.
Observational study of factors associated with morbidity and mortality from
COVID-19 in Lebanon, 2020-2021.
Nader M(1), Zmerli O(2), Platt DE(3), Hamdan H(1), Hamdash S(4), Tayeh RA(2),
Azar J(2), Kadi D(2), Sultan Y(2), Bazarbachi T(4), Karayakoupoglou G(4),
Zalloua P(1)(5), Azar E(2).
Author information:
(1)College of Medicine and Health Sciences, Khalifa University, Abu Dhabi,
United Arab Emirates.
(2)Division of Infectious Diseases, Department of Medicine, Saint George
Hospital University Medical Center, Beirut, Lebanon.
(3)Computational Biology Center, IBM TJ Watson Research Centre, Yorktown Hgts,
New York, United States of America.
(4)Laboratory Medicine, Haykel Hospital, Tripoli, Lebanon.
(5)Harvard T.H. Chan School of Public Health, Boston, Mssachusets, United States
of America.
BACKGROUND: The COVID-19 pandemic claimed millions of lives worldwide without
clear signs of abating despite several mitigation efforts and vaccination
campaigns. There have been tremendous interests in understanding the etiology of
the disease particularly in what makes it severe and fatal in certain patients.
Studies have shown that COVID-19 patients with kidney injury on admission were
more likely to develop severe disease, and acute kidney disease was associated
with high mortality in COVID-19 hospitalized patients.
METHODS: This study investigated 819 COVID-19 patients admitted between January
2020-April 2021 to the COVID-19 ward at a tertiary care center in Lebanon and
evaluated their vital signs and biomarkers while probing for two main outcomes:
intubation and fatality. Logistic and Cox regressions were performed to
investigate the association between clinical and metabolic variables and disease
outcomes, mainly intubation and mortality. Times were defined in terms of
admission and discharge/fatality for COVID-19, with no other exclusions.
RESULTS: Regression analysis revealed that the following are independent risk
factors for both intubation and fatality respectively: diabetes (p = 0.021 and p
= 0.04), being overweight (p = 0.021 and p = 0.072), chronic kidney disease (p =
0.045 and p = 0.001), and gender (p = 0.016 and p = 0.114). Further, shortness
of breath (p<0.001), age (p<0.001) and being overweight (p = 0.014) associated
with intubation, while fatality with shortness of breath (p<0.001) in our group
of patients. Elevated level of serum creatinine was the highest factor
associated with fatality (p = 0.002), while both white blood count (p<0.001) and
serum glutamic-oxaloacetic transaminase levels (p<0.001) emerged as independent
risk factors for intubation.
CONCLUSIONS: Collectively our data show that high creatinine levels were
significantly associated with fatality in our COVID-19 study patients,
underscoring the importance of kidney function as a main modulator of SARS-CoV-2
morbidity and favor a careful and proactive management of patients with elevated
creatinine levels on admission.
DOI: 10.1371/journal.pone.0275101
PMCID: PMC9581355
PMID: 36260598 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/33592063 | 1. PLoS One. 2021 Feb 16;16(2):e0247205. doi: 10.1371/journal.pone.0247205.
eCollection 2021.
An integrated clinical and genetic model for predicting risk of severe COVID-19:
A population-based case-control study.
Dite GS(1), Murphy NM(1), Allman R(1).
Author information:
(1)Genetic Technologies Ltd., Fitzroy, Victoria, Australia.
Up to 30% of people who test positive to SARS-CoV-2 will develop severe COVID-19
and require hospitalisation. Age, gender, and comorbidities are known to be risk
factors for severe COVID-19 but are generally considered independently without
accurate knowledge of the magnitude of their effect on risk, potentially
resulting in incorrect risk estimation. There is an urgent need for accurate
prediction of the risk of severe COVID-19 for use in workplaces and healthcare
settings, and for individual risk management. Clinical risk factors and a panel
of 64 single-nucleotide polymorphisms were identified from published data. We
used logistic regression to develop a model for severe COVID-19 in 1,582 UK
Biobank participants aged 50 years and over who tested positive for the
SARS-CoV-2 virus: 1,018 with severe disease and 564 without severe disease.
Model discrimination was assessed using the area under the receiver operating
characteristic curve (AUC). A model incorporating the SNP score and clinical
risk factors (AUC = 0.786; 95% confidence interval = 0.763 to 0.808) had 111%
better discrimination of disease severity than a model with just age and gender
(AUC = 0.635; 95% confidence interval = 0.607 to 0.662). The effects of age and
gender are attenuated by the other risk factors, suggesting that it is those
risk factors-not age and gender-that confer risk of severe disease. In the whole
UK Biobank, most are at low or only slightly elevated risk, but one-third are at
two-fold or more increased risk. We have developed a model that enables accurate
prediction of severe COVID-19. Continuing to rely on age and gender alone (or
only clinical factors) to determine risk of severe COVID-19 will unnecessarily
classify healthy older people as being at high risk and will fail to accurately
quantify the increased risk for younger people with comorbidities.
DOI: 10.1371/journal.pone.0247205
PMCID: PMC7886160
PMID: 33592063 [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: All authors are
employed by Genetic Technologies Limited and have a patent pending
(AU_2020901739 – Methods of assessing risk developing a severe response to
Coronavirus infection) for the work in this manuscript. A product to predict
risk of severe COVID-19 is in development. This does not alter our adherence to
PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/33206661 | 1. PLoS One. 2020 Nov 18;15(11):e0241541. doi: 10.1371/journal.pone.0241541.
eCollection 2020.
Factors associated with disease severity and mortality among patients with
COVID-19: A systematic review and meta-analysis.
Chidambaram V(1), Tun NL(1), Haque WZ(1), Majella MG(2), Sivakumar RK(3), Kumar
A(4), Hsu AT(1), Ishak IA(1), Nur AA(1), Ayeh SK(5), Salia EL(6), Zil-E-Ali
A(1), Saeed MA(7), Sarena APB(8), Seth B(9), Ahmadzada M(7), Haque EF(10),
Neupane P(5), Wang KH(1), Pu TM(1), Ali SMH(11), Arshad MA(12), Wang L(1), Baksh
S(1), Karakousis PC(5), Galiatsatos P(9).
Author information:
(1)Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United
States of America.
(2)Department of Preventive and Social Medicine, Jawaharlal Institute of
Postgraduate Medical Education and Research, Puducherry, India.
(3)Department of Anaesthesia and Intensive Care, Prince of Wales Hospital, The
Chinese University of Hong Kong, Shatin, Hong Kong, China.
(4)Department of Internal Medicine, University of Arkansas for Medical Sciences,
Little Rock, Arkansas, United States of America.
(5)Division of Infectious Diseases, Department of Medicine, Johns Hopkins School
of Medicine, Baltimore, Maryland, United States of America.
(6)Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore,
Maryland, United States of America.
(7)Johns Hopkins University, Baltimore, Maryland, United States of America.
(8)Bhayangkara Setukpa Hospital, Sukabumi, Indonesia.
(9)Division of Pulmonary and Critical Care Medicine, Department of Medicine,
Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
(10)Southern Methodist University, Dallas, Texas, United States of America.
(11)Fatima Memorial Hospital, Lahore, Pakistan.
(12)Nishtar Hospital, Multan, Pakistan.
BACKGROUND: Understanding the factors associated with disease severity and
mortality in Coronavirus disease (COVID-19) is imperative to effectively triage
patients. We performed a systematic review to determine the demographic,
clinical, laboratory and radiological factors associated with severity and
mortality in COVID-19.
METHODS: We searched PubMed, Embase and WHO database for English language
articles from inception until May 8, 2020. We included Observational studies
with direct comparison of clinical characteristics between a) patients who died
and those who survived or b) patients with severe disease and those without
severe disease. Data extraction and quality assessment were performed by two
authors independently.
RESULTS: Among 15680 articles from the literature search, 109 articles were
included in the analysis. The risk of mortality was higher in patients with
increasing age, male gender (RR 1.45, 95%CI 1.23-1.71), dyspnea (RR 2.55, 95%CI
1.88-2.46), diabetes (RR 1.59, 95%CI 1.41-1.78), hypertension (RR 1.90, 95%CI
1.69-2.15). Congestive heart failure (OR 4.76, 95%CI 1.34-16.97), hilar
lymphadenopathy (OR 8.34, 95%CI 2.57-27.08), bilateral lung involvement (OR
4.86, 95%CI 3.19-7.39) and reticular pattern (OR 5.54, 95%CI 1.24-24.67) were
associated with severe disease. Clinically relevant cut-offs for
leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive
protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe
disease and greater risk of mortality.
CONCLUSION: Knowledge of the factors associated of disease severity and
mortality identified in our study may assist in clinical decision-making and
critical-care resource allocation for patients with COVID-19.
DOI: 10.1371/journal.pone.0241541
PMCID: PMC7673562
PMID: 33206661 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34334081 | 1. Acta Oncol. 2021 Nov;60(11):1459-1465. doi: 10.1080/0284186X.2021.1958005.
Epub 2021 Aug 2.
Clinical characteristics and factors associated with COVID-19-related death and
morbidity among hospitalized patients with cancer: a Swedish cohort study.
Ullgren H(1)(2)(3), Camuto A(4), Rosas S(3), Pahnke S(4), Ginman B(4), Enblad
G(4), Glimelius I(4), Fransson P(1), Friesland S(3)(5), Liu LL(3)(5).
Author information:
(1)Department of Nursing, Umeå University, Umeå, Sweden.
(2)Regional Cancer Center, Stockholm-Gotland, Sweden.
(3)Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
(4)Department of Immunology, Genetics and Pathology, Experimental and Clinical
Oncology, Uppsala University, Uppsala, Sweden.
(5)Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
INTRODUCTION: Cancer patients are considered to have a higher risk of dying and
developing severe Coronavirus Disease 2019 (COVID-19). To date, there are few
studies including co-morbidities and sociodemographic factors when investigating
the outcome of COVID-19 in a cohort of cancer patients. In this study, we
analyzed cancer patients that have been hospitalized due to COVID-19 during the
first wave of the pandemic in Sweden to investigate the impact of COVID-19 on
mortality and morbidity.
PATIENTS AND METHODS: We retrospectively collected data on all patients with
cancer that were hospitalized due to COVID-19-related symptoms at Uppsala
University Hospital and Karolinska University Hospital between 1 March and 31
August 2020. The primary endpoint was COVID-19-related death and the secondary
endpoint was to describe COVID-19 severity, defined as symptom severity (grades
0-4) and length of stay (LOS) at the university hospitals.
RESULTS: In total, 193 patients were included among which 31% died due to
COVID-19 and 8% died of other causes. In a multivariable analysis, older age >70
(OR 3.6; 95% CI [1.8-7.3], p < 0.001) and male gender (OR 2.8 [1.4-5.8],
p = 0.005) were factors associated with higher likelihood of COVID-19-related
death. Several comorbidities ≥2 (OR 5.4 [2.0-14.3], p = 0.001) was independently
associated with COVID-19 severity. Treatment with chemotherapy within 90 days
prior to COVID-19 diagnosis were not associated with COVID-19-related death or
severity.
CONCLUSION: Factors associated with higher likelihood of COVID-19-related death
were older age and male gender. More severe COVID-19 symptoms were seen in
patients with multiple comorbidities. We did not see any associations between
COVID-19-related death or severity and recent treatment including chemotherapy.
In summary, this supports a thorough assessment regarding potential risks with
COVID-19 infection in patients with cancer, with a combination of individual
risk factors in addition to cancer treatments.
DOI: 10.1080/0284186X.2021.1958005
PMID: 34334081 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34935038 | 1. Pediatrics. 2022 Jan 1;149(1):e2021053418. doi: 10.1542/peds.2021-053418. Epub
2021 Dec 22.
Risk Factors for Severe COVID-19 in Children.
Woodruff RC(1)(2), Campbell AP(1), Taylor CA(1), Chai SJ(2)(3)(4), Kawasaki
B(5), Meek J(6), Anderson EJ(7)(8)(9), Weigel A(10), Monroe ML(11), Reeg L(12),
Bye E(13), Sosin DM(14)(15), Muse A(16), Bennett NM(17), Billing LM(18), Sutton
M(19), Talbot HK(20), McCaffrey K(21), Pham H(1), Patel K(1)(22), Whitaker M(1),
L McMorrow M(1)(2), P Havers F(1)(2).
Author information:
(1)CDC COVID-19 Response Team.
(2)US Public Health Service Commissioned Corps, Rockville, Maryland.
(3)Division of State and Local Readiness, Center for Preparedness and Response,
Centers for Disease Control and Prevention, Atlanta, Georgia.
(4)California Emerging Infections Program, Oakland, California.
(5)Colorado Department of Public Health and Environment, Denver, Colorado.
(6)Connecticut Emerging Infections Program, Yale School of Public Health, New
Haven, Connecticut.
(7)Departments of Medicine and Pediatrics, Emory School of Medicine, Atlanta,
Georgia.
(8)Georgia Emerging Infections Program, Georgia Department of Public Health,
Atlanta, Georgia.
(9)Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
(10)Iowa Department of Public Health, Des Moines, Iowa.
(11)Maryland Department of Health, Baltimore, Maryland.
(12)Michigan Department of Health and Human Services, Lansing, Michigan.
(13)Minnesota Department of Health, St Paul, Minnesota.
(14)New Mexico Emerging Infections Program, Santa Fe, New Mexico.
(15)New Mexico Department of Health, Santa Fe, New Mexico.
(16)New York State Department of Health, Albany, New York.
(17)University of Rochester School of Medicine and Dentistry, Rochester, New
York.
(18)Ohio Department of Health, Columbus, Ohio.
(19)Public Health Division, Oregon Health Authority, Portland, Oregon.
(20)Vanderbilt University Medical Center, Nashville, Tennesee.
(21)Utah Department of Health, Salt Lake City, Utah.
(22)General Dynamics Information Technology, Atlanta, Georgia.
OBJECTIVES: Describe population-based rates and risk factors for severe
coronavirus disease 2019 (COVID-19) (ie, ICU admission, invasive mechanical
ventilation, or death) among hospitalized children.
METHODS: During March 2020 to May 2021, the COVID-19-Associated Hospitalization
Surveillance Network identified 3106 children hospitalized with
laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection
in 14 states. Among 2293 children primarily admitted for COVID-19, multivariable
generalized estimating equations generated adjusted risk ratios (aRRs) and 95%
confidence intervals (CIs) of the associations between demographic and medical
characteristics abstracted from medical records and severe COVID-19. We
calculated age-adjusted cumulative population-based rates of severe COVID-19
among all children.
RESULTS: Approximately 30% of hospitalized children had severe COVID-19; 0.5%
died during hospitalization. Among hospitalized children aged <2 years, chronic
lung disease (aRR: 2.2; 95% CI: 1.1-4.3), neurologic disorders (aRR: 2.0; 95%
CI: 1.5‒2.6), cardiovascular disease (aRR: 1.7; 95% CI: 1.2‒2.3), prematurity
(aRR: 1.6; 95% CI: 1.1‒2.2), and airway abnormality (aRR: 1.6; 95% CI: 1.1‒2.2)
were associated with severe COVID-19. Among hospitalized children aged 2 to 17
years, feeding tube dependence (aRR: 2.0; 95% CI: 1.5‒2.5), diabetes mellitus
(aRR: 1.9; 95% CI: 1.6‒2.3) and obesity (aRR: 1.2; 95% CI: 1.0‒1.4) were
associated with severe COVID-19. Severe COVID-19 occurred among 12.0 per 100 000
children overall and was highest among infants, Hispanic children, and
non-Hispanic Black children.
CONCLUSIONS: Results identify children at potentially higher risk of severe
COVID-19 who may benefit from prevention efforts, including vaccination. Rates
establish a baseline for monitoring changes in pediatric illness severity after
increased availability of COVID-19 vaccines and the emergence of new variants.
Copyright © 2022 by the American Academy of Pediatrics.
DOI: 10.1542/peds.2021-053418
PMCID: PMC9213563
PMID: 34935038 [Indexed for MEDLINE]
Conflict of interest statement: POTENTIAL CONFLICT OF INTEREST: Mr Meek and Dr
Sutton report receiving funding from the Centers for Disease Control and
Prevention (CDC) Emerging Infections Program cooperative agreement. Ms Reeg and
Ms Billing report receiving a CDC federal grant from the Council of State and
Territorial Epidemiologists. Ms Billing reports receiving Epidemiology and
Laboratory Capacity grant funding from CDC to support vaccine preventable
disease epidemiology staffing and additionally report receiving Immunizations
and Vaccines for Children grant funding from CDC. Dr Anderson has consulted for
Pfizer, Sanofi Pasteur, Janssen, and Medscape, and his institution receives
funds to conduct clinical research unrelated to this article from MedImmune,
Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi Pasteur, Janssen, and Micron. He
also serves on a safety monitoring board for Kentucky BioProcessing, Inc. and
Sanofi Pasteur. His institution has also received funding from National
Institutes of Health to conduct clinical trials of Moderna and Janssen COVID-19
vaccines. |
http://www.ncbi.nlm.nih.gov/pubmed/32588943 | 1. Diabetes Metab Res Rev. 2021 Feb;37(2):e3377. doi: 10.1002/dmrr.3377. Epub
2020 Jul 20.
Obesity and diabetes as high-risk factors for severe coronavirus disease 2019
(Covid-19).
Zhou Y(1), Chi J(1), Lv W(1), Wang Y(1).
Author information:
(1)Department of Endocrinology, Affiliated Hospital of Medical College Qingdao
University, Qingdao, China.
The outbreak of the coronavirus disease 2019 (Covid-19) has become an evolving
worldwide health crisis. With the rising prevalence of obesity and diabetes has
come an increasing awareness of their impacts on infectious diseases, including
increased risk for various infections, post-infection complications and
mortality from critical infections. Although epidemiological and clinical
characteristics of Covid-19 have been constantly reported, no article has
systematically illustrated the role of obesity and diabetes in Covid-19, or how
Covid-19 affects obesity and diabetes, or special treatment in these at-risk
populations. Here, we present a synthesis of the recent advances in our
understanding of the relationships between obesity, diabetes and Covid-19 along
with the underlying mechanisms, and provide special treatment guidance for these
at-risk populations.
© 2020 John Wiley & Sons Ltd.
DOI: 10.1002/dmrr.3377
PMCID: PMC7361201
PMID: 32588943 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no potential conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34165257 | 1. HLA. 2021 Aug;98(2):122-131. doi: 10.1111/tan.14349. Epub 2021 Jun 29.
HLA-A homozygosis is associated with susceptibility to COVID-19.
De Marco R(1), Faria TC(1), Mine KL(1), Cristelli M(2), Medina-Pestana JO(2),
Tedesco-Silva H(2), Gerbase-DeLima M(1).
Author information:
(1)Instituto de Imunogenética, Associação Fundo de Incentivo à Pesquisa, São
Paulo, Brazil.
(2)Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São
Paulo, Brazil.
The purpose of this single center retrospective study was to investigate the
relationship between HLA and ABO polymorphisms and COVID-19 susceptibility and
severity in kidney transplant recipients. It included 720 recipients who had
COVID-19 and 1680 controls composed by recipients in follow-up who did not
contact the transplantation center for COVID-19 symptoms, up to the moment of
their inclusion in the study. HLA-A, -B, and -DRB1 allele groups and ABO
frequencies were compared between recipients with COVID-19 (all cases, or
separately mild/moderate and severe disease) and controls. The HLA association
study was conducted in two case-control series and only associations that showed
a p-value <0.05 in both series were considered. No HLA association regarding
COVID-19 occurrence or severity met this criterion. Homozygosity at HLA-A locus
was associated with COVID-19 susceptibility (odds ratio 1.4) but not severity.
Blood groups A and O were associated with susceptibility and resistance to
COVID-19, respectively. COVID-19 severity was associated only with older age and
cardiac disease, in a multivariate analysis. We conclude that an influence of
HLA on COVID-19 susceptibility is supported by the association with homozygosity
at HLA-A locus but that there is no evidence for a role of any particular HLA-A,
-B, or -DRB1 polymorphism. Thus, we suggest that what matters is the overall
capability of an individual's HLA molecules to present SARS-CoV-2 peptides to T
cells, a factor that might have a great influence on the breadth of the immune
response.
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/tan.14349
PMCID: PMC8446943
PMID: 34165257 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no potential conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32167524 | 1. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi:
10.1001/jamainternmed.2020.0994.
Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in
Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.
Wu C(1)(2)(3), Chen X(3), Cai Y(2), Xia J(4), Zhou X(2), Xu S(2), Huang H(4),
Zhang L(4), Zhou X(4), Du C(1), Zhang Y(3), Song J(3), Wang S(3), Chao Y(3),
Yang Z(5), Xu J(6), Zhou X(7), Chen D(8), Xiong W(9), Xu L(10), Zhou F(1), Jiang
J(3), Bai C(3)(11), Zheng J(12), Song Y(1)(3)(11)(13).
Author information:
(1)Department of Pulmonary Medicine, QingPu Branch of Zhongshan Hospital
Affiliated to Fudan University, Shanghai, China.
(2)Infection Division, Wuhan Jinyintan Hospital, Wuhan, China.
(3)Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan
University, Shanghai, China.
(4)Tuberculosis and Respiratory Department, Wuhan Jinyintan Hospital, Wuhan,
China.
(5)Department of Anesthesiology, International Peace Maternity and Child Health
Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
(6)Department of Infectious Diseases, Fengxian Guhua Hospital, Shanghai, China.
(7)Department of Pulmonary Medicine, Shanghai General Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai, China.
(8)Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, China.
(9)Department of Respiratory Medicine, Shanghai Ninth People's Hospital,
Shanghai Jiao Tong University School of Medicine, Shanghai, China.
(10)Department of Emergency Medicine, Shanghai Pudong New Area Gongli Hospital,
Shanghai, China.
(11)Shanghai Respiratory Research Institute, Shanghai, China.
(12)Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, China.
(13)National Clinical Research Center for Aging and Medicine, Huashan Hospital,
Fudan University, Shanghai, China.
Erratum in
JAMA Intern Med. 2020 Jul 1;180(7):1031. doi:
10.1001/jamainternmed.2020.1429.
Comment in
Signal Transduct Target Ther. 2020 Apr 28;5(1):57. doi:
10.1038/s41392-020-0158-2.
JAMA Intern Med. 2020 Jul 1;180(7):1028-1029. doi:
10.1001/jamainternmed.2020.1576.
J Intern Med. 2021 Feb;289(2):259-263. doi: 10.1111/joim.13145.
JAMA Intern Med. 2021 Jan 1;181(1):140. doi:
10.1001/jamainternmed.2020.2444.
JAMA Intern Med. 2021 Jan 1;181(1):139-140. doi:
10.1001/jamainternmed.2020.2438.
JAMA Intern Med. 2020 Dec 1;180(12):1715-1716. doi:
10.1001/jamainternmed.2020.3532.
IMPORTANCE: Coronavirus disease 2019 (COVID-19) is an emerging infectious
disease that was first reported in Wuhan, China, and has subsequently spread
worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not
yet been well delineated.
OBJECTIVE: To describe the clinical characteristics and outcomes in patients
with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS)
or died.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 201 patients
with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China
between December 25, 2019, and January 26, 2020. The final date of follow-up was
February 13, 2020.
EXPOSURES: Confirmed COVID-19 pneumonia.
MAIN OUTCOMES AND MEASURES: The development of ARDS and death. Epidemiological,
demographic, clinical, laboratory, management, treatment, and outcome data were
also collected and analyzed.
RESULTS: Of 201 patients, the median age was 51 years (interquartile range,
43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%)
developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who
developed ARDS, compared with those who did not, more patients presented with
dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively
[difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as
hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients,
respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84
[19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%;
95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors
associated with the development of ARDS and progression from ARDS to death
included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95%
CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and
HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation
dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and
HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI,
1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C)
was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI,
1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among
patients with ARDS, treatment with methylprednisolone decreased the risk of
death (HR, 0.38; 95% CI, 0.20-0.72).
CONCLUSIONS AND RELEVANCE: Older age was associated with greater risk of
development of ARDS and death likely owing to less rigorous immune response.
Although high fever was associated with the development of ARDS, it was also
associated with better outcomes among patients with ARDS. Moreover, treatment
with methylprednisolone may be beneficial for patients who develop ARDS.
DOI: 10.1001/jamainternmed.2020.0994
PMCID: PMC7070509
PMID: 32167524 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: None reported. |
http://www.ncbi.nlm.nih.gov/pubmed/35132841 | 1. J Korean Med Sci. 2022 Feb 7;37(5):e35. doi: 10.3346/jkms.2022.37.e35.
Risk Factors for Severe COVID-19 in Children: A Systematic Review and
Meta-Analysis.
Choi JH(1), Choi SH(2), Yun KW(3).
Author information:
(1)Department of Pediatrics, Jeju National University School of Medicine, Jeju,
Korea.
(2)Department of Pediatrics, Pusan National University Hospital, Busan, Korea.
(3)Department of Pediatrics, Seoul National University College of Medicine,
Seoul, Korea. [email protected].
BACKGROUND: Coronavirus disease 2019 (COVID-19) has been the most important
global issue since December 2019. Although the clinical course of COVID-19 is
known to be milder in children than in adults, associated hospitalizations among
children have increased since the emergence of contagious severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the achievement of
a high vaccination rate in adults. Considering these global and domestic
situations, we believe that risk stratification in children with COVID-19 is
urgently needed for decision making regarding hospitalization priority in
children infected with SARS-CoV-2 and vaccination priority against COVID-19.
METHODS: This systematic review and meta-analysis was performed by
comprehensively searching the PubMed, EMBASE, Scopus and KoreaMed databases
through August 25, 2021. The criteria for enrollment were "severe COVID-19" as
poor outcomes (intensive care unit admission, invasive mechanical ventilation,
and/or death) and underlying comorbidities before SARS-CoV-2 infection.
RESULTS: Among 872 screened studies, 17 articles were included in the systematic
review, and 10 articles were included in the meta-analysis. Neonate (risk ratio
[RR], 2.69; 95% confidence interval [CI], 1.83-3.97), prematurity in young
infants (RR, 2.00; 95% CI, 1.63-2.46), obesity (RR, 1.43; 95% CI, 1.24-1.64),
diabetes (RR, 2.26; 95% CI, 1.95-2.62), chronic lung disease (RR, 2.62; 95% CI,
1.71-4.00), heart disease (RR, 1.82; 95% CI, 1.58-2.09), neurologic disease (RR,
1.18; 95% CI, 1.05-1.33), and immunocompromised status (RR, 1.44; 95% CI,
1.01-2.04) were significant risk factors for severe COVID-19 in children. In the
subgroup analysis, age younger than 3 months (RR, 0.26; 95% CI, 0.11-0.66),
asthma (RR, 1.08; 95% CI, 0.98-1.20), and neurodevelopmental disorders (RR,
0.88; 95% CI, 0.75-1.04) were not risk factors for severe COVID-19.
