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http://www.ncbi.nlm.nih.gov/pubmed/23527808 | 1. Chin Med Sci J. 2013 Mar;28(1):50-4. doi: 10.1016/s1001-9294(13)60019-x.
Generation of transgene-free induced pluripotent stem cells with non-viral
methods.
Wang T(1), Zhao HS, Zhang QL, Xu CL, Liu CB.
Author information:
(1)Institute of Molecular Biology, Third Clinical Medical School, China.
Induced pluripotent stem (iPS) cells were originally generated from mouse
fibroblasts by enforced expression of Yamanaka factors (Oct3/4, Sox2, Klf4, and
c-Myc). The technique was quickly reproduced with human fibroblasts or
mesenchymal stem cells. Although having been showed therapeutic potential in
animal models of sickle cell anemia and Parkinson's disease, iPS cells generated
by viral methods do not suit all the clinical applications. Various non-viral
methods have appeared in recent years for application of iPS cells in cell
transplantation therapy. These methods mainly include DNA vector-based
approaches, transfection of mRNA, and transduction of reprogramming proteins.
This review summarized these non-viral methods and compare the advantages,
disadvantages, efficiency, and safety of these methods.
DOI: 10.1016/s1001-9294(13)60019-x
PMID: 23527808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23166588 | 1. PLoS One. 2012;7(11):e48533. doi: 10.1371/journal.pone.0048533. Epub 2012 Nov
15.
HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell
transcriptional networks.
Shah SN(1), Kerr C, Cope L, Zambidis E, Liu C, Hillion J, Belton A, Huso DL,
Resar LM.
Author information:
(1)Hematology Division, the Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA.
BACKGROUND: Although recent studies have identified genes expressed in human
embryonic stem cells (hESCs) that induce pluripotency, the molecular
underpinnings of normal stem cell function remain poorly understood. The high
mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly
differentiated, stem-like cancers; however, its role in these settings has been
unclear.
METHODS/PRINCIPAL FINDINGS: We show that HMGA1 is highly expressed in fully
reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in
fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and
parallels that of other pluripotency factors. Conversely, forced expression of
HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances
cellular reprogramming of somatic cells to iPSCs together with the Yamanaka
factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of
iPSC colonies compared to OSKM controls. Surprisingly, there was normal
differentiation in vitro and benign teratoma formation in vivo of the
HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the
expression of pluripotency genes, including SOX2, LIN28, and cMYC, while
knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin
immunoprecipitation shows that HMGA1 binds to the promoters of these
pluripotency genes in vivo. In addition, interfering with HMGA1 function using a
short hairpin RNA or a dominant-negative construct blocks cellular reprogramming
to a pluripotent state.
CONCLUSIONS: Our findings demonstrate for the first time that HMGA1 enhances
cellular reprogramming from a somatic cell to a fully pluripotent stem cell.
These findings identify a novel role for HMGA1 as a key regulator of the stem
cell state by inducing transcriptional networks that drive pluripotency.
Although further studies are needed, these HMGA1 pathways could be exploited in
regenerative medicine or as novel therapeutic targets for poorly differentiated,
stem-like cancers.
DOI: 10.1371/journal.pone.0048533
PMCID: PMC3499526
PMID: 23166588 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/19030024 | 1. Cell Res. 2008 Dec;18(12):1177-89. doi: 10.1038/cr.2008.309.
Yamanaka factors critically regulate the developmental signaling network in
mouse embryonic stem cells.
Liu X(1), Huang J, Chen T, Wang Y, Xin S, Li J, Pei G, Kang J.
Author information:
(1)Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell
Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of
Sciences, Shanghai 200031, China.
Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic
stem (ES) cells, and their over-expression can induce pluripotency in both mouse
and human somatic cells, indicating that these factors regulate the
developmental signaling network necessary for ES cell pluripotency. However,
systemic analysis of the signaling pathways regulated by Yamanaka factors has
not yet been fully described. In this study, we identified the target promoters
of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin
immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these
four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were
analyzed as core factors, Klf4 functioned to enhance the core factors for
development regulation, whereas c-Myc seemed to play a distinct role in
regulating metabolism. The pathway analysis revealed that Yamanaka factors
collectively regulate a developmental signaling network composed of 16
developmental signaling pathways, nine of which represent earlier unknown
pathways in ES cells, including apoptosis and cell-cycle pathways. We further
analyzed data from a recent study examining Yamanaka factors in mouse ES cells.
Interestingly, this analysis also revealed 16 developmental signaling pathways,
of which 14 pathways overlap with the ones revealed by this study, despite that
the target genes and the signaling pathways regulated by each individual
Yamanaka factor differ significantly between these two datasets. We suggest that
Yamanaka factors critically regulate a developmental signaling network composed
of approximately a dozen crucial developmental signaling pathways to maintain
the pluripotency of ES cells and probably also to induce pluripotent stem cells.
DOI: 10.1038/cr.2008.309
PMID: 19030024 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25044876 | 1. J Am Assoc Nurse Pract. 2014 Sep;26(9):465-470. doi: 10.1002/2327-6924.12156.
Epub 2014 Jul 14.
Hypertrophic cardiomyopathy in adults: an overview.
Jacobs C(1).
Author information:
(1)(ARNP Graduate Student), Venice Regional Medical Center, Gulf Coast
Cardiovascular Consultants, University of Cincinnati, Sarasota, Florida.
PURPOSE: To present an overview of clinical issues related to adults with
hypertrophic cardiomyopathy (HCM), their presenting symptoms, diagnosis,
physical examination findings, treatment, and follow-up care.
DATA SOURCES: A comprehensive search of Medline (PubMed) and CINAHL was
conducted using the key terms HCM, treatment, diagnosis, sudden cardiac death
(SCD), and complications. This search yielded 21 articles used for this article.
There were three reference books used for background, diagnosis, and treatment
information as well.
CONCLUSIONS: Although HCM is the most prevalent genetic disorder affecting the
heart, it often goes undiagnosed until midlife after patients show symptoms of
myocardial remodeling. Adults with cardiomyopathy suffer SCD or adverse events
such as stroke and heart failure from HCM. Early diagnosis will prevent SCD,
improve quality of life, and slow patient's progression to heart failure.
IMPLICATIONS FOR PRACTICE: Early recognition of HCM in adults by their primary
care providers will improve patients' quality of life and reduce incidence of
SCD, heart failure, and stroke.
©2014 American Association of Nurse Practitioners.
DOI: 10.1002/2327-6924.12156
PMID: 25044876 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22991675 | 1. Case Rep Dent. 2012;2012:483867. doi: 10.1155/2012/483867. Epub 2012 Sep 6.
Rubinstein-taybi syndrome: a case report.
Münevveroglu AP(1), Akgöl BB.
Author information:
(1)Department of Pedodontics, Faculty of Dentistry, Istanbul Medipol University,
Fatih, 34093 Istanbul, Turkey.
Rubinstein-Taybi syndrome or Broad Thumb-Hallux syndrome is a genetic disorder
characterized by facial dysmorphism, growth retardation, and mental deficiency.
A seven-year-old girl had come to the Department of Pedodontics, Istanbul
Medipol University, Faculty of Dentistry, Turkey, with a complaint of caries and
bleeding of gingivae. The patient was mentally retarded. Extraoral features
revealed distinctive facial appearance with a broad fore head, hypertelorism,
broad nasal bridge, and beaked nose. Intraoral features observed were talons
cusps in the upper lateral incisors, carious teeth, and plaque accumulation.
Since the patient was mentally retarded, the dental treatment was done under GA.
The treatment plan and dental management of this patient are discussed in this
case report.
DOI: 10.1155/2012/483867
PMCID: PMC3443573
PMID: 22991675 |
http://www.ncbi.nlm.nih.gov/pubmed/23782526 | 1. Circ J. 2013;77(9):2358-65. doi: 10.1253/circj.cj-13-0294. Epub 2013 Jun 19.
Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic
cardiomyopathy.
Núñez L(1), Gimeno-Blanes JR, Rodríguez-García MI, Monserrat L, Zorio E, Coats
C, McGregor CG, Hernandez del Rincón JP, Castro-Beiras A, Hermida-Prieto M.
Author information:
(1)Instituto de Investigación Biomédica de la Universidad de A Coruña (INIBIC),
Complexo Hospitalario Universitario de A Coruña (CHUAC)-Universidad de A Coruña.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous
genetic heart disease characterized by left ventricular hypertrophy in the
absence of another disease that could explain the wall thickening. Elucidation
of the genetic basis of HCM lead to the identification of several genes encoding
sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric
genes are mutated in approximately 40% of HCM patients and a possible
explanation for the incomplete yield of mutation-positive HCM may be somatic
mutations.
METHODS AND RESULTS: We studied 104 unrelated patients with non-familial HCM.
Patients underwent clinical evaluation and mutation screening of 5 genes
implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated
from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as
several patients carried the same mutations, the total amount of different
mutations was 37; 20 of these mutations have been previously described, and
pathogenicity has been assessed. To determine the effect of the 17 new mutations
an in silico assay was performed and it predicted that 4 variants were damaging
mutations. All identified variants were also seen in the DNA isolated from the
corresponding blood, which demonstrated the absence of somatic mutations.
CONCLUSIONS: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not
represent an important etiologic pathway in HCM.
DOI: 10.1253/circj.cj-13-0294
PMID: 23782526 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22303793 | 1. Genet Couns. 2011;22(4):341-6.
A boy with classical Rubinstein-Taybi syndrome but no detectable mutation in the
CREBBP and EP300 genes.
Caglayan AO(1), Lechno S, Gumus H, Bartsch O, Fryns JP.
Author information:
(1)Kayseri Education and Research Hospital Department of Medical Genetics,
Kayseri, Turkey.
Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant genetic disorder
and is characterized by mental retardation, distinctive facial features, broad
and often angulated thumbs and great toes. We report on a 7 year old boy with
classical Rubinstein-Taybi syndrome. His facial and clinical features were very
typical, including broad thumbs with radial angulation and broad great toes.
Rigorous genetic analysis of the CREBBP and EP300 genes using DNA sequencing and
multiple ligation-dependent probe amplification (MLPA) revealed no causative
mutation in this boy, only a hitherto unreported but paternally inherited
heterozygous sequence alteration, c.506 1+9C>T in IVS 30-31, which most likely
represents a normal variant (NetGene 2 splice prediction software). We question
if this boy could have a hitherto undetectable mutation type.
PMID: 22303793 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23253012 | 1. J Proteome Res. 2013 Jan 4;12(1):6-22. doi: 10.1021/pr300864k. Epub 2012 Dec
20.
A fresh look at the male-specific region of the human Y chromosome.
Jangravi Z(1), Alikhani M, Arefnezhad B, Sharifi Tabar M, Taleahmad S,
Karamzadeh R, Jadaliha M, Mousavi SA, Ahmadi Rastegar D, Parsamatin P, Vakilian
H, Mirshahvaladi S, Sabbaghian M, Mohseni Meybodi A, Mirzaei M, Shahhoseini M,
Ebrahimi M, Piryaei A, Moosavi-Movahedi AA, Haynes PA, Goodchild AK,
Nasr-Esfahani MH, Jabbari E, Baharvand H, Sedighi Gilani MA, Gourabi H, Salekdeh
GH.
Author information:
(1)Department of Molecular Systems Biology, Cell Science Research Center, Royan
Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
The Chromosome-centric Human Proteome Project (C-HPP) aims to systematically map
the entire human proteome with the intent to enhance our understanding of human
biology at the cellular level. This project attempts simultaneously to establish
a sound basis for the development of diagnostic, prognostic, therapeutic, and
preventive medical applications. In Iran, current efforts focus on mapping the
proteome of the human Y chromosome. The male-specific region of the Y chromosome
(MSY) is unique in many aspects and comprises 95% of the chromosome's length.
The MSY continually retains its haploid state and is full of repeated sequences.
It is responsible for important biological roles such as sex determination and
male fertility. Here, we present the most recent update of MSY protein-encoding
genes and their association with various traits and diseases including sex
determination and reversal, spermatogenesis and male infertility, cancers such
as prostate cancers, sex-specific effects on the brain and behavior, and
graft-versus-host disease. We also present information available from RNA
sequencing, protein-protein interaction, post-translational modification of MSY
protein-coding genes and their implications in biological systems. An overview
of Human Y chromosome Proteome Project is presented and a systematic approach is
suggested to ensure that at least one of each predicted protein-coding gene's
major representative proteins will be characterized in the context of its major
anatomical sites of expression, its abundance, and its functional relevance in a
biological and/or medical context. There are many technical and biological
issues that will need to be overcome in order to accomplish the full scale
mapping.
DOI: 10.1021/pr300864k
PMID: 23253012 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21507890 | 1. J Renin Angiotensin Aldosterone Syst. 2011 Dec;12(4):521-30. doi:
10.1177/1470320311405247. Epub 2011 Apr 20.
Impact of polymorphisms in the renin-angiotensin-aldosterone system on
hypertrophic cardiomyopathy.
Orenes-Piñero E(1), Hernández-Romero D, Jover E, Valdés M, Lip GY, Marín F.
Author information:
(1)Department of Cardiology, Hospital Universitario Virgen de la Arrixaca,
Murcia, Spain. [email protected]
Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous autosomal
dominant heart disease characterised by left ventricular hypertrophy in the
absence of another cardiac or systemic disease that is capable of producing
significant wall thickening. Microscopically it is characterised by
cardiomyocyte hypertrophy, myofibrillar disarray and fibrosis. The phenotypic
expression of HCM is multifactorial, with the majority of cases occurring
secondary to mutations in genes encoding the sarcomere proteins. In conjunction
with the genetic heterogeneity of HCM, phenotypic expression also exhibits a
high level of variability even within families with the same aetiological
mutation, and may be influenced by additional genetic factors. Polymorphisms of
the renin-angiotensin-aldosterone system (RAAS) represent an attractive
hypothesis as potential disease modifiers, as these genetic variants alter the
'activation status' of the RAAS, which leads to more left ventricular
hypertrophy through different pathways. The main objective of this review is to
provide an overview of the role of different polymorphisms identified in the
RAAS, in patients with HCM.
DOI: 10.1177/1470320311405247
PMID: 21507890 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25309450 | 1. Front Physiol. 2014 Sep 15;5:350. doi: 10.3389/fphys.2014.00350. eCollection
2014.
Hypothesis and theory: mechanical instabilities and non-uniformities in
hereditary sarcomere myopathies.
Månsson A(1).
Author information:
(1)Department of Chemistry and Biomedical Sciences, Linnaeus University Kalmar,
Sweden.
Familial hypertrophic cardiomyopathy (HCM), due to point mutations in genes for
sarcomere proteins such as myosin, occurs in 1/500 people and is the most common
cause of sudden death in young individuals. Similar mutations in skeletal
muscle, e.g., in the MYH7 gene for slow myosin found in both the cardiac
ventricle and slow skeletal muscle, may also cause severe disease but the
severity and the morphological changes are often different. In HCM, the modified
protein function leads, over years to decades, to secondary remodeling with
substantial morphological changes, such as hypertrophy, myofibrillar disarray,
and extensive fibrosis associated with severe functional deterioration. Despite
intense studies, it is unclear how the moderate mutation-induced changes in
protein function cause the long-term effects. In hypertrophy of the heart due to
pressure overload (e.g., hypertension), mechanical stress in the myocyte is
believed to be major initiating stimulus for activation of relevant cell
signaling cascades. Here it is considered how expression of mutated proteins,
such as myosin or regulatory proteins, could have similar consequences through
one or both of the following mechanisms: (1) contractile instabilities within
each sarcomere (with more than one stable velocity for a given load), (2)
different tension generating capacities of cells in series. These mechanisms
would have the potential to cause increased tension and/or stretch of certain
cells during parts of the cardiac cycle. Modeling studies are used to illustrate
these ideas and experimental tests are proposed. The applicability of similar
ideas to skeletal muscle is also postulated, and differences between heart and
skeletal muscle are discussed.
DOI: 10.3389/fphys.2014.00350
PMCID: PMC4163974
PMID: 25309450 |
http://www.ncbi.nlm.nih.gov/pubmed/22977535 | 1. Exp Ther Med. 2011 May;2(3):523-528. doi: 10.3892/etm.2011.217. Epub 2011 Feb
22.
Imaging agents for in vivo molecular profiling of disseminated prostate cancer:
Cellular processing of [(111)In]-labeled CHX-A″DTPA-trastuzumab and anti-HER2
ABY-025 Affibody in prostate cancer cell lines.
Malmberg J(1), Tolmachev V, Orlova A.
Author information:
(1)Divisions of Biomedical Radiation Sciences, and.
The treatment of disseminated prostate cancer remains a great challenge in
current oncology practice. The proliferation of prostate cancer cells is
testosterone-driven, but clonal selection during androgen deprivation therapy
promotes the development of androgen-independent (hormone-refractory) cells,
which become phenotypically dominant. Human epidermal growth factor receptor
type 2 (HER2) is capable of activating the androgen receptor pathway, even in
the absence of the ligand. The detection of phenotypic changes associated with
the development of androgen independence may influence patient management,
suggesting the initiation of a second-line therapy. This study aimed to
establish the level of HER2 expression in a number of prostate cancer cell lines
(LNCaP, PC3 and DU145) in order that they be used as models in further studies,
and to evaluate the binding and cellular processing of [(111)In]-labeled
trastuzumab and the anti-HER2 synthetic Affibody molecule ABY-025 in these cell
lines. The expression of HER2 was demonstrated and quantified in all three
tested prostate cancer cell-lines. Studies on cellular processing demonstrated
that internalization of both conjugates increased continuously during the whole
incubation. The internalization rate was approximately equal for both monoclonal
antibodies and Affibody molecules. In both cases, internalization was moderately
rapid. Such features would definitely favor the use of radiometal labels for
trastuzumab and, most likely, for affibody molecules. The level of HER2
expression in these cell lines is sufficient for in vivo molecular imaging.
DOI: 10.3892/etm.2011.217
PMCID: PMC3440715
PMID: 22977535 |
http://www.ncbi.nlm.nih.gov/pubmed/22075965 | 1. Primates. 2012 Apr;53(2):205-13. doi: 10.1007/s10329-011-0283-1. Epub 2011 Nov
11.
Induction of pluripotent stem cells from fetal and adult cynomolgus monkey
fibroblasts using four human transcription factors.
Okahara-Narita J(1), Umeda R, Nakamura S, Mori T, Noce T, Torii R.
Author information:
(1)Research Center for Animal Life Science, Shiga University of Medical Science,
Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan.
Induced pluripotent stem (iPS) cells have the potential to become a universal
resource for cell-based therapies in regenerative medicine; however, prior to
the use of such iPS cell-based therapies, preclinical assessment of their safety
and efficacy is essential. Non-human primates serve as valuable animal models
for human diseases or biomedical research; therefore, in this study, we
generated cynomolgus monkey iPS cells from adult skin and fetal fibroblast cells
by the retrovirally mediated introduction of four human transcription factors:
c-Myc, Klf4, Oct3/4, and Sox2 (the so-called "Yamanaka factors"). Twenty to
30 days after the introduction of these factors, several cynomolgus monkey
embryonic stem (ES) cell-like colonies appeared on SNL and mouse embryonic
fibroblast (MEF) feeder layers. These colonies were picked and cultivated in
primate ES medium. Seven iPS cell lines were established, and we detected the
expression of pluripotent markers that are also expressed in ES cells. Reverse
transcription polymerase chain reaction (PCR) showed that these iPS cells
expressed endogenous c-Myc, Klf4, Oct3/4, and Sox2 genes, whereas several
transgenes were silenced. Embryoid body and teratoma formation showed that the
cynomolgus iPS cells had the developmental potential to differentiate into cells
of all three primary germ layers. In summary, we generated cynomolgus monkey iPS
cells by retrovirus-mediated transduction of the human transcription factors,
c-Myc, Klf4, Oct3/4, and Sox2 into adult cynomolgus monkey skin cells and fetal
fibroblasts. The cynomolgus monkey is the most relevant primate model for human
disease, and the highly efficient generation of monkey iPS cells would allow
investigation of the treatments of various diseases in this model via
therapeutic cloning.
DOI: 10.1007/s10329-011-0283-1
PMID: 22075965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23308364 | 1. J Proteome Res. 2013 Jun 7;12(6):2504-10. doi: 10.1021/pr301082p. Epub 2013
Jan 11.
Functional annotation of the human chromosome 7 "missing" proteins: a
bioinformatics approach.
Ranganathan S(1), Khan JM, Garg G, Baker MS.
Author information:
(1)Department of Chemistry and Biomolecular Sciences and ARC Centre of
Excellence in Bioinformatics, Macquarie University, Sydney, NSW, Australia.
[email protected]
The chromosome-centric human proteome project aims to systematically map all
human proteins, chromosome by chromosome, in a gene-centric manner through
dedicated efforts from national and international teams. This mapping will lead
to a knowledge-based resource defining the full set of proteins encoded in each
chromosome and laying the foundation for the development of a standardized
approach to analyze the massive proteomic data sets currently being generated.
The neXtProt database lists 946 proteins as the human proteome of chromosome 7.
However, 170 (18%) proteins of human chromosome 7 have no evidence at the
proteomic, antibody, or structural levels and are considered "missing" in this
study as they lack experimental support. We have developed a protocol for the
functional annotation of these "missing" proteins by integrating several
bioinformatics analysis and annotation tools, sequential BLAST homology
searches, protein domain/motif and gene ontology (GO) mapping, and Kyoto
Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Using the BLAST
search strategy, homologues for reviewed non-human mammalian proteins with
protein evidence were identified for 90 "missing" proteins while another 38 had
reviewed non-human mammalian homologues. Putative functional annotations were
assigned to 27 of the remaining 43 novel proteins. Proteotypic peptides have
been computationally generated to facilitate rapid identification of these
proteins. Four of the "missing" chromosome 7 proteins have been substantiated by
the ENCODE proteogenomic peptide data.