CONCLUSION: Children with comorbidities such as obesity, diabetes, heart
disease, chronic lung diseases other than asthma, seizure disorders, and an
immunocompromised status had a high prevalence of severe COVID-19. Neonate and
premature infants had a high risk of severe COVID-19. Defining the high-risk
group for severe COVID-19 could help to guide hospital admission and priority
for vaccination against SARS-CoV-2.
© 2022 The Korean Academy of Medical Sciences.
DOI: 10.3346/jkms.2022.37.e35
PMCID: PMC8822112
PMID: 35132841 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no potential conflicts of
interest to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/33063089 | 1. Cardiovasc Res. 2020 Dec 1;116(14):2197-2206. doi: 10.1093/cvr/cvaa284.
Higher mortality of COVID-19 in males: sex differences in immune response and
cardiovascular comorbidities.
Bienvenu LA(1)(2)(3), Noonan J(1)(3)(4)(5), Wang X(1)(2)(3)(6), Peter
K(1)(3)(4)(6).
Author information:
(1)Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes
Institute, 75 Commercial Rd, Melbourne, VIC 3004, Australia.
(2)Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes
Institute, Melbourne, VIC, Australia.
(3)Department of Cardiometabolic Health, University of Melbourne, VIC,
Australia.
(4)Deparment of Immunology, Monash University, Melbourne, VIC, Australia.
(5)Centre for Immunobiology, College of Medical, Veterinary and Life Sciences,
Institute of Infection, Immunity and Inflammation, University of Glasgow,
Glasgow, UK.
(6)Department of Medicine, Monash University, Melbourne, VIC, Australia.
The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) infection is a critical concern of the coronavirus disease 2019
(COVID-19) pandemic. Strikingly, men account for the majority of COVID-19
deaths, with current figures ranging from 59% to 75% of total mortality.
However, despite clear implications in relation to COVID-19 mortality, most
research has not considered sex as a critical factor in data analysis. Here, we
highlight fundamental biological differences that exist between males and
females, and how these may make significant contributions to the male-biased
COVID-19 mortality. We present preclinical evidence identifying the influence of
biological sex on the expression and regulation of angiotensin-converting enzyme
2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However,
we note that there is a lack of reports showing that sexual dimorphism of ACE2
expression exists and is of functional relevance in humans. In contrast, there
is strong evidence, especially in the context of viral infections, that sexual
dimorphism plays a central role in the genetic and hormonal regulation of immune
responses, both of the innate and the adaptive immune system. We review evidence
supporting that ineffective anti-SARS-CoV-2 responses, coupled with a
predisposition for inappropriate hyperinflammatory responses, could provide a
biological explanation for the male bias in COVID-19 mortality. A prominent
finding in COVID-19 is the increased risk of death with pre-existing
cardiovascular comorbidities, such as hypertension, obesity, and age. We
contextualize how important features of sexual dimorphism and inflammation in
COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain
their increased mortality risk. Ultimately, we demonstrate that biological sex
is a fundamental variable of critical relevance to our mechanistic understanding
of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and
therapeutic strategies.
Published on behalf of the European Society of Cardiology. All rights reserved.
© The Author(s) 2020. For permissions, please email:
[email protected].
DOI: 10.1093/cvr/cvaa284
PMCID: PMC7665363
PMID: 33063089 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33661992 | 1. PLoS One. 2021 Mar 4;16(3):e0247461. doi: 10.1371/journal.pone.0247461.
eCollection 2021.
Population risk factors for severe disease and mortality in COVID-19: A global
systematic review and meta-analysis.
Booth A(1), Reed AB(1), Ponzo S(1), Yassaee A(1), Aral M(1), Plans D(1)(2),
Labrique A(3), Mohan D(3).
Author information:
(1)Huma Therapeutics Limited, London, United Kingdom.
(2)INDEX Group, Department of Science, Innovation, Technology, and
Entrepreneurship, University of Exeter, Exeter, United Kingdom.
(3)Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
of America.
AIM: COVID-19 clinical presentation is heterogeneous, ranging from asymptomatic
to severe cases. While there are a number of early publications relating to risk
factors for COVID-19 infection, low sample size and heterogeneity in study
design impacted consolidation of early findings. There is a pressing need to
identify the factors which predispose patients to severe cases of COVID-19. For
rapid and widespread risk stratification, these factors should be easily
obtainable, inexpensive, and avoid invasive clinical procedures. The aim of our
study is to fill this knowledge gap by systematically mapping all the available
evidence on the association of various clinical, demographic, and lifestyle
variables with the risk of specific adverse outcomes in patients with COVID-19.
METHODS: The systematic review was conducted using standardized methodology,
searching two electronic databases (PubMed and SCOPUS) for relevant literature
published between 1st January 2020 and 9th July 2020. Included studies reported
characteristics of patients with COVID-19 while reporting outcomes relating to
disease severity. In the case of sufficient comparable data, meta-analyses were
conducted to estimate risk of each variable.
RESULTS: Seventy-six studies were identified, with a total of 17,860,001
patients across 14 countries. The studies were highly heterogeneous in terms of
the sample under study, outcomes, and risk measures reported. A large number of
risk factors were presented for COVID-19. Commonly reported variables for
adverse outcome from COVID-19 comprised patient characteristics, including age
>75 (OR: 2.65, 95% CI: 1.81-3.90), male sex (OR: 2.05, 95% CI: 1.39-3.04) and
severe obesity (OR: 2.57, 95% CI: 1.31-5.05). Active cancer (OR: 1.46, 95% CI:
1.04-2.04) was associated with increased risk of severe outcome. A number of
common symptoms and vital measures (respiratory rate and SpO2) also suggested
elevated risk profiles.
CONCLUSIONS: Based on the findings of this study, a range of easily assessed
parameters are valuable to predict elevated risk of severe illness and mortality
as a result of COVID-19, including patient characteristics and detailed
comorbidities, alongside the novel inclusion of real-time symptoms and vital
measurements.
DOI: 10.1371/journal.pone.0247461
PMCID: PMC7932512
PMID: 33661992 [Indexed for MEDLINE]
Conflict of interest statement: A.B, A.B.R., S.P., D.P., A.Y., M.A., are
employees of Huma Therapeutics Ltd. D.M & AL declare that they have no conflict
of interests to report. This does not alter our adherence to PLOS ONE policies
on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/32949592 | 1. Metabolism. 2021 Apr;117:154373. doi: 10.1016/j.metabol.2020.154373. Epub 2020
Sep 16.
Association of body mass index (BMI) with critical COVID-19 and in-hospital
mortality: A dose-response meta-analysis.
Du Y(1), Lv Y(2), Zha W(3), Zhou N(4), Hong X(5).
Author information:
(1)MOE-LCSM, School of Mathematics and Statistics, Hunan Normal University,
Changsha, Hunan Province 410081, China.
(2)Key Laboratory of Molecular Epidemiology, Medical College of Hunan Normal
University, Changsha, Hunan Province 410013, China. Electronic address:
[email protected].
(3)Key Laboratory of Molecular Epidemiology, Medical College of Hunan Normal
University, Changsha, Hunan Province 410013, China. Electronic address:
[email protected].
(4)Key Laboratory of Molecular Epidemiology, Medical College of Hunan Normal
University, Changsha, Hunan Province 410013, China.
(5)Hunan Provincial People's Hospital, Scientific Research, Department,
Changsha, Hunan Province 410005, China.
BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic
presents an unprecedented health crisis to the entire world. As reported, the
body mass index (BMI) may play an important role in COVID-19; however, this
still remains unclear. The aim of this study was to explore the association
between BMI and COVID-19 severity and mortality.
METHODS: The Medline, PubMed, Embase and Web of science were systematically
searched until August 2020. Random-effects models and dose-response
meta-analysis were used to synthesize the results. Combined odds ratios (ORs)
with their 95% confidence intervals (CIs) were calculated, and the effect of
covariates were analyzed using subgroup analysis and meta-regression analyses.
RESULTS: A total of 16 observational studies involving 109,881 patients with
COVID-19 were included in the meta-analysis. The pooled results showed that
patients with a BMI ≥ 30 kg/m2 had a 2.35-fold risk (OR = 2.35,
95%CI = 1.64-3.38, P < 0.001) for critical COVID-19 and a 2.68-fold risk for
COVID-19 mortality (OR = 2.68, 95%CI = 1.65-4.37, P < 0.001) compared with
patients with a BMI <30 kg/m2. Subgroup analysis results showed that patients
with obesity and age > 60 years was associated with a significantly increased
risk of critical COVID-19 (OR = 3.11, 95%CI = 1.73-5.61, P < 0.001) and COVID-19
mortality (OR = 3.93, 95%CI = 2.18-7.09, P < 0.001). Meta-regression analysis
results also showed that age had a significant influence on the association
between BMI and COVID-19 mortality (Coef. = 0.036, P = 0.048). Random-effects
dose-response meta-analysis showed a linear association between BMI and both
critical COVID-19(Pnon-linearity = 0.242) and mortality
(Pnon-linearity = 0.116). The risk of critical COVID-19 and mortality increased
by 9%(OR = 1.09, 95%CI = 1.04-1.14, P < 0.001) and 6%(OR = 1.06,
95%CI = 1.02-1.10, P = 0.002) for each 1 kg/m2 increase in BMI, respectively.
CONCLUSIONS: Evidence from this meta-analysis suggested that a linear
dose-response association between BMI and both COVID-19 severity and mortality.
Further, obesity (BMI ≥ 30 kg/m2) was associated with a significantly increased
risk of critical COVID-19 and in-hospital mortality of COVID-19.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.metabol.2020.154373
PMCID: PMC7493748
PMID: 32949592 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that there are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32491116 | 1. Rev Saude Publica. 2020;54:60. doi: 10.11606/s1518-8787.2020054002481. Epub
2020 Jun 1.
A brief-review of the risk factors for covid-19 severity.
Rod JE(1), Oviedo-Trespalacios O(2), Cortes-Ramirez J(1).
Author information:
(1)School of Public Health and Social Work, Queensland University of Technology,
Brisbane, Queensland, Australia.
(2)Institute of Health and Biomedical Innovation, Queensland University of
Technology, Brisbane, Queensland, Australia.
The World Health Organization has emphasized that one of the most important
questions to address regarding the covid-19 pandemic is to understand risk
factors for disease severity. We conducted a brief review that synthesizes the
available evidence and provides a judgment on the consistency of the association
between risk factors and a composite end-point of severe-fatal covid-19.
Additionally, we also conducted a comparability analysis of risk factors across
17 studies. We found evidence supporting a total of 60 predictors for disease
severity, of which seven were deemed of high consistency, 40 of medium and 13 of
low. Among the factors with high consistency of association, we found age,
C-reactive protein, D-dimer, albumin, body temperature, SOFA score and diabetes.
The results suggest that diabetes might be the most consistent comorbidity
predicting disease severity and that future research should carefully consider
the comparability of reporting cases, factors, and outcomes along the different
stages of the natural history of covid-19.
DOI: 10.11606/s1518-8787.2020054002481
PMCID: PMC7263798
PMID: 32491116 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest: The authors declare no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32472676 | 1. Clin Infect Dis. 2020 Nov 5;71(8):1962-1968. doi: 10.1093/cid/ciaa674.
Predictors for Severe COVID-19 Infection.
Bhargava A(1), Fukushima EA(1), Levine M(1), Zhao W(1), Tanveer F(1), Szpunar
SM(1), Saravolatz L(1).
Author information:
(1)Ascension St John Hospital, Detroit, Michigan, USA.
Comment in
Clin Infect Dis. 2021 May 18;72(10):1868-1869. doi: 10.1093/cid/ciaa956.
Clin Infect Dis. 2021 May 18;72(10):1870. doi: 10.1093/cid/ciaa960.
BACKGROUND: COVID-19 is a pandemic disease caused by a novel coronavirus, severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Predictors for severe
COVID-19 infection have not been well defined. Determination of risk factors for
severe infection would enable identifying patients who may benefit from
aggressive supportive care and early intervention.
METHODS: We conducted a retrospective observational study of 197 patients with
confirmed COVID-19 admitted to a tertiary academic medical center.
RESULTS: Of 197 hospitalized patients, the mean (SD) age of the cohort was 60.6
(16.2) years, 103 (52.3%) were male, and 156 (82.1%) were black. Severe COVID-19
infection was noted in 74 (37.6%) patients, requiring intubation. Patients aged
above 60 were significantly more likely to have severe infection. Patients with
severe infection were significantly more likely to have diabetes, renal disease,
and chronic pulmonary disease and had significantly higher white blood cell
counts, lower lymphocyte counts, and increased C-reactive protein (CRP) than
patients with nonsevere infection. In multivariable logistic regression
analysis, risk factors for severe infection included pre-existing renal disease
(odds ratio [OR], 7.4; 95% CI, 2.5-22.0), oxygen requirement at hospitalization
(OR, 2.9; 95% CI, 1.3-6.7), acute renal injury (OR, 2.7; 95% CI, 1.3-5.6), and
CRP on admission (OR, 1.006; 95% CI, 1.001-1.01). Race, age, and socioeconomic
status were not independent predictors.
CONCLUSIONS: Acute or pre-existing renal disease, supplemental oxygen upon
hospitalization, and admission CRP were independent predictors for the
development of severe COVID-19. Every 1-unit increase in CRP increased the risk
of severe disease by 0.06%.
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
[email protected].
DOI: 10.1093/cid/ciaa674
PMCID: PMC7314166
PMID: 32472676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35042956 | 1. Pediatr Res. 2022 Oct;92(4):1140-1145. doi: 10.1038/s41390-021-01902-y. Epub
2022 Jan 19.
No infectious SARS-CoV-2 in breast milk from a cohort of 110 lactating women.
Krogstad P(1)(2), Contreras D(3), Ng H(3), Tobin N(3), Chambers CD(4)(5),
Bertrand K(4)(5), Bode L(4)(6), Aldrovandi GM(3).
Author information:
(1)Department of Pediatrics, David Geffen Scool of Medicine at UCLAs, University
of California, Los Angeles, CA, USA. [email protected].
(2)Departments of Molecular and Medical Pharmacology, David Geffen School of
Medicine at UCLA, University of California, Los Angeles, CA, USA.
[email protected].
(3)Department of Pediatrics, David Geffen Scool of Medicine at UCLAs, University
of California, Los Angeles, CA, USA.
(4)Department of Pediatrics, University of California, San Diego, La Jolla, CA,
USA.
(5)Hebert Wertheim School of Public Health and Longevity Science, University of
California, San Diego, La Jolla, CA, USA.
(6)Larsson-RosenquistFoundation Mother-Milk-Infant Center of Research Excellence
(MOMI CORE), University of California, San Diego, La Jolla, CA, USA.
Update of
medRxiv. 2021 Apr 07:2021.04.05.21254897. doi: 10.1101/2021.04.05.21254897.
BACKGROUND: Genomic RNA of severe acute respiratory syndrome-associated
coronavirus type 2 (SARS-CoV-2) has been detected in the breast milk of
lactating women, but its pathological significance has remained uncertain due to
the small size of prior studies.
METHODS: Breast milk from 110 lactating women was analyzed by reverse
transcription-polymerase chain reaction (285 samples) and viral culture (160
samples). Those containing SARS-CoV-2 viral RNA (vRNA) were examined for the
presence of subgenomic RNA (sgRNA), a putative marker of infectivity.
RESULTS: Sixty-five women had a positive SARS-CoV-2 diagnostic test, 9 had
symptoms but negative diagnostic tests, and 36 symptomatic women were not
tested. SARS-CoV-2 vRNA was detected in the milk of 7 (6%) women with either a
confirmed infection or symptomatic illness, including 6 of 65 (9%) women with a
positive SARS-CoV-2 diagnostic test. Infectious virus was not detected in any
culture and none had detectable sgRNA. In control experiments, infectious
SARS-CoV-2 could be cultured after addition to breastmilk despite several
freeze-thaw cycles, as it occurs in the storage and usage of human milk.
CONCLUSIONS: SARS-CoV-2 RNA can be found infrequently in the breastmilk after
recent infection, but we found no evidence that breastmilk contains an
infectious virus or that breastfeeding represents a risk factor for transmission
of infection to infants.
IMPACT: This article goes beyond prior small studies to provide evidence that
infectious SARS-CoV-2 is not present in the milk of lactating women with recent
infection, even when SARS-CoV-2 RNA is detected. Recent SARS-CoV-2 infection or
detection of its RNA in human milk is not a contraindication to breastfeeding.
© 2021. The Author(s).
DOI: 10.1038/s41390-021-01902-y
PMCID: PMC9586866
PMID: 35042956 [Indexed for MEDLINE]
Conflict of interest statement: L.B. reported serving as the UC San Diego Chair
of Collaborative Human Milk Research, which is endowed by the Family
Larsson-Rosenquist Foundation. Medela Corporation provided milk sample
collection materials for this study. C.D.C. reports that shipping of milk
samples was financially supported by the Mothers’ Milk Bank at Austin, an
accredited milk bank and member of the Human Milk Banking Association of North
America. |
http://www.ncbi.nlm.nih.gov/pubmed/33555566 | 1. Indian J Pediatr. 2021 Aug;88(8):800-801. doi: 10.1007/s12098-021-03681-0.
Epub 2021 Feb 8.
Is SARS-CoV-2 Transmitted Through Breastfeeding?
Thanigainathan S(1), Kaliyaperumal V(2), Sivanandan S(1), Rengaraj S(3),
Dhodapkar R(2), Bethou A(4).
Author information:
(1)Department of Neonatology, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Pondicherry, 605 006, India.
(2)Department of Microbiology, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Pondicherry, India.
(3)Department of Obstetrics and Gynecology, Jawaharlal Institute of Postgraduate
Medical Education and Research (JIPMER), Pondicherry, India.
(4)Department of Neonatology, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Pondicherry, 605 006, India.
[email protected].
There are concerns regarding the transmission of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) from mother to child during this COVID
pandemic. This descriptive study was done to check the possible transmission of
the virus through breastfeeding in the Indian context. RT-qPCR for SARS-CoV-2
was done in breast milk samples from 30 COVID-positive mothers. Paired
oropharyngeal swabs of the same neonates were also sent for RT-PCR at 48 h and
on day 5 of life. All the breast milk samples were negative for SARS-CoV-2
except one. A repeat sample of breast milk from the same mother was also
negative when rechecked the next day. All the paired neonatal oropharyngeal
swabs were also negative for SARS-CoV-2. The authors could not find evidence for
transmission of SARS-CoV-2 from mother to child through breastmilk in the
population studied.
© 2021. Dr. K C Chaudhuri Foundation.
DOI: 10.1007/s12098-021-03681-0
PMCID: PMC7868520
PMID: 33555566 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/32995804 | 1. medRxiv [Preprint]. 2020 Sep 18:2020.09.16.20196071. doi:
10.1101/2020.09.16.20196071.
COVID-19 and human milk: SARS-CoV-2, antibodies, and neutralizing capacity.
Pace RM(1), Williams JE(2), Järvinen KM(3), Belfort MB(4), Pace CDW(1), Lackey
KA(1), Gogel AC(1), Nguyen-Contant P(5), Kanagaiah P(5), Fitzgerald T(5), Ferri
R(3), Young B(3), Rosen-Carole C(3), Diaz N(3), Meehan CL(6), Caffe B(6),
Sangster MY(5), Topham D(5), McGuire MA(2), Seppo A(3), McGuire MK(1).
Author information:
(1)Margaret Ritchie School of Family and Consumer Sciences, University of Idaho,
Moscow, ID 83844.
(2)Department of Animal, Veterinary, and Food Sciences, University of Idaho,
Moscow, ID 83844.
(3)Department of Pediatrics, Division of Allergy and Immunology, University of
Rochester School of Medicine and Dentistry, Rochester, NY 14642.
(4)Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, MA 02115.
(5)David H. Smith Center for Vaccine Biology and Immunology, Department of
Microbiology and Immunology, University of Rochester Medical Center, Rochester,
NY 14642.
(6)Department of Anthropology, Washington State University, Pullman, WA 99164.
Update in
This article has been published with doi: 10.1128/mbio.03192-20.
BACKGROUND: It is not known whether SARS-CoV-2 can be transmitted from mother to
infant during breastfeeding, and if so whether the benefits of breastfeeding
outweigh this risk. This study was designed to evaluate 1) if SARS-CoV-2 RNA can
be detected in milk and on the breast of infected women, 2) concentrations of
milk-borne anti-SARS-CoV-2 antibodies, and 3) the capacity of milk to neutralize
SARS-CoV-2 infectivity.
METHODS: We collected 37 milk samples and 70 breast swabs (before and after
breast washing) from 18 women recently diagnosed with COVID-19. Samples were
analyzed for SARS-CoV-2 RNA using RT-qPCR. Milk was also analyzed for IgA and
IgG specific for the nucleocapsid protein, receptor binding domain (RBD), S2
subunit of the spike protein of SARS-CoV-2, as well as 2 seasonal coronaviruses
using ELISA; and for its ability to neutralize SARS-CoV-2.
RESULTS: We did not detect SARS-CoV-2 RNA in any milk sample. In contrast,
SARS-CoV-2 RNA was detected on several breast swabs, although only one was
considered conclusive. All milk contained SARS-CoV-2-specific IgA and IgG, and
levels of anti-RBD IgA correlated with SARS-CoV-2 neutralization. Strong
correlations between levels of IgA and IgG to SARS-CoV-2 and seasonal
coronaviruses were noted.
CONCLUSIONS: Our data do not support maternal-to-child transmission of
SARS-CoV-2 via milk; however, risk of transmission via breast skin should be
further evaluated. Importantly, milk produced by infected mothers is a source of
anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results
support recommendations to continue breastfeeding during mild-to-moderate
maternal COVID-19 illness.
DOI: 10.1101/2020.09.16.20196071
PMCID: PMC7523143
PMID: 32995804 |
http://www.ncbi.nlm.nih.gov/pubmed/33394459 | 1. Curr Nutr Rep. 2021 Mar;10(1):71-75. doi: 10.1007/s13668-020-00343-z. Epub
2021 Jan 4.
Should COVID-19 Mother Breastfeed her Newborn Child? A Literature Review on the
Safety of Breastfeeding for Pregnant Women with COVID-19.
Bhatt H(1)(2).
Author information:
(1)Goshen Hospital, Goshen, IN, USA. [email protected].
(2)Indiana University School of Medicine, South Bend, IN, USA.
[email protected].
PURPOSE OF REVIEW: Breastfeeding is beneficial to both the newborn and the
mother. During the COVID-19 pandemic, concerns have been raised on whether the
SARS-CoV-2 virus could be transmitted from COVID-19 positive mother to the
newborn through breastmilk. The purpose of this review is to examine the
available evidence on the risks of transmission of infection from COVID-19
mothers to their newborns through breastfeeding.
RECENT FINDINGS: Data is very limited in this regard, with only a few smaller
case series, and case reports have been published so far. In most of the
studies, breastmilk samples from COVID-19 mothers tested negative for the virus.
In the case reports where the virus was detected in breastmilk and the infants
were diagnosed with COVID-19, it remained unclear whether the disease was
transmitted through breastmilk or direct contact or through delivery. Another
hypothesis is that the viral antibodies could pass to the newborn passively
through breastmilk of COVID-19 positive mothers and give immunity to the child,
but data is minimal. Based on the currently available limited evidence and
recognizing the benefits of breastfeeding, it may be concluded that if the
health of the mother and her newborn allows, direct breastfeeding or extracted
breastmilk should be encouraged by the healthcare providers after a careful
discussion of the risks of vertical transmission to the mother and her family.
Preventive measures should be taken by COVID-19 mothers to prevent droplet
transmission of infection to the infants while breastfeeding.
DOI: 10.1007/s13668-020-00343-z
PMCID: PMC7780073
PMID: 33394459 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32860259 | 1. Ann N Y Acad Sci. 2021 Jan;1484(1):32-54. doi: 10.1111/nyas.14477. Epub 2020
Aug 28.
Transmission of SARS-CoV-2 through breast milk and breastfeeding: a living
systematic review.
Centeno-Tablante E(1), Medina-Rivera M(1), Finkelstein JL(1), Rayco-Solon P(2),
Garcia-Casal MN(3), Rogers L(3), Ghezzi-Kopel K(4), Ridwan P(1), Peña-Rosas
JP(3), Mehta S(1).
Author information:
(1)Division of Nutritional Sciences, Cornell University, Ithaca, New York.
(2)Department of Maternal, Newborn, Child and Adolescent Health and Ageing,
World Health Organization, Geneva, Switzerland.
(3)Department of Nutrition and Food Safety, World Health Organization, Geneva,
Switzerland.
(4)Albert R. Mann Library, Cornell University, Ithaca, New York.
The pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with
a novel coronavirus strain, the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). At present, there is limited information on potential transmission
of the infection from mother to child, particularly through breast milk and
breastfeeding. Here, we provide a living systematic review to capture
information that might necessitate changes in the guidance on breast milk and
breastfeeding given the uncertainty in this area. Our search retrieved 19,414
total records; 605 were considered for full-text eligibility and no ongoing
trials were identified. Our review includes 340 records, 37 with breast milk
samples and 303 without. The 37 articles with analyzed breast milk samples
reported on 77 mothers who were breastfeeding their children; among them, 19 of
77 children were confirmed COVID-19 cases based on RT-PCR assays, including 14
neonates and five older infants. Nine of the 68 analyzed breast milk samples
from mothers with COVID-19 were positive for SARS-CoV-2 RNA; of the exposed
infants, four were positive and two were negative for COVID-19. Currently, there
is no evidence of SARS-CoV-2 transmission through breast milk. Studies are
needed with longer follow-up periods that collect data on infant feeding
practices and on viral presence in breast milk.
© 2020 The Authors. Annals of the New York Academy of Sciences. The World Health
Organization retains copyright and all other rights in the manuscript of this
article as submitted for publication.
DOI: 10.1111/nyas.14477
PMCID: PMC7970667
PMID: 32860259 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33344466 | 1. Front Med (Lausanne). 2020 Dec 2;7:562700. doi: 10.3389/fmed.2020.562700.
eCollection 2020.
Persistent SARS-CoV-2 RNA Positive in Feces but Negative in Breastmilk: A Case
Report of COVID-19 in a Breastfeeding Patient.
Chu H(1), Li J(1), Yan J(1), Bai T(1), Schnabl B(2), Zou L(3), Yang L(1), Hou
X(1).
Author information:
(1)Division of Gastroenterology, Tongji Medical College, Union Hospital,
Huazhong University of Science and Technology, Wuhan, China.
(2)Department of Medicine, University of California, San Diego, La Jolla, CA,
United States.
(3)Department of Obstetrics & Gynecology, Tongji Medical College, Union
Hospital, Huazhong University of Science and Technology, Wuhan, China.
COVID-19 is a pandemic infectious disease. Whether SARS-CoV-2 was transmitted
through breast milk is unknown. Here, we report a breastfeeding woman with
COVID-19 presenting with gastrointestinal symptoms and persistent SARS-CoV-2 RNA
positivity in both her oropharyngeal swabs and feces, but negativity in her
breastmilk. After appearance of serum SARS-CoV-2-IgG, she began to bottle feed
her baby with breastmilk without transmission. This report facilitates the
understanding of breastfeeding-related risks in COVID-19.
Copyright © 2020 Chu, Li, Yan, Bai, Schnabl, Zou, Yang and Hou.
DOI: 10.3389/fmed.2020.562700
PMCID: PMC7738631
PMID: 33344466
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/33538539 | 1. Pediatr Infect Dis J. 2021 Apr 1;40(4):e137-e145. doi:
10.1097/INF.0000000000003043.
Risk Factors for Severe COVID-19 in Children.
Graff K(1), Smith C(1), Silveira L(1), Jung S(2), Curran-Hays S(1), Jarjour
J(1), Carpenter L(3), Pickard K(3), Mattiucci M(1), Fresia J(3), McFarland
EJ(1), Dominguez SR(1)(2), Abuogi L(1).
Author information:
(1)Department of Pediatrics, School of Medicine, University of Colorado, Aurora,
CO.
(2)Department of Pathology and Laboratory Medicine, Children's Hospital
Colorado, Aurora, CO.
(3)University of Colorado School of Medicine, Aurora, CO.
BACKGROUND: There are limited pediatric data regarding severe COVID-19 disease.
Our study aims to describe the epidemiology and identify risk factors for severe
COVID-19 disease in children.
METHODS: This is a retrospective cohort study among children with positive
SARS-CoV-2 PCR from March to July 2020 at Children's Hospital Colorado. Risk
factors for severe disease were analyzed as defined by hospital admission,
respiratory support, or critical care. Univariable and multivariable analyses
were conducted.
RESULTS: Among 454 patients identified with SARS-CoV-2, 191 (42.1%) were
females, median age 11 years. Fifty-five percent of all patients identified as
Hispanic compared with 29% among all hospital visits in 2019 (P < 0.0001). In
multivariable analyses, age 0-3 months or >20 years [adjusted odds ratio (aOR),
7.85; P < 0.0001 and aOR, 5.1; P = 0.03, respectively], preterm birth history
(aOR, 3.7; P = 0.03), comorbidities [including immunocompromise (aOR, 3.5;
P = 0.004), gastrointestinal condition (aOR, 2.7; P = 0.009), diabetes (aOR,
6.6; P = 0.04), asthma (aOR, 2.2; P = 0.04)], and specific symptoms at
presentation were predictors for admission. Age 0-3 months or >20 years, asthma,
gastrointestinal condition, and similar symptoms at presentation were also
predictors for respiratory support. Elevated C-reactive protein was associated
with the need for critical care with median of 17.7 mg/dL (IQR, 5.3-22.9) versus
1.95 mg/dL (IQR, 0.7-5.5) among patients requiring critical versus no critical
care (OR, 1.2; P = 0.02).
CONCLUSIONS: Extremes of age, comorbid conditions, and elevated CRP are
predictors of severe disease in children. Findings from this study can inform
pediatric providers and public health officials to tailor clinical management,
pandemic planning, and resource allocation.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/INF.0000000000003043
PMID: 33538539 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interest to
disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/34013217 | 1. Lancet Reg Health West Pac. 2020 Nov;4:100045. doi:
10.1016/j.lanwpc.2020.100045. Epub 2020 Nov 10.
A study of breastfeeding practices, SARS-CoV-2 and its antibodies in the breast
milk of mothers confirmed with COVID-19.
Peng S(1), Zhu H(1), Yang L(2), Cao L(1), Huang X(3), Dynes M(4), Narayan A(3),
Xia J(5), Chen Y(1), Zhang P(1), Liu H(1), Li H(1), Xia S(1).
Author information:
(1)Department of Neonatology, Maternal and Child Health Hospital of Hubei
Province, Wuhan, Hubei 430070, China.
(2)Department of Neonatology, Xiaochang First People's Hospital, Xiaochang,
Hubei, China.
(3)Health, Nutrition and WASH, UNICEF China, Beijing, China.
(4)UNICEF East Asia and Pacific Regional Office, Bangkok, Thailand.
(5)Department of Laboratory Medicine, Maternal and Child Health Hospital of
Hubei Province, Wuhan, Hubei, China.
BACKGROUND: The possibility of 2019 novel coronavirus disease (COVID-19)
transmission to neonates through breast milk remains unverified.
METHODS: This paper presents the interim results of a longitudinal study being
carried out in Hubei province. As of 1 April 2020, 24 mothers confirmed with
COVID-19, 19 mothers suspected with COVID-19 but Polymerase chain reaction
negative, and 21 mothers without COVID-19 and their neonates have been
recruited. Telephone follow-up was conducted to collect information on
breastfeeding practices. Forty-four breast milk samples were collected from 16
of the 24 mothers with confirmed COVID-19 for the severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2) ribonucleic acid (RNA) and antibodies (IgM
and IgG) testing.
FINDINGS: The average mother-child separation time was 36•7 ± 21•1 days among
mothers confirmed with COVID-19, significantly longer than that of the suspected
group (16•6 ± 13•1 days) and control group (10•5 ± 8•2 days). Both the COVID-19
confirmed (58•3%) and suspected (52•6%) groups presented significantly lower
rates of breastfeeding as compared with the control group (95•2%). All 44 breast
milk samples tested negative for the SARS-CoV-2 nucleic acid. Thirty-eight
breast milk samples underwent antibody testing and all tested negative for IgG.
Twenty-one breast milk samples from 8 women tested positive for IgM, while the
remaining samples from 11 women tested negative.
INTERPRETATION: Considering the lack of evidence for SARS-CoV-2 transmission
through breast milk, breastfeeding counselling along with appropriate hand
hygiene precautions and facemasks should be provided to all pregnant women.
FUNDING: The study was funded by the Hong Kong Committee for UNICEF.
© 2020 Published by Elsevier Ltd.
DOI: 10.1016/j.lanwpc.2020.100045
PMCID: PMC7654387
PMID: 34013217
Conflict of interest statement: The authors of this paper have no conflict of
interest. The opinions expressed in this paper are solely those of the authors
and do not necessarily represent the official position of UNICEF. |
http://www.ncbi.nlm.nih.gov/pubmed/34182576 | 1. Am J Perinatol. 2021 Sep;38(11):1209-1216. doi: 10.1055/s-0041-1731451. Epub
2021 Jun 28.
Breast Milk and Breastfeeding of Infants Born to SARS-CoV-2 Positive Mothers: A
Prospective Observational Cohort Study.
Kunjumon B(1), Wachtel EV(1), Lumba R(1), Quan M(1), Remon J(1), Louie M(1),
Verma S(1), Moffat MA(1), Kouba I(2), Bennett TA(3)(2), Mejia CM(4), Mally
PV(1), Lin X(4), Hanna N(4).
Author information:
(1)Department of Pediatrics, New York University Grossman School of Medicine,
New York City, New York.
(2)Department of Obstetrics and Gynecology, New York University Grossman School
of Medicine, New York City, New York.
(3)Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology,
New York University Grossman School of Medicine, New York City, New York.
(4)Department of Pediatrics, New York University Long Island School of Medicine,
New York City, New York.
OBJECTIVE: There are limited published data on the transmission of the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus from mothers to
newborns through breastfeeding or from breast milk. The World Health
Organization released guidelines encouraging mothers with suspected or confirmed
COVID-19 to breastfeed as the benefits of breastfeeding outweighs the possible
risk of transmission. The objective of this study was to determine if SARS-CoV-2
was present in the breast milk of lactating mothers who had a positive
SARS-CoV-2 nasopharyngeal swab test prior to delivery, and the clinical outcomes
for their newborns.
STUDY DESIGN: This was a single-center, observational, prospective cohort study.
Maternal-newborn dyads that delivered at New York University Langone Hospital
Brooklyn with confirmed maternal SARS-CoV-2 positive screen test at the time of
admission were recruited for the study. Breast milk samples were collected
during postpartum hospitalization and tested for the presence of SARS-CoV-2
genes N1 and N2 by two-step reverse transcription polymerase chain reaction.
Additionally, the clinical characteristics of the maternal newborn dyad, results
of nasopharyngeal SARS-CoV-2 testing, and neonatal follow-up data were
collected.
RESULTS: A total of 19 mothers were included in the study and their infants who
were all fed breast milk. Breast milk samples from 18 mothers tested negative
for SARS-CoV-2, and 1 was positive for SARS-CoV-2 RNA. The infant who ingested
the breast milk that tested positive had a negative nasopharyngeal test for
SARS-CoV-2, and had a benign clinical course. There was no evidence of
significant clinical infection during the hospital stay or from outpatient
neonatal follow-up data for all the infants included in this study.
CONCLUSION: In a small cohort of SARS-CoV-2 positive lactating mothers giving
birth at our institution, most of their breast milk samples (95%) contained no
detectable virus, and there was no evidence of COVID-19 infection in their
breast milk-fed neonates.
KEY POINTS: · Breast milk may rarely contain detectable SARS-CoV-2 RNA and was
not detected in asymptomatic mothers.. · Breast milk with detectable SARS-CoV-2
RNA from a symptomatic mother had no clinical significance for her infant.. ·
Breast feeding with appropriate infection control instructions appears to be
safe in mother with COVID infection..
Thieme. All rights reserved.
DOI: 10.1055/s-0041-1731451
PMID: 34182576 [Indexed for MEDLINE]
Conflict of interest statement: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/32472745 | 1. Matern Child Nutr. 2020 Oct;16(4):e13032. doi: 10.1111/mcn.13032. Epub 2020
May 30.
SARS-CoV-2 and human milk: What is the evidence?
Lackey KA(1), Pace RM(1), Williams JE(2), Bode L(3), Donovan SM(4), Järvinen
KM(5), Seppo AE(5), Raiten DJ(6), Meehan CL(7), McGuire MA(2), McGuire MK(1).
Author information:
(1)Margaret Ritchie School of Family and Consumer Sciences, University of Idaho,
Moscow, Idaho, USA.
(2)Department of Animal and Veterinary Sciences, University of Idaho, Moscow,
Idaho, USA.
(3)Department of Pediatrics and Larsson-Rosenquist Foundation Mother-Milk-Infant
Center of Research Excellence (MOMI CORE), University of California, San Diego,
California, USA.
(4)Department of Food Science and Human Nutrition and Institute of Genomic
Biology, University of Illinois, Urbana, Illinois, USA.
(5)Department of Pediatrics, Division of Allergy and Immunology, University of
Rochester School of Medicine and Dentistry, Rochester, New York, USA.
(6)Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland,
USA.
(7)Department of Anthropology, Washington State University, Pullman, Washington,
USA.
Update of
medRxiv. 2020 Apr 11:2020.04.07.20056812. doi: 10.1101/2020.04.07.20056812.
The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling and
concerning public health challenges of our time. To address the myriad issues
generated by this pandemic, an interdisciplinary breadth of research, clinical
and public health communities has rapidly engaged to collectively find answers
and solutions. One area of active inquiry is understanding the mode(s) of
SARS-CoV-2 transmission. Although respiratory droplets are a known mechanism of
transmission, other mechanisms are likely. Of particular importance to global
health is the possibility of vertical transmission from infected mothers to
infants through breastfeeding or consumption of human milk. However, there is
limited published literature related to vertical transmission of any human
coronaviruses (including SARS-CoV-2) via human milk and/or breastfeeding.
Results of the literature search reported here (finalized on 17 April 2020)
revealed a single study providing some evidence of vertical transmission of
human coronavirus 229E; a single study evaluating presence of SARS-CoV in human
milk (it was negative); and no published data on MERS-CoV and human milk. We
identified 13 studies reporting human milk tested for SARS-CoV-2; one study (a
non-peer-reviewed preprint) detected the virus in one milk sample, and another
study detected SARS-CoV-2 specific IgG in milk. Importantly, none of the studies
on coronaviruses and human milk report validation of their collection and
analytical methods for use in human milk. These reports are evaluated here, and
their implications related to the possibility of vertical transmission of
coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.
© 2020 The Authors. Maternal & Child Nutrition published by John Wiley & Sons
Ltd.
DOI: 10.1111/mcn.13032
PMCID: PMC7300480
PMID: 32472745 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33563823 | 1. mBio. 2021 Feb 9;12(1):e03192-20. doi: 10.1128/mBio.03192-20.
Characterization of SARS-CoV-2 RNA, Antibodies, and Neutralizing Capacity in
Milk Produced by Women with COVID-19.
Pace RM(#)(1), Williams JE(#)(2), Järvinen KM(3), Belfort MB(4), Pace CDW(1),
Lackey KA(1), Gogel AC(1), Nguyen-Contant P(5), Kanagaiah P(5), Fitzgerald T(5),
Ferri R(3), Young B(3), Rosen-Carole C(3), Diaz N(3), Meehan CL(6), Caffé B(6),
Sangster MY(5), Topham D(5), McGuire MA(2), Seppo A(7), McGuire MK(8).
Author information:
(1)Margaret Ritchie School of Family and Consumer Sciences, University of Idaho,
Moscow, Idaho, USA.
(2)Department of Animal, Veterinary, and Food Sciences, University of Idaho,
Moscow, Idaho, USA.
(3)Department of Pediatrics, Division of Allergy and Immunology, University of
Rochester School of Medicine and Dentistry, Rochester, New York, USA.
(4)Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts, USA.
(5)David H. Smith Center for Vaccine Biology and Immunology, Department of
Microbiology and Immunology, University of Rochester Medical Center, Rochester,
New York, USA.
(6)Department of Anthropology, Washington State University, Pullman, Washington,
USA.
(7)Department of Pediatrics, Division of Allergy and Immunology, University of
Rochester School of Medicine and Dentistry, Rochester, New York, USA
[email protected] [email protected].
(8)Margaret Ritchie School of Family and Consumer Sciences, University of Idaho,
Moscow, Idaho, USA [email protected] [email protected].
(#)Contributed equally
Whether mother-to-infant SARS-CoV-2 transmission can occur during breastfeeding
and, if so, whether the benefits of breastfeeding outweigh this risk during
maternal COVID-19 illness remain important questions. Using RT-qPCR, we did not
detect SARS-CoV-2 RNA in any milk sample (n = 37) collected from 18 women
following COVID-19 diagnosis. Although we detected evidence of viral RNA on 8
out of 70 breast skin swabs, only one was considered a conclusive positive
result. In contrast, 76% of the milk samples collected from women with COVID-19
contained SARS-CoV-2-specific IgA, and 80% had SARS-CoV-2-specific IgG. In
addition, 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity
in vitro, whereas milk samples collected prior to the COVID-19 pandemic were
unable to do so. Taken together, our data do not support mother-to-infant
transmission of SARS-CoV-2 via milk. Importantly, milk produced by infected
mothers is a beneficial source of anti-SARS-CoV-2 IgA and IgG and neutralizes
SARS-CoV-2 activity. These results support recommendations to continue
breastfeeding during mild-to-moderate maternal COVID-19 illness.IMPORTANCE
Results from prior studies assaying human milk for the presence of SARS-CoV-2,
the causative virus of COVID-19, have suggested milk may act as a potential
vehicle for mother-to-child transmission. Most previous studies are limited
because they followed only a few participants, were cross-sectional, and/or
failed to report how milk was collected and/or analyzed. As such, considerable
uncertainty remains regarding whether human milk is capable of transmitting
SARS-CoV-2 from mother to child. Here, we report that repeated milk samples
collected from 18 women following COVID-19 diagnosis did not contain SARS-CoV-2
RNA; however, risk of transmission via breast skin should be further evaluated.
Importantly, we found that milk produced by infected mothers is a source of
anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results
support recommendations to continue breastfeeding during mild-to-moderate
maternal COVID-19 illness as milk likely provides specific immunologic benefits
to infants.
Copyright © 2021 Pace et al.
DOI: 10.1128/mBio.03192-20
PMCID: PMC7885115
PMID: 33563823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32454808 | 1. Rev Panam Salud Publica. 2020 Apr 27;44:e59. doi: 10.26633/RPSP.2020.59.
eCollection 2020.
To breastfeed or not to breastfeed? Lack of evidence on the presence of
SARS-CoV-2 in breastmilk of pregnant women with COVID-19.
Martins-Filho PR(1), Santos VS(2), Santos HP Jr(3).
Author information:
(1)Federal University of Sergipe Federal University of Sergipe São Cristóvão
Brazil Federal University of Sergipe, São Cristóvão, Brazil.
(2)Universidade Federal de Alagoas Universidade Federal de Alagoas Arapiraca
Brazil Universidade Federal de Alagoas, Arapiraca, Brazil.
(3)University of North Carolina at Chapel Hill University of North Carolina at
Chapel Hill Chapel Hill United States of America University of North Carolina at
Chapel Hill, Chapel Hill, United States of America.
A rapid systematic review was carried out to evaluate the current evidence
related to the presence of SARS-CoV-2 in breast milk from pregnant women with
COVID-19. Eight studies analyzing the presence of SARS-CoV-2 RNA in the breast
milk of 24 pregnant women with COVID-19 during the third trimester of pregnancy
were found. All patients had fever and/or symptoms of acute respiratory illness
and chest computed tomography images indicative of COVID-19 pneumonia. Most
pregnant women had cesarean delivery (91.7%) and two neonates had low
birthweight (< 2 500 g). Biological samples collected immediately after birth
from upper respiratory tract (throat or nasopharyngeal) of neonates and
placental tissues showed negative results for the presence SARS-CoV-2 by RT-PCR
test. No breast milk samples were positive for SARS-CoV-2 and, to date, there is
no evidence on the presence of SARS-CoV-2 in breast milk of pregnant women with
COVID-19. However, data are still limited and breastfeeding of women with
COVID-19 remains a controversial issue. There are no restrictions on the use of
milk from a human breast milk bank.
Publisher: Se llevó a cabo una revisión sistemática rápida para evaluar la
evidencia disponible sobre la presencia de SARS-CoV-2 en la leche materna de
mujeres embarazadas afectadas con COVID-19. Se encontraron ocho estudios que
analizaron la presencia de ARN de SARS-CoV-2 en la leche materna de 24 mujeres
embarazadas con COVID-19 durante el tercer trimestre del embarazo. Todas las
pacientes tenían fiebre o síntomas de enfermedad respiratoria aguda e imágenes
de tomografía computarizada de tórax indicativas de neumonía por COVID-19. La
mayoría de las mujeres embarazadas (91,7%) tuvieron un parto por cesárea y dos
neonatos presentaron bajo peso al nacer (< 2 500 g). Las muestras biológicas
recogidas inmediatamente después del parto de las vías respiratorias superiores
(faringe o nasofaringe) de los neonatos y los tejidos placentarios mostraron
resultados negativos para SARS-CoV-2 mediante RT-PCR. Ninguna muestra de leche
materna fue positiva para SARS-CoV-2 y, hasta la fecha, no hay evidencia de la
presencia de SARS-CoV-2 en la leche materna de las mujeres embarazadas con
COVID-19. Sin embargo, los datos disponibles todavía son limitados y la
lactancia materna en las mujeres con COVID-19 sigue siendo un tema
controvertido. No hay restricciones para el uso de leche materna de banco.
Publisher: Foi realizada uma revisão sistemática rápida para avaliar as
evidências atuais relacionadas à presença da SARS-CoV-2 no leite materno de
mulheres grávidas com COVID-19. Foram encontrados oito estudos analisando a
presença de RNA do SARS-CoV-2 no leite materno de 24 gestantes com COVID-19
durante o terceiro trimestre de gravidez. Todas as pacientes apresentavam febre
ou sintomas de doença respiratória aguda e imagens de tomografia computadorizada
do tórax indicativas de pneumonia pela COVID-19. A maioria das gestantes teve
parto cesáreo (91,7%) e dois recém-nascidos tiveram baixo peso ao nascer (< 2
500 g). As amostras biológicas coletadas imediatamente após o nascimento do
trato respiratório superior (faringe ou nasofaringe) de neonatos e tecidos
placentários apresentaram resultados negativos para a presença do SARS-CoV-2
pelo teste RT-PCR. Nenhuma amostra de leite materno foi positiva para o
SARS-CoV-2 e, até à data, não há evidências da presença do SARS-CoV-2 no leite
materno de mulheres grávidas com COVID-19. No entanto, os dados ainda são
limitados e a amamentação de mulheres com COVID-19 continua a ser uma questão
controversa. Não há restrições ao uso de leite de um banco de leite materno
humano.
DOI: 10.26633/RPSP.2020.59
PMCID: PMC7241574
PMID: 32454808
Conflict of interest statement: Conflict of interest. None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/32511431 | 1. medRxiv [Preprint]. 2020 Apr 11:2020.04.07.20056812. doi:
10.1101/2020.04.07.20056812.
SARS-CoV-2 and human milk: what is the evidence?
Lackey KA(1), Pace RM(1), Williams JE(2), Bode L(3), Donovan SM(4), Järvinen
KM(5), Seppo AE(5), Raiten DJ(6), Meehan CL(7), McGuire MA(2), McGuire MK(1).
Author information:
(1)Margaret Ritchie School of Family and Consumer Sciences, University of Idaho,
Moscow, ID, USA.
(2)Department of Animal and Veterinary Sciences, University of Idaho, Moscow,
ID, USA.
(3)Department of Pediatrics and Larsson-Rosenquist Foundation Mother-Milk-Infant
Center of Research Excellence (MOMI CORE), University of California, San Diego,
La Jolla, CA, USA.
(4)Department of Food Science and Human Nutrition and Institute of Genomic
Biology, University of Illinois, Urbana, IL USA.
(5)Department of Pediatrics, Division of Allergy and Immunology, University of
Rochester School of Medicine and Dentistry, Rochester, NY, USA.
(6)Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.
(7)Department of Anthropology, Washington State University, Pullman, WA, USA.
Update in
Matern Child Nutr. 2020 Oct;16(4):e13032. doi: 10.1111/mcn.13032.
The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling
public health challenges of our time. To address the myriad issues generated by
this pandemic, an interdisciplinary breadth of research, clinical, and public
health communities have rapidly engaged to find answers and solutions. One area
of active inquiry is understanding the mode(s) of SARS-CoV-2 transmission. While
respiratory droplets are a known mechanism of transmission, other mechanisms are
possible. Of particular importance to global health is the possibility of
vertical transmission from infected mothers to infants through breastfeeding or
consumption of human milk. However, there is limited published literature
related to vertical transmission of any human coronavirus (including SARS-CoV-2)
via human milk and/or breastfeeding. There is a single study providing some
evidence of vertical transmission of human coronavirus 229E, a single study
evaluating presence of SARS-CoV in human milk (it was negative), and no
published data on MERS-CoV and human milk. There are 9 case studies of human
milk tested for SARS-CoV-2; none detected the virus. Importantly, none of the
published studies on coronaviruses and human milk report validation of their
analytical methods for use in human milk. These reports are evaluated here, and
their implications related to the possibility of vertical transmission of
coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.
DOI: 10.1101/2020.04.07.20056812
PMCID: PMC7217082
PMID: 32511431
Conflict of interest statement: CONFLICT OF INTEREST STATEMENTS The authors
declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20444609 | 1. Trends Biochem Sci. 2010 Sep;35(9):476-89. doi: 10.1016/j.tibs.2010.04.001.
Epub 2010 May 3.
The histone shuffle: histone chaperones in an energetic dance.
Das C(1), Tyler JK, Churchill ME.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Colorado
School of Medicine, Aurora, CO 80045, USA.
Our genetic information is tightly packaged into a rather ingenious
nucleoprotein complex called chromatin in a manner that enables it to be rapidly
accessed during genomic processes. Formation of the nucleosome, which is the
fundamental unit of chromatin, occurs via a stepwise process that is reversed to
enable the disassembly of nucleosomes. Histone chaperone proteins have prominent
roles in facilitating these processes as well as in replacing old histones with
new canonical histones or histone variants during the process of histone
exchange. Recent structural, biophysical and biochemical studies have begun to
shed light on the molecular mechanisms whereby histone chaperones promote
chromatin assembly, disassembly and histone exchange to facilitate DNA
replication, repair and transcription.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tibs.2010.04.001
PMCID: PMC4004086
PMID: 20444609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15868422 | 1. Chromosome Res. 2005;13(3):289-98. doi: 10.1007/s10577-005-2166-z.
Whole-genome views of chromatin structure.
Lodén M(1), van Steensel B.
Author information:
(1)Netherlands Cancer Institute, Amsterdam, 1066CX, The Netherlands.
DNA in eukaryotes is packed into chromatin. The basic component of chromatin is
the nucleosome consisting of DNA wrapped around a histone octamer. Inside the
cell nucleus, chromatin is folded into higher-order structures through various
mechanisms, including repositioning of nucleosomes along the DNA, packing of
nucleosomes into more condensed 3-dimensional configurations, looping of
chromatin fibres, and tethering of chromosomal regions to nuclear structures.
Over the past few years, new microarray-based methods have been developed for
the genome-wide mapping of various aspects of chromatin structure. These methods
are beginning to provide insights into the different types of chromatin and the
architectural principles that govern the 3-dimensional organisation of the
genome inside the nucleus.
DOI: 10.1007/s10577-005-2166-z
PMID: 15868422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28058066 | 1. Biophys Rev. 2016;8(Suppl 1):33-49. doi: 10.1007/s12551-016-0212-z. Epub 2016
Oct 18.
Recent insights from in vitro single-molecule studies into nucleosome structure
and dynamics.
Ordu O(1), Lusser A(2), Dekker NH(1).
Author information:
(1)Bionanoscience Department, Kavli Institute of Nanoscience,, Delft University
of Technology, Van der Maasweg 9,, 2629 HZ Delft, The Netherlands.
(2)Division of Molecular Biology, Biocenter, Medical University of Innsbruck,
Innrain 80-82, 6020 Innsbruck, Austria.