DOI: 10.1021/pr301082p
PMID: 23308364 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19675515 | 1. Neuro Endocrinol Lett. 2009;30(2):209-14.
Radioiodine therapy in patients with amiodarone-induced thyrotoxicosis (AIT).
Czarnywojtek A(1), Czepczynski R, Ruchala M, Wasko R, Zgorzalewicz-Stachowiak M,
Szczepanek E, Zamyslowska H, Bartkowiak Z, Florek E, Sowinski J.
Author information:
(1)Department of Endocrinology, Metabolism and Internal Medicine, Poznan
University of Medical Sciences, Poland. [email protected]
INTRODUCTION: Amiodarone (AM) is frequently used in the therapy of patients with
cardiac disorders. However, due to high iodine content, it has side effects on
thyroid function. The use of radioiodine therapy (RIT) in amiodarone-induced
thyrotoxicosis (AIT) with low radioactive iodine uptake (RAIU) is still
controversial. In these patients therapeutic choices for refractory disease
include surgery, antithyroid drugs, or glu ocorticosteriods.
AIM: The aim of the study was to evaluate the efficacy of RIT in patients
presenting AIT and low RAIU in two-year follow-up.
PATIENTS AND METHODS: 40 patients (25 men and 15 women) aged from 63 to 83 years
(x +/- SD: 66.2 +/- 5.0 years; median: 65 years) treated with RIT were included
into the study. In these patients AM therapy was essential for the underlying
heart disorder, while surgery, antithyroid drugs or glucocorticosteroids, were
contraindicated. Forty seven patients with toxic multinodular goiter (TMNG) (39
women and 8 men), matched for age (67 +/- 12 yr; range 54-89 yr), were enrolled
into the study as a comparative group. The diagnostic procedures included
baseline thyroid function tests (thyrothropin - TSH, free triiodothyronine - fT3
and free thyroxine - fT4 levels), thyroid autoantibodies measurement
(antithyroglobulin autoantibodies - TgAb, antithyroid peroxidase autoantibodies
- TPOAb, anti-TSH receptor autoantibodies - TRAb), thyroid ultrasonography,
thyroid scintiscan and RAIU assessment.
RESULTS: Serum values of TSH, TgAb, TPOAb and TRAb were undetectable in both
groups. In patients with AIT fT4 level was 18.7 to 38.7 pmol/l (mean: 27.1 +/-
5.8) and fT3 concentration was 3.9 to 5.6 pmo/l (mean: 5.7 +/- 1.4), while in
TMNG patients level of fT4 was 31.5 to 22.2 pmol/l (mean: 25,3 +/- 5,8) and fT3
concentration was 3.8 to 4,2 pmo/l (mean: 4,2 +/- 0,2). Mean RAIU values after
5h and 24h in AIT patients were 2.3 +/- 0.5 and 3.1 +/- 0.9%, while in TMNG
patients were 18,0 +/- 3,8 and 35,7 +/- 9,1%, respectively. A significant
difference (p<0.001) between 5h and 24h RAIU in AIT compared to TMNG was noted.
In all patients with AIT, a dose of 800 MBq of 131I was administered. During
two-year-observation recurrence of hyperthyroidism was observed in two patients
(5%) with TMNG. These patients received a second radioiodine dose 16.2 +/- 15
months later (the mean re-treatment dose was 735.93 +/- 196.1 MBq). In
comparison, none of the patients with AIT required a second 131I dose and only
one patient (2.5%) 6 months after ablative 131I dose needed anti-thyroid
medication. Transient hypothyroidism was observed in only two patients (5%) with
AIH, though was not observed in TMNG. During follow-up time, no sudden deaths in
AIT patients were observed; one patient was diagnosed with prostate cancer, and
in one patient acute toxic hepatitis after AM occurred.
CONCLUSION: RIT may be a safe and useful method of AIT therapy in patients with
low RAIU, in whom other treatment methods are contraindicated.
PMID: 19675515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21640101 | 1. Exp Cell Res. 2011 Aug 1;317(13):1895-903. doi: 10.1016/j.yexcr.2011.05.017.
Epub 2011 May 26.
Selection of alkaline phosphatase-positive induced pluripotent stem cells from
human amniotic fluid-derived cells by feeder-free system.
Lu HE(1), Tsai MS, Yang YC, Yuan CC, Wang TH, Lin XZ, Tseng CP, Hwang SM.
Author information:
(1)Bioresource Collection and Research Center, Food Industry Research and
Development Institute, Hsinchu, Taiwan, ROC.
Generation of induced pluripotent stem (iPS) cells from somatic cells has been
successfully achieved by ectopic expression of four transcription factors, Oct4,
Sox2, Klf4 and c-Myc, also known as the Yamanaka factors. In practice, initial
iPS colonies are picked based on their embryonic stem (ES) cell-like morphology,
but often may go on to fail subsequent assays, such as the alkaline phosphate
(AP) assay. In this study, we co-expressed through lenti-viral delivery the
Yamanaka factors in amniotic fluid-derived (AF) cells. ES-like colonies were
picked onto a traditional feeder layer and a high percentage AF-iPS with partial
to no AP activity was found. Interestingly, we obtained an overwhelming majority
of fully stained AP positive (AP+) AF-iPS colonies when colonies were first
seeded on a feeder-free culture system, and then transferred to a feeder layer
for expansion. Furthermore, colonies with no AP activity were not detected. This
screening step decreased the variation seen between morphology and AP assay. We
observed the AF-iPS colonies grown on the feeder layer with 28% AP+ colonies,
45% AP partially positive (AP+/-) colonies and 27% AP negative (AP-) colonies,
while colonies screened by the feeder-free system were 84% AP+ colonies, 16%
AP+/- colonies and no AP- colonies. The feeder-free screened AP+ AF-iPS colonies
were also positive for pluripotent markers, OCT4, SOX2, NANOG, TRA-1-60,
TRA-1-81, SSEA-3 and SSEA-4 as well as having differentiation abilities into
three germ layers in vitro and in vivo. In this study, we report a simplistic,
one-step method for selection of AP+ AF-iPS cells via feeder-free screening.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yexcr.2011.05.017
PMID: 21640101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7630403 | 1. Nature. 1995 Jul 27;376(6538):348-51. doi: 10.1038/376348a0.
Rubinstein-Taybi syndrome caused by mutations in the transcriptional
co-activator CBP.
Petrij F(1), Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N,
van Ommen GJ, Goodman RH, Peters DJ, et al.
Author information:
(1)Department of Human Genetics, Leiden University, Sylvius Laboratories, The
Netherlands.
Comment in
Nature. 1995 Jul 27;376(6538):292-3. doi: 10.1038/376292a0.
The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial
abnormalities, broad thumbs, broad big toes and mental retardation as the main
clinical features. Many patients with RTS have been shown to have breakpoints
in, and microdeletions of, chromosome 16p13.3 (refs 4-8). Here we report that
all these breakpoints are restricted to a region that contains the gene for the
human CREB binding protein (CBP), a nuclear protein participating as a
co-activator in cyclic-AMP-regulated gene expression. We show that RTS results
not only from gross chromosomal rearrangements of chromosome 16p, but also from
point mutations in the CBP gene itself. Because the patients are heterozygous
for the mutations, we propose that the loss of one functional copy of the CBP
gene underlies the developmental abnormalities in RTS and possibly the
propensity for malignancy.
DOI: 10.1038/376348a0
PMID: 7630403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16544025 | 1. Arq Bras Endocrinol Metabol. 2005 Dec;49(6):991-5. doi:
10.1590/s0004-27302005000600021. Epub 2006 Mar 16.
[Use of lithium carbonate for the treatment of amiodarone-induced
thyrotoxicosis].
[Article in Portuguese]
Boeving A(1), Cubas ER, Santos CM, Carvalho GA, Graf H.
Author information:
(1)Serviço de Endocrinologia e Metabologia, Hospital de Clínicas, Universidade
Federal do Paraná, SEMPR, Curitiba, PR.
Among the amiodarone-induced thyroid dysfunctions, thyrotoxicosis is the most
troublesome and with the highest rate of morbidity and mortality. Treatment
consists in the use of a high dose of anti-thyroid drugs and steroids in an
isolated form or in combination. Association of several other drugs have been
proposed for the treatment of refractory cases. In this study we report the case
of a 40 y.o. patient, with a history of idiopatic dilated miocardiopathy, who
developed severe amioradone-induced thyrotoxicosis after heart transplantation.
Since the patient did not respond to an initial treatment consisting of a high
dose of anti-thyroid drugs combined with steroids, a low dose of lithium
carbonate was added for a short period of time, which resulted in normalization
of the thyroid function. In this case, the addition of lithium carbonate to the
two other drugs resulted in a successful and safety therapy in controlling
amiodarone-induced thyrotoxicosis.
DOI: 10.1590/s0004-27302005000600021
PMID: 16544025 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23704989 | 1. PLoS One. 2013 May 21;8(5):e64496. doi: 10.1371/journal.pone.0064496. Print
2013.
Efficient generation of integration-free ips cells from human adult peripheral
blood using BCL-XL together with Yamanaka factors.
Su RJ(1), Baylink DJ, Neises A, Kiroyan JB, Meng X, Payne KJ, Tschudy-Seney B,
Duan Y, Appleby N, Kearns-Jonker M, Gridley DS, Wang J, Lau KH, Zhang XB.
Author information:
(1)Department of Medicine, Loma Linda University, Loma Linda, California, United
States of America.
The ability to efficiently generate integration-free induced pluripotent stem
cells (iPSCs) from the most readily available source-peripheral blood-has the
potential to expedite the advances of iPSC-based therapies. We have successfully
generated integration-free iPSCs from cord blood (CB) CD34(+) cells with
improved oriP/EBNA1-based episomal vectors (EV) using a strong spleen focus
forming virus (SFFV) long terminal repeat (LTR) promoter. Here we show that
Yamanaka factors (OCT4, SOX2, MYC, and KLF4)-expressing EV can also reprogram
adult peripheral blood mononuclear cells (PBMNCs) into pluripotency, yet at a
very low efficiency. We found that inclusion of BCL-XL increases the
reprogramming efficiency by approximately 10-fold. Furthermore, culture of
CD3(-)/CD19(-) cells or T/B cell-depleted MNCs for 4-6 days led to the
generation of 20-30 iPSC colonies from 1 ml PB, an efficiency that is
substantially higher than previously reported. PB iPSCs express pluripotency
markers, form teratomas, and can be induced to differentiate in vitro into
mesenchymal stem cells, cardiomyocytes, and hepatocytes. Used together, our
optimized factor combination and reprogramming strategy lead to efficient
generation of integration-free iPSCs from adult PB. This discovery has potential
applications in iPSC banking, disease modeling and regenerative medicine.
DOI: 10.1371/journal.pone.0064496
PMCID: PMC3660366
PMID: 23704989 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/9217642 | 1. Am J Med. 1997 May;102(5):454-8. doi: 10.1016/S0002-9343(97)00047-8.
Lithium treatment in amiodarone-induced thyrotoxicosis.
Dickstein G(1), Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S.
Author information:
(1)Division of Endocrinology, Haifa Medical Center, Bnai Zion, Haifa, Israel.
PURPOSE: Amiodarone hydrochloride is an iodine-rich drug effective in the
control of various tachyarrhythmias. It is known to cause refractory to
thyrotoxicosis, which usually does not respond to regular antithyroid drugs.
Lithium bicarbonate is a medication used to treat psychiatric disorders; it also
influences thyroid production and release of hormones. We tried it in
combination with propylthiouracil (PTU) for the treatment of amiodarone-induced
thyrotoxicosis.
PATIENTS AND METHODS: Twenty-one patients were studied. The first group (n = 5)
was treated by amiodarone withdrawal only. The second group (n = 7) received PTU
(300 to 600 mg), and the third (n = 9) PTU (300 mg) and lithium (900 to 1350 mg)
daily. Patient selection was not randomized. The PTU + lithium group had more
severe symptoms and signs of thyrotoxicosis, as well as thyroxine levels at
least 50% above the upper limit of normal. They also had been on a longer course
of amiodarone treatment (34.3 +/- 11.9 months) than the PTU-only (11.4 +/- 7.5)
and the no-treatment (7.8 +/- 4.2) groups.
RESULTS: While there was no difference between the first two groups in time
until recovery (10.6 +/- 4.0 versus 11.6 +/- 0.5 weeks, respectively), the group
receiving lithium normalized their thyroid function tests in only 4.3 +/- 0.5
weeks (P < 0.01 versus both other groups). T3 levels normalized even earlier-by
3 weeks of lithium treatment. No adverse effects of lithium were encountered,
and the medication was stopped 4 to 6 weeks after achieving a normal clinical
and biochemical state.
CONCLUSIONS: We conclude that lithium is a useful and safe medication for
treatment of iodine-induced thyrotoxicosis caused by amiodarone. We would
reserve this treatment for severe cases only. Further studies are needed to find
out whether in patients with this troublesome complication lithium therapy could
permit continuation of amiodarone treatment.
DOI: 10.1016/S0002-9343(97)00047-8
PMID: 9217642 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24150221 | 1. Leukemia. 2014 May;28(5):1071-80. doi: 10.1038/leu.2013.304. Epub 2013 Oct 22.
Reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells.
Liu Y(1), Cheng H(1), Gao S(2), Lu X(3), He F(4), Hu L(1), Hou D(1), Zou Z(3),
Li Y(1), Zhang H(1), Xu J(1), Kang L(2), Wang Q(4), Yuan W(1), Gao S(2), Cheng
T(1).
Author information:
(1)State Key Laboratory of Experimental Hematology, Institute of Hematology &
Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of
Medical Sciences & Peking Union Medical College, Tianjin, China.
(2)National Institute of Biological Sciences, Beijing, China.
(3)1] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute
of Genomics, Chinese Academy of Sciences, Beijing, China [2] University of
Chinese Academy of Sciences, Beijing, China.
(4)CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of
Genomics, Chinese Academy of Sciences, Beijing, China.
Comment in
Stem Cells. 2020 Jul;38(7):818-821. doi: 10.1002/stem.3173.
The 'Yamanaka factors' (Oct4, Sox2, Klf4 and c-Myc) are able to generate induced
pluripotent stem (iPS) cells from different cell types. However, to what degree
primary malignant cells can be reprogrammed into a pluripotent state has not
been vigorously assessed. We established an acute myeloid leukemia (AML) model
by overexpressing the human mixed-lineage leukemia-AF9 (MLL-AF9) fusion gene in
mouse hematopoietic cells that carry Yamanaka factors under the control of
doxycycline (Dox). On addition of Dox to the culture, the transplantable
leukemia cells were efficiently converted into iPS cells that could form
teratomas and produce chimeras. Interestingly, most chimeric mice spontaneously
developed the same type of AML. Moreover, both iPS reprogramming and leukemia
reinitiation paths could descend from the same leukemia-initiating cell. RNA-seq
analysis showed reversible global gene expression patterns between these
interchangeable leukemia and iPS cells on activation or reactivation of MLL-AF9,
suggesting a sufficient epigenetic force in driving the leukemogenic process.
This study represents an important step for further defining the potential
interplay between oncogenic molecules and reprogramming factors during MLL
leukemogenesis. More importantly, our reprogramming approach may be expanded to
characterize a range of hematopoietic malignancies in order to develop new
strategies for clinical diagnosis and treatment.
DOI: 10.1038/leu.2013.304
PMCID: PMC4017259
PMID: 24150221 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21844010 | 1. Clin Cancer Res. 2011 Oct 1;17(19):6218-28. doi:
10.1158/1078-0432.CCR-11-1548. Epub 2011 Aug 15.
Dual EGFR/HER2 inhibition sensitizes prostate cancer cells to androgen
withdrawal by suppressing ErbB3.
Chen L(1), Mooso BA, Jathal MK, Madhav A, Johnson SD, van Spyk E, Mikhailova M,
Zierenberg-Ripoll A, Xue L, Vinall RL, deVere White RW, Ghosh PM.
Author information:
(1)VA Northern California Health Care System, Mather, California, USA.
PURPOSE: Patients with recurrent prostate cancer are commonly treated with
androgen withdrawal therapy (AWT); however, almost all patients eventually
progress to castration resistant prostate cancer (CRPC), indicating failure of
AWT to eliminate androgen-sensitive prostate cancer. The overall goal of these
studies is to determine whether dual inhibition of the receptor tyrosine kinases
epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness
of this treatment in prostate cancer.
EXPERIMENTAL DESIGN: We used androgen-dependent LNCaP cells and its CRPC
sublines LNCaP-AI and C4-2. Additional data were collected in pRNS-1-1 cells
stably expressing a mutant androgen receptor (AR-T877A), and in nude mice
harboring CWR22 tumors. Studies utilized EGFR inhibitors erlotinib and AG1478,
and HER2 inhibitors trastuzumab and AG879.
RESULTS: Dual EGFR/HER2 inhibition induced apoptosis selectively in
androgen-sensitive prostate cancer cells undergoing AWT, but not in the presence
of androgens, or in CRPC cells. We show that AWT alone failed to induce
significant apoptosis in androgen-dependent cells, due to AWT-induced increase
in HER2 and ErbB3, which promoted survival by increasing Akt phosphorylation.
AWT-induced ErbB3 stabilized the AR and stimulated PSA, while it was inactivated
only by inhibition of both its dimerization partners EGFR and HER2 (prostate
cancer cells do not express ErbB4); but not the inhibition of any one receptor
alone, explaining the success of dual EGFR/HER2 inhibition in sensitizing
androgen-dependent cells to AWT. The effectiveness of the inhibitors in
suppressing growth correlated with its ability to prevent Akt phosphorylation.
CONCLUSION: These studies indicate that dual EGFR/HER2 inhibition, administered
together with AWT, sensitize prostate cancer cells to apoptosis during AWT.
©2011 AACR
DOI: 10.1158/1078-0432.CCR-11-1548
PMCID: PMC3186857
PMID: 21844010 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15264245 | 1. Prostate. 2004 Sep 1;60(4):332-7. doi: 10.1002/pros.20065.
The use of trastuzumab in the treatment of hormone refractory prostate cancer;
phase II trial.
Ziada A(1), Barqawi A, Glode LM, Varella-Garcia M, Crighton F, Majeski S,
Rosenblum M, Kane M, Chen L, Crawford ED.
Author information:
(1)UCHSC, 4200 E. 9th Ave. C-319, Denver, CO, USA. [email protected]
PURPOSE: To investigate the efficacy and toxicity of the antibody to the
HER-2/neu receptor (trastuzumab, Herceptin) in the treatment of advanced
hormone-refractory prostate cancer (HRPC).
MATERIALS AND METHODS: Eighteen patients with HRPC were recruited for this phase
II trial in which they received trastuzumab for 12 weeks or until disease
progression or unacceptable toxicity was documented. HER-2 receptor
overexpression was evaluated using immunohistochemistry (IHC) and dual-color
fluorescence in-situ hybridization (FISH) assays.
RESULTS: Trastuzumab as a single agent demonstrated little efficacy in treating
HRPC. Two patients demonstrated stable disease based on a decrease in PSA level
to less than 50% of baseline. No patient demonstrated a regression of
radiographic bony or soft tissue metastatic disease. The medication was well
tolerated in 16 patients (89%), and 2 patients (11%) had to be hospitalized for
cardiac complications.
CONCLUSIONS: Trastuzumab (Herceptin) as a single agent demonstrated poor
efficacy in treating HRPC. Based on promising results in treating breast cancer
with regimens using Herceptin and cytotoxic agents, a similar combination
approach might demonstrate better efficacy in treating HRPC.
DOI: 10.1002/pros.20065
PMID: 15264245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24182356 | 1. Dev Med Child Neurol. 2014 Jul;56(7):686-94. doi: 10.1111/dmcn.12319. Epub
2013 Nov 3.
Spastic diplegia in children with HIV encephalopathy: first description of gait
and physical status.
Langerak NG(1), du Toit J, Burger M, Cotton MF, Springer PE, Laughton B.
Author information:
(1)Neurosurgery Division, Department of Surgery, Faculty of Health Sciences,
University of Cape Town, Cape Town, South Africa; Physiotherapy Division,
Department of Interdisciplinary Health Sciences, Faculty of Medicine and Health
Sciences, Stellenbosch University, Tygerberg, South Africa.
AIM: The aim of this study was to explore the physical status and gait patterns
of children with spastic diplegia secondary to human immunodeficiency virus
encephalopathy (HIVE).
METHOD: A cross-sectional study was conducted on children diagnosed with HIVE
and spastic diplegia. Sociodemographic and clinical background information was
obtained, followed by three-dimensional gait analysis (3DGA) and a physical
examination including assessments of muscle tone, strength, motor control,
contractures, and bony deformities of the lower extremities.
RESULTS: Fourteen children (eight males, six females; mean age 5 y 8 mo [SD 9
mo], range 4 y 4 mo-6 y 10 mo) were studied. The cohort was divided into two
groups based on distinctive gait patterns. Nine participants in group I showed
only limited abnormalities. Group II displayed a more pathological gait pattern
including stiff knee and equinus ankle abnormalities. Results of 3DGA, as with
the physical examination outcomes, showed increased impairments from proximal to
distal (except for hip extension).
INTERPRETATION: This study provides a first description of distinctive gait
patterns and related physical characteristics of children with HIVE and spastic
diplegia. Further research is necessary.
© 2013 Mac Keith Press.
DOI: 10.1111/dmcn.12319
PMID: 24182356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16323217 | 1. Muscle Nerve. 2006 May;33(5):697-700. doi: 10.1002/mus.20486.
Brachial plexopathy due to malignant peripheral nerve sheath tumor in
neurofibromatosis type 1: case report and subject review.
Pacelli J(1), Whitaker CH.
Author information:
(1)Department of Neurology, University of Connecticut Health Center, 263
Farmington Avenue, Farmington, Connecticut 06030, USA.