Eukaryotic DNA is tightly packed into a hierarchically ordered structure called
chromatin in order to fit into the micron-scaled nucleus. The basic unit of
chromatin is the nucleosome, which consists of a short piece of DNA wrapped
around a core of eight histone proteins. In addition to their role in packaging
DNA, nucleosomes impact the regulation of essential nuclear processes such as
replication, transcription, and repair by controlling the accessibility of DNA.
Thus, knowledge of this fundamental DNA-protein complex is crucial for
understanding the mechanisms of gene control. While structural and biochemical
studies over the past few decades have provided key insights into both the
molecular composition and functional aspects of nucleosomes, these approaches
necessarily average over large populations and times. In contrast,
single-molecule methods are capable of revealing features of subpopulations and
dynamic changes in the structure or function of biomolecules, rendering them a
powerful complementary tool for probing mechanistic aspects of DNA-protein
interactions. In this review, we highlight how these single-molecule approaches
have recently yielded new insights into nucleosomal and subnucleosomal
structures and dynamics.
DOI: 10.1007/s12551-016-0212-z
PMCID: PMC5167136
PMID: 28058066
Conflict of interest statement: Compliance with ethical standards Funding
Funding for this work was provided by the European Research Council (ERC) via a
Consolidator Grant DynGenome (No:312221) to N.H.D and the Austrian Science Fund
(FWF) [START Y275-B12] to A.L. Conflict of interest Orkide Ordu declares that
she does not have any conflicts of interest. Alexandra Lusser declares that she
does not have any conflicts of interest. Nynke H. Dekker declares that she does
not have any conflicts of interest. Ethical approval This article does not
contain any studies with human participants or animals performed by any of the
authors. |
http://www.ncbi.nlm.nih.gov/pubmed/23109894 | 1. Int J Mol Sci. 2012;13(9):11954-11973. doi: 10.3390/ijms130911954. Epub 2012
Sep 20.
The emerging roles of ATP-dependent chromatin remodeling enzymes in nucleotide
excision repair.
Czaja W(1), Mao P(1), Smerdon MJ(1).
Author information:
(1)Department of Biochemistry and Biophysics, School of Molecular Biosciences,
Washington State University, Pullman, WA, USA.
DNA repair in eukaryotic cells takes place in the context of chromatin, where
DNA, including damaged DNA, is tightly packed into nucleosomes and higher order
chromatin structures. Chromatin intrinsically restricts accessibility of DNA
repair proteins to the damaged DNA and impacts upon the overall rate of DNA
repair. Chromatin is highly responsive to DNA damage and undergoes specific
remodeling to facilitate DNA repair. How damaged DNA is accessed, repaired and
restored to the original chromatin state, and how chromatin remodeling
coordinates these processes in vivo, remains largely unknown. ATP-dependent
chromatin remodelers (ACRs) are the master regulators of chromatin structure and
dynamics. Conserved from yeast to humans, ACRs utilize the energy of ATP to
reorganize packing of chromatin and control DNA accessibility by sliding,
ejecting or restructuring nucleosomes. Several studies have demonstrated that
ATP-dependent remodeling activity of ACRs plays important roles in coordination
of spatio-temporal steps of different DNA repair pathways in chromatin. This
review focuses on the role of ACRs in regulation of various aspects of
nucleotide excision repair (NER) in the context of chromatin. We discuss current
understanding of ATP-dependent chromatin remodeling by various subfamilies of
remodelers and regulation of the NER pathway in vivo.
DOI: 10.3390/ijms130911954
PMCID: PMC3472786
PMID: 23109894 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31794465 | 1. Continuum (Minneap Minn). 2019 Dec;25(6):1662-1681. doi:
10.1212/CON.0000000000000801.
Facioscapulohumeral Muscular Dystrophies.
Wagner KR.
PURPOSE OF REVIEW: Facioscapulohumeral muscular dystrophy (FSHD) is a common
muscular dystrophy affecting both pediatric and adult patients. This article
reviews the phenotype and pathophysiology of the disease as well as the recent
efforts in clinical outcome measures and clinical trials.
RECENT FINDINGS: As the name implies, FSHD involves weakness of facial muscles,
muscles that fix the scapula, and muscles overlying the humerus (biceps and
triceps). The distinctive phenotype of FSHD occurs secondary to two different
genetic mechanisms. FSHD type 1 (FSHD1) is due to a deletion on chromosome 4q,
leading to hypomethylation and derepression of DUX4. FSHD type 2 (FSHD2) is due
to mutations in SMCHD1 with resulting hypomethylation of the same subtelomeric
region of chromosome 4q and derepression of DUX4. Understanding the central role
of DUX4 has opened up the possibility of disease-modifying treatments. In
preparation for clinical trials of novel agents, researchers are in the process
of validating a number of clinical trial outcome measures including MRI, the
6-minute walk test, the FSHD Composite Outcome Measure, reachable workspace,
electrical impedance myography, and the FSHD Health Index.
SUMMARY: The treatment of FSHD is currently supportive only. While past clinical
trials in FSHD have been largely disappointing, novel agents in development,
including antisense oligonucleotides, gene therapy, and small molecules, hold
promise for future meaningful therapies.
DOI: 10.1212/CON.0000000000000801
PMID: 31794465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34255854 | 1. Nucleic Acids Res. 2021 Aug 20;49(14):7925-7938. doi: 10.1093/nar/gkab553.
RoboCOP: jointly computing chromatin occupancy profiles for numerous factors
from chromatin accessibility data.
Mitra S(1), Zhong J(2), Tran TQ(1), MacAlpine DM(2)(3)(4), Hartemink
AJ(1)(2)(4).
Author information:
(1)Department of Computer Science, Duke University, Durham, NC 27708, USA.
(2)Program in Computational Biology and Bioinformatics, Duke University, Durham,
NC 27708, USA.
(3)Department of Pharmacology and Cancer Biology, Duke University Medical
Center, Durham, NC 27710, USA.
(4)Center for Genomic and Computational Biology, Duke University, Durham, NC
27708, USA.
Chromatin is a tightly packaged structure of DNA and protein within the nucleus
of a cell. The arrangement of different protein complexes along the DNA
modulates and is modulated by gene expression. Measuring the binding locations
and occupancy levels of different transcription factors (TFs) and nucleosomes is
therefore crucial to understanding gene regulation. Antibody-based methods for
assaying chromatin occupancy are capable of identifying the binding sites of
specific DNA binding factors, but only one factor at a time. In contrast,
epigenomic accessibility data like MNase-seq, DNase-seq, and ATAC-seq provide
insight into the chromatin landscape of all factors bound along the genome, but
with little insight into the identities of those factors. Here, we present
RoboCOP, a multivariate state space model that integrates chromatin
accessibility data with nucleotide sequence to jointly compute genome-wide
probabilistic scores of nucleosome and TF occupancy, for hundreds of different
factors. We apply RoboCOP to MNase-seq and ATAC-seq data to elucidate the
protein-binding landscape of nucleosomes and 150 TFs across the yeast genome,
and show that our model makes better predictions than existing methods. We also
compute a chromatin occupancy profile of the yeast genome under cadmium stress,
revealing chromatin dynamics associated with transcriptional regulation.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkab553
PMCID: PMC8373080
PMID: 34255854 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35428982 | 1. Muscle Nerve. 2022 Jul;66(1):50-62. doi: 10.1002/mus.27558. Epub 2022 May 9.
Randomized phase 2 study of ACE-083, a muscle-promoting agent, in
facioscapulohumeral muscular dystrophy.
Statland JM(1), Campbell C(2), Desai U(3), Karam C(4), Díaz-Manera J(5)(6)(7),
Guptill JT(8), Korngut L(9), Genge A(10), Tawil RN(11), Elman L(12), Joyce
NC(13), Wagner KR(14), Manousakis G(15), Amato AA(16), Butterfield RJ(17), Shieh
PB(18), Wicklund M(19), Gamez J(20), Bodkin C(21), Pestronk A(22), Weihl CC(22),
Vilchez-Padilla JJ(23)(6), Johnson NE(24), Mathews KD(25), Miller B(26), Leneus
A(26), Fowler M(26), van de Rijn M(26), Attie KM(26).
Author information:
(1)Department of Neurology, University of Kansas Medical Center, Kansas City,
Kansas, USA.
(2)Department of Pediatrics and Clinical Neurological Sciences, University of
Western Ontario, London, Ontario, Canada.
(3)Carolinas MDA Care Center, Atrium Health, Charlotte, North Carolina, USA.
(4)Neuromuscular Division, Oregon Health & Science University, Portland, Oregon,
USA.
(5)Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu
I Sant Pau, Barcelona, Spain.
(6)Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de
Enfermedades Raras, Madrid, Spain.
(7)John Walton Muscular Dystrophy Research Centre, Newcastle University
Translational and Clinical Research Institute, Newcastle, UK.
(8)Department of Neurology, Duke University School of Medicine, Durham, North
Carolina, USA.
(9)University of Calgary, Calgary, Alberta, Canada.
(10)Montreal Neurological Institute, Montreal, Quebec, Canada.
(11)University of Rochester School of Medicine, Rochester, New York, USA.
(12)University of Pennsylvania, Philadelphia, Pennsylvania, USA.
(13)University of California Davis Medical Center, Davis, California, USA.
(14)Johns Hopkins School of Medicine, Kennedy Krieger Institute, Baltimore,
Maryland, USA.
(15)Department of Neurology, University of Minnesota, Minneapolis, Minnesota,
USA.
(16)Brigham and Women's Hospital, Boston, Massachusetts, USA.
(17)Departments of Neurology and Pediatrics, University of Utah, Salt Lake City,
Utah, USA.
(18)University of California Los Angeles, Los Angeles, California, USA.
(19)University of Colorado, Aurora, Colorado, USA.
(20)Department of Medicine, GMA Clinic, European Reference Network on Rare
Neuromuscular Diseases (ERN EURO-NMD) and Universitat Autònoma de Barcelona,
Barcelona, Spain.
(21)Indiana University School of Medicine, Indianapolis, Indiana, USA.
(22)Washington University School of Medicine, St. Louis, Missouri, USA.
(23)Hospital UIP La Fe, Neuromuscular Reference Centre, Valencia, Spain.
(24)Virginia Commonwealth University, Richmond, Virginia, USA.
(25)Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
(26)Acceleron Pharma, Cambridge, Massachusetts, USA.
INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly
progressive muscular dystrophy without approved therapies. In this study we
evaluated whether locally acting ACE-083 could safely increase muscle volume and
improve functional outcomes in adults with FSHD.
METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was
open label, ascending dose, assessing safety and tolerability (primary
objective). Part 2 was randomized, double-blind for 6 months, evaluating
ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps
brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open
label. Magnetic resonance imaging measures included total muscle volume (TMV;
primary objective), fat fraction (FF), and contractile muscle volume (CMV).
Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair
climb (TA group), and performance of upper limb midlevel/elbow score (BB group).
Strength, patient-reported outcomes (PROs), and safety were also evaluated.
RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55
participants evaluable in Part 2, the least-squares mean (90% confidence
interval, analysis of covariance) treatment difference for TMV was 16.4%
(9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group
(P = .01). CMV increased significantly in the BB and TA groups and FF decreased
in the TA group. There were no consistent improvements in functional or PRO
measures in either group. The most common adverse events were mild or moderate
injection-site reactions.
DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result
in consistent functional or PRO improvements with up to 12 months of treatment.
© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
DOI: 10.1002/mus.27558
PMCID: PMC9321022
PMID: 35428982 [Indexed for MEDLINE]
Conflict of interest statement: J.M. Statland received grant support from the
NIH, MDA, FSHD Society, and the Friends of FSH Research; he is a consultant or
has served on advisory boards for Dyne, Fulcrum, Acceleron, Avidity,
Strongbridge, Sarepta, and Genzyme. U. Desai has served on advisory boards for
Alexion, CSL Behring, Argenx, Akcea, and Stealth Biotherapeutics and has served
on the speaker's bureau for Alexion. C. Karam has undertaken consulting or
educational activities for Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring,
Medscape, and Sanofi Genzyme and has received research grants from Sanofi
Genzyme and Akcea. J. Díaz‐Manera has served as a consultant or on advisory
boards for Sanofi‐Genzyme, Amicus, Audentes, Sarepta, and Spark. He has also
received industry grant support from Sanofi Genzyme and Boehringer Ingelheim.
J.T. Guptill has served as a consultant or on advisory boards for Immunovant,
Alexion, Momenta, Ra Pharma, Grifols, Argenx, Jacobus, Becton Dickinson,
Cabaletta, Regeneron, and Piedmont Pharmaceuticals and receives industry grant
support from UCB for a fellowship training grant. A. Genge serves as a
consultant for Mitsubishi Tanabe Pharma America, Sanofi Genzyme, AL‐S Pharma, AB
Sciences, Biogen, Novartis, CSL Behring, Anavex, AveXis, Alexion, Wave Life
Sciences, Revalesio, Roche, Cytokinetics, Orion, Akcea, Clene, Bayshore, and
QurAlis. She participates as CRU Medical Director, PI, or sub‐PI on trials
sponsored by AB Sciences, AL‐S Pharma, Acceleron, Amicus, Alnylam, Bioblast,
Biogen, BMS, Boston Biomedical Cytokinetics, Sanofi Genzyme, Grifols, Ionis, Eli
Lilly, Mallinckrodt, MedImmune, Novartis, Orion, Orphazyme, Pfizer, Ra
Pharmaceuticals, Roche, Teva, and UCB. R.N. Tawil serves as an advisory board
member or consultant for Acceleron Pharma, Fulcrum Therapeutics, MT Pharma, and
Arrowhead Pharma. L. Elman has served on advisory boards for Roche/Genentech and
Biogen and received royalties from UpToDate (Wolters Kluwer). K.R. Wagner has
served on advisory boards or consulted for AskBio, Dyne, Arrowhead Pharma,
Catabasis, Santhera, and Vita. G. Manousakis has served on advisory boards for
Stealth Biotherapeutics and Argenx. A.A. Amato is an associate editor for
Neurology and has served as a medical consultant or on advisory boards for
Sarepta, Alexion, and Serono; he received royalties from UpToDate (Wolters
Kluwer) and Harrison's Principles of Internal Medicine, Neuromuscular Disorders,
2nd ed. R.J. Butterfield is receiving funding via contracts for clinical trials
from AveXis, PTC Therapeutics, Sarepta Therapeutics, Pfizer, Biogen, Capricorn,
and Catabasis; he serves on scientific advisory boards for Sarepta Therapeutics,
Biogen, AveXis, and Pfizer. M. Wicklund has received research funding from the
NIH, MDA, Acceleron, Alexion, Baxalta, ML Bio, Orphazyme, and Sarepta
Therapeutics and has served on advisory boards or in consultation for Affinia,
Amicus, ML Bio, Sanofi, and Sarepta. J. Gamez has received grant funding from
Fondo de Investigación Sanitaria (FIS‐FEDER) (grants PI16/01673 and PI19/00593).
N.E. Johnson has received grant funding from the NINDS (4K23NS091511;
R01NS104010), CDC (DD19‐002), and the FDA (7R01FD006071‐02); he receives
royalties from the Congenital and Childhood Onset Myotonic Dystrophy Health
Index and the Charcot‐Marie‐Tooth Health Index; receives research funds from
Dyne, AveXis, CSL Behring, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio,
Sarepta, and Acceleron Pharma; and has provided consultation for AveXis, AMO
Pharma, Strongbridge BioPharma, Acceleron Pharma, Fulcrum Therapeutics, Dyne,
Avidity, and Vertex Pharmaceuticals. B. Miller, A. Leneus, M. Fowler, M. van de
Rijn, and K. Attie were employed by Acceleron Pharma during the study and had
stock ownership and/or options. The remaining authors declare no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34016622 | 1. Cancer Res. 2021 Aug 15;81(16):4174-4182. doi: 10.1158/0008-5472.CAN-20-4010.
Epub 2021 May 20.
Implications of Enhancer Transcription and eRNAs in Cancer.
Adhikary S(1)(2), Roy S(2), Chacon J(3), Gadad SS(4)(5)(6)(7), Das C(8)(9).
Author information:
(1)Biophysics and Structural Genomics Division, Saha Institute of Nuclear
Physics, Kolkata, India.
(2)Structural Biology and Bioinformatics Division, CSIR-Indian Institute of
Chemical Biology, Kolkata, India.
(3)Paul L. Foster School of Medicine, Texas Tech University Health Sciences
Center El Paso, El Paso, Texas.
(4)Paul L. Foster School of Medicine, Texas Tech University Health Sciences
Center El Paso, El Paso, Texas. [email protected]
[email protected].
(5)Center of Emphasis in Cancer, Department of Molecular and Translational
Medicine, Paul L. Foster School of Medicine, Texas Tech University Health
Sciences Center El Paso, El Paso, Texas.
(6)Graduate School of Biomedical Sciences, Texas Tech University Health Sciences
Center El Paso, El Paso, Texas.
(7)Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department
of Obstetrics and Gynaecology, University of Texas Southwestern Medical Center,
Dallas, Texas.
(8)Biophysics and Structural Genomics Division, Saha Institute of Nuclear
Physics, Kolkata, India. [email protected] [email protected].
(9)Homi Bhaba National Institute, Mumbai, Maharashtra, India.
Despite extensive progress in developing anticancer therapies, therapy
resistance remains a major challenge that promotes disease relapse. The changes
that lead to therapy resistance can be intrinsically present or may be initiated
during treatment. Genetic and epigenetic heterogeneity in tumors make it more
challenging to deal with therapy resistance. Recent advances in genome-wide
analyses have revealed that the deregulation of distal gene regulatory elements,
such as enhancers, appears in several pathophysiological conditions, including
cancer. Beyond the conventional function of enhancers in recruiting
transcription factors to gene promoters, enhancer elements are also transcribed
into noncoding RNAs known as enhancer RNAs (eRNA). Accumulating evidence
suggests that uncontrolled enhancer activity with aberrant eRNA expression
promotes oncogenesis. Interestingly, tissue-specific, transcribed eRNAs from
active enhancers can serve as potential therapeutic targets or biomarkers in
several cancer types. This review provides a comprehensive overview of the
mechanisms of enhancer transcription and eRNAs as well as their potential roles
in cancer and drug resistance.
©2021 American Association for Cancer Research.
DOI: 10.1158/0008-5472.CAN-20-4010
PMID: 34016622 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35277481 | 1. Cell Death Dis. 2022 Mar 11;13(3):228. doi: 10.1038/s41419-022-04673-4.
Super-enhancers and novel therapeutic targets in colorectal cancer.
Liu Q(1)(2), Guo L(1)(3), Lou Z(1)(3), Xiang X(4)(5), Shao J(6)(7)(8).
Author information:
(1)Department of Pathology & Pathophysiology, and Cancer Institute of the Second
Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
(2)Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University
School of Medicine, Hangzhou, China.
(3)Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of
Cancer Prevention and Intervention of China National Ministry of Education,
Zhejiang University School of Medicine, Hangzhou, China.
(4)Department of Pathology & Pathophysiology, and Cancer Institute of the Second
Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
[email protected].
(5)Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of
Cancer Prevention and Intervention of China National Ministry of Education,
Zhejiang University School of Medicine, Hangzhou, China.
[email protected].
(6)Department of Pathology & Pathophysiology, and Cancer Institute of the Second
Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
[email protected].
(7)Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of
Cancer Prevention and Intervention of China National Ministry of Education,
Zhejiang University School of Medicine, Hangzhou, China. [email protected].
(8)Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
Transcription factors, cofactors, chromatin regulators, and transcription
apparatuses interact with transcriptional regulatory elements, including
promoters, enhancers, and super-enhancers (SEs), to coordinately regulate the
transcription of target genes and thereby control cell behaviors. Among these
transcriptional regulatory components and related elements, SEs often play a
central role in determining cell identity and tumor initiation and progression.
Therefore, oncogenic SEs, which are generated within cancer cells in oncogenes
and other genes important in tumor pathogenesis, have emerged as attractive
targets for novel cancer therapeutic strategies in recent years. Herein, we
review the identification, formation and activation modes, and regulatory
mechanisms for downstream genes and pathways of oncogenic SEs. We also review
the therapeutic strategies and compounds targeting oncogenic SEs in colorectal
cancer and other malignancies.
© 2022. The Author(s).
DOI: 10.1038/s41419-022-04673-4
PMCID: PMC8917125
PMID: 35277481 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33934105 | 1. Oncogene. 2021 May;40(20):3475-3491. doi: 10.1038/s41388-021-01793-7. Epub
2021 May 1.
Enhancer rewiring in tumors: an opportunity for therapeutic intervention.
Richart L(1)(2), Bidard FC(3)(4)(5), Margueron R(6)(7).
Author information:
(1)Institut Curie, Paris Sciences et Lettres Research University, Paris, France.
(2)INSERM U934/CNRS UMR3215, Paris, France.
(3)Department of Medical Oncology, Institut Curie, Saint-Cloud, Paris, France.
(4)Circulating Tumor Biomarkers Laboratory, SIRIC2 Institut Curie, Paris,
France.
(5)UVSQ, Université Paris-Saclay, Saint-Cloud, Paris, France.
(6)Institut Curie, Paris Sciences et Lettres Research University, Paris, France.
[email protected].
(7)INSERM U934/CNRS UMR3215, Paris, France. [email protected].
Enhancers are cis-regulatory sequences that fine-tune expression of their target
genes in a spatiotemporal manner. They are recognized by sequence-specific
transcription factors, which in turn recruit transcriptional coactivators that
facilitate transcription by promoting assembly and activation of the basal
transcriptional machinery. Their functional importance is underscored by the
fact that they are often the target of genetic and nongenetic events in human
disease that disrupt their sequence, interactome, activation potential, and/or
chromatin environment. Dysregulation of transcription and addiction to
transcriptional effectors that interact with and modulate enhancer activity are
common features of cancer cells and are amenable to therapeutic intervention.
Here, we discuss the current knowledge on enhancer biology, the broad spectrum
of mechanisms that lead to their malfunction in tumor cells, and recent progress
in developing drugs that efficaciously target their dependencies.
DOI: 10.1038/s41388-021-01793-7
PMID: 33934105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33299103 | 1. NPJ Precis Oncol. 2020 Nov 19;4(1):31. doi: 10.1038/s41698-020-00137-0.
Super-enhancer in prostate cancer: transcriptional disorders and therapeutic
targets.
Chen X(1), Ma Q(1), Shang Z(2), Niu Y(3).
Author information:
(1)Department of Urology, Tianjin Institute of Urology, The Second Hospital of
Tianjin Medical University, 300211, Tianjin, China.
(2)Department of Urology, Tianjin Institute of Urology, The Second Hospital of
Tianjin Medical University, 300211, Tianjin, China. [email protected].
(3)Department of Urology, Tianjin Institute of Urology, The Second Hospital of
Tianjin Medical University, 300211, Tianjin, China. [email protected].
Abnormal activity of oncogenic and tumor-suppressor signaling pathways
contributes to cancer and cancer risk in humans. Transcriptional dysregulation
of these pathways is commonly associated with tumorigenesis and the development
of cancer. Genetic and epigenetic alterations may mediate dysregulated
transcriptional activity. One of the most important epigenetic alternations is
the non-coding regulatory element, which includes both enhancers and
super-enhancers (SEs). SEs, characterized as large clusters of enhancers with
aberrant high levels of transcription factor binding, have been considered as
key drivers of gene expression in controlling and maintaining cancer cell
identity. In cancer cells, oncogenes acquire SEs and the cancer phenotype relies
on these abnormal transcription programs driven by SEs, which leads to cancer
cells often becoming addicted to the SEs-related transcription programs,
including prostate cancer. Here, we summarize recent findings of SEs and
SEs-related gene regulation in prostate cancer and review the potential
pharmacological inhibitors in basic research and clinical trials.
DOI: 10.1038/s41698-020-00137-0
PMCID: PMC7677538
PMID: 33299103
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/25473436 | 1. Genome Med. 2014 Sep 23;6(9):77. doi: 10.1186/s13073-014-0077-3. eCollection
2014.
Enhancer alterations in cancer: a source for a cell identity crisis.
Kron KJ(1), Bailey SD(1), Lupien M(2).
Author information:
(1)The Princess Margaret Cancer Centre - University Health Network, Toronto, ON
M5G 1 L7 Canada ; Department of Medical Biophysics, University of Toronto,
Toronto, ON M5G 1 L7 Canada.
(2)The Princess Margaret Cancer Centre - University Health Network, Toronto, ON
M5G 1 L7 Canada ; Department of Medical Biophysics, University of Toronto,
Toronto, ON M5G 1 L7 Canada ; Ontario Institute for Cancer Research, Toronto, ON
M5G 0A3 Canada.
Enhancers are selectively utilized to orchestrate gene expression programs that
first govern pluripotency and then proceed to highly specialized programs
required for the process of cellular differentiation. Whereas gene-proximal
promoters are typically active across numerous cell types, distal enhancer
activation is cell-type-specific and central to cell fate determination, thereby
accounting for cell identity. Recent studies have highlighted the diversity of
enhancer usage, cataloguing millions of such elements in the human genome. The
disruption of enhancer activity, through genetic or epigenetic alterations, can
impact cell-type-specific functions, resulting in a wide range of pathologies.
In cancer, these alterations can promote a 'cell identity crisis', in which
enhancers associated with oncogenes and multipotentiality are activated, while
those promoting cell fate commitment are inactivated. Overall, these alterations
favor an undifferentiated cellular phenotype. Here, we review the current
knowledge regarding the role of enhancers in normal cell function, and discuss
how genetic and epigenetic changes in enhancer elements potentiate oncogenesis.
In addition, we discuss how understanding the mechanisms regulating enhancer
activity can inform therapeutic opportunities in cancer cells and highlight key
challenges that remain in understanding enhancer biology as it relates to
oncology.
DOI: 10.1186/s13073-014-0077-3
PMCID: PMC4254433
PMID: 25473436 |
http://www.ncbi.nlm.nih.gov/pubmed/35750313 | 1. Biochim Biophys Acta Gene Regul Mech. 2022 Aug;1865(6):194839. doi:
10.1016/j.bbagrm.2022.194839. Epub 2022 Jun 22.
Multifaceted regulation of enhancers in cancer.
Xiao Q(1), Xiao Y(1), Li LY(1), Chen MK(2), Wu M(3).
Author information:
(1)Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory
of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease,
College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University,
Wuhan, Hubei 430072, China.
(2)Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory
of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease,
College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University,
Wuhan, Hubei 430072, China. Electronic address: [email protected].
(3)Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory
of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease,
College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University,
Wuhan, Hubei 430072, China. Electronic address: [email protected].