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome
affecting approximately 1 in 4,000 persons. It is an autosomal-dominant disorder
with half of the cases resulting from spontaneous mutations. This genetic defect
leads to the formation of benign tumors or neurofibromas of the peripheral
nervous system. Dermal neurofibromas may cause local discomfort and itching but
are rarely associated with neurological deficit and do not undergo malignant
change. The more extensive plexiform neurofibromas produce neurological
complications in 27%-43% of patients with NF1 and may undergo malignant
degeneration in 5% of cases. Patients with NF1 who develop pain or new
neurological symptoms should have a rapid and thorough assessment for
malignancy. In this report, we illustrate this point by presenting a patient who
developed acute shoulder pain and weakness due to malignant degeneration of a
plexiform neurofibroma involving the left brachial plexus, and review the
literature on this subject.
DOI: 10.1002/mus.20486
PMID: 16323217 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22966780 | 1. OMICS. 2012 Nov;16(11):604-11. doi: 10.1089/omi.2012.0034. Epub 2012 Sep 11.
Comparative ranking of human chromosomes based on post-genomic data.
Ponomarenko E(1), Poverennaya E, Pyatnitskiy M, Lisitsa A, Moshkovskii S,
Ilgisonis E, Chernobrovkin A, Archakov A.
Author information:
(1)Institute of Biomedical Chemistry of Russian Academy of Medical Sciences,
Moscow, Russia.
The goal of the Human Proteome Project (HPP) is to fully characterize the 21,000
human protein-coding genes with respect to the estimated two million proteins
they encode. As such, the HPP aims to create a comprehensive, detailed resource
to help elucidate protein functions and to advance medical treatment. Similarly
to the Human Genome Project (HGP), the HPP chose a chromosome-centric approach,
assigning different chromosomes to different countries. Here we introduce a
scoring method for chromosome ranking based on several characteristics,
including relevance to health problems, existing published knowledge, and
current transcriptome and proteome coverage. The score of each chromosome was
computed as a weighted combination of indexes reflecting the aforementioned
characteristics. The approach is tailored to the chromosome-centric HPP (C-HPP),
and is advantageous in that it takes into account currently available
information. We ranked the human chromosomes using the proposed score, and
observed that Chr Y, Chr 13, and Chr 18 were top-ranked, whereas the scores of
Chr 19, Chr 11, and Chr 17 were comparatively low. For Chr 18, selected for the
Russian part of C-HPP, about 25% of the encoded genes were associated with
diseases, including cancers and neurodegenerative and psychiatric diseases, as
well as type 1 diabetes and essential hypertension. This ranking approach could
easily be adapted to prioritize research for other sets of genes, such as
metabolic pathways and functional categories.
DOI: 10.1089/omi.2012.0034
PMID: 22966780 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22540148 | 1. Stem Cells Dev. 2012 Oct 10;21(15):2878-90. doi: 10.1089/scd.2012.0097. Epub
2012 Jun 11.
Aire promotes the self-renewal of embryonic stem cells through Lin28.
Bin G(1), Jiarong Z, Shihao W, Xiuli S, Cheng X, Liangbiao C, Ming Z.
Author information:
(1)Institute of Genetics, College of Life Sciences, Zhejiang University,
Hangzhou, China .
Abstract Autoimmune regulator (Aire) is one of the most well-characterized
molecules in autoimmunity, but its function outside the immune system is largely
unknown. The recent discovery of Aire expression in stem cells and early
embryonic cells and its function in the self-renewal of embryonic stem (ES)
cells highlight the importance of Aire in these cells. In this study, we present
evidence that Aire promotes the expression of the pluripotent factor Lin28 and
the self-renewal of ES cells. We presented the first evidence that the let-7
microRNA family contributed to the self-renewal promoting effect of Aire on ES
cells. Moreover, we showed that Aire and Lin28 are co-expressed in the genital
ridge, oocytes, and cleavage-stage embryos, and the expression level of Lin28 is
correlated with the expression level of Aire. Although it is widely considered
to be a promiscuous gene expression activator, these results indicated that Aire
promotes the self-renewal of ES cells through a specific pathway (i.e., the
activation of Lin28 and the inhibition of the let-7 microRNA family). The
correlation between Aire and Lin28 expression in germ cells and early embryos
indicated an in vivo function for Aire in toti- and pluripotent stem cells. This
study presents the first molecular pathway that incorporates Aire into the
pluripotency network. Moreover, it presents the first evidence that microRNAs
contribute to the regulatory function of Aire and highlights a novel function of
Aire in stem cell biology and reproduction. These functions reveal novel
perspectives for studying the molecular mechanisms behind the establishment and
sustenance of pluripotent identity.
DOI: 10.1089/scd.2012.0097
PMCID: PMC3464070
PMID: 22540148 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11901034 | 1. Circulation. 2002 Mar 19;105(11):1275-7.
Successful treatment of amiodarone-induced thyrotoxicosis.
Osman F(1), Franklyn JA, Sheppard MC, Gammage MD.
Author information:
(1)Division of Medical Sciences, University of Birmingham, Birmingham, UK.
BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a difficult management
problem about which there are little published data. We examined whether
continuing amiodarone or differentiating AIT into 2 subtypes affected outcome.
METHODS AND RESULTS: The type and duration of antithyroid treatment and response
were recorded in a consecutive series of 28 cases. Comparisons were made between
those in whom amiodarone either was continued or stopped and between those with
either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous
resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy.
Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five
became hypothyroid and required long-term thyroxine. Five relapsed after
stopping CBZ treatment and were rendered euthyroid with either long-term CBZ
(n=3) or radioiodine (n=2). Four were intolerant of CBZ and received
propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide
alone (CBZ then PTU) and responded to adjunctive steroids. No difference in
presentation or outcome was noted between those in whom amiodarone was continued
or stopped or between possible type 1 or type 2 AIT.
CONCLUSIONS: Continuing amiodarone has no adverse influence on response to
treatment of AIT. First-line therapy with a thionamide alone is appropriate in
iodine-replete areas, thus avoiding potential complications of other drugs.
Differentiating between 2 possible types of AIT does not influence management or
outcome.
PMID: 11901034 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21135419 | 1. Hong Kong Med J. 2010 Dec;16(6):434-9.
Amiodarone-induced thyroid dysfunction in the Hong Kong Chinese population.
Lee KF(1), Lee KM, Fung TT.
Author information:
(1)Department of Medicine and Geriatrics, Kwong Wah Hospital, 25 Waterloo Road,
Hong Kong.
OBJECTIVE: To determine the frequency, risk factors, clinical features, and
management of amiodarone-induced thyroid dysfunctions.
DESIGN: Retrospective study.
SETTING: A regional hospital in Hong Kong.
PATIENTS: Patients who had been prescribed amiodarone for at least 6 months from
1 October 2005 to 30 September 2007.
RESULTS: A total of 390 patients (mean age, 70 years; standard deviation, 9
years; 54% male) with a median follow-up of 43 (interquartile range, 25-69)
months were studied. Hypothyroidism developed in 87 (22%) of the patients (mean
age, 72 years; standard deviation, 7 years; 56% male) and thyrotoxicosis in 24
(6%) of the patients (65 years; 11 years; 54% male). Increased baseline
thyrotropin (thyroid-stimulating hormone) level appeared to be predictive of
amiodarone-induced hypothyroidism, in which a thyroid-stimulating hormone level
of 4 mIU/L or above was associated with a 4.7-fold increase in the risk (95%
confidence interval, 1.9-11.7; P<0.001). Compared with those who remained
euthyroid on amiodarone, thyrotoxicosis developed in younger patients. In these
patients, the classical symptoms of thyroid dysfunction were frequently absent,
although worsening of underlying arrhythmias, their cardiac condition, weight
loss, and over-warfarinisation were suggestive of amiodarone-induced
thyrotoxicosis. In both amiodarone-induced thyrotoxicosis and hypothyroidism,
the disease course was benign. Patients with the former showed a good response
to anti-thyroid drugs and steroid therapy.
CONCLUSIONS: Amiodarone-induced thyroid dysfunction is common among our
population. As the clinical presentations are usually vague and atypical,
regular biochemical monitoring of thyroid function is warranted, particularly in
patients with elevated baseline thyroid-stimulating hormone level. The disease
course of amiodarone-induced thyrotoxicosis is usually benign and remits with
timely administration of anti-thyroid medications, with or without
corticosteroids.
PMID: 21135419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23249167 | 1. J Proteome Res. 2013 Jan 4;12(1):135-50. doi: 10.1021/pr3008607. Epub 2012 Dec
18.
Chromosome 19 annotations with disease speciation: a first report from the
Global Research Consortium.
Nilsson CL(1), Berven F, Selheim F, Liu H, Moskal JR, Kroes RA, Sulman EP,
Conrad CA, Lang FF, Andrén PE, Nilsson A, Carlsohn E, Lilja H, Malm J, Fenyö D,
Subramaniyam D, Wang X, Gonzales-Gonzales M, Dasilva N, Diez P, Fuentes M,
Végvári Á, Sjödin K, Welinder C, Laurell T, Fehniger TE, Lindberg H, Rezeli M,
Edula G, Hober S, Marko-Varga G.
Author information:
(1)Department of Pharmacology and Toxicology, UTMB Cancer Center, University of
Texas Medical Branch, Galveston, Texas 77555, United States.
A first research development progress report of the Chromosome 19 Consortium
with members from Sweden, Norway, Spain, United States, China and India, a part
of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is
presented ( http://www.c-hpp.org ). From the chromosome 19 peptide-targeted
library constituting 6159 peptides, a pilot study was conducted using a subset
with 125 isotope-labeled peptides. We applied an annotation strategy with triple
quadrupole, ESI-Qtrap, and MALDI mass spectrometry platforms, comparing the
quality of data within and in between these instrumental set-ups. LC-MS
conditions were outlined by multiplex assay developments, followed by MRM assay
developments. SRM was applied to biobank samples, quantifying kallikrein 3
(prostate specific antigen) in plasma from prostate cancer patients. The
antibody production has been initiated for more than 1200 genes from the entire
chromosome 19, and the progress developments are presented. We developed a
dedicated transcript microarray to serve as the mRNA identifier by screening
cancer cell lines. NAPPA protein arrays were built to align with the transcript
data with the Chromosome 19 NAPPA chip, dedicated to 90 proteins, as the first
development delivery. We have introduced an IT-infrastructure utilizing a LIMS
system that serves as the key interface for the research teams to share and
explore data generated within the project. The cross-site data repository will
form the basis for sample processing, including biological samples as well as
patient samples from national Biobanks.
DOI: 10.1021/pr3008607
PMCID: PMC3539432
PMID: 23249167 [Indexed for MEDLINE]
Conflict of interest statement: 8. CONFLICT OF INTEREST Dr. Hans Lilja holds
patents for free PSA, intact PSA, and hK2 assays. |
http://www.ncbi.nlm.nih.gov/pubmed/19008896 | 1. Nat Rev Immunol. 2008 Dec;8(12):948-57. doi: 10.1038/nri2450.
Transcriptional regulation by AIRE: molecular mechanisms of central tolerance.
Peterson P(1), Org T, Rebane A.
Author information:
(1)Institute of General and Molecular Pathology, University of Tartu, Tartu
5O411, Estonia. [email protected]
The negative selection of T cells in the thymus is necessary for the maintenance
of self tolerance. Medullary thymic epithelial cells have a key function in this
process as they express a large number of tissue-specific self antigens that are
presented to developing T cells. Mutations in the autoimmune regulator (AIRE)
protein cause a breakdown of central tolerance that is associated with decreased
expression of self antigens in the thymus. In this Review, we discuss the role
of AIRE in the thymus and recent advances in our understanding of how AIRE might
function at the molecular level to regulate gene expression.
DOI: 10.1038/nri2450
PMCID: PMC2785478
PMID: 19008896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16910349 | 1. Eur Rev Med Pharmacol Sci. 2006 Jul-Aug;10(4):187-90.
Total thyroidectomy in amiodarone-induced thyrotoxicosis. Preoperative,
intraoperative and postoperative considerations.
Batori M(1), Nardi M, Chatelou E, Straniero A, Makrypodi M, Ruggieri M.
Author information:
(1)Unit of Endocrine Surgery, Department of Surgical Sciences and Applied
Medical Technologies, La Sapienza University, Rome, Italy.
[email protected]
A female patient was admitted to our Department for total thyroidectomy in
amiodarone-induced thyrotoxicosis. The drug was prescribed for ventricular
arrhythmia and atrial paroxysmal fibrillation in dilated cardiomyopathy due to
chronic aortic regurgitation with left ventricular dysfunction (ejection
fraction 35%; Class Functional NYHA III) and moderate-severe respiratory
insufficiency. The cardiologist-anesthetist team has allowed to evaluate the
surgical-cardiovascular-anesthesiologic risks and the balance between the
improvement by the amiodarone administration for the arrhythmia, and the
discontinuation of this treatment in order to prevent aggravation of the
thyrotoxicosis. These hypotheses were subsequently discharged for the two
reasons listed below: - several other antiarrhytmic drugs (that didn't show
equivalent efficacy as amiodarone in preventing or converting such ventricular
and atrial arrhythmias) may be proposed in the place of amiodarone. However,
this could expose the patient to an arrhythmia; - a clear proof that the
suspension of amiodarone can allow restoring normalization of the thyroid
function doesn't exist. Therefore, the patient has been successfully submitted
to the surgical intervention and in the follow-up we brought her back to a state
of normalized thyroid function and cardiovascular conditions. In patients that
cannot safely discontinue amiodarone or when medical therapy is ineffective in
controlling thyrotoxicosis, thyroidectomy is the treatment of choice.
PMID: 16910349 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25429138 | 1. J Neurosci. 2014 Nov 26;34(48):15962-74. doi: 10.1523/JNEUROSCI.2526-14.2014.
Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in
a Drosophila model of amyotrophic lateral sclerosis.
Coyne AN(1), Siddegowda BB(2), Estes PS(2), Johannesmeyer J(2), Kovalik T(3),
Daniel SG(2), Pearson A(2), Bowser R(3), Zarnescu DC(4).
Author information:
(1)Departments of Molecular and Cellular Biology, Neuroscience, and.
(2)Departments of Molecular and Cellular Biology.
(3)Divisions of Neurobiology and Neurology, Barrow Neurological Institute,
Phoenix, Arizona 85013.
(4)Departments of Molecular and Cellular Biology, Neuroscience, and Neurology,
University of Arizona, Tucson, Arizona 85721, and [email protected].
TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS)
that is known to regulate the splicing, transport, and storage of specific mRNAs
into stress granules. Although TDP-43 has been shown to interact with
translation factors, its role in protein synthesis remains unclear, and no in
vivo translation targets have been reported to date. Here we provide evidence
that TDP-43 associates with futsch mRNA in a complex and regulates its
expression at the neuromuscular junction (NMJ) in Drosophila. In the context of
TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at
the NMJ compared with motor neuron cell bodies where we find higher levels of
transcript compared with controls. TDP-43 also leads to a significant reduction
in Futsch protein expression at the NMJ. Polysome fractionations coupled with
quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift
from actively translating polysomes to nontranslating ribonuclear protein
particles, suggesting that in addition to its effect on localization, TDP-43
also regulates the translation of futsch mRNA. We also show that futsch
overexpression is neuroprotective by extending life span, reducing TDP-43
aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ
abnormalities linked to microtubule and synaptic stabilization. Furthermore, the
localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal
cords in a manner similar to our observations in Drosophila motor neurons.
Together, our results suggest a microtubule-dependent mechanism in motor neuron
disease caused by TDP-43-dependent alterations in futsch mRNA localization and
translation in vivo.
Copyright © 2014 the authors 0270-6474/14/3415962-13$15.00/0.
DOI: 10.1523/JNEUROSCI.2526-14.2014
PMCID: PMC4244467
PMID: 25429138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26557057 | 1. Front Cell Neurosci. 2015 Oct 23;9:423. doi: 10.3389/fncel.2015.00423.
eCollection 2015.
Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to
pathological inclusions in ALS?
Aulas A(1), Vande Velde C(2).
Author information:
(1)Centre de Recherche du Centre Hospitalier de l'Université de Montréal
Montréal, QC, Canada ; Department of Biochemistry, Université de Montréal
Montréal, QC, Canada.
(2)Centre de Recherche du Centre Hospitalier de l'Université de Montréal
Montréal, QC, Canada ; Department of Neurosciences, Université de Montréal
Montréal, QC, Canada.
Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to
stress exposure. Since their discovery in 1999, over 120 proteins have been
described to be localized to these structures (in 154 publications). Most of
these components are RNA binding proteins (RBPs) or are involved in RNA
metabolism and translation. SGs have been linked to several pathologies
including inflammatory diseases, cancer, viral infection, and neurodegenerative
diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
(FTD). In ALS and FTD, the majority of cases have no known etiology and exposure
to external stress is frequently proposed as a contributor to either disease
initiation or the rate of disease progression. Of note, both ALS and FTD are
characterized by pathological inclusions, where some well-known SG markers
localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43
and FUS serve as an interface between genetic susceptibility and environmental
stress exposure in disease pathogenesis. Here, we will discuss the role of
TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this
process.
DOI: 10.3389/fncel.2015.00423
PMCID: PMC4615823
PMID: 26557057 |
http://www.ncbi.nlm.nih.gov/pubmed/24336168 | 1. Nat Genet. 2014 Feb;46(2):152-60. doi: 10.1038/ng.2853. Epub 2013 Dec 15.
Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in
amyotrophic lateral sclerosis disease models.
Kim HJ(1), Raphael AR(2), LaDow ES(3), McGurk L(4), Weber RA(4), Trojanowski
JQ(5), Lee VM(5), Finkbeiner S(3), Gitler AD(2), Bonini NM(4).
Author information:
(1)1] Department of Biology, University of Pennsylvania, Philadelphia,
Pennsylvania, USA. [2].
(2)Department of Genetics, Stanford University School of Medicine, Stanford,
California, USA.
(3)Gladstone Institute of Neurological Disease, San Francisco, California, USA.
(4)Department of Biology, University of Pennsylvania, Philadelphia,
Pennsylvania, USA.
(5)Department of Pathology and Laboratory Medicine, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative
disease primarily affecting motor neurons. A unifying feature of many proteins
associated with ALS, including TDP-43 and ataxin-2, is that they localize to
stress granules. Unexpectedly, we found that genes that modulate stress granules
are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and
Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity
in flies, and TDP-43 interacts with a central stress granule component,
polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates
abnormally, suggesting that prolonged stress granule dysfunction may contribute
to pathogenesis. We investigated the efficacy of a small molecule inhibitor of
eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated
TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the
dysfunction induced by prolonged stress granule formation might contribute
directly to ALS and that compounds that mitigate this process may represent a
novel therapeutic approach.
DOI: 10.1038/ng.2853
PMCID: PMC3934366
PMID: 24336168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2129297 | 1. Cancer Surv. 1990;9(4):689-702.
Progress towards the isolation and characterization of the genes causing
neurofibromatosis.
Menon AG(1), Gusella JF, Seizinger BR.
Author information:
(1)Molecular Neurogenetics Laboratory, Massachusetts General Hospital, Boston
02114.
The locus for the gene causing neurofibromatosis type 1 (NF1) was bracketed to a
region on the long arm of chromosome 17 by means of genetic linkage analysis.
When the limits of resolution for genetic mapping were reached physical mapping
methods were used to map the NF1 gene precisely, with reference to translocation
breakpoints in NF1 affected individuals who harboured constitutional chromosomal
translocations on chromosome 17. The region of DNA located between two
translocation breakpoints has been cloned and a DNA sequence encoding a 11-13 kb
mRNA identified. That this sequence shows deletions and point mutations in NF1
affected individuals and not in normal controls provides strong evidence that it
is indeed the NF1 gene. The genetic defect in NF2 has been mapped to chromosome
22 by studies of chromosomal loss in tumours associated with this disease.
Subsequent linkage analysis of NF2 pedigrees has confirmed this location. DNA
markers that bracket the NF2 locus to a region of 5-10 Mb have been identified.
PMID: 2129297 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25216585 | 1. Neurobiol Aging. 2014 Dec;35(12):2822-2831. doi:
10.1016/j.neurobiolaging.2014.07.026. Epub 2014 Jul 27.
Autophagy regulates amyotrophic lateral sclerosis-linked fused in
sarcoma-positive stress granules in neurons.
Ryu HH(1), Jun MH(2), Min KJ(2), Jang DJ(3), Lee YS(4), Kim HK(5), Lee JA(6).
Author information:
(1)Department of Biotechnology and Biological Sciences, Hannam University,
Daejeon, Korea; Department of Life Science, Chung-Ang University, Seoul, Korea.
(2)Department of Biotechnology and Biological Sciences, Hannam University,
Daejeon, Korea.
(3)Department of Applied Biology, Kyungpook National University, Kyungbuk,
Korea.
(4)Department of Life Science, Chung-Ang University, Seoul, Korea. Electronic
address: [email protected].
(5)Department of Medicine and Microbiology, Chungbuk National University,
Cheongju, Korea. Electronic address: [email protected].
(6)Department of Biotechnology and Biological Sciences, Hannam University,
Daejeon, Korea. Electronic address: [email protected].
Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been
associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal
neurodegenerative disease that causes progressive muscular weakness and has
overlapping clinical and pathologic characteristics with frontotemporal lobar
degeneration. However, the role of autophagy in regulation of FUS-positive
stress granules (SGs) and aggregates remains unclear. We found that the
ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under
oxidative stress, leading to a disruption in the release of FUS from SGs in
cultured neurons. Autophagy controls the quality of proteins or organelles;
therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs.
Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive
autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse
embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However,
FUS(R521C) expression did not significantly impair autophagic degradation.
Moreover, autophagy activation with rapamycin reduced the accumulation of
FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced
neurite fragmentation and cell death in neurons expressing mutant FUS under
oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS
associated with a FUS mutation under oxidative stress, as well as therapeutic
insight regarding FUS pathology associated with excessive SGs.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2014.07.026
PMID: 25216585 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12727944 | 1. J Clin Endocrinol Metab. 2003 May;88(5):1999-2002. doi:
10.1210/jc.2002-021874.
Treatment of type II amiodarone-induced thyrotoxicosis by either iopanoic acid
or glucocorticoids: a prospective, randomized study.
Bogazzi F(1), Bartalena L, Cosci C, Brogioni S, Dell'Unto E, Grasso L,
Aghini-Lombardi F, Rossi G, Pinchera A, Braverman LE, Martino E.
Author information:
(1)Department of Endocrinology and Metabolism, University of Pisa, Italy.
[email protected]
Amiodarone-induced thyrotoxicosis (AIT) may occur either in the presence of
underlying thyroid disease (type I AIT) or in apparently normal thyroid glands
(type II AIT). Type II AIT, a destructive thyroiditis, often favorably responds
to glucocorticoids. Iopanoic acid (IopAc) is an iodinated cholecystographic
agent that inhibits deiodinase activity and reduces the conversion of T(4)
toT(3). It has recently been reported that cholecystographic agents restore
euthyroidism in patients with type II AIT. We describe the results of a
prospective randomized study conducted in 12 patients with type II AIT treated
with either iopanoic acid (group A, n = 6) or glucocorticoids (group B, n = 6).
Serum free T(3) levels normalized rapidly in both groups after 7 d, from 0.75
+/- 0.20 ng/dl (11.5 +/- 3.1 pmol/liter) to 0.46 +/- 0.10 ng/d (7.1 +/- 1.7
pmol/liter), P < 0.01, and from 0.58 +/- 0.10 ng/dl (9.0 +/- 1.2 pmol/liter) to
0.34 +/- 0.03 ng/dl (5.2 +/- 0.5 pmol/liter), P < 0.003, in groups A and B,
respectively (P = NS). Serum free T(4) levels reduced at 6 months in group B
[from 2.70 +/- 0.32 ng/dl (35.1 +/- 4.1 pmol/liter) to 1.0 +/- 0.04 ng/dl (13.4
+/- 0.6 pmol/liter), P < 0.0001] but not in group A (from 2.90 +/- 0.6 ng/dl
(38.0 +/- 7.5 pmol/liter) to 2.30 +/- 0.4 ng/dl (35.6 +/- 6.1 pmol/liter, P =
0.39; P = 0.005 group B vs. group A). All patients in both groups became
euthyroid and had their amiodarone-induced destructive thyroiditis cured as
defined by normalization of both serum free T(4) and free T(3) levels, during
both drugs therapy. However, patients in group B were cured more rapidly than
patients in group A (43 +/- 34 d vs. 221 +/- 111 d, respectively, P < 0.002).
This study shows that, albeit both drugs are effective, glucocorticoids are
probably the drug of choice for more rapidly curing type II AIT.
DOI: 10.1210/jc.2002-021874
PMID: 12727944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15157997 | 1. Neurosci Lett. 2004 Jun 3;363(1):62-4. doi: 10.1016/j.neulet.2004.03.043.
Proton magnetic resonance spectroscopy in children with spastic diplegia.
Kulak W(1), Sobaniec W, Kubas B, Walecki J.
Author information:
(1)Department of Pediatric Neurology, Medical University of Bialystok,
Waszyngtona 17, 15-274 Bialystok, Poland. [email protected]
The objective of this prospective study was the application of proton magnetic
resonance spectroscopy in children with spastic diplegia (SD) to determine the
metabolite profile of SD children in the left basal ganglia, and to assess the
relationship of this profile with motor and mental development. Patients with SD
showed reduced ratios of N-acetylaspartate (NAA)/creatine (Cr), NAA/choline
(Cho), NAA/myo-inositol (mI), Cho/NAA, Cho/Cr and Cho/mI in the basal ganglia
compared to a well-matched control group. On the other hand, we noted increased
Cr/NAA, Cr/Cho and mI/NAA ratios in the SD patients as compared with controls.
NAA/mI ratios were positively correlated with the severity scale of cerebral
palsy in SD children. There was also a significant correlation between Cr/NAA
and mental retardation. Increased Cr/NAA, Cr/Cho and mI/NAA ratios in SD
children may suggest the existence of the compensatory mechanisms in these
patients. The NAA/mI ratio could be used as an additional marker of SD severity
and Cr/NAA as a marker of the mental retardation.
DOI: 10.1016/j.neulet.2004.03.043
PMID: 15157997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21567923 | 1. Am J Med Genet A. 2011 Jun;155A(6):1360-6. doi: 10.1002/ajmg.a.33996. Epub
2011 May 12.
Lethal presentation of neurofibromatosis and Noonan syndrome.
Prada CE(1), Zarate YA, Hagenbuch S, Lovell A, Schorry EK, Hopkin RJ.
Author information:
(1)Division of Human Genetics, Cincinnati Children's Hospital Medical Center,
Ohio 45229, USA.
Neurofibromatosis type 1 and Noonan syndrome are both common genetic disorders
with autosomal dominant inheritance. Similarities between neurofibromatosis type
1 and Noonan syndrome have been noted for over 20 years and patients who share
symptoms of both conditions are often given the diagnosis of
neurofibromatosis-Noonan syndrome (NFNS). The molecular basis of these combined
phenotypes was poorly understood and controversially discussed over several
decades until the discovery that the syndromes are related through disturbances
of the Ras pathway. We present an infant male with coarse facial features,
severe supravalvar pulmonic stenosis, automated atrial tachycardia, hypertrophic
cardiomyopathy, airway compression, severe neurological involvement, and
multiple complications that lead to death during early infancy. The severity of
clinical presentation and significant dysmorphic features suggested the
possibility of a double genetic disorder in the Ras pathway instead of NFNS.
Molecular analysis showed a missense mutation in exon 25 of the NF1 gene
(4288A>G, p.N1430D) and a pathogenic mutation on exon 8 (922A>G, p.N308D) of the
PTPN11 gene. Cardiovascular disease has been well described in patients with
Noonan syndrome with PTPN11 mutations but the role of haploinsufficiency for
neurofibromin in the heart development and function is not yet well understood.
Our case suggests that a double genetic defect resulting in the hypersignaling
of the Ras pathway may lead to complex cardiovascular abnormalities,
cardiomyopathy, refractory arrhythmia, severe neurological phenotype, and early
death.
Copyright © 2011 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.33996
PMID: 21567923 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10692426 | 1. J Biol Chem. 2000 Mar 3;275(9):6288-94. doi: 10.1074/jbc.275.9.6288.
Selenoprotein P expression, purification, and immunochemical characterization.
Tujebajeva RM(1), Harney JW, Berry MJ.
Author information:
(1)Thyroid Division, Department of Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts 02115, USA.
Most selenoproteins contain a single selenocysteine residue per polypeptide
chain, encoded by an in-frame UGA codon. Selenoprotein P is unique in that its
mRNA encodes 10-12 selenocysteine residues, depending on species. In addition to
the high number of selenocysteines, the protein is cysteine- and histidine-rich.
The function of selenoprotein P has remained elusive, in part due to the
inability to express the recombinant protein. This has been attributed to
presumed inefficient translation through the selenocysteine/stop codons. Herein,
we report for the first time the expression of recombinant rat selenoprotein P
in a transiently transfected human epithelial kidney cell line, as well as the
endogenously expressed protein from HepG2 and Chinese hamster ovary cells. The
majority of the expressed protein migrates with the predicted 57-kDa size of
full-length glycosylated selenoprotein P. Based on the histidine-rich nature of
selenoprotein P, we have purified the recombinant and endogenously expressed
proteins using nickel-agarose affinity chromatography. We show that the
recombinant rat and endogenous human proteins react in Western blotting and
immunoprecipitation assays with commercial anti-histidine antibodies. The
ability to express, purify, and immunochemically detect the recombinant protein
provides a foundation for investigating the functions and efficiency of
expression of this intriguing protein.
DOI: 10.1074/jbc.275.9.6288
PMID: 10692426 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24239880 | 1. Arch Phys Med Rehabil. 2014 Feb;95(2):369-74. doi: 10.1016/j.apmr.2013.10.025.
Epub 2013 Nov 12.
Validity and clinical utility of functional assessments in children with
cerebral palsy.
Chrysagis N(1), Skordilis EK(2), Koutsouki D(3).
Author information:
(1)Department of Physical Therapy, Technological Educational Institute of
Athens, Athens, Greece; Laboratory of Adapted Physical Activity/Developmental
and Physical Disabilities, Athens, Greece.
(2)Department of Physical Education and Sport Sciences, National and
Kapodistrian University of Athens, Athens, Greece. Electronic address:
[email protected].
(3)Laboratory of Adapted Physical Activity/Developmental and Physical
Disabilities, Athens, Greece; Department of Physical Education and Sport
Sciences, National and Kapodistrian University of Athens, Athens, Greece.
OBJECTIVE: To examine the validity and clinical utility of functional
assessments (1-minute walk test, 10-meter walk test, Timed Up & Go [TUG] test,
Timed Up and Down Stairs [TUDS] test, sit-to-stand [STS] test, and lateral
step-up [LSU] test).
DESIGN: Cross-sectional study.
SETTING: Four special schools for adolescents with physical disabilities.
PARTICIPANTS: Adolescents with spastic tetraplegia and diplegia (at levels
I-III) were selected through convenience sampling (N=35; mean age, 14.97±2.03y).
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: GMFM-88 (dimensions D and E), 1-minute walk, 10-meter
walk, TUG, TUDS, STS, and LSU tests. Data were analyzed using Pearson
intercorrelations, multiple regression analysis, and multivariate analysis of
variance (MANOVA).
RESULTS: Significant moderate to high intercorrelations were found. Three
significant positive predictors emerged (1-minute walk, 10-meter walk, and LSU)
with the following regression equation: YGMFM-88 (dimensions D and E) = 5.708 +
.402 × X1-minute walk + .920 × XLSU + .404 × X10-meter walk The MANOVA was
significant (Λ=.163, F=14.732, P<.001, η(2)=.596), and post hoc comparisons
revealed significant differences across Gross Motor Function Classification
System Expanded and Revised levels in all paired comparisons for the 1-minute
walk and LSU tests. For the 10-meter walk test, significant differences were
evident in the level I versus level III and level II versus level III
comparisons. No significant differences were found in the 10-meter walk test
between levels I and II.
CONCLUSIONS: These functional assessments (1-minute walk, LSU, and 10-meter walk
tests) are simple to administer, quick, low cost, and user-friendly. Although
these assessments are not a substitute for the criterion standard (GMFM-88),
they may be used for a quick assessment in adolescents with cerebral palsy
(levels I-III) either at school or during rehabilitation, especially when time
is limited.
Copyright © 2014 American Congress of Rehabilitation Medicine. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.apmr.2013.10.025
PMID: 24239880 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25700542 | 1. Arch Dis Child. 2015 May;100(5):500-4. doi: 10.1136/archdischild-2014-307443.
Epub 2014 Nov 18.
The differential diagnosis of spastic diplegia.
Huntsman R(1), Lemire E(2), Norton J(3), Dzus A(4), Blakley P(5), Hasal S(1).
Author information:
(1)Division of Pediatric Neurology, Department of Pediatrics, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
(2)Division of Medical Genetics, Department of Pediatrics, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
(3)Division of Neurosurgery, Department of Surgery, University of Saskatchewan,
Saskatoon, Saskatchewan, Canada.
(4)Division of Pediatric Orthopedics, Department of Surgery, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
(5)Division of Developmental Pediatrics, Department of Pediatrics, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
Spastic diplegia is the most common form of cerebral palsy worldwide. Many
disorders mimic spastic diplegia, which can result in misdiagnosis for the child
with resultant negative treatment and family counselling implications. In this
paper, the authors provide a brief review of spastic diplegia and the various
disorders in the differential diagnosis. We also provide a diagnostic algorithm
to assist physicians in making the correct diagnosis.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.
DOI: 10.1136/archdischild-2014-307443
PMID: 25700542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20397744 | 1. Twin Res Hum Genet. 2010 Apr;13(2):135-42. doi: 10.1375/twin.13.2.135.
Heritability and genome-wide linkage scan of subjective happiness.
Bartels M(1), Saviouk V, de Moor MH, Willemsen G, van Beijsterveldt TC, Hottenga
JJ, de Geus EJ, Boomsma DI.
Author information:
(1)Department of Biological Psychology, VU University, Amsterdam, the
Netherlands. [email protected]
Causes of individual differences in happiness, as assessed with the Subjective
Happiness Scale, are investigated in a large of sample twins and siblings from
the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7
years (range 12 to 88), took part in the study. A genetic model with an age by
sex design was fitted to the data with structural equation modeling in Mx. The
heritability of happiness was estimated at 22% for males and 41% in females. No
effect of age was observed. To identify the genomic regions contributing to this
heritability, a genome-wide linkage study for happiness was conducted in sibling
pairs. A subsample of 1157 offspring from 441 families was genotyped with an
average of 371 micro-satellite markers per individual. Phenotype and genotype
data were analyzed in MERLIN with multipoint variance component linkage analysis
and age and sex as covariates. A linkage signal (logarithm of odds score 2.73,
empirical p value 0.095) was obtained at the end of the long arm of chromosome
19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at
the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical
p value of .209). These two regions of interest are not overlapping with the
regions found for contrasting phenotypes (such as depression, which is
negatively associated with happiness). Further linkage and future association
studies are warranted.
DOI: 10.1375/twin.13.2.135
PMID: 20397744 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22885141 | 1. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:122-5. doi:
10.1016/j.pnpbp.2012.07.018. Epub 2012 Aug 4.
The MAOA gene predicts happiness in women.
Chen H(1), Pine DS, Ernst M, Gorodetsky E, Kasen S, Gordon K, Goldman D, Cohen
P.
Author information:
(1)Department of Epidemiology & Biostatistics, College of Public Health,
University of South Florida, Tampa, FL 33612, USA. [email protected]
Psychologists, quality of life and well-being researchers have grown
increasingly interested in understanding the factors that are associated with
human happiness. Although twin studies estimate that genetic factors account for
35-50% of the variance in human happiness, knowledge of specific genes is
limited. However, recent advances in molecular genetics can now provide a window
into neurobiological markers of human happiness. This investigation examines
association between happiness and monoamine oxidase A (MAOA) genotype. Data were
drawn from a longitudinal study of a population-based cohort, followed for three
decades. In women, low expression of MAOA (MAOA-L) was related significantly to
greater happiness (0.261 SD increase with one L-allele, 0.522 SD with two
L-alleles, P=0.002) after adjusting for the potential effects of age, education,
household income, marital status, employment status, mental disorder, physical
health, relationship quality, religiosity, abuse history, recent negative life
events and self-esteem use in linear regression models. In contrast, no such
association was found in men. This new finding may help explain the gender
difference on happiness and provide a link between MAOA and human happiness.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pnpbp.2012.07.018
PMCID: PMC6299830
PMID: 22885141 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11122377 | 1. Genes Cells. 2000 Nov;5(11):897-903. doi: 10.1046/j.1365-2443.2000.00375.x.
Expression and characterization of nonmammalian selenoprotein P in the
zebrafish, Danio rerio.
Tujebajeva RM(1), Ransom DG, Harney JW, Berry MJ.
Author information:
(1)Department of Medicine, Brigham and Women's Hospital and Harvard Medical
School, Boston, MA 02115, USA.
BACKGROUND: Selenoprotein P is a protein of considerable intrigue, due to its
unusual composition and requirements for its biosynthesis. Whereas most
selenoproteins contain a single selenocysteine residue, the human, bovine and
rodent selenoprotein P genes encode proteins containing 10-12 selenocysteines.
Selenoprotein P genes have, to date, only been reported in mammals, and the
function of the protein remains elusive.
RESULTS: Herein, we report the identification and characterization of
nonmammalian selenoprotein P in the zebrafish Danio rerio. Sequencing of the
cDNA revealed the presence of 17 selenocysteine codons, the highest number
reported in any protein. Two histidine-rich regions present in the mammalian
selenoprotein P sequences are conserved in the zebrafish protein, and two SECIS
elements are present in the 3' untranslated region. Whole-mount in situ
hybridization of zebrafish embryos revealed high levels of expression of
selenoprotein P mRNA in fertilized eggs and in the yolk sac of developing
embryos. Transient transfection of the cDNA in mammalian cells resulted in
efficient expression of the full-length secreted selenoprotein. A single
N-glycosylation site is predicted, and shown to be utilized.
CONCLUSIONS: Discovery of selenoprotein P in the zebrafish opens a previously
unavailable avenue for genetic investigation of the functions of this unusual
protein.
DOI: 10.1046/j.1365-2443.2000.00375.x
PMID: 11122377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23257289 | 1. Hum Mol Genet. 2013 Mar 15;22(6):1193-205. doi: 10.1093/hmg/dds526. Epub 2012
Dec 20.
RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic
mislocalization and incorporation into stress granules associated with FUS
carrying ALS-linked mutations.
Daigle JG(1), Lanson NA Jr, Smith RB, Casci I, Maltare A, Monaghan J, Nichols
CD, Kryndushkin D, Shewmaker F, Pandey UB.
Author information:
(1)Department of Genetics, Louisiana State University Health Sciences Center,
New Orleans, LA, USA.
Amyotrophic lateral sclerosis (ALS) is an uncommon neurodegenerative disease
caused by degeneration of upper and lower motor neurons. Several genes,
including SOD1, TDP-43, FUS, Ubiquilin 2, C9orf72 and Profilin 1, have been
linked with the sporadic and familiar forms of ALS. FUS is a DNA/RNA-binding
protein (RBP) that forms cytoplasmic inclusions in ALS and frontotemporal
lobular degeneration (FTLD) patients' brains and spinal cords. However, it is
unknown whether the RNA-binding ability of FUS is required for causing ALS
pathogenesis. Here, we exploited a Drosophila model of ALS and neuronal cell
lines to elucidate the role of the RNA-binding ability of FUS in regulating
FUS-mediated toxicity, cytoplasmic mislocalization and incorporation into stress
granules (SGs). To determine the role of the RNA-binding ability of FUS in ALS,
we mutated FUS RNA-binding sites (F305L, F341L, F359L, F368L) and generated
RNA-binding-incompetent FUS mutants with and without ALS-causing mutations
(R518K or R521C). We found that mutating the aforementioned four phenylalanine
(F) amino acids to leucines (L) (4F-L) eliminates FUS RNA binding. We observed
that these RNA-binding mutations block neurodegenerative phenotypes seen in the
fly brains, eyes and motor neurons compared with the expression of
RNA-binding-competent FUS carrying ALS-causing mutations. Interestingly,
RNA-binding-deficient FUS strongly localized to the nucleus of Drosophila motor
neurons and mammalian neuronal cells, whereas FUS carrying ALS-linked mutations
was distributed to the nucleus and cytoplasm. Importantly, we determined that
incorporation of mutant FUS into the SG compartment is dependent on the
RNA-binding ability of FUS. In summary, we demonstrate that the RNA-binding
ability of FUS is essential for the neurodegenerative phenotype in vivo of
mutant FUS (either through direct contact with RNA or through interactions with
other RBPs).
DOI: 10.1093/hmg/dds526
PMCID: PMC3578413
PMID: 23257289 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18985280 | 1. Mol Cell Biochem. 2009 Feb;322(1-2):25-36. doi: 10.1007/s11010-008-9936-9.
Epub 2008 Nov 5.
Role of healing-specific-matricellular proteins and matrix metalloproteinases in
age-related enhanced early remodeling after reperfused STEMI in dogs.
Jugdutt BI(1), Palaniyappan A, Uwiera RR, Idikio H.
Author information:
(1)Division of Cardiology, Department of Medicine, 2C2 Walter MacKenzie Health
Sciences Centre, University of Alberta, Edmonton, AB, Canada.
[email protected]
We assessed whether aging augments left ventricular (LV) damage, remodeling, and
dysfunction and alters expression of healing-specific-matricellular proteins
(HSMPs), matrix metalloproteinases (MMPs) and other pertinent proteins after
acute reperfused-ST-segment-elevation myocardial infarction (RSTEMI) in the dog
model. The findings suggest a novel role for HSMPs, MMPs, and the other proteins
in the age-related increase in LV damage, remodeling, and dysfunction.
Potentially detrimental effects of the altered proteins appear to outweigh
beneficial effects and contribute to adverse outcome. Deleterious changes
include the increase in matrix-degrading MMPs, inducible nitric oxide synthase
(iNOS) and pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis
factor (TNF)-alpha, HSMPs such as secreted-protein-acidic-and-rich-in-cysteine
(SPARC) and osteopontin (OPN), the blunted increase in endothelial-NOS (eNOS),
and the decrease in IL-10 and neuronal NOS (nNOS). Potentially beneficial
changes include increases in the HSMP secretory-leucocyte-protease-inhibitor
(SLPI) and cytokine transforming growth factor (TGF)-beta(1). Targeting these
proteins may mitigate enhanced LV remodeling and dysfunction with aging.
DOI: 10.1007/s11010-008-9936-9
PMID: 18985280 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24148813 | 1. Neuropharmacology. 2014 Feb;77:334-41. doi: 10.1016/j.neuropharm.2013.10.014.
Epub 2013 Oct 19.
Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey
following administration of opicapone, a third generation nitrocatechol COMT
inhibitor.
Bonifácio MJ(1), Sutcliffe JS(2), Torrão L(1), Wright LC(1), Soares-da-Silva
P(3).
Author information:
(1)Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado,
Portugal.
(2)Maccine Pte Ltd., 10 Science Park Road, #01-05 The Alpha, Singapore Science
Park II, Singapore.
(3)Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado,
Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine,
University Porto, Porto, Portugal. Electronic address: [email protected].
OBJECTIVE: The present study aimed at evaluating the effect of opicapone, a
third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on
the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine
(levodopa) and related metabolites in the cynomolgus monkey.