Enhancer is one kind of cis-elements regulating gene transcription, whose
activity is tightly controlled by epigenetic enzymes and histone modifications.
Active enhancers are classified into typical enhancers, super-enhancers and
over-active enhancers, according to the enrichment and location of histone
modifications. Epigenetic factors control the level of histone modifications on
enhancers to determine their activity, such as histone methyltransferases and
acetylases. Transcription factors, cofactors and mediators co-operate together
and are required for enhancer functions. In turn, abnormalities in these
trans-acting factors affect enhancer activity. Recent studies have revealed
enhancer dysregulation as one of the important features for cancer. Variations
in enhancer regions and mutations of enhancer regulatory genes are frequently
observed in cancer cells, and altering the activity of onco-enhancers is able to
repress oncogene expression, and suppress tumorigenesis and metastasis. Here we
summarize the recent discoveries about enhancer regulation in cancer and discuss
their potential application in diagnosis and treatment.
Copyright © 2022. Published by Elsevier B.V.
DOI: 10.1016/j.bbagrm.2022.194839
PMID: 35750313 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27364481 | 1. Nat Rev Cancer. 2016 Aug;16(8):483-93. doi: 10.1038/nrc.2016.62. Epub 2016 Jul
1.
The role of enhancers in cancer.
Sur I(1), Taipale J(1)(2).
Author information:
(1)Division of Functional Genomics and Systems Biology, Department of Medical
Biochemistry and Biophysics, and Department of Biosciences and Nutrition,
Karolinska Institutet, Stockholm SE-171 77, Sweden.
(2)Genome-Scale Biology Program, University of Helsinki, Biomedicum, PO Box 63,
Helsinki 00014, Finland.
Enhancer elements function as the logic gates of the genetic regulatory
circuitry. One of their most important functions is the integration of
extracellular signals with intracellular cell fate information to generate cell
type-specific transcriptional responses. Mutations occurring in cancer often
misregulate enhancers that normally control the signal-dependent expression of
growth-related genes. This misregulation can result from trans-acting
mechanisms, such as activation of the transcription factors or epigenetic
regulators that control enhancer activity, or can be caused in cis by direct
mutations that alter the activity of the enhancer or its target gene
specificity. These processes can generate tumour type-specific super-enhancers
and establish a 'locked' gene regulatory state that drives the uncontrolled
proliferation of cancer cells. Here, we review the role of enhancers in cancer,
and their potential as therapeutic targets.
DOI: 10.1038/nrc.2016.62
PMID: 27364481 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35911061 | 1. Epigenet Insights. 2022 Jul 26;15:25168657221115656. doi:
10.1177/25168657221115656. eCollection 2022.
Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation.
Jones CA(1), Tansey WP(2)(3), Weissmiller AM(1).
Author information:
(1)Department of Biology, Middle Tennessee State University, Murfreesboro, TN,
USA.
(2)Department of Cell and Developmental Biology, Vanderbilt University School of
Medicine, Nashville, TN, USA.
(3)Department of Biochemistry, Vanderbilt University School of Medicine,
Nashville, TN, USA.
The SWI/SNF chromatin remodeling complex uses the energy of ATP hydrolysis to
alter contacts between DNA and nucleosomes, allowing regions of the genome to
become accessible for biological processes such as transcription. The SWI/SNF
chromatin remodeler is also one of the most frequently altered protein complexes
in cancer, with upwards of 20% of all cancers carrying mutations in a SWI/SNF
subunit. Intense studies over the last decade have probed the molecular events
associated with SWI/SNF dysfunction in cancer and common themes are beginning to
emerge in how tumor-associated SWI/SNF mutations promote malignancy. In this
review, we summarize current understanding of SWI/SNF complexes, their
alterations in cancer, and what is known about the impact of these mutations on
tumor-relevant transcriptional events. We discuss how enhancer dysregulation is
a common theme in SWI/SNF mutant cancers and describe how resultant alterations
in enhancer and super-enhancer activity conspire to block development and
differentiation while promoting stemness and self-renewal. We also identify a
second emerging theme in which SWI/SNF perturbations intersect with potent
oncoprotein transcription factors AP-1 and MYC to drive malignant
transcriptional programs.
© The Author(s) 2022.
DOI: 10.1177/25168657221115656
PMCID: PMC9329810
PMID: 35911061
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/35170113 | 1. Cell Prolif. 2022 Apr;55(4):e13202. doi: 10.1111/cpr.13202. Epub 2022 Feb 16.
Enhancer RNA: What we know and what we can achieve.
Han Z(1), Li W(1).
Author information:
(1)Stem Cell and Cancer Center, The First Hospital of Jilin University,
Changchun, China.
Enhancers are important cis-acting elements that can regulate gene transcription
and cell fate alongside promoters. In fact, many human cancers and diseases are
associated with the malfunction of enhancers. Recent studies have shown that
enhancers can produce enhancer RNAs (eRNAs) by RNA polymerase II. In this
review, we discuss eRNA production, characteristics, functions and mechanics.
eRNAs can determine chromatin accessibility, histone modification and gene
expression by constructing a 'chromatin loop', thereby bringing enhancers to
their target gene. eRNA can also be involved in the phase separation with
enhancers and other proteins. eRNAs are abundant, and importantly,
tissue-specific in tumours, various diseases and stem cells; thus, eRNAs can be
a potential target for disease diagnosis and treatment. As eRNA is produced from
the active transcription of enhancers and is involved in the regulation of cell
fate, its manipulation will influence cell function, and therefore, it can be a
new target for biological therapy.
© 2022 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
DOI: 10.1111/cpr.13202
PMCID: PMC9055912
PMID: 35170113 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31916476 | 1. RNA Biol. 2020 Nov;17(11):1550-1559. doi: 10.1080/15476286.2020.1712895. Epub
2020 Jan 19.
Enhancer RNAs in cancer: regulation, mechanisms and therapeutic potential.
Lee JH(1), Xiong F(1), Li W(1)(2).
Author information:
(1)Department of Biochemistry and Molecular Biology, McGovern Medical School,
University of Texas Health Science Center , Houston, TX, USA.
(2)Graduate School of Biomedical Sciences, University of Texas MD Anderson
Cancer Center and UTHealth , Houston, TX, USA.
Enhancers are distal genomic elements critical for gene regulation and cell
identify control during development and diseases. Many human cancers were found
to associate with enhancer malfunction, due to genetic and epigenetic
alterations, which in some cases directly drive tumour growth. Conventionally,
enhancers are known to provide DNA binding motifs to recruit transcription
factors (TFs) and to control target genes. However, recent progress found that
most, if not all, active enhancers pervasively transcribe noncoding RNAs that
are referred to as enhancer RNAs (eRNAs). Increasing evidence points to
functional roles of at least a subset of eRNAs in gene regulation in both normal
and cancer cells, adding new insights into the action mechanisms of enhancers.
eRNA expression was observed to be widespread but also specific to tumour types
and individual patients, serving as opportunities to exploit them as potential
diagnosis markers or therapeutic targets. In this review, we discuss the brief
history of eRNA research, their functional mechanisms and importance in cancer
gene regulation, as well as their therapeutic and diagnostic values in cancer.
We propose that further studies of eRNAs in cancer will offer a promising 'eRNA
targeted therapy' for human cancer intervention.
DOI: 10.1080/15476286.2020.1712895
PMCID: PMC7567500
PMID: 31916476 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported
by the authors. |
http://www.ncbi.nlm.nih.gov/pubmed/35967935 | 1. Nagoya J Med Sci. 2022 May;84(2):216-229. doi: 10.18999/nagjms.84.2.216.
The molecular understanding of super-enhancer dysregulation in cancer.
Yoshino S(1), Suzuki HI(1)(2).
Author information:
(1)Division of Molecular Oncology, Center for Neurological Diseases and Cancer,
Nagoya University Graduate School of Medicine, Nagoya, Japan.
(2)Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, Japan.
Abnormalities in the regulation of gene expression are associated with various
pathological conditions. Among the distal regulatory elements in the genome, the
activation of target genes by enhancers plays a central role in the formation of
cell type-specific gene expression patterns. Super-enhancers are a subclass of
enhancers that frequently contain multiple enhancer-like elements and are
characterized by dense binding of master transcription factors and Mediator
complexes and high signals of active histone marks. Super-enhancers have been
studied in detail as important regulatory regions that control cell identity and
contribute to the pathogenesis of diverse diseases. In cancer, super-enhancers
have multifaceted roles by activating various oncogenes and other cancer-related
genes and shaping characteristic gene expression patterns in cancer cells.
Alterations in super-enhancer activities in cancer involve multiple mechanisms,
including the dysregulation of transcription factors and the
super-enhancer-associated genomic abnormalities. The study of super-enhancers
could contribute to the identification of effective biomarkers and the
development of cancer therapeutics targeting transcriptional addiction. In this
review, we summarize the roles of super-enhancers in cancer biology, with a
particular focus on hematopoietic malignancies, in which multiple super-enhancer
alteration mechanisms have been reported.
DOI: 10.18999/nagjms.84.2.216
PMCID: PMC9350580
PMID: 35967935 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35406623 | 1. Cancers (Basel). 2022 Apr 6;14(7):1852. doi: 10.3390/cancers14071852.
Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in
Triple-Negative Breast Cancer.
Lewis MW(1), Wisniewska K(1), King CM(1), Li S(1), Coffey A(1), Kelly MR(1)(2),
Regner MJ(1)(2), Franco HL(1)(2)(3).
Author information:
(1)The Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599, USA.
(2)Bioinformatics and Computational Biology Graduate Program, University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
(3)The Department of Genetics, School of Medicine, University of North Carolina
at Chapel Hill, Chapel Hill, NC 27599, USA.
Enhancers are critical regulatory elements in the genome that help orchestrate
spatiotemporal patterns of gene expression during development and normal
physiology. In cancer, enhancers are often rewired by various genetic and
epigenetic mechanisms for the activation of oncogenes that lead to initiation
and progression. A key feature of active enhancers is the production of
non-coding RNA molecules called enhancer RNAs, whose functions remain unknown
but can be used to specify active enhancers de novo. Using a combination of eRNA
transcription and chromatin modifications, we have identified a novel enhancer
located 30 kb upstream of Colony Stimulating Factor 1 (CSF1). Notably, CSF1 is
implicated in the progression of breast cancer, is overexpressed in
triple-negative breast cancer (TNBC) cell lines, and its enhancer is primarily
active in TNBC patient tumors. Genomic deletion of the enhancer (via
CRISPR/Cas9) enabled us to validate this regulatory element as a bona fide
enhancer of CSF1 and subsequent cell-based assays revealed profound effects on
cancer cell proliferation, colony formation, and migration. Epigenetic silencing
of the enhancer via CRISPR-interference assays (dCas9-KRAB) coupled to
RNA-sequencing, enabled unbiased identification of additional target genes, such
as RSAD2, that are predictive of clinical outcome. Additionally, we repurposed
the RNA-guided RNA-targeting CRISPR-Cas13 machinery to specifically degrade the
eRNAs transcripts produced at this enhancer to determine the consequences on
CSF1 mRNA expression, suggesting a post-transcriptional role for these
non-coding transcripts. Finally, we test our eRNA-dependent model of CSF1
enhancer function and demonstrate that our results are extensible to other forms
of cancer. Collectively, this work describes a novel enhancer that is active in
the TNBC subtype, which is associated with cellular growth, and requires eRNA
transcripts for proper enhancer function. These results demonstrate the
significant impact of enhancers in cancer biology and highlight their potential
as tractable targets for therapeutic intervention.
DOI: 10.3390/cancers14071852
PMCID: PMC8997997
PMID: 35406623
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30885876 | 1. Pharmacol Ther. 2019 Jul;199:129-138. doi: 10.1016/j.pharmthera.2019.02.014.
Epub 2019 Mar 16.
Super-enhancers in cancer.
Thandapani P(1).
Author information:
(1)Department of Pathology, New York University School of Medicine, New York, NY
10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School
of Medicine, New York, NY 10016, USA. Electronic address:
[email protected].
Cancer is fueled by the aberrant activity of oncogenic and tumor suppressive
pathways. Transcriptional dysregulation of these pathways play a major role both
in the genesis and development of cancer. Dysregulation of transcriptional
programs can be mediated by genetic and epigenetic alterations targeting both
protein coding genes and non-coding regulatory elements like enhancers and
super-enhancers. Super-enhancers, characterized as large clusters of enhancers
in close proximity, have been identified as essential oncogenic drivers required
for the maintenance of cancer cell identity. As a result, cancer cells are often
addicted to the super-enhancer driven transcriptional programs. Furthermore,
pharmacological inhibitors targeting key components of super-enhancer assembly
and activation have shown great promise in reducing tumor growth and
proliferation in several pre-clinical tumor models. This article reviews the
current understanding of super-enhancer assembly and activation, the different
mechanisms by which cancer cells acquire oncogenic super-enhancers and, finally,
the potential of targeting super-enhancers as future therapeutics.
Copyright © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pharmthera.2019.02.014
PMID: 30885876 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36387198 | 1. Front Oncol. 2022 Oct 27;12:1036648. doi: 10.3389/fonc.2022.1036648.
eCollection 2022.
Super-enhancers in esophageal carcinoma: Transcriptional addictions and
therapeutic strategies.
Shi Y(1)(2), Wang M(3), Liu D(1)(2), Ullah S(1)(2), Ma X(4), Yang H(1)(2), Liu
B(1)(2).
Author information:
(1)Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou
University, Zhengzhou, China.
(2)State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou
University, Zhengzhou, China.
(3)Academy of Medical Sciences Zhengzhou University, Zhengzhou, China.
(4)Department of Nuclear Medicine, The Affiliated Cancer Hospital of Zhengzhou
University & Henan Cancer Hospital, Zhengzhou, China.
The tumorigenesis of esophageal carcinoma arises from transcriptional
dysregulation would become exceptionally dependent on specific regulators of
gene expression, which could be preferentially attributed to the larger
non-coding cis-regulatory elements, i.e. super-enhancers (SEs). SEs, large
genomic regulatory entity in close genomic proximity, are underpinned by control
cancer cell identity. As a consequence, the transcriptional addictions driven by
SEs could offer an Achilles' heel for molecular treatments on patients of
esophageal carcinoma and other types of cancer as well. In this review, we
summarize the recent findings about the oncogenic SEs upon which esophageal
cancer cells depend, and discuss why SEs could be seen as the hallmark of
cancer, how transcriptional dependencies driven by SEs, and what opportunities
could be supplied based on this cancer-specific SEs.
Copyright © 2022 Shi, Wang, Liu, Ullah, Ma, Yang and Liu.
DOI: 10.3389/fonc.2022.1036648
PMCID: PMC9647064
PMID: 36387198
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/34210001 | 1. Cancers (Basel). 2021 Jun 29;13(13):3270. doi: 10.3390/cancers13133270.
Enhancing B-Cell Malignancies-On Repurposing Enhancer Activity towards Cancer.
Kasprzyk ME(1), Sura W(1), Dzikiewicz-Krawczyk A(1).
Author information:
(1)Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznań,
Poland.
B-cell lymphomas and leukemias derive from B cells at various stages of
maturation and are the 6th most common cancer-related cause of death. While the
role of several oncogenes and tumor suppressors in the pathogenesis of B-cell
neoplasms was established, recent research indicated the involvement of
non-coding, regulatory sequences. Enhancers are DNA elements controlling gene
expression in a cell type- and developmental stage-specific manner. They ensure
proper differentiation and maturation of B cells, resulting in production of
high affinity antibodies. However, the activity of enhancers can be redirected,
setting B cells on the path towards cancer. In this review we discuss different
mechanisms through which enhancers are exploited in malignant B cells, from the
well-studied translocations juxtaposing oncogenes to immunoglobulin loci,
through enhancer dysregulation by sequence variants and mutations, to enhancer
hijacking by viruses. We also highlight the potential of therapeutic targeting
of enhancers as a direction for future investigation.
DOI: 10.3390/cancers13133270
PMCID: PMC8269369
PMID: 34210001
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35454885 | 1. Cancers (Basel). 2022 Apr 14;14(8):1978. doi: 10.3390/cancers14081978.
Enhancer RNAs (eRNAs) in Cancer: The Jacks of All Trades.
Napoli S(1), Munz N(1), Guidetti F(1), Bertoni F(1)(2).
Author information:
(1)Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500
Bellinzona, Switzerland.
(2)Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, 6500
Bellinzona, Switzerland.
Enhancer RNAs (eRNAs) are non-coding RNAs (ncRNAs) transcribed in enhancer
regions. They play an important role in transcriptional regulation, mainly
during cellular differentiation. eRNAs are tightly tissue- and cell-type
specific and are induced by specific stimuli, activating promoters of target
genes in turn. eRNAs usually have a very short half-life but in some cases, once
activated, they can be stably expressed and acquire additional functions. Due to
their critical role, eRNAs are often dysregulated in cancer and growing number
of interactions with chromatin modifiers, transcription factors, and splicing
machinery have been described. Enhancer activation and eRNA transcription have
particular relevance also in inflammatory response, placing the eRNAs at the
interplay between cancer and immune cells. Here, we summarize all the possible
molecular mechanisms recently reported in association with eRNAs activity.
DOI: 10.3390/cancers14081978
PMCID: PMC9030334
PMID: 35454885
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29625054 | 1. Cell. 2018 Apr 5;173(2):386-399.e12. doi: 10.1016/j.cell.2018.03.027.
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.
Chen H(1), Li C(2), Peng X(1), Zhou Z(3), Weinstein JN(3); Cancer Genome Atlas
Research Network; Liang H(4).
Collaborators: Caesar-Johnson SJ, Demchok JA, Felau I, Kasapi M, Ferguson ML,
Hutter CM, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang JJ,
Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Cho J,
DeFreitas T, Frazer S, Gehlenborg N, Getz G, Heiman DI, Kim J, Lawrence MS, Lin
P, Meier S, Noble MS, Saksena G, Voet D, Zhang H, Bernard B, Chambwe N, Dhankani
V, Knijnenburg T, Kramer R, Leinonen K, Liu Y, Miller M, Reynolds S, Shmulevich
I, Thorsson V, Zhang W, Akbani R, Broom BM, Hegde AM, Ju Z, Kanchi RS, Korkut A,
Li J, Liang H, Ling S, Liu W, Lu Y, Mills GB, Ng KS, Rao A, Ryan M, Wang J,
Weinstein JN, Zhang J, Abeshouse A, Armenia J, Chakravarty D, Chatila WK, de
Bruijn I, Gao J, Gross BE, Heins ZJ, Kundra R, La K, Ladanyi M, Luna A, Nissan
MG, Ochoa A, Phillips SM, Reznik E, Sanchez-Vega F, Sander C, Schultz N,
Sheridan R, Sumer SO, Sun Y, Taylor BS, Wang J, Zhang H, Anur P, Peto M,
Spellman P, Benz C, Stuart JM, Wong CK, Yau C, Hayes DN, Parker JS, Wilkerson
MD, Ally A, Balasundaram M, Bowlby R, Brooks D, Carlsen R, Chuah E, Dhalla N,
Holt R, Jones SJM, Kasaian K, Lee D, Ma Y, Marra MA, Mayo M, Moore RA, Mungall
AJ, Mungall K, Robertson AG, Sadeghi S, Schein JE, Sipahimalani P, Tam A,
Thiessen N, Tse K, Wong T, Berger AC, Beroukhim R, Cherniack AD, Cibulskis C,
Gabriel SB, Gao GF, Ha G, Meyerson M, Schumacher SE, Shih J, Kucherlapati MH,
Kucherlapati RS, Baylin S, Cope L, Danilova L, Bootwalla MS, Lai PH, Maglinte
DT, Van Den Berg DJ, Weisenberger DJ, Auman JT, Balu S, Bodenheimer T, Fan C,
Hoadley KA, Hoyle AP, Jefferys SR, Jones CD, Meng S, Mieczkowski PA, Mose LE,
Perou AH, Perou CM, Roach J, Shi Y, Simons JV, Skelly T, Soloway MG, Tan D,
Veluvolu U, Fan H, Hinoue T, Laird PW, Shen H, Zhou W, Bellair M, Chang K,
Covington K, Creighton CJ, Dinh H, Doddapaneni H, Donehower LA, Drummond J,
Gibbs RA, Glenn R, Hale W, Han Y, Hu J, Korchina V, Lee S, Lewis L, Li W, Liu X,
Morgan M, Morton D, Muzny D, Santibanez J, Sheth M, Shinbrot E, Wang L, Wang M,
Wheeler DA, Xi L, Zhao F, Hess J, Appelbaum EL, Bailey M, Cordes MG, Ding L,
Fronick CC, Fulton LA, Fulton RS, Kandoth C, Mardis ER, McLellan MD, Miller CA,
Schmidt HK, Wilson RK, Crain D, Curley E, Gardner J, Lau K, Mallery D, Morris S,
Paulauskis J, Penny R, Shelton C, Shelton T, Sherman M, Thompson E, Yena P,
Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC,
Wise L, Zmuda E, Corcoran N, Costello T, Hovens C, Carvalho AL, de Carvalho AC,
Fregnani JH, Longatto-Filho A, Reis RM, Scapulatempo-Neto C, Silveira HCS, Vidal
DO, Burnette A, Eschbacher J, Hermes B, Noss A, Singh R, Anderson ML, Castro PD,
Ittmann M, Huntsman D, Kohl B, Le X, Thorp R, Andry C, Duffy ER, Lyadov V,
Paklina O, Setdikova G, Shabunin A, Tavobilov M, McPherson C, Warnick R,
Berkowitz R, Cramer D, Feltmate C, Horowitz N, Kibel A, Muto M, Raut CP, Malykh
A, Barnholtz-Sloan JS, Barrett W, Devine K, Fulop J, Ostrom QT, Shimmel K,
Wolinsky Y, Sloan AE, De Rose A, Giuliante F, Goodman M, Karlan BY, Hagedorn CH,
Eckman J, Harr J, Myers J, Tucker K, Zach LA, Deyarmin B, Hu H, Kvecher L,
Larson C, Mural RJ, Somiari S, Vicha A, Zelinka T, Bennett J, Iacocca M, Rabeno
B, Swanson P, Latour M, Lacombe L, Têtu B, Bergeron A, McGraw M, Staugaitis SM,
Chabot J, Hibshoosh H, Sepulveda A, Su T, Wang T, Potapova O, Voronina O,
Desjardins L, Mariani O, Roman-Roman S, Sastre X, Stern MH, Cheng F, Signoretti
S, Berchuck A, Bigner D, Lipp E, Marks J, McCall S, McLendon R, Secord A, Sharp
A, Behera M, Brat DJ, Chen A, Delman K, Force S, Khuri F, Magliocca K, Maithel
S, Olson JJ, Owonikoko T, Pickens A, Ramalingam S, Shin DM, Sica G, Van Meir EG,
Zhang H, Eijckenboom W, Gillis A, Korpershoek E, Looijenga L, Oosterhuis W,
Stoop H, van Kessel KE, Zwarthoff EC, Calatozzolo C, Cuppini L, Cuzzubbo S,
DiMeco F, Finocchiaro G, Mattei L, Perin A, Pollo B, Chen C, Houck J,
Lohavanichbutr P, Hartmann A, Stoehr C, Stoehr R, Taubert H, Wach S, Wullich B,
Kycler W, Murawa D, Wiznerowicz M, Chung K, Edenfield WJ, Martin J, Baudin E,
Bubley G, Bueno R, De Rienzo A, Richards WG, Kalkanis S, Mikkelsen T, Noushmehr
H, Scarpace L, Girard N, Aymerich M, Campo E, Giné E, Guillermo AL, Van Bang N,
Hanh PT, Phu BD, Tang Y, Colman H, Evason K, Dottino PR, Martignetti JA, Gabra
H, Juhl H, Akeredolu T, Stepa S, Hoon D, Ahn K, Kang KJ, Beuschlein F, Breggia
A, Birrer M, Bell D, Borad M, Bryce AH, Castle E, Chandan V, Cheville J, Copland
JA, Farnell M, Flotte T, Giama N, Ho T, Kendrick M, Kocher JP, Kopp K, Moser C,
Nagorney D, O'Brien D, O'Neill BP, Patel T, Petersen G, Que F, Rivera M, Roberts
L, Smallridge R, Smyrk T, Stanton M, Thompson RH, Torbenson M, Yang JD, Zhang L,
Brimo F, Ajani JA, Gonzalez AMA, Behrens C, Bondaruk J, Broaddus R, Czerniak B,
Esmaeli B, Fujimoto J, Gershenwald J, Guo C, Lazar AJ, Logothetis C,
Meric-Bernstam F, Moran C, Ramondetta L, Rice D, Sood A, Tamboli P, Thompson T,
Troncoso P, Tsao A, Wistuba I, Carter C, Haydu L, Hersey P, Jakrot V, Kakavand
H, Kefford R, Lee K, Long G, Mann G, Quinn M, Saw R, Scolyer R, Shannon K,
Spillane A, Stretch J, Synott M, Thompson J, Wilmott J, Al-Ahmadie H, Chan TA,
Ghossein R, Gopalan A, Levine DA, Reuter V, Singer S, Singh B, Tien NV, Broudy
T, Mirsaidi C, Nair P, Drwiega P, Miller J, Smith J, Zaren H, Park JW, Hung NP,
Kebebew E, Linehan WM, Metwalli AR, Pacak K, Pinto PA, Schiffman M, Schmidt LS,
Vocke CD, Wentzensen N, Worrell R, Yang H, Moncrieff M, Goparaju C, Melamed J,
Pass H, Botnariuc N, Caraman I, Cernat M, Chemencedji I, Clipca A, Doruc S,
Gorincioi G, Mura S, Pirtac M, Stancul I, Tcaciuc D, Albert M, Alexopoulou I,
Arnaout A, Bartlett J, Engel J, Gilbert S, Parfitt J, Sekhon H, Thomas G, Rassl
DM, Rintoul RC, Bifulco C, Tamakawa R, Urba W, Hayward N, Timmers H, Antenucci
A, Facciolo F, Grazi G, Marino M, Merola R, de Krijger R, Gimenez-Roqueplo AP,
Piché A, Chevalier S, McKercher G, Birsoy K, Barnett G, Brewer C, Farver C,
Naska T, Pennell NA, Raymond D, Schilero C, Smolenski K, Williams F, Morrison C,
Borgia JA, Liptay MJ, Pool M, Seder CW, Junker K, Omberg L, Dinkin M, Manikhas
G, Alvaro D, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Chesla D, Cottingham
S, Dubina M, Moiseenko F, Dhanasekaran R, Becker KF, Janssen KP,
Slotta-Huspenina J, Abdel-Rahman MH, Aziz D, Bell S, Cebulla CM, Davis A, Duell
R, Elder JB, Hilty J, Kumar B, Lang J, Lehman NL, Mandt R, Nguyen P, Pilarski R,
Rai K, Schoenfield L, Senecal K, Wakely P, Hansen P, Lechan R, Powers J,
Tischler A, Grizzle WE, Sexton KC, Kastl A, Henderson J, Porten S, Waldmann J,
Fassnacht M, Asa SL, Schadendorf D, Couce M, Graefen M, Huland H, Sauter G,
Schlomm T, Simon R, Tennstedt P, Olabode O, Nelson M, Bathe O, Carroll PR, Chan
JM, Disaia P, Glenn P, Kelley RK, Landen CN, Phillips J, Prados M, Simko J,
Smith-McCune K, VandenBerg S, Roggin K, Fehrenbach A, Kendler A, Sifri S, Steele
R, Jimeno A, Carey F, Forgie I, Mannelli M, Carney M, Hernandez B, Campos B,
Herold-Mende C, Jungk C, Unterberg A, von Deimling A, Bossler A, Galbraith J,
Jacobus L, Knudson M, Knutson T, Ma D, Milhem M, Sigmund R, Godwin AK, Madan R,
Rosenthal HG, Adebamowo C, Adebamowo SN, Boussioutas A, Beer D, Giordano T,
Mes-Masson AM, Saad F, Bocklage T, Landrum L, Mannel R, Moore K, Moxley K,
Postier R, Walker J, Zuna R, Feldman M, Valdivieso F, Dhir R, Luketich J, Pinero
EMM, Quintero-Aguilo M, Carlotti CG Jr, Dos Santos JS, Kemp R, Sankarankuty A,
Tirapelli D, Catto J, Agnew K, Swisher E, Creaney J, Robinson B, Shelley CS,
Godwin EM, Kendall S, Shipman C, Bradford C, Carey T, Haddad A, Moyer J,
Peterson L, Prince M, Rozek L, Wolf G, Bowman R, Fong KM, Yang I, Korst R,
Rathmell WK, Fantacone-Campbell JL, Hooke JA, Kovatich AJ, Shriver CD, DiPersio
J, Drake B, Govindan R, Heath S, Ley T, Van Tine B, Westervelt P, Rubin MA, Lee
JI, Aredes ND, Mariamidze A.