METHODS: Four monkeys, implanted with guiding cannulas for microdialysis probes,
in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized
in two groups that received, in a crossover design, vehicle or 100 mg/kg
opicapone for 14 days. Twenty-three hours after last administration of vehicle
or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg).
Extracellular dialysate and blood samples were collected over 360 min (at 30 min
intervals) for the assays of catecholamine and COMT activity.
RESULTS: Opicapone increased levodopa systemic exposure by 2-fold not changing
Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by
5-fold. These changes were accompanied by ∼76-84% reduction in erythrocyte COMT
activity. In dorsal striatum and substantia nigra, opicapone increased levodopa
exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and
7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia
nigra. In the prefrontal cortex, opicapone increased levodopa exposure and
reduced 3-OMD levels by 2.3- and 2.4-fold, respectively.
CONCLUSIONS: Opicapone behaved as long-acting COMT inhibitor that markedly
increased systemic and central levodopa bioavailability. Opicapone is a strong
candidate to fill the unmet need for COMT inhibitors that lead to more sustained
levodopa levels in Parkinson's disease patients.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropharm.2013.10.014
PMID: 24148813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23248072 | 1. Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7.
Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel
catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow
enzyme-inhibitor complex dissociation of a short-living and very long-acting
inhibitor.
Almeida L(1), Rocha JF, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ,
Wright LC, Nunes T, Soares-da-Silva P.
Author information:
(1)Health Sciences Department, University of Aveiro, Aveiro, Portugal.
BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase
(COMT) inhibitor. The purpose of this study was to evaluate the tolerability,
pharmacokinetics (including the effect of food) and pharmacodynamics (effect on
COMT activity) following single oral doses of opicapone in young healthy male
volunteers.
METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800
and 1,200 mg) were administered to eight groups of eight subjects per group (two
subjects randomized to placebo and six subjects to opicapone), under a
double-blind, randomized, placebo-controlled design. In an additional group of
12 subjects, a 50 mg single dose of opicapone was administered on two occasions,
once having fasted overnight and once with a high-fat high-calorie meal.
RESULTS: Opicapone was well tolerated at all doses tested. The extent of
systemic exposure (area under the plasma concentration-time curve and maximum
plasma concentration) to opicapone and metabolites increased in an approximately
dose-proportional manner and showed a decrease following concomitant ingestion
of a high-fat high-calorie meal. The apparent terminal elimination half-life of
opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway
for opicapone, and both opicapone and the main sulphated metabolite are likely
excreted by the biliary route. Maximum COMT inhibition by opicapone was dose
dependent, ranged from 36.1% (10 mg) to 100% (200 mg and above), and reached
statistical significance at all doses tested. The long duration of COMT
inhibition by opicapone, however, tended to be independent from the dose taken.
The observed half-life of opicapone-induced COMT inhibition in human
erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an
underlying dissociative process with a kinetic rate constant of 3.1 × 10(-6)
s(-1) (SD = 1.9 × 10(-6) s(-1)). Such a process compares well to the estimated
dissociation rate constant (k(off)) of the COMT-opicapone molecular complex
(k(off) = 1.9 × 10(-6) s(-1)).
CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional
kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte
soluble COMT activity. Based on the observation that the half-life of COMT
inhibition is independent of the dose and that it reflects an underlying kinetic
process that is consistent with the k(off) value of the COMT-opicapone complex,
we propose that the sustained COMT inhibition, far beyond the observable point
of clearance of circulating drug, is due to the long residence time of the
reversible complex formed between COMT and opicapone. Globally, these promising
results provide a basis for further clinical development of opicapone.
DOI: 10.1007/s40262-012-0024-7
PMID: 23248072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24271646 | 1. Eur J Clin Pharmacol. 2014 Mar;70(3):279-86. doi: 10.1007/s00228-013-1602-9.
Epub 2013 Nov 24.
Effect of moderate liver impairment on the pharmacokinetics of opicapone.
Rocha JF(1), Santos A, Falcão A, Lopes N, Nunes T, Pinto R, Soares-da-Silva P.
Author information:
(1)Department of Research and Development, Bial (Portela and Cª, S.A.), Av. da
Siderurgia Nacional, 4745-457, S. Mamede do Coronado, Portugal.
PURPOSE: Opicapone (OPC) is a novel catechol-O-methyltransferase (COMT)
inhibitor to be used as adjunctive therapy in levodopa-treated patients with
Parkinson's disease. The purpose of this study was to evaluate the effect of
moderate liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD;
effect on COMT activity) of OPC.
METHODS: An open-label, parallel-group study in patients (n = 8) with moderate
liver impairment (Child-Pugh category B, score of 7 to 9) and matched healthy
subjects (n = 8, control) with normal liver function. All subjects received a
single 50-mg oral dose of OPC, with plasma and urine concentrations of opicapone
and its metabolites measured up to 72 h post-dose, including soluble COMT
(S-COMT) activity. A one-way analysis of variance (ANOVA) was used to compare
the main PK and PD parameters between groups. Point estimates (PE) of geometric
mean ratios (GMR) and corresponding 90 % confidence intervals (90%CI) for the
ratio hepatic/control subjects of each parameter were calculated and compared
with the reference interval (80-125 %).
RESULTS: Exposure to opicapone (AUC and Cmax) increased significantly in
patients with moderate hepatic impairment (PE [90%CI]: AUC0-∞, 184 %
[135-250 %]; Cmax, 189 % [144-249 %]). Although apparent total clearance (CL/F)
of opicapone was decreased by ∼35 %, similar elimination half-life and
unbound/bound fractions of opicapone were observed between the two groups. Both
rate and extent of exposure to BIA 9-1103 were higher in the hepatically
impaired group, but not statistically significant compared with the control
group. Similar to the parent (opicapone), the observed increase in exposure to
BIA 9-1106 was statistically significant in the hepatically impaired group over
the control group. BIA 9-1106 was the only metabolite detected in urine and its
urine PK parameters were in accordance with plasma data. Maximum S-COMT
inhibition (Emax) occurred earlier for the hepatically impaired group with
values of 100 % and 91.2 % for the hepatically impaired and control groups
respectively. Both Emax and AUEC for the hepatically impaired group reached
statistical significance over the control group. OPC was well tolerated in both
hepatically impaired and control groups.
CONCLUSION: The bioavailability of an orally administered single dose of 50 mg
OPC was significantly higher in patients with moderate chronic hepatic
impairment, perhaps by a reduced first-pass effect. As the tolerability profile
of OPC was favourable under the conditions of this study and its exposure is
completely purged from systemic circulation before the subsequent dose
administration, no OPC dose adjustment is needed in patients with mild to
moderate chronic hepatic impairment. However, as OPC is under clinical
development for use as adjunctive therapy in levodopa-treated patients with
Parkinson's disease, an adjustment of levodopa and/or OPC regimens in patients
should be carefully considered based on a potentially enhanced levodopa
dopaminergic response and the associated tolerability.
DOI: 10.1007/s00228-013-1602-9
PMID: 24271646 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24297750 | 1. J Cell Biol. 2013 Dec 9;203(5):737-46. doi: 10.1083/jcb.201306058. Epub 2013
Dec 2.
The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP
granules.
Yasuda K(1), Zhang H, Loiselle D, Haystead T, Macara IG, Mili S.
Author information:
(1)Laboratory of Cellular and Molecular Biology, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892.
RNA localization pathways direct numerous mRNAs to distinct subcellular regions
and affect many physiological processes. In one such pathway the
tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell
protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs).
Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS
(fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP
localization but is required for efficient translation of associated
transcripts. Labeling of newly synthesized proteins revealed that Fus promotes
translation preferentially within protrusions. Mutations in Fus cause
amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that
appear to correspond to stress granules. We show that overexpression or mutation
of Fus results in formation of granules, which preferentially recruit APC-RNPs.
Remarkably, these granules are not translationally silent. Instead, APC-RNP
transcripts are translated within cytoplasmic Fus granules. These results
unexpectedly show that translation can occur within stress-like granules.
Importantly, they identify a new local function for cytoplasmic Fus with
implications for ALS pathology.
DOI: 10.1083/jcb.201306058
PMCID: PMC3857475
PMID: 24297750 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23336248 | 1. Br J Clin Pharmacol. 2013 Nov;76(5):763-75. doi: 10.1111/bcp.12081.
Opicapone: a short lived and very long acting novel catechol-O-methyltransferase
inhibitor following multiple dose administration in healthy subjects.
Rocha JF(1), Almeida L, Falcão A, Palma PN, Loureiro AI, Pinto R, Bonifácio MJ,
Wright LC, Nunes T, Soares-da-Silva P.
Author information:
(1)Department of Research & Development, Mamede do Coronado, Portugal.
AIMS: The aim of this study was to assess the tolerability, pharmacokinetics and
inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT)
activity following repeated doses of opicapone.
METHODS: This randomized, placebo-controlled, double-blind study enrolled
healthy male subjects who received either once daily placebo or opicapone 5, 10,
20 or 30 mg for 8 days.
RESULTS: Opicapone was well tolerated. Its systemic exposure increased in an
approximately dose-proportional manner with an apparent terminal half-life of
1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites
recovered in urine accounted for less than 3% of the amount of opicapone
administered suggesting that bile is likely the main route of excretion. Maximum
S-COMT inhibition (Emax ) ranged from 69.9% to 98.0% following the last dose of
opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess
of 100 h, which was dose-independent and much longer than plasma drug exposure.
Such a half-life translates into a putative underlying rate constant that is
comparable with the estimated dissociation rate constant of the COMT-opicapone
complex.
CONCLUSION: Despite its short elimination half-life, opicapone markedly and
sustainably inhibited erythrocyte S-COMT activity making it suitable for a once
daily regimen.
© 2013 BIAL - Portela and Cª S.A. British Journal of Clinical Pharmacology ©
2013 The British Pharmacological Society.
DOI: 10.1111/bcp.12081
PMCID: PMC3853535
PMID: 23336248 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17258946 | 1. Biochim Biophys Acta. 2007 Mar;1774(3):368-72. doi:
10.1016/j.bbapap.2006.12.004. Epub 2006 Dec 20.
The human urine mannose 6-phosphate glycoproteome.
Sleat DE(1), Zheng H, Lobel P.
Author information:
(1)Center for Advanced Biotechnology and Medicine, University of Medicine and
Dentistry of New Jersey, Piscataway, NJ 08854, USA. [email protected]
Glycoproteins containing the mannose 6-phosphate (Man-6-P) modification
represent a class of proteins of considerable biomedical importance. They
include over sixty different soluble lysosomal hydrolases and accessory
proteins, deficiencies of which result in over forty different known human
genetic diseases. In addition, there are patients with lysosomal storage
diseases of unknown etiology and lysosomal proteins have been implicated in
pathophysiological processes associated with Alzheimer disease, arthritis, and
cancer. The aim of this study was to explore urine as a source for the proteomic
investigation of lysosomal storage disorders as well as for biomarker studies on
the role of Man-6-P containing proteins in other human diseases. To this end,
urinary proteins were affinity purified on immobilized Man-6-P receptors,
digested with trypsin, and analyzed using nanospray LC/MS/MS. This resulted in
identification of 67 proteins, including 48 known lysosomal proteins and 9
proteins that may be lysosomal. The identification of a large proportion of the
known set of soluble lysosomal proteins with relatively few contaminants
suggests that urine represents a promising substrate for the development of
comparative proteomic methods for the investigation of lysosomal disorders and
other diseases involving Man-6-P glycoproteins.
DOI: 10.1016/j.bbapap.2006.12.004
PMCID: PMC1859868
PMID: 17258946 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18370023 | 1. Methods Mol Biol. 2008;432:243-58. doi: 10.1007/978-1-59745-028-7_17.
Affinity purification of soluble lysosomal proteins for mass spectrometric
identification.
Jaquinod SK(1), Chapel A, Garin J, Journet A.
Author information:
(1)CEA, DSV, DRDC, Laboratoire de Chimie des Protéines, Grenoble, France.
This chapter describes the process of production, purification, separation, and
mass spectrometry identification of soluble lysosomal proteins. The rationale
for purification of these proteins resides in their characteristic sugar, the
mannose-6-phosphate (M6P), which allows an easy purification by affinity
chromatography on immobilized M6P receptor (MPR). The secretion of M6P proteins
(essentially soluble lysosomal proteins) from cells in culture is induced by
adding a weak base in the culture medium. Secreted proteins are ammonium sulfate
precipitated, dialyzed, and loaded onto the immobilized MPR column. After
specific elution and collection of the M6P proteins, these are resolved by
either bidimensional or monodimensional gel electrophoresis (designated as 2-DE
or 1-DE, respectively). Mass spectrometry analysis is performed on spots excised
from the 2-DE gel, or on discrete bands covering altogether the whole length of
the 1-DE gel lane: these spots or bands are in-gel digested with trypsin and
protein identification is obtained, thanks to peptide mass fingerprints
[provided by analysis of the digests by matrix-assisted laser desorption
ionization-mass spectrometry (MALDI-MS)] or peptide amino acid sequences
(provided by analysis of the digests by the coupling between liquid
chromatography and tandem mass spectrometry, LC-MS/MS).
DOI: 10.1007/978-1-59745-028-7_17
PMID: 18370023 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16842199 | 1. Curr Med Chem. 2006;13(16):1877-93. doi: 10.2174/092986706777585086.
Targeting the inflammatory response in healing myocardial infarcts.
Frangogiannis NG(1).
Author information:
(1)Section of Cardiovascular Sciences, Baylor College of Medicine, Houston TX
77030, USA. [email protected]
Healing of myocardial infarcts depends on an inflammatory cascade that
ultimately results in clearance of dead cells and matrix debris and formation of
a scar. Myocardial necrosis activates complement, Nuclear Factor (NF)-kappaB and
Toll-like Receptor (TLR)-dependent pathways, and generates free radicals,
triggering an inflammatory response. Chemokines and cytokines are markedly
induced in the infarct and mediate recruitment and activation of neutrophils and
mononuclear cells. Extravasation of platelets and plasma proteins, such as
fibrinogen and fibronectin, results in formation of a clot, consisting of
platelets embedded in a mesh of crosslinked fibrin. This provisional matrix
provides a scaffold for migration of cells into the infarct. Monocytes
differentiate into macrophages and secrete fibrogenic and angiogenic growth
factors inducing formation of granulation tissue, containing myofibroblasts and
neovessels. Repression of proinflammatory cytokine and chemokine synthesis,
mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin
(IL)-10, is critical for resolution of the inflammatory infiltrate and
transition to fibrous tissue deposition. Infarct myofibroblasts deposit
extracellular matrix proteins and a collagen-based scar is formed. As the wound
matures, fibroblasts undergo apoptosis and neovessels regress, resulting in
formation of a scar with a low cellular content containing dense, cross-linked
collagen. The pathologic and structural changes associated with infarct healing
directly influence ventricular remodeling and affect prognosis in patients with
myocardial infarction. Understanding the mechanisms involved in the regulation
of the post-infarction inflammatory response, and the spatial and temporal
parameters of wound healing is necessary in order to identify specific molecular
targets for therapeutic intervention.
DOI: 10.2174/092986706777585086
PMID: 16842199 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19569406 | 1. AJS. 2008;114 Suppl:S233-59. doi: 10.1086/592424.
Happiness and success: genes, families, and the psychological effects of
socioeconomic position and social support.
Schnittker J(1).
Author information:
(1)Department of Sociology, University of Pennsylvania, 3718 Locust Walk,
Philadelphia, Pennsylvania 19104-6299, USA. [email protected]
Although there is considerable evidence linking success -- including wealth,
marriage, and friendships -- to happiness, this relationship might not reflect,
as is often assumed, the effects of the proximate environment on well-being.
Such an interpretation is contravened by evidence that both happiness and the
environment are influenced by genetic factors and family upbringing. Using the
National Survey of Midlife Development in the United States, which includes a
subsample of twins, this study evaluates the relationship between happiness and
various features of success before and after eliminating the influence of
endowments. The results suggest that many putative indicators of the environment
are highly heritable and, indeed, that the same genes that affect the
environment may affect happiness as well. Yet the results also suggest that the
role of genetic endowments varies considerably across different features of
success, suggesting complex patterns of selection, reinforcement, and causation
among genes and the environment.
DOI: 10.1086/592424
PMID: 19569406 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16145712 | 1. Proteomics. 2005 Oct;5(15):3966-78. doi: 10.1002/pmic.200401247.
Identification of novel lysosomal matrix proteins by proteome analysis.
Kollmann K(1), Mutenda KE, Balleininger M, Eckermann E, von Figura K, Schmidt B,
Lübke T.
Author information:
(1)Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II,
Georg-August Universität Göttingen, Göttingen, Germany.
The lysosomal matrix is estimated to contain about 50 different proteins. Most
of the matrix proteins are acid hydrolases that depend on mannose 6-phosphate
receptors (MPR) for targeting to lysosomes. Here, we describe a comprehensive
proteome analysis of MPR-binding proteins from mouse. Mouse embryonic
fibroblasts defective in both MPR (MPR 46-/- and MPR 300-/-) are known to
secrete the lysosomal matrix proteins. Secretions of these cells were affinity
purified using an affinity matrix derivatized with MPR46 and MPR300. In the
protein fraction bound to the affinity matrix and eluted with mannose
6-phosphate, 34 known lysosomal matrix proteins, 4 candidate proteins of the
lysosomal matrix and 4 non-lysosomal contaminants were identified by mass
spectrometry after separation by two-dimensional gel electrophoresis or by
multidimensional protein identification technology. For 3 of the candidate
proteins, mammalian ependymin-related protein-2 (MERP-2), retinoid-inducible
serine carboxypeptidase (RISC) and the hypothetical 66.3-kDa protein we could
verify that C-terminally tagged forms bound in an M6P-dependent manner to an
MPR-affinity matrix and were internalized via MPR-mediated endocytosis. Hence
these 3 proteins are likely to represent hitherto unrecognized lysosomal matrix
proteins.
DOI: 10.1002/pmic.200401247
PMID: 16145712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16399764 | 1. Mol Cell Proteomics. 2006 Apr;5(4):686-701. doi: 10.1074/mcp.M500343-MCP200.
Epub 2006 Jan 5.
Identification of sites of mannose 6-phosphorylation on lysosomal proteins.
Sleat DE(1), Zheng H, Qian M, Lobel P.
Author information:
(1)Center for Advanced Biotechnology and Medicine, University of Medicine and
Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Most newly synthesized soluble lysosomal proteins contain mannose 6-phosphate
(Man-6-P), a specific carbohydrate modification that is recognized by Man-6-P
receptors (MPRs) that direct targeting to the lysosome. A number of proteomic
studies have focused on lysosomal proteins, exploiting the fact that
Man-6-P-containing forms can be purified by affinity chromatography on
immobilized MPRs. These studies have identified many known lysosomal proteins as
well as many proteins not previously classified as lysosomal. The latter are of
considerable biological interest with potential implications for lysosomal
function and as candidates for lysosomal storage diseases of unknown etiology.
However, a significant problem in interpreting the biological relevance of such
proteins has been in distinguishing true Man-6-P glycoproteins from simple
contaminants and from proteins associated with true Man-6-P glycoproteins (e.g.
protease inhibitors and lectins). In this report, we describe a mass
spectrometric approach to the verification of Man-6-phosphorylation based upon
LC-MS of MPR-purified proteolytic glycopeptides. This provided a useful tool in
validating novel MPR-purified proteins as true Man-6-P glycoproteins and also
allowed identification of low abundance components not observed in the analysis
of the total Man-6-P glycoprotein mixture. In addition, this approach allowed
the global mapping of 99 Man-6-phosphorylation sites from 44 known lysosomal
proteins purified from mouse and human brain. This information is likely to
provide useful insights into protein determinants for this modification and may
be of significant value in protein engineering approaches designed to optimize
protein delivery to the lysosome in therapeutic applications such as gene and
enzyme replacement therapies.
DOI: 10.1074/mcp.M500343-MCP200
PMID: 16399764 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15789345 | 1. Proteomics. 2005 Apr;5(6):1520-32. doi: 10.1002/pmic.200401054.
The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of
multiple isoforms of many soluble lysosomal proteins.
Sleat DE(1), Lackland H, Wang Y, Sohar I, Xiao G, Li H, Lobel P.
Author information:
(1)Center for Advanced Biotechnology and Medicine, University of Medicine and
Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Erratum in
Proteomics. 2005 May;5(8):2272.
The lysosome is a membrane delimited cytoplasmic organelle that contains at
least 50 hydrolytic enzymes and associated cofactors. The biomedical importance
of these enzymes is highlighted by the many lysosomal storage disorders that are
associated with mutations in genes encoding lysosomal proteins, and there is
also evidence that lysosomal activities may be involved in more widespread human
diseases. The aim of this study was to characterize the human brain lysosomal
proteome with the goal of establishing a reference map to investigate human
diseases of unknown etiology and to gain insights into the cellular function of
the lysosome. Proteins containing mannose 6-phosphate (Man6-P), a carbohydrate
modification used for targeting resident soluble lysosomal proteins to the
lysosome, were affinity-purified using immobilized Man6-P receptor.
Fractionation by two-dimensional electrophoresis resolved a complex mixture
comprising approximately 800 spots. Constituent proteins in each spot were
identified using a combination of matrix-assisted laser
desorption/ionization-time of flight mass spectrometry (both peptide mass
fingerprinting and tandem mass spectrometry) [corrected] on in-gel tryptic
digests and N-terminal sequencing. In a complementary analysis, we also analyzed
a tryptic digest of the unfractionated mixture by liquid chromatography MS/MS.
In total, 61 different proteins were identified. Seven were likely contaminants
associated with true Man6-P glycoproteins. Forty-one were known lysosomal
proteins of which 11 have not previously been reported to contain Man6-P. An
additional nine proteins were either uncharacterized or proteins not previously
reported to have lysosomal function. We found that the human brain
Man6-P-containing lysosomal proteome is highly complex and contains more
proteins with a much greater number of individual isoforms than found in
previous studies of Man6-P glycoproteomes.