Author information:
(1)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
(2)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of
Genomic and Precision Medicine, Gastrointestinal Cancer Research Center, Beijing
Institute of Genomics, Chinese Academy of Sciences, 100101 Beijing, China.
(3)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems
Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030,
USA.
(4)Department of Bioinformatics and Computational Biology, The University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems
Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030,
USA. Electronic address: [email protected].
The role of enhancers, a key class of non-coding regulatory DNA elements, in
cancer development has increasingly been appreciated. Here, we present the
detection and characterization of a large number of expressed enhancers in a
genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA
RNA-seq data. Compared with matched normal tissues, global enhancer activation
was observed in most cancers. Across cancer types, global enhancer activity was
positively associated with aneuploidy, but not mutation load,
suggesting a hypothesis centered on "chromatin-state" to explain their
interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we
developed a computational method to infer causal enhancer-gene interactions,
revealing enhancers of clinically actionable genes. Having identified an
enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated
it experimentally. This study provides a systematic view of enhancer activity in
diverse tumor contexts and suggests the clinical implications of enhancers.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2018.03.027
PMCID: PMC5890960
PMID: 29625054 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34361106 | 1. Int J Mol Sci. 2021 Aug 3;22(15):8337. doi: 10.3390/ijms22158337.
Regulation Network of Colorectal-Cancer-Specific Enhancers in the Progression of
Colorectal Cancer.
Chen B(1), Ma Y(1), Bi J(1), Wang W(1), He A(1), Su G(1), Zhao Z(1), Shi J(1),
Zhang L(1).
Author information:
(1)State Key Laboratory of Medicinal Chemical Biology and College of Life
Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Enhancers regulate multiple genes via higher-order chromatin structures, and
they further affect cancer progression. Epigenetic changes in cancer cells
activate several cancer-specific enhancers that are silenced in normal cells.
These cancer-specific enhancers are potential therapeutic targets of cancer.
However, the functions and regulation networks of colorectal-cancer-specific
enhancers are still unknown. In this study, we profile
colorectal-cancer-specific enhancers and reveal their regulation network through
the analysis of HiChIP data that were derived from a colorectal cancer cell line
and Hi-C and RNA-seq data that were derived from tissue samples by in silico
analysis and in vitro experiments. Enhancer-promoter loops in colorectal cancer
cells containing colorectal-cancer-specific enhancers are involved in more than
50% of the topological associated domains (TADs) changed in colorectal cancer
cells compared to normal colon cells. In addition, colorectal-cancer-specific
enhancers interact with 152 genes that are significantly and highly expressed in
colorectal cancer cells. These colorectal-cancer-specific enhancer target genes
include ITGB4, RECQL4, MSLN, and GDF15. We propose that the regulation network
of colorectal-cancer-specific enhancers plays an important role in the
progression of colorectal cancer.
DOI: 10.3390/ijms22158337
PMCID: PMC8348541
PMID: 34361106 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35869079 | 1. Nat Commun. 2022 Jul 22;13(1):4247. doi: 10.1038/s41467-022-31919-8.
A multi-omic dissection of super-enhancer driven oncogenic gene expression
programs in ovarian cancer.
Kelly MR(#)(1)(2), Wisniewska K(#)(1), Regner MJ(1)(2), Lewis MW(1), Perreault
AA(3), Davis ES(2), Phanstiel DH(1)(3)(4), Parker JS(1)(2)(5), Franco
HL(6)(7)(8).
Author information:
(1)Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA.
(2)Bioinformatics and Computational Biology Graduate Program, University of
North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
(3)Thurston Arthritis Research Center, University of North Carolina at Chapel
Hill, Chapel Hill, NC, 27599, USA.
(4)Department of Cell Biology & Physiology, University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA.
(5)Department of Genetics, School of Medicine, University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA.
(6)Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
(7)Bioinformatics and Computational Biology Graduate Program, University of
North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
(8)Department of Genetics, School of Medicine, University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
(#)Contributed equally
The human genome contains regulatory elements, such as enhancers, that are often
rewired by cancer cells for the activation of genes that promote tumorigenesis
and resistance to therapy. This is especially true for cancers that have little
or no known driver mutations within protein coding genes, such as ovarian
cancer. Herein, we utilize an integrated set of genomic and epigenomic datasets
to identify clinically relevant super-enhancers that are preferentially
amplified in ovarian cancer patients. We systematically probe the top 86
super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to
RNA-sequencing, to nominate two salient super-enhancers that drive proliferation
and migration of cancer cells. Utilizing Hi-C, we construct chromatin
interaction maps that enable the annotation of direct target genes for these
super-enhancers and confirm their activity specifically within the cancer cell
compartment of human tumors using single-cell genomics data. Together, our
multi-omic approach examines a number of fundamental questions about how
regulatory information encoded into super-enhancers drives gene expression
networks that underlie the biology of ovarian cancer.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-31919-8
PMCID: PMC9307778
PMID: 35869079 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33502116 | 1. Mol Syst Biol. 2021 Jan;17(1):e9873. doi: 10.15252/msb.20209873.
Transcriptionally active enhancers in human cancer cells.
Lidschreiber K(1)(2), Jung LA(2)(3), von der Emde H(1), Dave K(4), Taipale
J(4)(5)(6), Cramer P(1)(2), Lidschreiber M(1)(2).
Author information:
(1)Department of Molecular Biology, Max Planck Institute for Biophysical
Chemistry, Göttingen, Germany.
(2)Department of Biosciences and Nutrition, Karolinska Institutet, NEO,
Huddinge, Sweden.
(3)Department of Cell and Molecular Biology, Karolinska Institutet, Biomedicum,
Solna, Sweden.
(4)Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Biomedicum, Solna, Sweden.
(5)Department of Biochemistry, University of Cambridge, Cambridge, UK.
(6)Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.
The growth of human cancer cells is driven by aberrant enhancer and gene
transcription activity. Here, we use transient transcriptome sequencing (TT-seq)
to map thousands of transcriptionally active putative enhancers in fourteen
human cancer cell lines covering seven types of cancer. These enhancers were
associated with cell type-specific gene expression, enriched for genetic
variants that predispose to cancer, and included functionally verified
enhancers. Enhancer-promoter (E-P) pairing by correlation of transcription
activity revealed ~ 40,000 putative E-P pairs, which were depleted for
housekeeping genes and enriched for transcription factors, cancer-associated
genes, and 3D conformational proximity. The cell type specificity and
transcription activity of target genes increased with the number of paired
putative enhancers. Our results represent a rich resource for future studies of
gene regulation by enhancers and their role in driving cancerous cell growth.
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
DOI: 10.15252/msb.20209873
PMCID: PMC7838827
PMID: 33502116 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30867030 | 1. Clin Epigenetics. 2019 Mar 12;11(1):48. doi: 10.1186/s13148-019-0645-x.
The hyper-activation of transcriptional enhancers in breast cancer.
Li QL(1)(2), Wang DY(1), Ju LG(3), Yao J(1)(2), Gao C(1)(2), Lei PJ(1)(2), Li
LY(1)(2), Zhao XL(4), Wu M(5)(6).
Author information:
(1)Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan
University, Wuhan, 430072, Hubei, China.
(2)Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key
Laboratory of Enteropathy, Wuhan University, Wuhan, 430072, Hubei, China.
(3)Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, 430072,
Hubei, China.
(4)Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan
University, Wuhan, 430072, Hubei, China. [email protected].
(5)Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan
University, Wuhan, 430072, Hubei, China. [email protected].
(6)Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key
Laboratory of Enteropathy, Wuhan University, Wuhan, 430072, Hubei, China.
[email protected].
BACKGROUND: Activation of transcription enhancers, especially super-enhancers,
is one of the critical epigenetic features of tumorigenesis. However, very few
studies have systematically identified the enhancers specific in cancer tissues.
METHODS: Here, we studied the change of histone modifications in MMTV-PyVT
breast cancer model, combining mass spectrometry-based proteomics and
ChIP-seq-based epigenomics approaches. Some of the proteomic results were
confirmed with western blotting and IHC staining. An inhibitor of H3K27ac was
applied to study its effect on cancer development.
RESULTS: H3K27ac and H4K8ac are elevated in cancer, which was confirmed in
patient tissue chips. ChIP-seq revealed that H4K8ac is co-localized with H3K27ac
on chromatin, especially on distal enhancers. Epigenomic studies further
identified a subgroup of super-enhancers marked by H3K4me3 peaks in the
intergenic regions. The H3K4me3-enriched regions enhancers are associated with
higher level of H3K27ac and H4K8ac compared with the average level of
conventional super-enhancers and are associated with higher transcription level
of their adjacent genes. We identified 148 H3K4me3-enriched super-enhancers with
higher gene expression in tumor, which may be critical for breast cancer. One
inhibitor for p300 and H3K27ac, C646, repressed tumor formation probably through
inhibiting Vegfa and other genes.
CONCLUSIONS: Taken together, our work identifies novel regulators and provides
important resource to the genome-wide enhancer studies in breast cancer and
raises the possibility of cancer treatment through modulating enhancer activity.
DOI: 10.1186/s13148-019-0645-x
PMCID: PMC6417266
PMID: 30867030 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All
the animal operations were following the laboratory animal guidelines of Wuhan
University and were approved by the Animal Experimentations Ethics Committee of
Wuhan University (Protocol NO. 14110B). No patient study was involved and the
consent to participate is not applicable. CONSENT FOR PUBLICATION: All the
authors have read the manuscript and agreed to publish the manuscript. COMPETING
INTERESTS: The authors declare that they have no competing interests.
PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/31874597 | 1. BMC Bioinformatics. 2019 Dec 24;20(Suppl 15):598. doi:
10.1186/s12859-019-3180-z.
DEEPSEN: a convolutional neural network based method for super-enhancer
prediction.
Bu H(1), Hao J(1), Gan Y(2), Zhou S(3), Guan J(4).
Author information:
(1)Department of Computer Science and Technology, Tongji University, 4800 Cao'an
Road, Shanghai, 201804, China.
(2)School of Computer Science and Technology, Donghua University, 2999 North
Renmin Road, Shanghai, 201620, China.
(3)Shanghai Key Lab of Intelligent Information Processing, and School of
Computer Science, Fudan University, 220 Handan Road, Shanghai, 200433, China.
(4)Department of Computer Science and Technology, Tongji University, 4800 Cao'an
Road, Shanghai, 201804, China. [email protected].
BACKGROUND: Super-enhancers (SEs) are clusters of transcriptional active
enhancers, which dictate the expression of genes defining cell identity and play
an important role in the development and progression of tumors and other
diseases. Many key cancer oncogenes are driven by super-enhancers, and the
mutations associated with common diseases such as Alzheimer's disease are
significantly enriched with super-enhancers. Super-enhancers have shown great
potential for the identification of key oncogenes and the discovery of
disease-associated mutational sites.
RESULTS: In this paper, we propose a new computational method called DEEPSEN for
predicting super-enhancers based on convolutional neural network. The proposed
method integrates 36 kinds of features. Compared with existing approaches, our
method performs better and can be used for genome-wide prediction of
super-enhancers. Besides, we screen important features for predicting
super-enhancers.
CONCLUSION: Convolutional neural network is effective in boosting the
performance of super-enhancer prediction.
DOI: 10.1186/s12859-019-3180-z
PMCID: PMC6929276
PMID: 31874597 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/24656127 | 1. Mol Cell. 2014 Mar 20;53(6):859-66. doi: 10.1016/j.molcel.2014.02.033.
Enhancer malfunction in cancer.
Herz HM(1), Hu D(1), Shilatifard A(2).
Author information:
(1)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
(2)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Electronic address: [email protected].
Why certain point mutations in a general transcription factor are associated
with specific forms of cancer has been a major question in cancer biology.
Enhancers are DNA regulatory elements that are key regulators of tissue-specific
gene expression. Recent studies suggest that enhancer malfunction through point
mutations in either regulatory elements or factors modulating enhancer-promoter
communication could be the cause of tissue-specific cancer development. In this
Perspective, we will discuss recent findings in the identification of
cancer-related enhancer mutations and the role of Drosophila Trr and its human
homologs, the MLL3 and MLL4/COMPASS-like complexes, as enhancer histone H3
lysine 4 (H3K4) monomethyltransferases functioning in enhancer-promoter
communication. Recent genome-wide studies in the cataloging of somatic mutations
in cancer have identified mutations in intergenic sequences encoding regulatory
elements-and in MLL3 and MLL4 in both hematological malignancies and solid
tumors. We propose that cancer-associated mutations in MLL3 and MLL4 exert their
properties through the malfunction of Trr/MLL3/MLL4-dependent enhancers.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2014.02.033
PMCID: PMC4049186
PMID: 24656127 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26356674 | 1. Oncotarget. 2015 Oct 20;6(32):32509-25. doi: 10.18632/oncotarget.5085.
The search for cis-regulatory driver mutations in cancer genomes.
Poulos RC(1), Sloane MA(1), Hesson LB(1), Wong JW(1).
Author information:
(1)Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW
Australia, Sydney, Australia.
With the advent of high-throughput and relatively inexpensive whole-genome
sequencing technology, the focus of cancer research has begun to shift toward
analyses of somatic mutations in non-coding cis-regulatory elements of the
cancer genome. Cis-regulatory elements play an important role in gene
regulation, with mutations in these elements potentially resulting in changes to
the expression of linked genes. The recent discoveries of recurrent TERT
promoter mutations in melanoma, and recurrent mutations that create a
super-enhancer regulating TAL1 expression in T-cell acute lymphoblastic
leukaemia (T-ALL), have sparked significant interest in the search for other
somatic cis-regulatory mutations driving cancer development. In this review, we
look more closely at the TERT promoter and TAL1 enhancer alterations and use
these examples to ask whether other cis-regulatory mutations may play a role in
cancer susceptibility. In doing so, we make observations from the data emerging
from recent research in this field, and describe the experimental and analytical
approaches which could be adopted in the hope of better uncovering the true
functional significance of somatic cis-regulatory mutations in cancer.
DOI: 10.18632/oncotarget.5085
PMCID: PMC4741709
PMID: 26356674 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICTS OF INTEREST The authors declare no
conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32128448 | 1. NPJ Precis Oncol. 2020 Feb 12;4:2. doi: 10.1038/s41698-020-0108-z. eCollection
2020.
Super-enhancer function and its application in cancer targeted therapy.
Tang F(#)(1), Yang Z(#)(2), Tan Y(1), Li Y(1).
Author information:
(1)1Department of Clinical Laboratory, Hunan Cancer Hospital and the Affiliated
Cancer Hospital of Xiangya School of Medicine, Central South University, 410013
Changsha, China.
(2)2Department of Clinical Laboratory, Zhuhai People's Hospital & Zhuhai
Hospital of Jinan University, 519000 Zhuhai, China.
(#)Contributed equally
Recently, super-enhancers (SEs) have been identified as a unique type of
transcriptional regulation involved in cancer development. SEs exhibit a size,
high transcription factor density, and strong binding to the transcriptional
machinery compared with typical enhancers. SEs play an essential role in cell
growth, differentiation, and disease initiation and progression including
tumorigenesis. In particular, cancer-specific SEs have been proven to be key
oncogenic drivers types of tumor cells. Furthermore, it has been confirmed that
cancer-specific SEs can mediate the dysregulation of signaling pathways and
promote cancer cell growth. Additionally, therapeutic strategies directly
targeting SE components, for example, by disrupting SE structure or inhibiting
SE cofactors, have shown a good curative effect on various cancers.
© The Author(s) 2020.
DOI: 10.1038/s41698-020-0108-z
PMCID: PMC7016125
PMID: 32128448
Conflict of interest statement: Competing interestsThe authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35437236 | 1. Yi Chuan. 2022 Apr 20;44(4):275-288. doi: 10.16288/j.yczz.21-440.
The regulatory mechanisms by enhancers during cancer initiation and progression.
Qi SH(1)(2), Wang QL(1)(2), Zhang JY(1)(2), Liu Q(1)(2), Li CY(1)(2)(3)(4).
Author information:
(1)School of Engineering Medicine, Beihang University, Beijing 100191, China.
(2)School of Biological Science and Medical Engineering, Beihang University,
Beijing 100191, China.
(3)Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,
Beihang University, Beijing 100191, China.
(4)Key Laboratory of Big Data-Based Precision Medicine (Ministry of Industry and
Information Technology), Beihang University, Beijing 100191, China.
Enhancer is a DNA sequence, and mainly acts in cis to regulate gene
transcription. Due to the uncertainty in both location and distance between
enhancers and their target genes, it is more complex and difficult to study the
underlying regulatory mechanism of enhancers. Accumulating evidences indicate
that enhancers are closely associated with the occurrence and development of
diseases, such as cancer. Therefore, the studies of enhancers in cancer will be
helpful to deeply unravel cancer pathogenesis and to promote the development of
antitumor drugs. The related research is with great social significance and
economic value. Currently, the identification of enhancers is insufficient. The
regulatory mechanisms by enhancers during the initiation and progression of
cancer and other diseases have not been fully delineated. In this review, we
provide an overview of enhancers, super enhancers and their properties, followed
by a description of enhancer prediction and identification at the genome-wide
level. Finally, we summarize the regulatory roles of enhancers during diseases
such as cancer in recent years, thereby providing a reference for the future
exploration on enhancer regulatory mechanisms as well as cancer diagnosis and
treatment.
Publisher:
增强子是一段具有转录调控功能的DNA序列,主要通过顺式调控方式发挥作用。由于增强子及其调控基因在位置和距离上的不确定性,大大增加了研究增强子作用机制的复杂性和困难性。越来越多的证据表明,增强子与癌症等疾病的发生发展密切相关,因此开展癌症相关增强子的研究,将有助于全面解析癌症发病机制,并推动抗肿瘤药物的高效研发,具有重要的社会意义和经济价值。目前对于增强子的鉴定不充分,增强子在癌症和其他疾病中的发生发展调控机制尚未得到完整的解析。本文主要对增强子和超级增强子及其特性进行介绍,并在全基因组水平上对增强子的预测和鉴定进行了描述,最后总结了近年来增强子在癌症等疾病发生过程中所发挥的调控作用,从而为未来解析增强子调控机制以及癌症的诊断和治疗提供参考。.
DOI: 10.16288/j.yczz.21-440
PMID: 35437236 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33858773 | 1. Trends Immunol. 2021 May;42(5):418-431. doi: 10.1016/j.it.2021.03.005. Epub
2021 Apr 12.
Deregulation of enhancer structure, function, and dynamics in acute
lymphoblastic leukemia.
Belver L(1), Albero R(2), Ferrando AA(3).
Author information:
(1)Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA;
Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, 08916, Spain.
(2)Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
(3)Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA;
Department of Systems Biology, Columbia University, New York, NY, 10032, USA;
Department of Pediatrics, Columbia University Medical Center, New York, NY,
10032, USA; Department of Pathology, Columbia University Medical Center, New
York, NY, 10032, USA. Electronic address: [email protected].
Enhancers control dynamic changes in gene expression and orchestrate the tightly
controlled transcriptional circuitries that direct and coordinate cell growth,
proliferation, survival, lineage commitment, and differentiation during lymphoid
development. Enhancer hijacking and neoenhancer formation at oncogene loci, as
well as aberrant activation of oncogene-associated enhancers, can induce
constitutive activation of self-perpetuating oncogenic transcriptional
circuitries, and contribute to the malignant transformation of immature lymphoid
progenitors in acute lymphoblastic leukemia (ALL). In this review, we present
recent discoveries of the role of enhancer dynamics in mouse and human lymphoid
development, and discuss how genetic and epigenetic alterations of enhancer
function can promote leukemogenesis, and potential strategies for targeting the
enhancer machinery in the treatment of ALL.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.it.2021.03.005
PMCID: PMC8091164
PMID: 33858773 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests None declared by
authors. |
http://www.ncbi.nlm.nih.gov/pubmed/29691590 | 1. Cell Mol Life Sci. 2018 Jul;75(14):2537-2555. doi: 10.1007/s00018-018-2820-1.
Epub 2018 Apr 24.
Enhancer reprogramming in tumor progression: a new route towards cancer cell
plasticity.
Fagnocchi L(1), Poli V(2), Zippo A(3)(4)(5).
Author information:
(1)Laboratory of Chromatin Biology and Epigenetics, Center for Integrative
Biology (CIBIO), University of Trento, 38123, Trento, Italy.
[email protected].
(2)Laboratory of Chromatin Biology and Epigenetics, Center for Integrative
Biology (CIBIO), University of Trento, 38123, Trento, Italy.
(3)Laboratory of Chromatin Biology and Epigenetics, Center for Integrative
Biology (CIBIO), University of Trento, 38123, Trento, Italy.
[email protected].
(4)Department of Epigenetics, Fondazione Istituto Nazionale di Genetica
Molecolare "Romeo ed Enrica Invernizzi", Via F. Sforza 35, 20122, Milan, Italy.
[email protected].
(5)Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore
Policlinico, Milan, Italy. [email protected].
Cancer heterogeneity arises during tumor progression as a consequence of genetic
insults, environmental cues, and reversible changes in the epigenetic state,
favoring tumor cell plasticity. The role of enhancer reprogramming is emerging
as a relevant field in cancer biology as it supports adaptation of cancer cells
to those environmental changes encountered during tumor progression and
metastasis seeding. In this review, we describe the cancer-related alterations
that drive oncogenic enhancer activity, leading to dysregulated transcriptional
programs. We discuss the molecular mechanisms of both cis- and trans-factors in
overriding the regulatory circuits that maintain cell-type specificity and
imposing an alternative, de-regulated enhancer activity in cancer cells. We
further comment on the increasing evidence which implicates stress response and
aging-signaling pathways in the enhancer landscape reprogramming during
tumorigenesis. Finally, we focus on the potential therapeutic implications of
these enhancer-mediated subverted transcriptional programs, putting particular
emphasis on the lack of information regarding tumor progression and the
metastatic outgrowth, which still remain the major cause of mortality related to
cancer.
DOI: 10.1007/s00018-018-2820-1
PMCID: PMC11105402
PMID: 29691590 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36250332 | 1. BMJ Open. 2022 Jul 19;12(7):e061841. doi: 10.1136/bmjopen-2022-061841.
Multicentre, randomised controlled trial to investigate the effects of parental
touch on relieving acute procedural pain in neonates (Petal).
Cobo MM(1)(2), Moultrie F(1), Hauck AGV(1), Crankshaw D(1), Monk V(1), Hartley
C(1), Evans Fry R(1), Robinson S(1), van der Vaart M(1), Baxter L(1), Adams
E(3), Poorun R(4)(5), Bhatt A(1), Slater R(6).
Author information:
(1)Department of Paediatrics, University of Oxford, Oxford, UK.
(2)Colegio de Ciencias Biologicas y Ambientales, Universidad San Francisco de
Quito USFQ, Quito, Ecuador.
(3)Newborn Care Unit, John Radcliffe Hospital, Oxford University Hospitals NHS
Foundation Trust, Oxford, UK.
(4)Children's Services, Royal Devon University Healthcare NHS Foundation Trust,
Exeter, UK.
(5)College of Medicine & Health, University of Exeter, Exeter, UK.
(6)Department of Paediatrics, University of Oxford, Oxford, UK
[email protected].
INTRODUCTION: Newborn infants routinely undergo minor painful procedures as part
of postnatal care, with infants born sick or premature requiring a greater
number of procedures. As pain in early life can have long-term
neurodevelopmental consequences and lead to parental anxiety and future
avoidance of interventions, effective pain management is essential.
Non-pharmacological comfort measures such as breastfeeding, swaddling and sweet
solutions are inconsistently implemented and are not always practical or
effective in reducing the transmission of noxious input to the brain. Stroking
of the skin can activate C-tactile fibres and reduce pain, and therefore could
provide a simple and safe parent-led intervention for the management of pain.
The trial aim is to determine whether parental touch prior to a painful clinical
procedure provides effective pain relief in neonates.
METHODS AND ANALYSIS: This is a multicentre randomised controlled trial. A total
of 112 neonates born at 35 weeks' gestation or more requiring a blood test in
the first week of life will be recruited and randomised to receive parental
stroking either preprocedure or postprocedure. We will record brain activity
(EEG), cardiac and respiratory dynamics, oxygen saturation and facial expression
to provide proxy pain outcome measures. The primary outcome will be the
reduction of noxious-evoked brain activity in response to a heel lance.