DOI: 10.1002/pmic.200401054
PMID: 15789345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26060713 | 1. Iran J Public Health. 2014 Nov;43(11):1468-77.
Happiness & Health: The Biological Factors- Systematic Review Article.
Dfarhud D(1), Malmir M(2), Khanahmadi M(3).
Author information:
(1)1. School of Public Health, Tehran University of Medical Sciences , Tehran,
Iran ; 2. Iranian Academy of Medical Sciences , Tehran, Iran.
(2)3. Dept. of Exceptional Children Psychology, Science & Research Branch,
Islamic Azad University , Tehran, Iran.
(3)4. Dept. of Psychology, Allame Tabataba'i University , Tehran, Iran.
Happiness underlying factors are considerable from two dimensions: endogenic
factors (biological, cognitive, personality and ethical sub-factors) and
exogenic factors (behavioral, socialcultural, economical, geographical, life
events and aesthetics sub-factors). Among all endogenic factors, biological
sub-factors are the significant predictors of happiness. Existence of
significant differences in temperament and happiness of infants is an indicator
of biological influences. Therefore, this study aimed to consider biological
factors that underlie happiness. At the first, all of the biological factors in
relation with happiness were searched from following websites: PubMed, Wiley&
Sons, Science direct (1990-2014). Then, the articles divided into five
sub-groups (genetic, brain and neurotransmitters, endocrinology and hormones,
physical health, morphology and physical attractiveness). Finally, a systematic
review performed based on existing information. Results of studies on genetic
factors indicated an average effectiveness of genetic about 35 -50 percent on
happiness. In spite of difficulties in finding special genes, several genes
distributed to emotion and mood. Neuroscience studies showed that some part of
brain (e.g. amygdala, hipocamp and limbic system) and neurotransmitters (e.g.
dopamine, serotonin, norepinefrine and endorphin) play a role in control of
happiness. A few studies pointed to the role of cortisol and adrenaline (adrenal
gland) and oxitocin (pituitary gland) in controlling happiness. Physical health
and typology also concluded in most related studies to have a significant role
in happiness. Therefore, according to previous research, it can be said that
biological and health factors are critical in underlying happiness and its role
in happiness is undeniable.
PMCID: PMC4449495
PMID: 26060713 |
http://www.ncbi.nlm.nih.gov/pubmed/16709564 | 1. Mol Cell Proteomics. 2006 Oct;5(10):1942-56. doi: 10.1074/mcp.M600030-MCP200.
Epub 2006 May 17.
Identification and validation of mannose 6-phosphate glycoproteins in human
plasma reveal a wide range of lysosomal and non-lysosomal proteins.
Sleat DE(1), Wang Y, Sohar I, Lackland H, Li Y, Li H, Zheng H, Lobel P.
Author information:
(1)Center for Advanced Biotechnology and Medicine, University of Medicine and
Dentistry of New Jersey, Piscataway, 08854, USA.
Acid hydrolase activities are normally confined within the cell to the lysosome,
a membrane-delimited cytoplasmic organelle primarily responsible for the
degradation of macromolecules. However, lysosomal proteins are also present in
human plasma, and a proportion of these retain mannose 6-phosphate (Man-6-P), a
modification on N-linked glycans that is recognized by Man-6-P receptors (MPRs)
that normally direct the targeting of these proteins to the lysosome. In this
study, we purified the Man-6-P glycoforms of proteins from human plasma by
affinity chromatography on immobilized MPRs and characterized this subproteome
by two-dimensional gel electrophoresis and by tandem mass spectrometry. As
expected, we identified many known and potential candidate lysosomal proteins.
In addition, we also identified a number of abundant classical plasma proteins
that were retained even after two consecutive rounds of affinity purification.
Given their abundance in plasma, we initially considered these proteins to be
likely contaminants, but a mass spectrometric study of Man-6-phosphorylation
sites using MPR-purified glycopeptides revealed that some proportion of these
classical plasma proteins contained the Man-6-P modification. We propose that
these glycoproteins are phosphorylated at low levels by the lysosomal enzyme
phosphotransferase, but their high abundance results in detection of Man-6-P
glycoforms in plasma. These results may provide useful insights into the
molecular processes underlying Man-6-phosphorylation and highlight circumstances
under which the presence of Man-6-P may not be indicative of lysosomal function.
In addition, characterization of the plasma Man-6-P glycoproteome should
facilitate development of mass spectrometry-based tools for the diagnosis of
lysosomal storage diseases and for investigating the involvement of
Man-6-P-containing glycoproteins in more widespread human diseases and their
potential utility as biomarkers.
DOI: 10.1074/mcp.M600030-MCP200
PMID: 16709564 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18927503 | 1. Cell Cycle. 2008 Oct;7(20):3127-32. doi: 10.4161/cc.7.20.6892. Epub 2008 Oct
2.
Microsatellites are EWS/FLI response elements: genomic "junk" is EWS/FLI's
treasure.
Gangwal K(1), Lessnick SL.
Author information:
(1)Department of Oncological Sciences, University of Utah School of Medicine,
Salt Lake City, Utah, USA.
Ewing's sarcoma is a solid tumor of the bone that primarily occurs in children
and young adults. Most cases harbor the (11;22) (q24;q12) chromosomal
translocation that encodes the EWS/FLI oncoprotein. EWS/FLI is an aberrant
ETS-type transcription factor that dysregulates a number of genes important in
the development of Ewing's sarcoma. Because EWS/FLI is the key oncoprotein in
this tumor and ETS proteins are often dysregulated in various human cancers,
Ewing's sarcoma serves as a useful paradigm for ETS-mediated oncogenesis. We
recently showed that EWS/FLI interacts with GGAA-microsatellites to regulate
some of its target genes, including NR0B1, an EWS/FLI-regulated gene that is
required for the oncogenic phenotype of Ewing's sarcoma. While microsatellites
typically have no ascribed function, and are sometimes considered "junk" DNA,
our findings provide a unique role for microsatellites in cancer development.
Furthermore, these findings may indicate a novel mechanism for normal ETS
protein function as well. Finally, it is tempting to speculate that
microsatellite polymorphisms may confer differences in susceptibility to Ewing's
sarcoma, both between individuals and between populations, and other diseases
mediated by ETS transcription factors. The observation of microsatellites as
transcriptional response elements for EWS/FLI suggest that these elements may
not be "junk" after all.
DOI: 10.4161/cc.7.20.6892
PMID: 18927503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19920188 | 1. Cancer Res. 2009 Dec 1;69(23):9047-55. doi: 10.1158/0008-5472.CAN-09-1540.
Epub 2009 Nov 17.
EWS/FLI and its downstream target NR0B1 interact directly to modulate
transcription and oncogenesis in Ewing's sarcoma.
Kinsey M(1), Smith R, Iyer AK, McCabe ER, Lessnick SL.
Author information:
(1)Department of Oncological Sciences, University of Utah School of Medicine,
Salt Lake City, Utah, USA.
Most Ewing's sarcomas harbor chromosomal translocations that encode fusions
between EWS and ETS family members. The most common fusion, EWS/FLI, consists of
an EWSR1-derived strong transcriptional activation domain fused, in-frame, to
the DNA-binding domain-containing portion of FLI1. EWS/FLI functions as an
aberrant transcription factor to regulate genes that mediate the oncogenic
phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a
corepressor protein, and likely plays a transcriptional role in tumorigenesis.
However, the genes that NR0B1 regulates and the transcription factors it
interacts with in Ewing's sarcoma are largely unknown. We used transcriptional
profiling and chromatin immunoprecipitation to identify genes that are regulated
by NR0B1, and compared these data to similar data for EWS/FLI. Although the
transcriptional profile overlapped as expected, we also found that the
genome-wide localization of NR0B1 and EWS/FLI overlapped as well, suggesting
that they regulate some genes coordinately. Further analysis revealed that NR0B1
and EWS/FLI physically interact. This protein-protein interaction is likely to
be relevant for the development of Ewing's sarcoma because mutations in NR0B1
that disrupt the interaction have transcriptional consequences and also abrogate
oncogenic transformation. Taken together, these data suggest that EWS/FLI and
NR0B1 physically interact, coordinately modulate gene expression, and mediate
the transformed phenotype of Ewing's sarcoma.
DOI: 10.1158/0008-5472.CAN-09-1540
PMCID: PMC2789197
PMID: 19920188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19383612 | 1. Mol Cell Proteomics. 2009 Jul;8(7):1708-18. doi: 10.1074/mcp.M900122-MCP200.
Epub 2009 Apr 20.
Mass spectrometry-based protein profiling to determine the cause of lysosomal
storage diseases of unknown etiology.
Sleat DE(1), Ding L, Wang S, Zhao C, Wang Y, Xin W, Zheng H, Moore DF, Sims KB,
Lobel P.
Author information:
(1)Center for Advanced Biotechnology and Medicine, Department of Pharmacology,
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical
School, Piscataway, New Jersey 08854, USA.
Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical
cases where clinical phenotype may overlap with other genetically distinct
disorders. In addition, LSDs may result from mutations in genes not yet
implicated in disease. Thus, there are individuals that are diagnosed with
apparent LSD based upon clinical criteria where the gene defect remains elusive.
The objective of this study was to determine whether comparative proteomics
approaches could provide useful insights into such cases. Most LSDs arise from
mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate,
a carbohydrate modification that acts as a signal for intracellular targeting to
the lysosome. We purified mannose 6-phosphorylated proteins by affinity
chromatography and estimated relative abundance of individual proteins in the
mixture by spectral counting of peptides detected by tandem mass spectrometry.
Our rationale was that proteins that are decreased or absent in patients
compared with controls could represent candidates for the primary defect,
directing biochemical or genetics studies. On a survey of brain autopsy
specimens from 23 patients with either confirmed or possible lysosomal disease,
this approach identified or validated the genetic basis for disease in eight
cases. These results indicate that this protein expression approach is useful
for identifying defects in cases of undiagnosed lysosomal disease, and we
demonstrated that it can be used with more accessible patient samples, e.g.
cultured cells. Furthermore this approach was instrumental in the identification
or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in
the adult form of neuronal ceroid lipofuscinosis.
DOI: 10.1074/mcp.M900122-MCP200
PMCID: PMC2709195
PMID: 19383612 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20850498 | 1. Biochimie. 2011 Feb;93(2):160-7. doi: 10.1016/j.biochi.2010.09.006. Epub 2010
Sep 17.
"Protoisochores" in certain archaeal species are formed by
replication-associated mutational pressure.
Khrustalev VV(1), Barkovsky EV.
Author information:
(1)Department of General Chemistry, Belarussian State Medical University,
Dzerzinskogo, 83, 220116 Minsk, Belarus. [email protected]
This report shows that isochore-like structures can be found not only in
warm-blooded animals, some reptiles, fishes and yeast, but also in certain
archaeal species. In perfectly shaped isochore-like structures (in
"protoisochores") from Sulfolobus acidocaldarius and Thermofilum pendens genomes
the difference in 3GC levels between genes from different "protoisochores" is
about 30%. In these archaeal species GC-poor "protoisochores" are situated near
the origin of replication, while GC-rich "protoisochores" are situated near the
terminus of replication. There is a strong linear dependence between position of
a gene and its 3GC level in S. acidocaldarius (an average difference in 3GC per
100,000 base pairs is equal to 3.6%). Detailed analyses of nucleotide usage
biases in genes from leading and lagging strands led us to the suggestion that
3GC in genes situated near terminus of replication grows due to higher rates of
thymine oxidation producing T to C transitions in lagging strands.
Copyright © 2010 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.biochi.2010.09.006
PMID: 20850498 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2541880 | 1. Can J Microbiol. 1989 Jan;35(1):96-100. doi: 10.1139/m89-015.
Genome structure of Halobacterium halobium: plasmid dynamics in gas vacuole
deficient mutants.
Pfeifer F(1), Blaseio U, Horne M.
Author information:
(1)Max-Planck-Institut für Biochemie, Martinsried, Federal Republic of Germany.
Halobacterium halobium contains two gas vacuole protein genes that are located
in plasmid pHH1 (p-vac) and in the chromosomal DNA (c-vac). The mutation
frequency for these genes is different: the constitutively expressed p-vac gene
is mutated with a frequency of 10(-2), while the chromosomal gene expressed in
the stationary phase of growth is mutated with a frequency of 10(-5). The
difference in the mutation susceptibility is due to the dynamics of plasmid
pHH1. p-vac gene mutations are caused (i) by the integration of an insertion
element or (ii) by a deletion event encompassing the p-vac gene region. In
contrast, c-vac mutants analyzed to date incurred neither insertion elements nor
deletions. Deletion events within pHH1 occur at high frequencies during the
development of a H. halobium culture. The investigation of the fusion regions
resulting from deletion events indicates that insertion elements are involved.
The analysis of pHH1 deletion variants led to a 4 kilobase pair DNA region
containing the origin of replication of the pHH1 plasmid.
DOI: 10.1139/m89-015
PMID: 2541880 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16697960 | 1. Cancer Cell. 2006 May;9(5):405-16. doi: 10.1016/j.ccr.2006.04.004.
Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in
Ewing's sarcoma.
Smith R(1), Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, Lessnick SL.
Author information:
(1)The Center for Children, Huntsman Cancer Institute, University of Utah, Salt
Lake City, Utah 84112, USA.
Erratum in
Cancer Cell. 2007 Jan;11(1):97.
Comment in
Cancer Cell. 2006 May;9(5):331-2. doi: 10.1016/j.ccr.2006.05.003.
Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion
protein has been limited by a lack of knowledge regarding the tumor cell of
origin. To circumvent this, we analyzed the function of EWS/FLI in Ewing's
sarcoma itself. By combining retroviral-mediated RNA interference with
reexpression studies, we show that ongoing EWS/FLI expression is required for
the tumorigenic phenotype of Ewing's sarcoma. We used this system to define the
full complement of EWS/FLI-regulated genes in Ewing's sarcoma. Functional
analysis revealed that NKX2.2 is an EWS/FLI-regulated gene that is necessary for
oncogenic transformation in this tumor. Thus, we developed a highly validated
transcriptional profile for the EWS/FLI fusion protein and identified a critical
target gene in Ewing's sarcoma development.
DOI: 10.1016/j.ccr.2006.04.004
PMID: 16697960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15197606 | 1. Extremophiles. 2004 Jun;8(3):253-8. doi: 10.1007/s00792-004-0385-4. Epub 2004
Apr 9.
Identification of replication origins in the genome of the methanogenic
archaeon, Methanocaldococcus jannaschii.
Zhang R(1), Zhang CT.
Author information:
(1)Department of Epidemiology and Biostatistics, Tianjin Cancer Institute and
Hospital, 300060 Tianjin, China.
Methanocaldococcus jannaschii has been notorious as an archaeon in which the
replication origins are difficult to identify. Although extensive efforts have
been exerted on this issue, the locations of replication origins still remain
elusive 7 years after the publication of its complete genome sequence in 1996.
Ambiguous results were obtained in identifying the replication origins of M.
jannaschii based on all theoretical and experimental approaches. In the genome
of M. jannaschii, we found that an ORF (MJ0774), annotated as a hypothetical
protein, is a homologue of the Cdc6 protein. The position of the gene is at a
global minimum of the x component of the Z curve, i.e., RY disparity curve,
which has been used to identify replication origins in other Archaea. In
addition, an intergenic region (694,540-695,226 bp) that is between the cdc6
gene and an adjacent ORF shows almost all the characteristics of known
replication origins, i.e., it is highly rich in AT composition (80%) and
contains multiple copies of repeat elements and AT stretches. Therefore, these
lines of evidence strongly suggest that the identified region is a replication
origin, which is designated as oriC1. The analysis of the y component of the Z
curve, i.e., MK disparity curve, suggests the presence of another replication
origin corresponding to one of the peaks in the MK disparity curve at around
1,388 kb of the genome.
Copyright 2004 Springer-Verlag
DOI: 10.1007/s00792-004-0385-4
PMID: 15197606 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24185008 | 1. Nature. 2013 Nov 28;503(7477):544-547. doi: 10.1038/nature12650. Epub 2013 Nov
3.
Accelerated growth in the absence of DNA replication origins.
Hawkins M(#)(1), Malla S(2), Blythe MJ(2), Nieduszynski CA(#)(1), Allers
T(#)(1).
Author information:
(1)School of Biology, University of Nottingham, Queen's Medical Centre,
Nottingham, NG7 2UH, UK.
(2)DeepSeq, University of Nottingham, Queen's Medical Centre, Nottingham, NG7
2UH, UK.
(#)Contributed equally
Comment in
Nat Rev Microbiol. 2014 Jan;12(1):4-5. doi: 10.1038/nrmicro3177.
DNA replication initiates at defined sites called origins, which serve as
binding sites for initiator proteins that recruit the replicative machinery.
Origins differ in number and structure across the three domains of life and
their properties determine the dynamics of chromosome replication. Bacteria and
some archaea replicate from single origins, whereas most archaea and all
eukaryotes replicate using multiple origins. Initiation mechanisms that rely on
homologous recombination operate in some viruses. Here we show that such
mechanisms also operate in archaea. We use deep sequencing to study replication
in Haloferax volcanii and identify four chromosomal origins of differing
activity. Deletion of individual origins results in perturbed replication
dynamics and reduced growth. However, a strain lacking all origins has no
apparent defects and grows significantly faster than wild type. Origin-less
cells initiate replication at dispersed sites rather than at discrete origins
and have an absolute requirement for the recombinase RadA, unlike strains
lacking individual origins. Our results demonstrate that homologous
recombination alone can efficiently initiate the replication of an entire
cellular genome. This raises the question of what purpose replication origins
serve and why they have evolved.
DOI: 10.1038/nature12650
PMCID: PMC3843117
PMID: 24185008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16249118 | 1. Curr Opin Microbiol. 2005 Dec;8(6):662-8. doi: 10.1016/j.mib.2005.10.008. Epub
2005 Oct 24.
Archaeal cell cycle progress.
Lundgren M(1), Bernander R.
Author information:
(1)Department of Molecular Evolution, Evolutionary Biology Center, Uppsala
University, Norbyvägen 18C, SE-752 36 Uppsala, Sweden.
The discovery of multiple chromosome replication origins in Sulfolobus species
has added yet another eukaryotic trait to the archaea, and brought new levels of
complexity to the cell cycle in terms of initiation of chromosome replication,
replication termination and chromosome decatenation. Conserved repeated DNA
elements--origin recognition boxes--have been identified in the origins of
replication, and shown to bind the Orc1/Cdc6 proteins involved in cell cycle
control. The origin recognition boxes aid in the identification and
characterization of new origins, and their conservation suggests that most
archaea have a similar replication initiation mechanism. Cell-cycle-dependent
variation in Orc1/Cdc6 levels has been demonstrated, reminiscent of variations
in cyclin levels during the eukaryotic cell cycle. Information about archaeal
chromosome segregation is also accumulating, including the identification of a
protein that binds to short regularly spaced repeats that might constitute
centromere-like elements. In addition, studies of cell-cycle-specific gene
expression have potential to reveal, in the near future, missing components in
crenarchaeal chromosome replication, genome segregation and cell division.
Together with an increased number of physiological and cytological
investigations of the overall organization of the cell cycle, rapid progress of
the archaeal cell cycle field is evident, and archaea, in particular Sulfolobus
species, are emerging as simple and powerful models for the eukaryotic cell
cycle.
DOI: 10.1016/j.mib.2005.10.008
PMID: 16249118 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11967086 | 1. Mol Microbiol. 2002 Apr;44(1):283-96. doi: 10.1046/j.1365-2958.2002.02890.x.
HF2: a double-stranded DNA tailed haloarchaeal virus with a mosaic genome.
Tang SL(1), Nuttall S, Ngui K, Fisher C, Lopez P, Dyall-Smith M.
Author information:
(1)Department of Microbiology and Immunology, University of Melbourne,
Parkville, Victoria 3010, Australia.
HF2 is a haloarchaeal virus infecting two Halorubrum species (Family
Halobacteriaceae). It is lytic, has a head-and-tail morphology and belongs to
the Myoviridae (contractile tails). The linear double-stranded DNA genome was
sequenced and found to be 77 670 bp in length, with a mol% G+C of 55.8. A total
of 121 likely open reading frames (ORFs) were identified, of which 37 overlapped
at start and stop codons. The predicted proteins were usually acidic (average pI
of 4.8), and less than about 12% of them had homologues in the sequence
databases. Four complete tRNA-like sequences (tRNA-Arg, -Asx, -Pro and -Tyr) and
an incomplete tRNA-Thr were detected. A transcription map showed that most of
the genome was transcribed and that the synthesis of transcripts occurred in a
highly organized and reproducible pattern over a 5 h infection cycle.
Transcripts often spanned multiple ORFs, suggesting that viral genes were
organized into operons. The predicted ORF and observed transcript directions
matched well and showed that transcription is mainly directed inwards from the
genome termini, meeting at about 45-48 kb, and this was also a turning point in
a cumulative GC-skew plot. The low point in cumulative GC-skew, near the left
end, was a region rich in short repeats and lacking ORFs, which is likely to be
an origin of replication. The HF2 genome is a mosaic of components from widely
different sources, demonstrating clearly that viruses of haloarchaea, like their
bacteriophage counterparts, are vectors for the exchange and transmission of
genetic material between wide taxonomic distances, even across domains.
DOI: 10.1046/j.1365-2958.2002.02890.x
PMID: 11967086 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14526006 | 1. J Bacteriol. 2003 Oct;185(20):5959-66. doi: 10.1128/JB.185.20.5959-5966.2003.
An archaeal chromosomal autonomously replicating sequence element from an
extreme halophile, Halobacterium sp. strain NRC-1.
Berquist BR(1), DasSarma S.
Author information:
(1)Molecular and Cell Biology Program, University of Maryland, Baltimore, and
Center of Marine Biotechnology, University of Maryland Biotechnology Institute,
Baltimore, Maryland 21202, USA.
We report on the identification and first cloning of an autonomously replicating
sequence element from the chromosome of an archaeon, the extreme halophile
Halobacterium strain NRC-1. The putative replication origin was identified by
association with the orc7 gene and replication ability in the host strain,
demonstrated by cloning into a nonreplicating plasmid. Deletion analysis showed
that sequences located up to 750 bp upstream of the orc7 gene translational
start, plus the orc7 gene and 50 bp downstream, are sufficient to endow the
plasmid with replication ability, as judged by expression of a plasmid-encoded
mevinolin resistance selectable marker and plasmid recovery after
transformation. Sequences located proximal to the two other chromosomally
carried haloarchaeal orc genes (orc6 and orc8) are not able to promote efficient
autonomous replication. Located within the 750-bp region upstream of orc7 is a
nearly perfect inverted repeat of 31 bp, which flanks an extremely AT-rich (44%)
stretch of 189 bp. The replication ability of the plasmid was lost when one copy
of the inverted repeat was deleted. Additionally, the inverted repeat structure
near orc7 homologs in the genomic sequences of two other halophiles, Haloarcula
marismortui and Haloferax volcanii, is highly conserved. Our results indicate
that, in halophilic archaea, a chromosomal origin of replication is physically
linked to orc7 homologs and that this element is sufficient to promote
autonomous replication. We discuss the finding of a functional haloarchaeal
origin in relation to the large number of orc1-cdc6 homologs identified in the
genomes of all haloarchaea to date.
DOI: 10.1128/JB.185.20.5959-5966.2003
PMCID: PMC225043
PMID: 14526006 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17350933 | 1. Archaea. 2007 May;2(2):127-35. doi: 10.1155/2007/745987.
The genome of Hyperthermus butylicus: a sulfur-reducing, peptide fermenting,
neutrophilic Crenarchaeote growing up to 108 degrees C.
Brügger K(1), Chen L, Stark M, Zibat A, Redder P, Ruepp A, Awayez M, She Q,
Garrett RA, Klenk HP.
Author information:
(1)Danish Archaea Centre, Institute of Molecular Biology, Copenhagen University,
Sølvgade 83H, 1307 Copenhagen K, Denmark.
Hyperthermus butylicus, a hyperthermophilic neutrophile and anaerobe, is a
member of the archaeal kingdom Crenarchaeota. Its genome consists of a single
circular chromosome of 1,667,163 bp with a 53.7% G+C content. A total of 1672
genes were annotated, of which 1602 are protein-coding, and up to a third are
specific to H. butylicus. In contrast to some other crenarchaeal genomes, a high
level of GUG and UUG start codons are predicted. Two cdc6 genes are present, but
neither could be linked unambiguously to an origin of replication. Many of the
predicted metabolic gene products are associated with the fermentation of
peptide mixtures including several peptidases with diverse specificities, and
there are many encoded transporters. Most of the sulfur-reducing enzymes,
hydrogenases and electron-transfer proteins were identified which are associated
with energy production by reducing sulfur to H(2)S. Two large clusters of
regularly interspaced repeats (CRISPRs) are present, one of which is associated
with a crenarchaeal-type cas gene superoperon; none of the spacer sequences
yielded good sequence matches with known archaeal chromosomal elements. The
genome carries no detectable transposable or integrated elements, no inteins,
and introns are exclusive to tRNA genes. This suggests that the genome structure
is quite stable, possibly reflecting a constant, and relatively uncompetitive,
natural environment.
DOI: 10.1155/2007/745987
PMCID: PMC2686385
PMID: 17350933 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23375370 | 1. Cell Rep. 2013 Feb 21;3(2):485-96. doi: 10.1016/j.celrep.2013.01.002. Epub
2013 Jan 31.
Specificity and function of archaeal DNA replication initiator proteins.
Samson RY(1), Xu Y, Gadelha C, Stone TA, Faqiri JN, Li D, Qin N, Pu F, Liang YX,
She Q, Bell SD.
Author information:
(1)Sir William Dunn School of Pathology, Oxford University, South Parks Road,
Oxford OX1 3RE, UK.
Chromosomes with multiple DNA replication origins are a hallmark of Eukaryotes
and some Archaea. All eukaryal nuclear replication origins are defined by the
origin recognition complex (ORC) that recruits the replicative helicase MCM(2-7)
via Cdc6 and Cdt1. We find that the three origins in the single chromosome of
the archaeon Sulfolobus islandicus are specified by distinct initiation factors.
While two origins are dependent on archaeal homologs of eukaryal Orc1 and Cdc6,
the third origin is instead reliant on an archaeal Cdt1 homolog. We exploit the
nonessential nature of the orc1-1 gene to investigate the role of ATP binding
and hydrolysis in initiator function in vivo and in vitro. We find that the
ATP-bound form of Orc1-1 is proficient for replication and implicates hydrolysis
of ATP in downregulation of origin activity. Finally, we reveal that ATP and DNA
binding by Orc1-1 remodels the protein's structure rather than that of the DNA
template.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2013.01.002
PMCID: PMC3607249
PMID: 23375370 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15777501 | 1. Zhonghua Zhong Liu Za Zhi. 2004 Nov;26(11):652-6.
[The apoptosis-inducing activity of human selenoprotein P shorter isoform].
[Article in Chinese]
Fang Q(1), Yi Y, Zheng YH, Chen Q, Ning L, Zha YY, Bi SL, Yang JG, Lin C.
Author information:
(1)Department of Molecular Oncology, Cancer Institute (Hospital), Chinese
Academy of Medical Sciences, Peking Union Medical College, Beijing 100021,
China.
OBJECTIVE: Human selenoprotein P (HSelP) is unique protein that contains 10
selenocysteines encoded by 10 inframe UGA, which typically function as stop
codon. The function of HSelP remains unclear, in part due to the inability to
express it by gene recombinant technique. This study is to investigate
expression and purification of recombinant HSelP in prokaryotic expression
system, and its activity to induce apoptosis in vitro.
METHODS: The shorter HSelP isoform was cloned. After the selenocysteine (SeCys)
at 40th position from N terminus of the HSelP shorter isoform was mutated into
cysteine by PCR, it was expressed in E. coli. The expressed product was purified
with DEAE column and identified by Western blot. Subsequently, its function on
induction of mitochondrial apoptotic activity was studied.
RESULTS: The mutant HSelP shorter isoform expressed in prokaryotic system was
purified by DEAE column to 90% homogeneity. The purified product, HSelP280m,
induced the opening of mitochondrial permeability transition pore (PTP) and
decreased the transmembrane potential in a dose-dependent manner. These events
could be abolished by PTP specific inhibitors.
CONCLUSION: HSelP280m can induce the opening of mitochondrial PTP, which
provides a basis for investigating the structure and function of recombinant
HSelP.
PMID: 15777501 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21839145 | 1. Neurosci Lett. 2011 Sep 20;502(3):219-24. doi: 10.1016/j.neulet.2011.07.048.
Epub 2011 Aug 4.
Induction of pluripotent stem cells from autopsy donor-derived somatic cells.
Hjelm BE(1), Rosenberg JB, Szelinger S, Sue LI, Beach TG, Huentelman MJ, Craig
DW.
Author information:
(1)Neurogenomics Division, The Translational Genomics Research Institute (TGen),
Phoenix, AZ, USA.
Human induced pluripotent stem cells (iPSCs) have become an intriguing approach
for neurological disease modeling, because neural lineage-specific cell types
that retain the donors' complex genetics can be established in vitro. The
statistical power of these iPSC-based models, however, is dependent on accurate
diagnoses of the somatic cell donors; unfortunately, many neurodegenerative
diseases are commonly misdiagnosed in live human subjects. Postmortem
histopathological examination of a donor's brain, combined with premortem
clinical criteria, is often the most robust approach to correctly classify an
individual as a disease-specific case or unaffected control. In this study, we
describe iPSCs generated from a skin biopsy collected postmortem during the
rapid autopsy of a 75-year-old male, whole body donor, defined as an unaffected
neurological control by both clinical and histopathological criteria. These
iPSCs were established in a feeder-free system by lentiviral transduction of the
Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Selected iPSC clones expressed
both nuclear and surface antigens recognized as pluripotency markers of human
embryonic stem cells (hESCs) and were able to differentiate in vitro into
neurons and glia. Statistical analysis also demonstrated that fibroblast
proliferation was significantly affected by biopsy site, but not donor age
(within an elderly cohort). These results provide evidence that autopsy
donor-derived fibroblasts can be successfully reprogrammed into iPSCs, and may
provide an advantageous approach for generating iPSC-based neurological disease
models.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.neulet.2011.07.048
PMCID: PMC3195418
PMID: 21839145 [Indexed for MEDLINE]
Conflict of interest statement: Author Disclosure Statement: The authors have no
conflicting financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/7875632 | 1. Fundam Clin Pharmacol. 1994;8(5):385-90. doi:
10.1111/j.1472-8206.1994.tb00817.x.
Classification and mechanism of action of antiarrhythmic drugs.
Scholz H(1).
Author information:
(1)University of Hamburg, Department of Pharmacology, Germany.
The present paper reviews classification and mode of action of agents that
suppress extrasystoles and tachyarrhythmias. These are classified according to
their electrophysiological effects observed in isolated cardiac tissues in vitro
(Vaughan Williams, 1989). Fast sodium channel blockers (class I) which reduce
the upstroke velocity of the action potential are usually subclassified into
three groups, class I A-C, according to their effect on the action potential
duration. Beta-adrenergic antagonists (class II) exert their effects by
antagonizing the electrophysiological effects of beta-adrenergic catecholamines.
Class III antiarrhythmic agents (eg amiodarone) prolong the action potential and
slow calcium channel blockers (class IV) suppress the calcium inward current and
calcium-dependent action potentials. The classification of antiarrhythmic drugs
is still under debate. This particularly applies to agents of class I and III.
The effect of class I agents is frequency-dependent because the binding affinity
of these drugs to the sodium channel is modulated by the state of the channel
(modulated receptor hypothesis). Class I agents bind to the channel in the
activated and inactivated state and dissociate from the channel in the rested
state. This occurs at a drug-specific rate so that class I agents can be
subclassified into only two groups, namely in those of the slow- and
fast-recovery type respectively (time constant of reactivation greater or
smaller than 1 s). Slow-recovery class I agents affect regular action potentials
at normal heart rates which can more easily lead to a lengthening of the QRS
duration in the ECG, to conduction disturbances and hence to pro-arrhythmic
effects.(ABSTRACT TRUNCATED AT 250 WORDS)
DOI: 10.1111/j.1472-8206.1994.tb00817.x
PMID: 7875632 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15876567 | 1. Archaea. 2005 May;1(5):335-46. doi: 10.1155/2005/509646.
Identification of replication origins in archaeal genomes based on the Z-curve
method.
Zhang R(1), Zhang CT.
Author information:
(1)Department of Epidemiology and Biostatistics, Tianjin Cancer Institute and
Hospital, Tianjin 300060, China.
The Z-curve is a three-dimensional curve that constitutes a unique
representation of a DNA sequence, i.e., both the Z-curve and the given DNA
sequence can be uniquely reconstructed from the other. We employed Z-curve
analysis to identify one replication origin in the Methanocaldococcus jannaschii
genome, two replication origins in the Halobacterium species NRC-1 genome and
one replication origin in the Methanosarcina mazei genome. One of the predicted
replication origins of Halobacterium species NRC-1 is the same as a replication
origin later identified by in vivo experiments. The Z-curve analysis of the
Sulfolobus solfataricus P2 genome suggested the existence of three replication
origins, which is also consistent with later experimental results. This review
aims to summarize applications of the Z-curve in identifying replication origins
of archaeal genomes, and to provide clues about the locations of as yet
unidentified replication origins of the Aeropyrum pernix K1, Methanococcus
maripaludis S2, Picrophilus torridus DSM 9790 and Pyrobaculum aerophilum str.
IM2 genomes.
DOI: 10.1155/2005/509646
PMCID: PMC2685548
PMID: 15876567 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20699327 | 1. Hum Mol Genet. 2010 Nov 1;19(21):4160-75. doi: 10.1093/hmg/ddq335. Epub 2010
Aug 10.
Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into
stress granules.
Bosco DA(1), Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ Jr, Sapp P,
McKenna-Yasek D, Brown RH Jr, Hayward LJ.
Author information:
(1)Department of Neurology, University of Massachusetts Medical School, 55 Lake
Avenue North, Worcester, MA 01655, USA. [email protected]
Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to
amyotrophic lateral sclerosis (ALS), but the mechanism by which these mutants
cause motor neuron degeneration is not known. We report a novel ALS truncation
mutant (R495X) that leads to a relatively severe ALS clinical phenotype compared
with FUS missense mutations. Expression of R495X FUS, which abrogates a putative
nuclear localization signal at the C-terminus of FUS, in HEK-293 cells and in
the zebrafish spinal cord caused a striking cytoplasmic accumulation of the
protein to a greater extent than that observed for recessive (H517Q) and
dominant (R521G) missense mutants. Furthermore, in response to oxidative stress
or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants,
but not wild-type FUS, assembled into perinuclear stress granules in proportion
to their cytoplasmic expression levels. These findings demonstrate a potential
link between FUS mutations and cellular pathways involved in stress responses
that may be relevant to altered motor neuron homeostasis in ALS.
DOI: 10.1093/hmg/ddq335
PMCID: PMC2981014
PMID: 20699327 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15883211 | 1. Circulation. 2005 May 17;111(19):2438-45. doi:
10.1161/01.CIR.0000167553.49133.81. Epub 2005 May 9.
Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo
transforming growth factor-beta-preprogrammed bone marrow stem cells.
Li TS(1), Hayashi M, Ito H, Furutani A, Murata T, Matsuzaki M, Hamano K.
Author information:
(1)Division of Cardiovascular Surgery, Department of Medical Bioregulation,
Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
Comment in
Circulation. 2005 May 17;111(19):2416-7. doi:
10.1161/01.CIR.0000167557.59069.D9.
BACKGROUND: Recent studies have shown that bone marrow-derived stem cells
differentiate into the phenotype of cardiomyocytes in vivo and in vitro. We
tried to regenerate infarcted myocardium by implanting ex vivo transforming
growth factor (TGF)-beta-preprogrammed CD117 (c-kit)-positive (CD117+) stem
cells intramyocardially.
METHODS AND RESULTS: CD117+ cells were isolated from the bone marrow mononuclear
cells of GFP-transgenic or normal C57/BL6 mice. The myogenic differentiation of
CD117+ cells was achieved by cultivation with TGF-beta. Using an acute
myocardial infarction model, we also tried to regenerate infarcted myocardium by
implanting untreated (newly isolated) or preprogrammed (24 hours of cultivation
with 5 ng/mL TGF-beta1) CD117+ cells intramyocardially. TGF-beta increased the
cellular expression of myosin, troponins, connexin-43, GATA-4, and NKx-2.5,
which suggested that it induced the myogenic differentiation of CD117+ cells.
Compared with the effects of PBS injection only, the microvessel density in the
infarcted myocardium was increased significantly 3 months after the implantation
of either TGF-beta-preprogrammed or untreated CD117+ cells. Moreover, many of
the TGF-beta-preprogrammed CD117+ cells were stained positively for myosin,
whereas few of the untreated CD117+ cells were. Histological analysis revealed
newly regenerated myocardium in the left ventricular anterior wall after the
implantation of TGF-beta-preprogrammed cells but not untreated cells.
Furthermore, the left ventricular percent fraction shortening was significantly
higher after the implantation of TGF-beta-preprogrammed cells than after the
implantation of untreated CD117+ cells.
CONCLUSIONS: TGF-beta conducted the myogenic differentiation of CD117+ stem
cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the
intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively
assisted the myocardial regeneration and induced therapeutic angiogenesis,
contributing to functional cardiac regeneration.
DOI: 10.1161/01.CIR.0000167553.49133.81
PMID: 15883211 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15492248 | 1. Cancer Res. 2004 Oct 15;64(20):7288-95. doi: 10.1158/0008-5472.CAN-04-1610.
The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell
lines.
Rorie CJ(1), Weissman BE.
Author information:
(1)Curriculum in Toxicology and Department of Pathology and Laboratory Medicine,
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina, USA.
One hallmark of Ewing's sarcoma/peripheral neuroectodermal tumors is the
presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of
neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation
program of neuroblastomas to Ewing's sarcoma/peripheral neuroectodermal tumors.
Here we examined the status of cytoplasmically sequestered wt-p53 in
neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed
that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a
punctate-pattern of cytoplasmic sequestration to increased nuclear localization.
Western blot analysis revealed that PARC was down-regulated in one neuroblastoma
cell line but not expressed in the second. Therefore, decreased PARC expression
could not fully account for relieving p53 sequestration in the neuroblastoma
tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked
increases in p53 protein expression without transcriptional up-regulation.
Interestingly, p53 was primarily phosphorylated, without activation of its
downstream target p21(WAF1). Western blot analysis revealed that whereas MDM2
gene expression does not change, p14(ARF), a negative protein regulator of MDM2,
increases. These observations suggest that the downstream p53 pathway may be
inactivated as a result of abnormal p53. We also found that p53 has an extended
half-life in the neuroblastoma-Ews/Fli-1 infectants despite the retention of a
wild-type sequence in neuroblastoma-Ews/Fli-1 infectant cell lines. We then
tested the p53 response pathway and observed that the neuroblastoma parent cells
responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants
did not. These results suggest that Ews/Fli-1 can directly abrogate the p53
pathway to promote tumorigenesis. These studies also provide additional insight
into the relationship among the p53 pathway proteins.
DOI: 10.1158/0008-5472.CAN-04-1610
PMID: 15492248 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20667100 | 1. BMC Genomics. 2010 Jul 28;11:454. doi: 10.1186/1471-2164-11-454.
Replication-biased genome organisation in the crenarchaeon Sulfolobus.
Andersson AF(1), Pelve EA, Lindeberg S, Lundgren M, Nilsson P, Bernander R.
Author information:
(1)Department of Ecology and Evolution, Evolutionary Biology Centre, Uppsala
University, Uppsala, Sweden. [email protected]
BACKGROUND: Species of the crenarchaeon Sulfolobus harbour three replication
origins in their single circular chromosome that are synchronously initiated
during replication.
RESULTS: We demonstrate that global gene expression in two Sulfolobus species is
highly biased, such that early replicating genome regions are more highly
expressed at all three origins. The bias by far exceeds what would be
anticipated by gene dosage effects alone. In addition, early replicating regions
are denser in archaeal core genes (enriched in essential functions), display
lower intergenic distances, and are devoid of mobile genetic elements.
CONCLUSION: The strong replication-biased structuring of the Sulfolobus
chromosome implies that the multiple replication origins serve purposes other
than simply shortening the time required for replication. The higher-level
chromosomal organisation could be of importance for minimizing the impact of DNA
damage, and may also be linked to transcriptional regulation.
DOI: 10.1186/1471-2164-11-454
PMCID: PMC3091651
PMID: 20667100 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18922777 | 1. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16737-42. doi:
10.1073/pnas.0806414105. Epub 2008 Oct 15.
Chromosome replication dynamics in the archaeon Sulfolobus acidocaldarius.
Duggin IG(1), McCallum SA, Bell SD.
Author information:
(1)Medical Research Council Cancer Cell Unit, Hutchison-Medical Research Council
Research Centre, Hills Road, Cambridge, CB2 0XZ, United Kingdom.
[email protected]
The "baby machine" provides a means of generating synchronized cultures of
minimally perturbed cells. We describe the use of this technique to establish
the key cell-cycle parameters of hyperthermophilic archaea of the genus
Sulfolobus. The 3 DNA replication origins of Sulfolobus acidocaldarius were
mapped by 2D gel analysis to near 0 (oriC2), 579 (oriC1), and 1,197 kb (oriC3)
on the 2,226-kb circular genome, and we present a direct demonstration of their
activity within the first few minutes of a synchronous cell cycle. We also
detected X-shaped DNA molecules at the origins in log-phase cells, but these
were not directly associated with replication initiation or ongoing chromosome
replication in synchronized cells. Whole-genome marker frequency analyses of
both synchronous and log-phase cultures showed that origin utilization was close
to 100% for all 3 origins per round of replication. However, oriC2 was activated
slightly later on average compared with oriC1 and oriC3. The DNA replication
forks moved bidirectionally away from each origin at approximately 88 bp per
second in synchronous culture. Analysis of the 3 Orc1/Cdc6 initiator proteins
showed a uniformity of cellular abundance and origin binding throughout the cell
cycle. In contrast, although levels of the MCM helicase were constant across the
cell cycle, its origin localization was regulated, because it was strongly
enriched at all 3 origins in early S phase.
DOI: 10.1073/pnas.0806414105
PMCID: PMC2575489
PMID: 18922777 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18071949 | 1. Handb Exp Pharmacol. 2008;(181):237-56. doi: 10.1007/978-3-540-73259-4_11.
Monoclonal antibody therapy for prostate cancer.
Jakobovits A(1).
Author information:
(1)Agensys Inc., 1545 17th Street, Santa Monica, CA 90404, USA.
[email protected]
Early detection of prostate cancer (PCa) and advances in hormonal and
chemotherapy treatments have provided great clinical benefits to patients with
early stages of the disease. However, a significant proportion of patients still
progress to advanced, metastatic disease, for which no effective therapies are
available. Therefore, there is a critical need for new treatment modalities,
ideally targeted specifically to prostate cancer cells. The recent clinical and
commercial successes of monoclonal antibodies (MAbs) have made them the most
rapidly expanding class of therapeutics being developed for many disease
indications, including cancer. PCa is well suited for antibody-based therapy due
to the size and location of recurrent and metastatic tumors, and the lack of
necessity to avoid targeting the normal prostate, a nonessential organ. These
properties have fostered interest in the development and clinical evaluation of
therapeutic MAbs directed to both well established and newly discovered targets
in PCa. MAbs directed to established targets include those approved for other
solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb
trastuzumab, anti-epidermal growth factor receptor (EGFR) MAbs cetuximab and
panitumumab, and the antivascular endothelial growth factor (VEGF) MAb
bevacizumab. Genomics efforts have yielded a large number of novel, clinically
relevant targets in PCa with the desirable expression profiling in tumor and
normal tissues, and with an implicated role in tumor growth and spread. Growing
efforts are directed to the development of naked or payload-conjugated
therapeutic antibodies to these targets, and a variety of MAb products are
currently progressing through preclinical and various stages of clinical
development. The clinical experience with some of the commercialized MAb
products points out specific challenges in conducting clinical trials with
targeted therapy in PCa.