Secondary outcomes will be a reduction in clinical pain scores (Premature Infant
Pain Profile-Revised), postprocedural tachycardia and parental anxiety.
ETHICS AND DISSEMINATION: The study has been approved by the London-South East
Research Ethics Committee (ref: 21/LO/0523). The results will be widely
disseminated through peer-reviewed publications, international conferences and
via our partner neonatal charities Bliss and Supporting the Sick Newborn And
their Parents (SSNAP). If the parental tactile intervention is effective,
recommendations will be submitted via the National Health Service clinical
guideline adoption process.
STUDY STATUS: Commenced September 2021.
TRIAL REGISTRATION NUMBER: NCT04901611; 14 135 962.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published
by BMJ.
DOI: 10.1136/bmjopen-2022-061841
PMCID: PMC9301810
PMID: 36250332 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/33664472 | 1. J Perinatol. 2021 Sep;41(9):2298-2303. doi: 10.1038/s41372-021-01025-6. Epub
2021 Mar 4.
New perspective for pain control in neonates: a comparative effectiveness
research.
Bresesti I(1)(2), Vanzù G(1), Redaelli F(2), Daniele I(1), Zuccotti GV(2),
Cerritelli F(3), Lista G(#)(4), Fabiano V(#)(2).
Author information:
(1)Division of Neonatology, "V. Buzzi" Children's Hospital, ASST-FBF-Sacco,
Milan, Italy.
(2)Department of Pediatrics, "V. Buzzi" Children's Hospital, University of
Milan, Milan, Italy.
(3)Clinical human-based research Department, Foundation COME collaboration,
Pescara, Italy.
(4)Division of Neonatology, "V. Buzzi" Children's Hospital, ASST-FBF-Sacco,
Milan, Italy. [email protected].
(#)Contributed equally
OBJECTIVE: To compare sucrose 24% oral gel formulation to liquid formula and
breastfeeding during a heel prick in neonates.
STUDY DESIGN: In this comparative effectiveness research 195 neonates >36 weeks'
gestation were randomised to three groups, receiving during heel stick: (i)
breastfeeding, (ii) sucrose 24% liquid with non-nutritive sucking and (iii)
sucrose 24% gel with non-nutritive sucking. The pain was assessed through the
Neonatal Infant Pain Scale.
RESULTS: All the methods analysed has shown to be effective in reducing pain.
There was an increase in odds of pain following liquid sucrose compared to
breastfeeding (OR = 1.60; 95% CI: 0.82-3.3; p = 0.17). A reduction of odds of
pain was showed comparing sucrose to breastfeeding (OR = 0.78; 0.38-1.6; 0.48),
and comparing sucrose gel to liquid formula (OR = 0.48; 0.23-0.96; p = 0.04).
CONCLUSION: Sucrose 24% gel with non-nutritive sucking seems to be a valid
alternative when breastfeeding is not possible. Further research is needed.
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
part of Springer Nature.
DOI: 10.1038/s41372-021-01025-6
PMID: 33664472 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31317627 | 1. J Paediatr Child Health. 2020 Feb;56(2):207-214. doi: 10.1111/jpc.14559. Epub
2019 Jul 17.
Oral sucrose for analgesia in children aged between 3 months and 3 years
undergoing transurethral bladder catheterisation: A randomised, double-blinded,
clinical trial.
London K(1), Watson H(1), Kwok S(2), Nanan R(2), Liu A(2).
Author information:
(1)Department of Nuclear Medicine, Children's Hospital at Westmead, Sydney, New
South Wales, Australia.
(2)Department of Paediatrics, Nepean Hospital, Sydney, New South Wales,
Australia.
AIM: Many children admitted to hospital undergo invasive, painful and stressful
procedures, including children who are not toilet trained undergoing
transurethral bladder catheterisation (TUBC). Oral sucrose is commonly given to
children to reduce procedural pain. In this study, we evaluated the
effectiveness of oral sucrose in reducing procedural pain in children aged
between 3 months and 3 years undergoing TUBC.
METHODS: This study was a randomised, double-blind, placebo-controlled study
conducted at Nepean Hospital, Sydney, Australia from June 2005 to June 2010. A
total of 40 participants requiring TUBC for diagnostic evaluation were included.
The participants were randomly assigned to receive 4 mL of 75% oral sucrose (n =
20) or a placebo (sterilised water) (n = 20). The primary outcomes were changes
in two paediatric pain scale scores (the FLACC pain scale and the OUCHER pain
scale), assessed by the parent/guardian(s), the doctor performing the TUBC and
the nurse assisting. The secondary outcomes were physiological (changes in heart
rate) and behavioural pain (crying) indicators.
RESULTS: Of the outcome measures, 65% favoured the oral sucrose group, 31%
favoured the placebo group, and 4% found no difference between the oral sucrose
and placebo groups.
CONCLUSION: While the trends favouring the sucrose group in this study were
encouraging, as the results were not statistically significant, there was
insufficient evidence to demonstrate the effectiveness of oral sucrose in
reducing procedural pain in children aged between 3 months and 3 years
undergoing TUBC.
© 2019 Paediatrics and Child Health Division (The Royal Australasian College of
Physicians).
DOI: 10.1111/jpc.14559
PMID: 31317627 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12867081 | 1. Biol Cell. 2003 May-Jun;95(3-4):169-78. doi: 10.1016/s0248-4900(03)00033-9.
Generation of protein isoform diversity by alternative initiation of translation
at non-AUG codons.
Touriol C(1), Bornes S, Bonnal S, Audigier S, Prats H, Prats AC, Vagner S.
Author information:
(1)Institut National de la Santé et de la Recherche Médicale U589, Hormones,
Facteurs de Croissance et Physiopathologie Vasculaire, Institut Fédératif de
Recherche Louis Bugnard, C.H.U. Rangueil, 31403 Toulouse cedex 04, France.
The use of several translation initiation codons in a single mRNA, by expressing
several proteins from a single gene, contributes to the generation of protein
diversity. A small, yet growing, number of mammalian mRNAs initiate translation
from a non-AUG codon, in addition to initiating at a downstream in-frame AUG
codon. Translation initiation on such mRNAs results in the synthesis of proteins
harbouring different amino terminal domains potentially conferring on these
isoforms distinct functions. Use of non-AUG codons appears to be governed by
several features, including the sequence context and the secondary structure
surrounding the codon. Selection of the downstream initiation codon can occur by
leaky scanning of the 43S ribosomal subunit, internal entry of ribosome or
ribosomal shunting. The biological significance of non-AUG alternative
initiation is demonstrated by the different subcellular localisations and/or
distinct biological functions of the isoforms translated from the single mRNA as
illustrated by the two main angiogenic factor genes encoding the fibroblast
growth factor 2 (FGF2) and the vascular endothelial growth factor (VEGF).
Consequently, the regulation of alternative initiation of translation might have
a crucial role for the biological function of the gene product.
DOI: 10.1016/s0248-4900(03)00033-9
PMID: 12867081 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21266472 | 1. Nucleic Acids Res. 2011 May;39(10):4220-34. doi: 10.1093/nar/gkr007. Epub 2011
Jan 25.
Identification of evolutionarily conserved non-AUG-initiated N-terminal
extensions in human coding sequences.
Ivanov IP(1), Firth AE, Michel AM, Atkins JF, Baranov PV.
Author information:
(1)BioSciences Institute, University College Cork, Cork, Ireland.
[email protected]
In eukaryotes, it is generally assumed that translation initiation occurs at the
AUG codon closest to the messenger RNA 5' cap. However, in certain cases,
initiation can occur at codons differing from AUG by a single nucleotide,
especially the codons CUG, UUG, GUG, ACG, AUA and AUU. While non-AUG initiation
has been experimentally verified for a handful of human genes, the full extent
to which this phenomenon is utilized--both for increased coding capacity and
potentially also for novel regulatory mechanisms--remains unclear. To address
this issue, and hence to improve the quality of existing coding sequence
annotations, we developed a methodology based on phylogenetic analysis of
predicted 5' untranslated regions from orthologous genes. We use evolutionary
signatures of protein-coding sequences as an indicator of translation initiation
upstream of annotated coding sequences. Our search identified novel conserved
potential non-AUG-initiated N-terminal extensions in 42 human genes including
VANGL2, FGFR1, KCNN4, TRPV6, HDGF, CITED2, EIF4G3 and NTF3, and also affirmed
the conservation of known non-AUG-initiated extensions in 17 other genes. In
several instances, we have been able to obtain independent experimental evidence
of the expression of non-AUG-initiated products from the previously published
literature and ribosome profiling data.
DOI: 10.1093/nar/gkr007
PMCID: PMC3105428
PMID: 21266472 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23748256 | 1. Pain Res Manag. 2013 May-Jun;18(3):153-61. doi: 10.1155/2013/956549.
A systematic review and meta-analyses of nonsucrose sweet solutions for pain
relief in neonates.
Bueno M(1), Yamada J, Harrison D, Khan S, Ohlsson A, Adams-Webber T, Beyene J,
Stevens B.
Author information:
(1)School of Nursing, Federal University of Minas Gerais, Belo Horizonte,
Brazil. [email protected]
BACKGROUND: Sucrose has been demonstrated to provide analgesia for minor painful
procedures in infants. However, results of trials investigating other sweet
solutions for neonatal pain relief have not yet been synthesized.
OBJECTIVE: To establish the efficacy of nonsucrose sweet-tasting solutions for
pain relief during painful procedures in neonates.
METHOD: The present article is a systematic review and meta-analyses of the
literature. Standard methods of the Cochrane Neonatal Collaborative Review Group
were used. Literature searches were reviewed for randomized controlled trials
investigating the use of sweet solutions, except sucrose, for procedural pain
management in neonates. Outcomes assessed included validated pain measures and
behavioural and physiological indicators.
RESULTS: Thirty-eight studies (3785 neonates) were included, 35 of which
investigated glucose. Heel lancing was performed in 21⁄38 studies and
venipuncture in 11⁄38 studies. A 3.6-point reduction in Premature Infant Pain
Profile scores during heel lances was observed in studies comparing 20% to 30%
glucose with no intervention (two studies, 124 neonates; mean difference -3.6
[95% CI -4.6 to -2.6]; P<0.001; I2=54%). A significant reduction in the
incidence of cry after venipuncture for infants receiving 25% to 30% glucose
versus water or no intervention was observed (three studies, 130 infants; risk
difference -0.18 [95% CI -0.31 to -0.05]; P=0.008, number needed to treat = 6
[95% CI 3 to 20]; I2=63%).
CONCLUSIONS: The present systematic review and meta-analyses demonstrate that
glucose reduces pain scores and crying during single heel lances and
venipunctures. Results indicate that 20% to 30% glucose solutions have analgesic
effects and can be recommended as an alternative to sucrose for procedural pain
reduction in healthy term and preterm neonates.
HISTORIQUE : Il est démontré que le saccharose sert d’analgésie lors
d’interventions mineures douloureuses chez les nourrissons. Cependant, il
n’existe pas de synthèse des résultats d’essais sur d’autres solutions sucrées
pour soulager la douleur.
OBJECTIFS : Établir l’efficacité de solutions au goût sucré sans saccharose pour
soulager la douleur pendant des interventions douloureuses chez les nouveau-nés.
MÉTHODOLOGIE : Le présent article se compose d’une analyse systématique et de
méta-analyses des publications. Il fait appel aux méthodes standards du Cochrane
Neonatal Collaborative Review Group. Les chercheurs ont analysé les recherches
dans les publications pour trouver des essais aléatoires et contrôlés sur
l’utilisation de solutions sucrées, à part le saccharose, pour gérer la douleur
causée par des interventions chez les nouveau-nés. Les issues évaluées
incluaient les mesures de douleur validées et les indicateurs comportementaux et
physiologiques.
RÉSULTATS : Trente-huit études (3 785 nouveau-nés) étaient incluses, dont 35
portaient sur le glucose. Des incisions au talon ont été exécutées dans 21 des
38 études et une veinopuncture, dans 11 des 38 études. On observait une
diminution de 3,6 points aux indices du profil de douleur des nourrissons
prématurés pendant l’incision au talon dans les études comparant de 20 % à 30 %
de glucose à l’absence d’intervention (deux études, 124 nouveau-nés, différence
moyenne de −3,6 [95 % IC −4,6 à −2,6]; P<0,001). On observait également une
réduction significative de l’incidence de pleurs après la veinopuncture chez les
nourrissons qui recevaient de 25 % à 30 % de glucose par rapport à de l’eau ou à
l’absence d’intervention (trois études, 130 nourrissons; différence de risque de
−0,18 [95 % IC −0,31 à −0,05]; P=0,008, nombre nécessaire pour traiter = 6 [95 %
IC 3 à 20]; I2=63 %).
CONCLUSIONS : La présente analyse systématique et les présentes méta-analyses
ont démontré que le glucose réduit les indices de douleur et les pleurs pendant
de simples incisions au talon et des veinopunctures. Selon les résultats, des
solutions de 20 % à 30 % de glucose ont des effets analgésiques et peuvent être
recommandées pour remplacer le saccharose en vue de réduire la douleur lors
d’interventions chez les nouveau-nés en santé à terme et prématurés.
DOI: 10.1155/2013/956549
PMCID: PMC3673933
PMID: 23748256 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28369664 | 1. Curr Protoc Protein Sci. 2017 Apr 3;88:6.14.1-6.14.3. doi: 10.1002/cpps.29.
N-Terminal Methionine Processing.
Wingfield PT(1).
Author information:
(1)Protein Expression Laboratory, NIAMS/NIH, Bethesda, Maryland.
Protein synthesis is initiated by methionine in eukaryotes and by
formylmethionine in prokaryotes. N-terminal methionine can be co-translationally
cleaved by the enzyme methionine aminopeptidase (MAP). When recombinant proteins
are expressed in bacterial and mammalian expression systems, there is a simple
universal rule that predicts whether the initiating methionine will be processed
by MAP based on the size of the residue adjacent (penultimate) to the
N-methionine. In general, if the side chains of the penultimate residues have a
radius of gyration of 1.29 Å or less, methionine is cleaved. © 2017 by John
Wiley & Sons, Inc.
Copyright © 2017 John Wiley & Sons, Inc.
DOI: 10.1002/cpps.29
PMCID: PMC5663234
PMID: 28369664 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28334756 | 1. Nucleic Acids Res. 2017 Apr 20;45(7):3615-3626. doi: 10.1093/nar/gkx070.
Measurements of translation initiation from all 64 codons in E. coli.
Hecht A(1)(2)(3), Glasgow J(1)(2)(3), Jaschke PR(3)(4), Bawazer LA(1)(2)(3),
Munson MS(1)(2)(3), Cochran JR(1)(3), Endy D(1)(3), Salit M(1)(2)(3).
Author information:
(1)Joint Initiative for Metrology in Biology, Stanford, CA 94305, USA.
(2)Genome-scale Measurements Group, National Institute of Standards and
Technology, Stanford, CA 94305, USA.
(3)Department of Bioengineering, Stanford, CA 94305, USA.
(4)Department of Chemistry and Biomolecular Sciences, Macquarie University,
Sydney, NSW 2109, Australia.
Our understanding of translation underpins our capacity to engineer living
systems. The canonical start codon (AUG) and a few near-cognates (GUG, UUG) are
considered as the 'start codons' for translation initiation in Escherichia coli.
Translation is typically not thought to initiate from the 61 remaining codons.
Here, we quantified translation initiation of green fluorescent protein and
nanoluciferase in E. coli from all 64 triplet codons and across a range of DNA
copy number. We detected initiation of protein synthesis above measurement
background for 47 codons. Translation from non-canonical start codons ranged
from 0.007 to 3% relative to translation from AUG. Translation from 17 non-AUG
codons exceeded the highest reported rates of non-cognate codon recognition.
Translation initiation from non-canonical start codons may contribute to the
synthesis of peptides in both natural and synthetic biological systems.
Published by Oxford University Press on behalf of Nucleic Acids Research 2017.
DOI: 10.1093/nar/gkx070
PMCID: PMC5397182
PMID: 28334756 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15215523 | 1. Protein Sci. 2004 Jul;13(7):1802-10. doi: 10.1110/ps.04679104.
Removal of N-terminal methionine from recombinant proteins by engineered E. coli
methionine aminopeptidase.
Liao YD(1), Jeng JC, Wang CF, Wang SC, Chang ST.
Author information:
(1)Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115.
[email protected]
The removal of N-terminal translation initiator Met by methionine aminopeptidase
(MetAP) is often crucial for the function and stability of proteins. On the
basis of crystal structure and sequence alignment of MetAPs, we have engineered
Escherichia coli MetAP by the mutation of three residues, Y168G, M206T, Q233G,
in the substrate-binding pocket. Our engineered MetAPs are able to remove the
Met from bulky or acidic penultimate residues, such as Met, His, Asp, Asn, Glu,
Gln, Leu, Ile, Tyr, and Trp, as well as from small residues. The penultimate
residue, the second residue after Met, was further removed if the
antepenultimate residue, the third residue after Met, was small. By the
coexpression of engineered MetAP in E. coli through the same or a separate
vector, we have successfully produced recombinant proteins possessing an innate
N terminus, such as onconase, an antitumor ribonuclease from the frog Rana
pipiens. The N-terminal pyroglutamate of recombinant onconase is critical for
its structural integrity, catalytic activity, and cyto-toxicity. On the basis of
N-terminal sequence information in the protein database, 85%-90% of recombinant
proteins should be produced in authentic form by our engineered MetAPs.
DOI: 10.1110/ps.04679104
PMCID: PMC2279930
PMID: 15215523 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9710598 | 1. Mol Cell Biol. 1998 Sep;18(9):5140-7. doi: 10.1128/MCB.18.9.5140.
Initiation of protein synthesis in mammalian cells with codons other than AUG
and amino acids other than methionine.
Drabkin HJ(1), RajBhandary UL.
Author information:
(1)Department of Biology, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA.
Protein synthesis is initiated universally with the amino acid methionine. In
Escherichia coli, studies with anticodon sequence mutants of the initiator
methionine tRNA have shown that protein synthesis can be initiated with several
other amino acids. In eukaryotic systems, however, a yeast initiator tRNA
aminoacylated with isoleucine was found to be inactive in initiation in
mammalian cell extracts. This finding raised the question of whether methionine
is the only amino acid capable of initiation of protein synthesis in eukaryotes.
In this work, we studied the activities, in initiation, of four different
anticodon sequence mutants of human initiator tRNA in mammalian COS1 cells,
using reporter genes carrying mutations in the initiation codon that are
complementary to the tRNA anticodons. The mutant tRNAs used are aminoacylated
with glutamine, methionine, and valine. Our results show that in the presence of
the corresponding mutant initiator tRNAs, AGG and GUC can initiate protein
synthesis in COS1 cells with methionine and valine, respectively. CAG initiates
protein synthesis with glutamine but extremely poorly, whereas UAG could not be
used to initiate protein synthesis with glutamine. We discuss the potential
applications of the mutant initiator tRNA-dependent initiation of protein
synthesis with codons other than AUG for studying the many interesting aspects
of protein synthesis initiation in mammalian cells.
DOI: 10.1128/MCB.18.9.5140
PMCID: PMC109099
PMID: 9710598 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8199241 | 1. Biochimie. 1993;75(12):1061-75. doi: 10.1016/0300-9084(93)90005-d.
Methionine as translation start signal: a review of the enzymes of the pathway
in Escherichia coli.
Meinnel T(1), Mechulam Y, Blanquet S.
Author information:
(1)Laboratoire de Biochimie, URA-CNRS no 240, Palaiseau, France.
Methionine is the universal translation start but the first methionine is
removed from most mature proteins. This review focuses on our present knowledge
of the five enzymes sustaining the methionine pathway in translation initiation
in Escherichia coli: methionyl-tRNA synthetase, methionyl-tRNA(fMet)
formyltransferase, peptidyl-tRNA hydrolase, peptide deformylase and methionine
aminopeptidase. The possible significance of retaining methionine as initiation
signal is discussed.
DOI: 10.1016/0300-9084(93)90005-d
PMID: 8199241 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36173861 | 1. Science. 2022 Sep 30;377(6614):1533-1537. doi: 10.1126/science.abq5082. Epub
2022 Sep 29.
Actin maturation requires the ACTMAP/C19orf54 protease.
Haahr P(1)(2), Galli RA(3), van den Hengel LG(1)(4), Bleijerveld OB(5),
Kazokaitė-Adomaitienė J(6), Song JY(7), Kroese LJ(8), Krimpenfort P(8),
Baltissen MP(9), Vermeulen M(9), Ottenheijm CAC(3), Brummelkamp TR(1)(4).
Author information:
(1)Division of Biochemistry, Netherlands Cancer Institute, 1066CX Amsterdam,
Netherlands.
(2)Novo Nordisk Foundation Center for Protein Research (NNF-CPR), Faculty of
Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
(3)Department of Physiology, Amsterdam UMC (VUmc), 1081HV Amsterdam,
Netherlands.
(4)Oncode Institute, Division of Biochemistry, Netherlands Cancer Institute,
1066CX Amsterdam, Netherlands.
(5)Proteomics Facility, Netherlands Cancer Institute, 1066CX Amsterdam,
Netherlands.
(6)Protein Facility, Division of Biochemistry, Netherlands Cancer Institute,
1066CX Amsterdam, Netherlands.
(7)Animal Pathology, Netherlands Cancer Institute, 1066CX Amsterdam,
Netherlands.
(8)Animal Modeling Facility, Netherlands Cancer Institute, 1066CX Amsterdam,
Netherlands.
(9)Department of Molecular Biology, Faculty of Science, Radboud Institute for
Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525GA
Nijmegen, Netherlands.
Protein synthesis generally starts with a methionine that is removed during
translation. However, cytoplasmic actin defies this rule because its synthesis
involves noncanonical excision of the acetylated methionine by an unidentified
enzyme after translation. Here, we identified C19orf54, named ACTMAP (actin
maturation protease), as this enzyme. Its ablation resulted in viable mice in
which the cytoskeleton was composed of immature actin molecules across all
tissues. However, in skeletal muscle, the lengths of sarcomeric actin filaments
were shorter, muscle function was decreased, and centralized nuclei, a common
hallmark of myopathies, progressively accumulated. Thus, ACTMAP encodes the
missing factor required for the synthesis of mature actin and regulates specific
actin-dependent traits in vivo.
DOI: 10.1126/science.abq5082
PMID: 36173861 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11738381 | 1. Trends Plant Sci. 2001 Dec;6(12):566-72. doi: 10.1016/s1360-1385(01)02151-3.
Organellar peptide deformylases: universality of the N-terminal methionine
cleavage mechanism.
Giglione C(1), Meinnel T.
Author information:
(1)Institut des Sciences du Végétal, UPR2355, Centre National de la Recherche
Scientifique, Bâtiment 23, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette
Cedex, France. [email protected]
Most mature proteins do not retain their initial N-terminal amino acid
(methionine in the cytosol and N-formyl methionine in the organelles). Recent
studies have shown that dedicated machinery is involved in this process in
plants. In addition to cytosolic and organelle-targeted methionine
aminopeptidases, organellar peptide deformylases have been identified. Here, we
attempt to answer questions about the mechanism, specificity and significance of
N-terminal methionine cleavage in plant organelles. It seems to be universal
because orthologues of plant deformylases are found in most living organisms.
DOI: 10.1016/s1360-1385(01)02151-3
PMID: 11738381 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25803486 | 1. Elife. 2015 Mar 24;4:e06857. doi: 10.7554/eLife.06857.
Transcription factor MITF and remodeller BRG1 define chromatin organisation at
regulatory elements in melanoma cells.
Laurette P(1), Strub T(1), Koludrovic D(1), Keime C(1), Le Gras S(1), Seberg
H(2), Van Otterloo E(2), Imrichova H(3), Siddaway R(4), Aerts S(3), Cornell
RA(2), Mengus G(1), Davidson I(1).
Author information:
(1)Department of Functional Genomics and Cancer, Institut de Génétique et de
Biologie Moléculaire et Cellulaire, Strasbourg, France.
(2)University of Iowa College of Medicine, Iowa City, United States.
(3)Laboratory of Computational Biology, Center for Human Genetics, University of
Leuven, Leuven, Belgium.
(4)Arthur and Sonia Labatt Brain Tumor Research Centre, Peter Gilgan Centre for
Research and Learning, Hospital for Sick Children, Toronto, Canada.
Microphthalmia-associated transcription factor (MITF) is the master regulator of
the melanocyte lineage. To understand how MITF regulates transcription, we used
tandem affinity purification and mass spectrometry to define a comprehensive
MITF interactome identifying novel cofactors involved in transcription, DNA
replication and repair, and chromatin organisation. We show that MITF interacts
with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is
essential for melanoma cell proliferation in vitro and for normal melanocyte
development in vivo. MITF and SOX10 actively recruit BRG1 to a set of
MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of
MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus
defining both a signature of transcription factors essential for the melanocyte
lineage and a specific chromatin organisation of the regulatory elements they
occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1
interplay thus plays an essential role in transcription regulation in melanoma.
DOI: 10.7554/eLife.06857
PMCID: PMC4407272
PMID: 25803486 [Indexed for MEDLINE]
Conflict of interest statement: ID: Reviewing editor, eLife. The other authors
declare that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21496633 | 1. Handb Clin Neurol. 2011;101:167-80. doi: 10.1016/B978-0-08-045031-5.00013-X.
Facioscapulohumeral dystrophy and scapuloperoneal syndromes.
Orrell RW(1).
Author information:
(1)University Department of Clinical Neurosciences, UCL Institute of Neurology,
London, UK.
Facioscapulohumeral dystrophy (FSHD) is the third most common muscular
dystrophy. It is named for its characteristic involvement of the muscles of the
face and upper arm. It is present worldwide, with a prevalence of around 4 per
100000 and an incidence of about 1 in 20000. Overall lifespan is not affected
significantly. The scapuloperoneal syndrome is a rarer presentation that may
cause some confusion. FSHD is an autosomal dominant condition. The molecular
genetics of FSHD are complex, with current understanding focusing on epigenetic
effects related to contraction-dependent (FSHD1) and contraction-independent
(FSHD2) effects of a hypomethylated repeat sequence (D4Z4), in the presence of a
specific 4qA161 phenotype. Molecular genetic diagnosis is available based on
these findings, but with some complexities which may lead to false-negative
results on routine laboratory investigation. No medication has been demonstrated
to alter the clinical course of the disease significantly. A range of supportive
measures may be applied. This chapter reviews the epidemiology, pathogenesis,
genetics, clinical features, investigation, prognosis, and management of
patients with FSHD and the scapuloperoneal syndrome.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-08-045031-5.00013-X
PMID: 21496633 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15277526 | 1. J Biol Chem. 2004 Oct 1;279(40):41911-7. doi: 10.1074/jbc.M404964200. Epub
2004 Jul 23.
Microphthalmia transcription factor induces both retinal pigmented epithelium
and neural crest melanocytes from neuroretina cells.
Planque N(1), Raposo G, Leconte L, Anezo O, Martin P, Saule S.
Author information:
(1)UMR 146, Institut Curie Section de Recherche, Bātiment 110, Centre
Universitaire, 91405 Orsay Cedex, France.
Mitf encodes a basic helix-loop-helix transcription factor that plays an
essential role in the differentiation of the retinal pigmented epithelium (RPE)
and neural crest-derived melanocytes. As cells containing melanogenic enzymes
(TRP2) are found in Mitf mouse mutants, it is not clear whether Mitf is a
downstream factor or a master regulator of melanocyte differentiation. To
further study the role of Mitf in committing cells to the melanocyte lineage, we
express Mitf in the cultured quail neuroretina cells. This leads to the
induction of two types of pigmented cells: neural crest-derived melanocytes,
according to their dendritic morphology, physiology, and gene expression pattern
are observed together with pigmented epithelial RPE-like cells. The expression
of Mitf is lower in pigmented epithelial RPE-like cells than in neural
crest-derived melanocytes. Accordingly, overexpression of Mitf in cultured quail
RPE causes cells to develop into neural crest-like pigmented cells. Thus, Mitf
is sufficient for the proper differentiation of crest-like pigmented cells from
retinal cells and its expression level may determine the type of pigment cell
induced.
DOI: 10.1074/jbc.M404964200
PMID: 15277526 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28649789 | 1. Pigment Cell Melanoma Res. 2017 Sep;30(5):454-466. doi: 10.1111/pcmr.12611.
Beyond MITF: Multiple transcription factors directly regulate the cellular
phenotype in melanocytes and melanoma.
Seberg HE(1), Van Otterloo E(2), Cornell RA(1)(3).
Author information:
(1)Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa
City, IA, USA.
(2)SDM-Craniofacial Biology, University of Colorado - Anschutz Medical Campus,
Aurora, CO, USA.
(3)Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA,
USA.
MITF governs multiple steps in the development of melanocytes, including
specification from neural crest, growth, survival, and terminal differentiation.
In addition, the level of MITF activity determines the phenotype adopted by
melanoma cells, whether invasive, proliferative, or differentiated. However,
MITF does not act alone. Here, we review literature on the transcription factors
that co-regulate MITF-dependent genes. ChIP-seq studies have indicated that the
transcription factors SOX10, YY1, and TFAP2A co-occupy subsets of regulatory
elements bound by MITF in melanocytes. Analyses at single loci also support
roles for LEF1, RB1, IRF4, and PAX3 acting in combination with MITF, while
sequence motif analyses suggest that additional transcription factors colocalize
with MITF at many melanocyte-specific regulatory elements. However, the precise
biochemical functions of each of these MITF collaborators and their
contributions to gene expression remain to be elucidated. Analogous to the
transcriptional networks in morphogen-patterned tissues during embryogenesis, we
anticipate that the level of MITF activity is controlled not only by the
concentration of activated MITF, but also by additional transcription factors
that either quantitatively or qualitatively influence the expression of
MITF-target genes.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/pcmr.12611
PMCID: PMC5939569
PMID: 28649789 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21258399 | 1. Oncogene. 2011 May 19;30(20):2319-32. doi: 10.1038/onc.2010.612. Epub 2011 Jan
24.
Essential role of microphthalmia transcription factor for DNA replication,
mitosis and genomic stability in melanoma.
Strub T(1), Giuliano S, Ye T, Bonet C, Keime C, Kobi D, Le Gras S, Cormont M,
Ballotti R, Bertolotto C, Davidson I.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM,
Université de Strasbourg, Illkirch, France.
Comment in
Oncogene. 2011 May 19;30(20):2304-6. doi: 10.1038/onc.2010.641.
Malignant melanoma is an aggressive cancer known for its notorious resistance to
most current therapies. The basic helix-loop-helix microphthalmia transcription
factor (MITF) is the master regulator determining the identity and properties of
the melanocyte lineage, and is regarded as a lineage-specific 'oncogene' that
has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell
proliferation, whereas sustained supression of MITF expression leads to
senescence. By combining chromatin immunoprecipitation coupled to high
throughput sequencing (ChIP-seq) and RNA sequencing analyses, we show that MITF
directly regulates a set of genes required for DNA replication, repair and
mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and
through defective replication and repair induces DNA damage, ultimately ending
in cellular senescence. These findings reveal a lineage-specific control of DNA
replication and mitosis by MITF, providing new avenues for therapeutic
intervention in melanoma. The identification of MITF-binding sites and
gene-regulatory networks establish a framework for understanding oncogenic basic
helix-loop-helix factors such as N-myc or TFE3 in other cancers.
DOI: 10.1038/onc.2010.612
PMID: 21258399 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12819038 | 1. Am J Pathol. 2003 Jul;163(1):333-43. doi: 10.1016/S0002-9440(10)63657-7.
MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in
melanocytes and melanoma.
Du J(1), Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE.
Author information:
(1)Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and
Children's Hospital, Harvard Medical School, Boston, USA.
The clinically important melanoma diagnostic antibodies HMB-45, melan-A, and
MITF (D5) recognize gene products of the melanocyte-lineage genes
SILV/PMEL17/GP100, MLANA/MART1, and MITF, respectively. MITF encodes a
transcription factor that is essential for normal melanocyte development and
appears to regulate expression of several pigmentation genes. In this report,
the possibility was examined that MITF might additionally regulate expression of
the SILV and MLANA genes. Both genes contain conserved MITF consensus DNA
sequences that were bound by MITF in vitro and in vivo, based on electrophoretic
mobility shift assay and chromatin-immunoprecipitation. In addition, MITF
regulated their promoter/enhancer regions in reporter assays, and up- or
down-regulation of MITF produced corresponding modulation of endogenous SILV and
MLANA in melanoma cells. Expression patterns were compared with these factors in
a series of melanoma cell lines whose mutational status of the proto-oncogene
BRAF was also known. SILV and MLANA expression correlated with MITF, while no
clear correlation was seen relative to BRAF mutation. Finally, mRNA expression
array analysis of primary human melanomas demonstrated a tight correlation in
their expression levels in clinical tumor specimens. Collectively, this study
links three important melanoma antigens into a common transcriptional pathway
regulated by MITF.
DOI: 10.1016/S0002-9440(10)63657-7
PMCID: PMC1868174
PMID: 12819038 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23935512 | 1. PLoS Genet. 2013;9(7):e1003644. doi: 10.1371/journal.pgen.1003644. Epub 2013
Jul 25.
A dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and
the differentiation of melanocyte stem cell progenitors.
Harris ML(1), Buac K, Shakhova O, Hakami RM, Wegner M, Sommer L, Pavan WJ.
Author information:
(1)Genetic Disease Research Branch, National Human Genome Institute, National
Institutes of Health, Bethesda, Maryland, United States of America.
During embryogenesis, the transcription factor, Sox10, drives the survival and
differentiation of the melanocyte lineage. However, the role that Sox10 plays in
postnatal melanocytes is not established. We show in vivo that melanocyte stem
cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs
remain undifferentiated. Sox10 knockout (Sox10(fl); Tg(Tyr::CreER)) results in
loss of both McSCs and differentiated melanocytes, while overexpression of Sox10
(Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to
hair graying. This suggests that levels of SOX10 are key to normal McSC function
and Sox10 must be downregulated for McSC establishment and maintenance. We
examined whether the mechanism of Tg(DctSox10) hair graying is through increased
expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf
(Mitf(vga9) ) can rescue hair graying in Tg(DctSox10) animals. Surprisingly,
Mitf(vga9) does not mitigate but exacerbates Tg(DctSox10) hair graying
suggesting that MITF participates in the negative regulation of Sox10 in McSCs.
These observations demonstrate that while SOX10 is necessary to maintain the
postnatal melanocyte lineage it is simultaneously prevented from driving
differentiation in the McSCs. This data illustrates how tissue-specific stem
cells can arise from lineage-specified precursors through the regulation of the
very transcription factors important in defining that lineage.
DOI: 10.1371/journal.pgen.1003644
PMCID: PMC3723529
PMID: 23935512 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/26206884 | 1. Hum Mol Genet. 2015 Oct 1;24(19):5433-50. doi: 10.1093/hmg/ddv267. Epub 2015
Jul 23.
Genomic analysis reveals distinct mechanisms and functional classes of
SOX10-regulated genes in melanocytes.
Fufa TD(1), Harris ML(1), Watkins-Chow DE(1), Levy D(1), Gorkin DU(2), Gildea
DE(3), Song L(4), Safi A(4), Crawford GE(4), Sviderskaya EV(5), Bennett DC(5),
Mccallion AS(2), Loftus SK(1), Pavan WJ(6).
Author information:
(1)Genetic Disease Research Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892, USA.
(2)McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD 21205, USA.
(3)Computational and Statistical Genomics Branch, National Human Genome Research
Institute, National Institutes of Health, Bethesda, MD 20892, USA.
(4)Center for Genomic and Computational Biology, Duke University, Durham, NC
27708, USA, Department of Pediatrics, Division of Molecular Genetics, Duke
University, Durham, NC 27708, USA and.
(5)Molecular Cell Sciences Research Centre, St George's, University of London,
London SW17 0RE, UK.
(6)Genetic Disease Research Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892, USA, [email protected].
SOX10 is required for melanocyte development and maintenance, and has been
linked to melanoma initiation and progression. However, the molecular mechanisms
by which SOX10 guides the appropriate gene expression programs necessary to
promote the melanocyte lineage are not fully understood. Here we employ genetic
and epigenomic analysis approaches to uncover novel genomic targets and
previously unappreciated molecular roles of SOX10 in melanocytes. Through global
analysis of SOX10-binding sites and epigenetic characteristics of chromatin
states, we uncover an extensive catalog of SOX10 targets genome-wide. Our
findings reveal that SOX10 predominantly engages 'open' chromatin regions and
binds to distal regulatory elements, including novel and previously known
melanocyte enhancers. Integrated chromatin occupancy and transcriptome analysis
suggest a role for SOX10 in both transcriptional activation and repression to
regulate functionally distinct classes of genes. We demonstrate that distinct
epigenetic signatures and cis-regulatory sequence motifs predicted to bind
putative co-regulatory transcription factors define SOX10-activated and
SOX10-repressed target genes. Collectively, these findings uncover a central
role of SOX10 as a global regulator of gene expression in the melanocyte lineage
by targeting diverse regulatory pathways.
Published by Oxford University Press 2015. This work is written by (a) US
Government employee(s) and is in the public domain in the US.
DOI: 10.1093/hmg/ddv267
PMCID: PMC4572067
PMID: 26206884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12789278 | 1. Oncogene. 2003 May 19;22(20):3035-41. doi: 10.1038/sj.onc.1206443.
Microphthalamia-associated transcription factor: a critical regulator of pigment
cell development and survival.
Widlund HR(1), Fisher DE.
Author information:
(1)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA 02115, USA.
The microphthalamia-associated transcription factor (MITF) is an integral
transcriptional regulator in melanocyte, the lineage from which melanoma cells
originate. This basic-helix-loop-helix-leucine-zipper (bHLHzip) protein is
critical for melanocyte cell-fate choice during commitment from pluripotent
precursor cells in the neural crest. Its role in differentiation pathways has
been highlighted by its potent transcriptional and lineage-specific regulation
of the three major pigment enzymes: tyrosinase, Tyrp1, and Dct as well as other
pigmentation factors. However, the cellular functions of MITF seem to be wider
than differentiation and cell-fate pathways alone, since melanocytes and
melanoma cells appear to require an expression of this factor. Here, we discuss
the transcriptional networks in which MITF is thought to reside and describe
signaling pathways in the cell which impinge on MITF. Accumulating evidence
supports the notion that MITF is involved in survival pathways during normal
development as well as during neoplastic growth of melanoma.
DOI: 10.1038/sj.onc.1206443
PMID: 12789278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17237008 | 1. Bull Cancer. 2007 Jan;94(1):81-92.
[Malignant melanoma and the role of the paradoxal protein Microphthalmia
transcription factor].
[Article in French]
Denat L(1), Larue L.
Author information:
(1)Developmental Genetics of Melanocytes, UMR146 CNRS, Institut Curie, Bât. 110,
91405, Orsay Cedex. [email protected]
Mitf protein is a transcription factor involved all along the life of pigmented
cells. This protein is located in the center of multiple signaling pathways
which control differentiation, morphology, proliferation and survival of the
various cells of the melanocyte lineage: melanoblasts, melanocytes and melanoma.
Mitf plays a major role in melanoblasts differentiation, by inducing the key
enzyme of melanogenesis, tyrosinase, and its secondary enzymes, Tyrp1 and Dct.
Mitf regulates morphology and migration of melanocytes, particularly by
regulating cytoskeleton organization and cell-cell adhesion. Mitf plays a double
role of inducer/repressor of cellular proliferation. This protein inhibits cell
cycle progression and prevents non-proper cell division. In few cases, Mitf can
also induce cell cycle. A minimal quantity/activity of Mitf is necessary for
melanoblast survival. Essential protein of the melanocyte lineage, Mitf was
proposed as diagnostic/pronostic marker for cutaneous melanoma. However, could
we then consider MITF as the unique marker of such a cancer?
PMID: 17237008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17000761 | 1. Mol Cell Biol. 2006 Dec;26(23):8914-27. doi: 10.1128/MCB.02299-05. Epub 2006
Sep 25.
The microphthalmia-associated transcription factor Mitf interacts with
beta-catenin to determine target gene expression.
Schepsky A(1), Bruser K, Gunnarsson GJ, Goodall J, Hallsson JH, Goding CR,
Steingrimsson E, Hecht A.
Author information:
(1)Biochemistry and Molecular Biology, Faculty of Medicine, University of
Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland.
Commitment to the melanocyte lineage is characterized by the onset of expression
of the microphthalmia-associated transcription factor (Mitf). This transcription
factor plays a fundamental role in melanocyte development and maintenance and
seems to be crucial for the survival of malignant melanocytes. Furthermore, Mitf
has been shown to be involved in cell cycle regulation and to play important
functions in self-renewal and maintenance of melanocyte stem cells. Although
little is known about how Mitf regulates these various processes, one
possibility is that Mitf interacts with other regulators. Here we show that Mitf
can interact directly with beta-catenin, the key mediator of the canonical Wnt
signaling pathway. The Wnt signaling pathway plays a critical role in melanocyte
development and is intimately involved in triggering melanocyte stem cell
proliferation. Significantly, constitutive activation of this pathway is a
feature of a number of cancers including malignant melanoma. Here we show that
Mitf can redirect beta-catenin transcriptional activity away from canonical Wnt
signaling-regulated genes toward Mitf-specific target promoters to activate
transcription. Thus, by a feedback mechanism, Mitf can diversify the output of
canonical Wnt signaling to enhance the repertoire of genes regulated by
beta-catenin. Our results reveal a novel mechanism by which Wnt signaling and
beta-catenin activate gene expression, with significant implications for our
understanding of both melanocyte development and melanoma.
DOI: 10.1128/MCB.02299-05
PMCID: PMC1636837
PMID: 17000761 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24769727 | 1. Cell Death Differ. 2014 Aug;21(8):1250-61. doi: 10.1038/cdd.2014.44. Epub 2014
Apr 25.
Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls
melanogenesis and melanoma progression.
Denecker G(1), Vandamme N(1), Akay O(1), Koludrovic D(2), Taminau J(1), Lemeire
K(3), Gheldof A(1), De Craene B(1), Van Gele M(4), Brochez L(4), Udupi GM(5),
Rafferty M(6), Balint B(6), Gallagher WM(5), Ghanem G(7), Huylebroeck D(8),
Haigh J(9), van den Oord J(10), Larue L(11), Davidson I(2), Marine JC(12), Berx
G(1).
Author information:
(1)1] Unit of Molecular and Cellular Oncology, Inflammation Research Center,
VIB, 9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent
University, 9052 Ghent, Belgium.
(2)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM,
Université de Strasbourg, Illkirch, France.
(3)Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent,
Belgium.
(4)Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium.
(5)1] UCD School of Biomolecular and Biomedical Science, UCD Conway Institute,
University College, Dublin 4, Ireland [2] OncoMark Limited, Nova UCD, Belfield
Innovation Park, University College Dublin, Belfield, Dublin 4, Ireland.
(6)OncoMark Limited, Nova UCD, Belfield Innovation Park, University College
Dublin, Belfield, Dublin 4, Ireland.
(7)Institute Jules Bordet, Brussels, Belgium.
(8)1] Laboratory of Molecular Biology (Celgen), Department of Development and
Regeneration, KU Leuven, 3000 Leuven, Belgium [2] Department of Cell Biology,
Erasmus MC, 3015 GE Rotterdam, The Netherlands.
(9)1] Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent,
Belgium [2] Vascular Cell Biology Unit, Department for Molecular Biomedical
Research, VIB, Ghent, Belgium.
(10)Department of Pathology, University Hospital Leuven, KU Leuven, Leuven,
Belgium.
(11)Curie Institute, Developmental Genetics of Melanocytes, Centre National de
la Recherche Scientifique (CNRS) UMR3347, Institut National de la Santé et de la
Recherche Médicale (INSERM) U1021, Orsay, France.
(12)1] Center for the Biology of Disease, Laboratory for Molecular Cancer
Biology, VIB, Leuven, Belgium [2] Center for Human Genetics, KU Leuven, Leuven,
Belgium.
Deregulation of signaling pathways that control differentiation, expansion and
migration of neural crest-derived melanoblasts during normal development
contributes also to melanoma progression and metastasis. Although several
epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box
binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell
biology, little is known about their role in melanocyte homeostasis and
melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit
a melanoblast migration defect and, unexpectedly, a severe melanocyte
differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a
downregulation of the Microphthalmia-associated transcription factor (Mitf) and
melanocyte differentiation markers concomitant with an upregulation of Zeb1. We
identify a transcriptional signaling network in which the EMT transcription
factor ZEB2 regulates MITF levels to control melanocyte differentiation.
Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2
expression is associated with reduced patient survival.
DOI: 10.1038/cdd.2014.44
PMCID: PMC4085532
PMID: 24769727 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28263292 | 1. Lab Invest. 2017 Jun;97(6):649-656. doi: 10.1038/labinvest.2017.9. Epub 2017
Mar 6.
The master role of microphthalmia-associated transcription factor in melanocyte
and melanoma biology.
Kawakami A(1), Fisher DE(1).
Author information:
(1)Cutaneous Biology Research Center, Department of Dermatology, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA.
Certain transcription factors have vital roles in lineage development, including
specification of cell types and control of differentiation.
Microphthalmia-associated transcription factor (MITF) is a key transcription
factor for melanocyte development and differentiation. MITF regulates expression
of numerous pigmentation genes to promote melanocyte differentiation, as well as
fundamental genes for maintaining cell homeostasis, including genes encoding
proteins involved in apoptosis (eg, BCL2) and the cell cycle (eg, CDK2).
Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose
phenotypes include depigmentation due to melanocyte loss, whereas amplification
or specific mutation of MITF can be an oncogenic event that is seen in a subset
of familial or sporadic melanomas. In this article, we review basic features of
MITF biological function and highlight key unresolved questions regarding this
remarkable transcription factor.
DOI: 10.1038/labinvest.2017.9
PMID: 28263292 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28249010 | 1. PLoS Genet. 2017 Mar 1;13(3):e1006636. doi: 10.1371/journal.pgen.1006636.
eCollection 2017 Mar.
TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF.
Seberg HE(1), Van Otterloo E(2), Loftus SK(3), Liu H(4), Bonde G(4), Sompallae
R(5), Gildea DE(6), Santana JF(7), Manak JR(1)(7), Pavan WJ(3), Williams T(2),
Cornell RA(1)(4).
Author information:
(1)Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa
City, Iowa, United States of America.
(2)SDM-Craniofacial Biology, University of Colorado - Anschutz Medical Campus,
Aurora, Colorado, United States of America.
(3)Genetic Disease Research Branch, National Human Genome Research Institute,
NIH, Bethesda, Maryland, United States of America.
(4)Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa,
United States of America.
(5)Bioinformatics Division, Iowa Institute of Human Genetics, University of
Iowa, Iowa City, Iowa, United States of America.
(6)Bioinformatics and Scientific Programming Core, Computational and Statistical
Genomics Branch, National Human Genome Research Institute, NIH, Bethesda,
Maryland, United States of America.
(7)Department of Biology, University of Iowa, Iowa City, Iowa, United States of
America.
Comment in
Pigment Cell Melanoma Res. 2017 Sep;30(5):449-451. doi: 10.1111/pcmr.12604.
Mutations in the gene encoding transcription factor TFAP2A result in
pigmentation anomalies in model organisms and premature hair graying in humans.
However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs
have made the precise contribution of TFAP2-type activity to melanocyte
differentiation unclear. Defining this contribution may help to explain why
TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi.
To identify genes with TFAP2A-dependent expression in melanocytes, we profile
zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that
expression of a small subset of genes underlying pigmentation phenotypes is
TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A
ChIP-seq in mouse and human melanocytes and find that a much larger subset of
pigmentation genes is associated with active regulatory elements bound by
TFAP2A. These elements are also frequently bound by MITF, which is considered
the "master regulator" of melanocyte development. For example, the promoter of
TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a
minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites.
However, the expression of Trpm1 is not TFAP2A-dependent, implying that
additional TFAP2 paralogs function redundantly to drive melanocyte
differentiation, which is consistent with previous results from zebrafish.
Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show
that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the
neural crest almost completely lack melanocytes but retain neural crest-derived
sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also
necessary for induction of the melanocyte lineage. Finally, we observe a genetic
interaction between tfap2a and mitfa in zebrafish, but find that artificially
elevating expression of tfap2a does not increase levels of melanin in mitfa
hypomorphic or loss-of-function mutants. Collectively, these results show that
TFAP2 paralogs, operating alongside lineage-specific transcription factors such
as MITF, directly regulate effectors of terminal differentiation in melanocytes.
In addition, they suggest that TFAP2A activity, like MITF activity, has the
potential to modulate the phenotype of melanoma cells.
DOI: 10.1371/journal.pgen.1006636
PMCID: PMC5352137
PMID: 28249010 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/11830592 | 1. J Biol Chem. 2002 Apr 26;277(17):15132-41. doi: 10.1074/jbc.M200004200. Epub
2002 Feb 5.
Pax3 down-regulation and shut-off of melanogenesis in melanoma B16/F10.9 by
interleukin-6 receptor signaling.
Kamaraju AK(1), Bertolotto C, Chebath J, Revel M.
Author information:
(1)Department of Molecular Genetics, Weizmann Institute of Science, 76100
Rehovot, Israel.
The microphthalmia-associated transcription factor (Mitf) is essential for
melanocytic lineage development and for expression of melanogenic enzymes, such
as tyrosinase. Interleukin-6 receptor/interleukin-6 chimera (IL6RIL6) induces in
B16/F10.9 melanoma cells a loss of melanogenesis preceded by a sharp decrease in
Mitf mRNA and gene promoter activity. In the Mitf promoter, the main cis-acting
element mediating the IL6RIL6 effect is shown to be the binding site of Pax3, a
paired homeodomain factor regulating among other things the development of
melanocytes. Pax3 protein and mRNA levels decline steadily after IL6RIL6
treatment, and overexpression of an ectopic Pax3 cDNA suppresses the Mitf
promoter inhibition. Loss of the synergism between Pax3 and Sox10, a high
mobility group domain costimulatory factor, seems to be critical in the rapid
decrease in Mitf gene expression. The Pax3 down-regulation in IL6RIL6-induced
F10.9 cell is linked to growth arrest and transdifferentiation to a glial cell
phenotype. IL6RIL6 stimulates the interleukin-6 family cytokine receptor gp130,
leading to the rapid phosphorylation of Stat3 on tyrosine 705. This
phosphorylation is required for Pax3 down-regulation and Mitf promoter silencing
since these are inhibited in F10.9 cells overexpressing the Stat3 DN-mutant
Y705F.
DOI: 10.1074/jbc.M200004200
PMID: 11830592 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10770922 | 1. J Biol Chem. 2000 Jul 21;275(29):21920-7. doi: 10.1074/jbc.M000035200.
The gene encoding the T-box factor Tbx2 is a target for the
microphthalmia-associated transcription factor in melanocytes.
Carreira S(1), Liu B, Goding CR.
Author information:
(1)Eukaryotic Transcription Laboratory, Marie Curie Research Institute, Oxted,
Surrey RH8 OTL, United Kingdom.
Commitment to the melanocyte lineage is characterized by the onset of
microphthalmia-associated transcription factor (Mitf) expression. Mitf plays a
fundamental role in melanocyte development, with mice lacking Mitf being
entirely devoid of pigment cells. In the absence of functional Mitf protein,
melanoblasts expressing Mitf mRNA disappear around 2 days after their first
appearance either by apoptosis or by losing their identity and adopting an
alternative cell fate. The role of Mitf must therefore be to regulate genes
required for melanoblast survival, proliferation, or the maintenance of
melanoblast identity. Yet to date, Mitf has been shown to regulate genes such as
Tyrosinase, Tyrp-1, and Dct, which are required for pigmentation, a
differentiation-specific process. Because expression of these genes cannot
account for the complete absence of pigment cells in Mitf-negative mice, Mitf
must regulate the expression of other as yet uncharacterized genes. Here we
provide several lines of evidence to suggest that Mitf may regulate the
expression of the Tbx2 transcription factor, a member of the T-box family of
proteins implicated in the maintenance of cell identity. First, isolation and
sequencing of the entire murine Tbx2 gene revealed that the Tbx2 promoter
contains a full consensus Mitf recognition element; second, Mitf could bind the
promoter in vitro and activate Tbx2 expression in vivo in an E box-dependent
fashion; and third, Tbx2 is expressed in melanoma cell lines expressing Mitf,
but not in a line in which Mitf expression was not detectable. Taken together,
with the fact that Tbx2 is expressed in Mitf-positive melanoblasts and
melanocytes, but not in Mitf-negative melanoblast precursor cells, the evidence
suggests that the Tbx2 gene may represent one of the first known targets for
Mitf that is not a gene involved directly in the manufacture of pigment.
DOI: 10.1074/jbc.M000035200
PMID: 10770922 [Indexed for MEDLINE] |