DOI: 10.1007/978-3-540-73259-4_11
PMID: 18071949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17511521 | 1. PLoS Genet. 2007 May 18;3(5):e77. doi: 10.1371/journal.pgen.0030077. Epub 2007
Apr 5.
Genetic and physical mapping of DNA replication origins in Haloferax volcanii.
Norais C(1), Hawkins M, Hartman AL, Eisen JA, Myllykallio H, Allers T.
Author information:
(1)Institut de Génétique et Microbiologie, Université Paris-Sud, Orsay, France.
The halophilic archaeon Haloferax volcanii has a multireplicon genome,
consisting of a main chromosome, three secondary chromosomes, and a plasmid.
Genes for the initiator protein Cdc6/Orc1, which are commonly located adjacent
to archaeal origins of DNA replication, are found on all replicons except
plasmid pHV2. However, prediction of DNA replication origins in H. volcanii is
complicated by the fact that this species has no less than 14 cdc6/orc1 genes.
We have used a combination of genetic, biochemical, and bioinformatic approaches
to map DNA replication origins in H. volcanii. Five autonomously replicating
sequences were found adjacent to cdc6/orc1 genes and replication initiation
point mapping was used to confirm that these sequences function as bidirectional
DNA replication origins in vivo. Pulsed field gel analyses revealed that
cdc6/orc1-associated replication origins are distributed not only on the main
chromosome (2.9 Mb) but also on pHV1 (86 kb), pHV3 (442 kb), and pHV4 (690 kb)
replicons. Gene inactivation studies indicate that linkage of the initiator gene
to the origin is not required for replication initiation, and genetic tests with
autonomously replicating plasmids suggest that the origin located on pHV1 and
pHV4 may be dominant to the principal chromosomal origin. The replication
origins we have identified appear to show a functional hierarchy or differential
usage, which might reflect the different replication requirements of their
respective chromosomes. We propose that duplication of H. volcanii replication
origins was a prerequisite for the multireplicon structure of this genome, and
that this might provide a means for chromosome-specific replication control
under certain growth conditions. Our observations also suggest that H. volcanii
is an ideal organism for studying how replication of four replicons is regulated
in the context of the archaeal cell cycle.
DOI: 10.1371/journal.pgen.0030077
PMCID: PMC1868953
PMID: 17511521 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests. The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22322558 | 1. Int J Oncol. 2012 Jun;40(6):1881-8. doi: 10.3892/ijo.2012.1357. Epub 2012 Feb
6.
Significant systemic therapeutic effects of high-LET immunoradiation by
212Pb-trastuzumab against prostatic tumors of androgen-independent human
prostate cancer in mice.
Tan Z(1), Chen P, Schneider N, Glover S, Cui L, Torgue J, Rixe O, Spitz HB, Dong
Z.
Author information:
(1)Division of Hematology-Oncology, University of Cincinnati Cancer Institute,
Cincinnati, OH 45267, USA.
The purpose of this study was to determine therapeutic effects and systemic
toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer
cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The
212Pb-trastuzumab generated from the procedure was intact and had high binding
affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which
expressed a lower level of HER2 both in culture and in tumors, were used in
therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced
tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the
survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause
significant changes in body weight, serum glutamic pyruvic transaminase (SGPT),
blood urea nitrogen (BUN), hematological profiles, and histological morphology
of several major organs of tumor-bearing mice. These findings suggest that a
systemic delivery of 212Pb-trastuzumab could be an effective modality for
management of advanced human prostate cancer.
DOI: 10.3892/ijo.2012.1357
PMID: 22322558 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11521661 | 1. Genome Biol. 2000;1(3):REVIEWS1020. doi: 10.1186/gb-2000-1-3-reviews1020.
Where does DNA replication start in archaea?
Vas A(1), Leatherwood J.
Author information:
(1)Department of Molecular Genetics and Microbiology, State University of New
York, Stony Brook, NY 11794-5222, USA. [email protected]
Genome-wide measures of DNA strand composition have been used to find archaeal
DNA replication origins. Archaea seem to replicate using a single origin (as do
eubacteria) even though archaeal replication factors are more like those of
eukaryotes.
DOI: 10.1186/gb-2000-1-3-reviews1020
PMCID: PMC138862
PMID: 11521661 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17956224 | 1. Biochem J. 2008 Jan 15;409(2):511-8. doi: 10.1042/BJ20070213.
A conserved mechanism for replication origin recognition and binding in archaea.
Majerník AI(1), Chong JP.
Author information:
(1)Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences,
900 28 Ivanka pri Dunaji, Slovak Republic.
To date, methanogens are the only group within the archaea where firing DNA
replication origins have not been demonstrated in vivo. In the present study we
show that a previously identified cluster of ORB (origin recognition box)
sequences do indeed function as an origin of replication in vivo in the archaeon
Methanothermobacter thermautotrophicus. Although the consensus sequence of ORBs
in M. thermautotrophicus is somewhat conserved when compared with ORB sequences
in other archaea, the Cdc6-1 protein from M. thermautotrophicus (termed
MthCdc6-1) displays sequence-specific binding that is selective for the MthORB
sequence and does not recognize ORBs from other archaeal species. Stabilization
of in vitro MthORB DNA binding by MthCdc6-1 requires additional conserved
sequences 3' to those originally described for M. thermautotrophicus. By testing
synthetic sequences bearing mutations in the MthORB consensus sequence, we show
that Cdc6/ORB binding is critically dependent on the presence of an invariant
guanine found in all archaeal ORB sequences. Mutation of a universally conserved
arginine residue in the recognition helix of the winged helix domain of archaeal
Cdc6-1 shows that specific origin sequence recognition is dependent on the
interaction of this arginine residue with the invariant guanine. Recognition of
a mutated origin sequence can be achieved by mutation of the conserved arginine
residue to a lysine or glutamine residue. Thus despite a number of differences
in protein and DNA sequences between species, the mechanism of origin
recognition and binding appears to be conserved throughout the archaea.
DOI: 10.1042/BJ20070213
PMID: 17956224 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22647225 | 1. Intern Med J. 2013 Feb;43(2):150-6. doi: 10.1111/j.1445-5994.2012.02847.x.
POLG mutations in Australian patients with mitochondrial disease.
Woodbridge P(1), Liang C, Davis RL, Vandebona H, Sue CM.
Author information:
(1)Department of Neurogenetics, Kolling Institute of Medical Research and
University of Sydney, Sydney, Australia.
BACKGROUND/AIM: The nuclear POLG gene encodes the catalytic subunit of DNA
polymerase gamma (polγ), the only polymerase involved in the replication and
proofreading of mitochondrial DNA. As a consequence, POLG mutations can cause
disease through impaired replication of mitochondrial DNA. To date, over 150
different mutations have been identified, with a growing number of associated
phenotypes described. The aim of this study was to determine the prevalence of
POLG mutations in an adult population of Australian patients with mitochondrial
disease, displaying symptoms commonly associated with POLG-related diseases.
METHODS: The clinical presentations of 322 patients from a specialist adult
mitochondrial disease clinic were reviewed. Nineteen exhibited a cluster of
three or more predefined clinical manifestations suggestive of POLG-related
disease: progressive external ophthalmoplegia, seizures and/or an abnormal
electroencephalogram, neuropathy, ataxia, liver function abnormalities, migraine
or dysphagia/dysarthria. Patients were screened for mutations by direct
nucleotide sequencing of the coding and exon-flanking intronic regions of POLG.
RESULTS: Five of the 19 patients (26%) displaying a phenotype suggestive of
POLG-related disease were found to have informative POLG coding mutations
(p.T851A, p.N468D, p.Y831C, p.G517V and novel p.P163S variant). Literature and
analysis of these mutations revealed that two of these patients had pathogenic
mutations known to cause POLG-related disease (patient #1: p.T851A and p.P163S;
patient #2: p.T851A and p.N468D).
CONCLUSIONS: We conclude that the prevalence of pathogenic POLG mutations in our
selected adult Australian cohort with suggestive clinical manifestations was
10%. A further 16% of patients had POLG variants but are unlikely to be
responsible for causing their disease.
© 2012 The Authors; Internal Medicine Journal © 2012 Royal Australasian College
of Physicians.
DOI: 10.1111/j.1445-5994.2012.02847.x
PMID: 22647225 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21838751 | 1. Br J Pharmacol. 2012 Mar;165(5):1457-66. doi:
10.1111/j.1476-5381.2011.01627.x.
Long-term treatment with ivabradine in post-myocardial infarcted rats
counteracts f-channel overexpression.
Suffredini S(1), Stillitano F, Comini L, Bouly M, Brogioni S, Ceconi C, Ferrari
R, Mugelli A, Cerbai E.
Author information:
(1)Center of Molecular Medicine (C.I.M.M.B.A.), Florence, Italy.
BACKGROUND AND PURPOSE: Recent clinical data suggest beneficial effects of
ivabradine, a specific heart rate (HR)-lowering drug, in heart failure patients.
However, the mechanisms responsible for these effects have not been completely
clarified. Thus, we investigated functional/molecular changes in I(f), the
specific target of ivabradine, in the failing atrial and ventricular myocytes
where this current is up-regulated as a consequence of maladaptive remodelling.
EXPERIMENTAL APPROACH: We investigated the effects of ivabradine (IVA; 10
mg·kg(-1) ·day(-1) for 90 days) on electrophysiological remodelling in left
atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from
post-mycardial infarcted (MI) rats, with sham-operated (sham or sham + IVA) rats
as controls. I(f) current was measured by patch-clamp;
hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms and
microRNA (miRNA-1 and miR-133) expression were evaluated by reverse
transcription quantitative PCR.
KEY RESULTS: Maximal specific conductance of I(f) was increased in MI, versus
sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both
MI and sham rats (P < 0.05). In MI + IVA, I(f) overexpression was attenuated and
HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively,
versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate
post-transcriptional expression of HCN2 and HCN4 genes, were significantly
increased in myocytes from MI + IVA.
CONCLUSION AND IMPLICATION: The beneficial effects of ivabradine may be due to
the reversal of electrophysiological cardiac remodelling in post-MI rats by
reduction of functional overexpression of HCN channels. This is attributable to
transcriptional and post-transcriptional mechanisms.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British
Pharmacological Society.
DOI: 10.1111/j.1476-5381.2011.01627.x
PMCID: PMC3372729
PMID: 21838751 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16321966 | 1. Nucleic Acids Res. 2005 Nov 30;33(21):6816-22. doi: 10.1093/nar/gki988. Print
2005.
A study on the correlation of nucleotide skews and the positioning of the origin
of replication: different modes of replication in bacterial species.
Nikolaou C(1), Almirantis Y.
Author information:
(1)Institute of Biology, National Centre of Scientific Research Demokritos,
15310 Athens, Greece. [email protected]
Deviations from Chargaff's 2nd parity rule, according to which A approximately T
and G approximately C in single stranded DNA, have been associated with
replication as well as with transcription in prokaryotes. Based on observations
regarding mainly the transcription-replication co-linearity in a large number of
prokaryotic species, we formulate the hypothesis that the replication procedure
may follow different modes between genomes throughout which the skews clearly
follow different patterns. We draw the conclusion that multiple functional sites
of origin of replication may exist in the genomes of most archaea and in some
exceptional cases of eubacteria, while in the majority of eubacteria,
replication occurs through a single fixed origin.
DOI: 10.1093/nar/gki988
PMCID: PMC1301597
PMID: 16321966 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17392430 | 1. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5806-11. doi:
10.1073/pnas.0700206104. Epub 2007 Mar 28.
Extrachromosomal element capture and the evolution of multiple replication
origins in archaeal chromosomes.
Robinson NP(1), Bell SD.
Author information:
(1)Medical Research Council Cancer Cell Unit, Hutchison Medical Research Council
Research Center, Hills Road, Cambridge CB2 0XZ, United Kingdom.
[email protected]
In all three domains of life, DNA replication begins at specialized loci termed
replication origins. In bacteria, replication initiates from a single, clearly
defined site. In contrast, eukaryotic organisms exploit a multitude of
replication origins, dividing their genomes into an array of short contiguous
units. Recently, the multiple replication origin paradigm has also been
demonstrated within the archaeal domain of life, with the discovery that the
hyperthermophilic archaeon Sulfolobus has three replication origins. However,
the evolutionary mechanism driving the progression from single to multiple
origin usage remains unclear. Here, we demonstrate that Aeropyrum pernix, a
distant relative of Sulfolobus, has two origins. Comparison with the Sulfolobus
origins provides evidence for evolution of replicon complexity by capture of
extrachromosomal genetic elements. We additionally identify a previously
unrecognized candidate archaeal initiator protein that is distantly related to
eukaryotic Cdt1. Our data thus provide evidence that horizontal gene transfer,
in addition to its well-established role in contributing to the information
content of chromosomes, may fundamentally alter the manner in which the host
chromosome is replicated.
DOI: 10.1073/pnas.0700206104
PMCID: PMC1851573
PMID: 17392430 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23067195 | 1. Vnitr Lek. 2012 Jul-Aug;58(7-8):612-17.
[Effects of selective heart rate reduction with ivabradine on left ventricular
remodelling and health related quality of life: results from the SHIFT
substudies].
[Article in Czech]
Vítovec J(1), Spinarová L, Spinar J.
Author information:
(1)Interni Kardioangiologicka klinika Lekarske fakulty MU a FN u sv. Anny Brno.
[email protected]
The SHIFT study showed a positive effect of ivabradine in patients with chronic
heart failure, sinus rhythm and heart rate at rest above 70 beats per minute.
The aim of the first sub-study was to ascertain the effect of ivabradine on
changes to the left ventricle function using echocardiography; ivabradine
significantly increased ejection fraction of the left ventricle and reduced
terminal left ventricular end-systolic and end-diastolic volumes. The second
sub-study explored changes to the quality of life in patients treated with
ivabradine or placebo. This study also showed statistically significantly
improved quality of life after treatment with ivabradine. Both sub-studies
confirmed the positive effect of ivabradine on patients with optimal treatment
of heart failure, including maximum tolerated dose of beta-blockers and sinus
heart rate above 70/min.
PMID: 23067195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21364800 | 1. Bioinformation. 2010 Nov 1;5(5):213-8. doi: 10.6026/97320630005213.
Mapping of origin of replication in Themococcales.
Ojha KK(1), Swati D.
Author information:
(1)Department of Bioinformatics, MMV, Banaras Hindu University, India.
Genome replication is a crucial and essential process for the continuity of
life.In all organisms it starts at a specific region of the genome known as
origin of replication (Ori) site. The number of Ori sites varies in prokaryotes
and eukaryotes. Replication starts at a single Ori site in bacteria, but in
eukaryotes multiple Ori sites are used for fast copying across all chromosomes.
The situation becomes complex in archaea, where some groups have single and
others have multiple origins of replication. Themococcales, are a
hyperthermophilic order of archaea. They are anaerobes and heterotrophs-peptide
fermenters, sulphate reducers, methanogens being some of the examples of
metabolic types. In this paper we have applied a combination of multiple in
silico approaches - Z curve, the cell division cycle (cdc6) gene location and
location of consensus origin recognition box (ORB) sequences for location of
origin of replication in Thermococcus onnurineus, Thermococcus gammatolerans and
other Themococcales and compared the results to that of the well-documented case
of Pyrococcus abyssi. The motivation behind this study is to find the number of
Ori sites based on the data available for members of this order. Results from
this in silico analysis show that the Themococcales have a single origin of
replication.
DOI: 10.6026/97320630005213
PMCID: PMC3041001
PMID: 21364800 |
http://www.ncbi.nlm.nih.gov/pubmed/19514618 | 1. Vnitr Lek. 2009 May;55(5):513-6.
[Ivabradine in patients with stable ischemic heart disease and left ventricular
systolic dysfunction: the results of the BEAUTIFUL study].
[Article in Czech]
Filipovský J(1).
Author information:
(1)II. interní klinika Lékarské fakulty UK a FN Plzeń. [email protected]
Ivabradine reduces heart rate by inhibiting the If channels mediated current,
while sinus rhythm is sustained. The aim of the BEAUTIFUL study was to assess
whether the administration of ivabradine to patients with stable ischemic heart
disease and ejection fraction < or = 40% will result in reduction of
cardiovascular morbidity and mortality. This was a double blind randomized study
including 10,917 patients. Half of the patients were administered placebo and
half were treated with ivabradine additional to the treatment normally used in
the secondary prevention ofischemic heart disease; the starting dose was 5 mg
twice a day and could be increased to 7.5 mg twice a day. The combined primary
endpoint was cardiovascular-event related death, hospitalization for acute
myocardial infarction and hospitalization for heart failure. The follow up was
19 months. Ivabradine decreased heart rate by 6 beats/min. The majority of
patients took beta-blockers (87%) and combination with ivabradine was well
tolerated. Ivabradine did not significantly affect the combined primary
endpoint. Significant reduction by 36% (p = 0.001) in myocardial infarction and
by 30% (p = 0.016) in coronary revascularization was observed in the pre-defined
subgroup of patients with heart rate > or = 70/min. Adverse events rate was the
same in the active and the control groups. It is possible to conclude that
ivabradine did not improve cardiovascular prognosis in all patients with stable
ischemic heart disease and decreased ejection fraction but was beneficial as an
additional add-on treatment to the current medication, including beta-blockers,
in patients whose heart rate was > or = 70/min.
PMID: 19514618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6109943 | 1. Lancet. 1981 Feb 7;1(8215):303-5. doi: 10.1016/s0140-6736(81)91913-9.
Is Wilson's disease caused by a controller gene mutation resulting in
perpetuation of the fetal mode of copper metabolism into childhood?
Epstein O, Sherlock S.
Wilson's disease is an inborn error of copper metabolism, characterised by
raised liver-copper concentrations and low serum levels of copper and
caeruloplasmin. The autosomal recessive mode of inheritance strongly suggests
that mutation of a single gene causes the impairment of both caeruloplasmin
synthesis and biliary copper excretion. The normal infant is born with the
biochemical features of Wilson's disease (very high liver-copper levels and low
serum copper and caeruloplasmin). Induction of normal copper metabolism after
birth results in a fall in liver-copper concentrations and rise in serum
caeruloplasmin. The repression of normal copper metabolism in the fetus and its
induction after birth is probably regulated by a controller gene. It is
suggested that mutation of a controller rather than a structural gene underlies
the pathogenesis of Wilson's disease and that the disease results from failure
to switch from the positive copper balance of the fetus to the normal copper
balance of the child.
DOI: 10.1016/s0140-6736(81)91913-9
PMID: 6109943 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23426135 | 1. J Invest Dermatol. 2013 Jul;133(7):1870-8. doi: 10.1038/jid.2013.76. Epub 2013
Feb 20.
Functional inactivation of CYLD promotes the metastatic potential of tumor
epidermal cells.
Alameda JP(1), Fernández-Aceñero MJ, Quintana RM, Page A, Ramírez Á, Navarro M,
Casanova ML.
Author information:
(1)Department of Molecular Oncology, CIEMAT, Madrid, Spain.
CYLD is a tumor-suppressor gene mutated in the skin appendage tumors
cylindromas, trichoepitheliomas, and spiradenomas. We have performed in vivo
metastasis assays in nude mice and found that the loss of the deubiquitinase
function of CYLD in squamous cell carcinoma (SCC) cells greatly enhances the
lung metastatic capability of these cells. These metastases showed several
characteristics that make them distinguishable from those carrying a functional
CYLD, such as robust angiogenesis, increased expression of tumor malignancy
markers of SCCs, and a decrease in the expression of the suppressor of
metastasis Maspin. Restoration of Maspin expression in the epidermal SCC cells
defective in CYLD deubiquitination function significantly reduces their ability
to form metastases, thereby suggesting that the decrease in the levels of Maspin
expression plays an important role in the acquisition of metastatic potential of
these cells. In addition, we have characterized Maspin downregulation in
cylindromas, trichoepitheliomas, and spiradenomas carrying functional
inactivating mutations of CYLD, also providing an evidence of the correlation
between impaired CYLD function and Maspin decreased expression in vivo in human
tumors.
DOI: 10.1038/jid.2013.76
PMID: 23426135 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11079561 | 1. Electrophoresis. 2000 Oct;21(16):3411-9. doi:
10.1002/1522-2683(20001001)21:16<3411::AID-ELPS3411>3.0.CO;2-M.
Towards a human repertoire of monocytic lysosomal proteins.
Journet A(1), Chapel A, Kieffer S, Louwagie M, Luche S, Garin J.
Author information:
(1)Laboratoire de Chimie des Protéines, CEA-Grenoble, France. [email protected]
The lysosomal compartment of human monocytic cells has never been investigated
by a proteomic approach. By a combination of one-dimensional (1-D) and
two-dimensional (2-D) gel electrophoresis, protein identification by N-terminal
sequencing, matrix assisted laser desorption/ionization-mass spectrometry
(MALDI-MS) peptide mass fingerprinting and tandem mass spectrometry (MS/MS)
peptide sequence analysis, we initiated an exhaustive study of the human
lyososomal proteome, which aims at establishing a 2-D reference map of human
soluble lyososomal proteins. Human monocytic U937 cells were induced to secrete
lysosomal soluble hydrolases by addition of NH4Cl in the culture medium. Since
lysosomal soluble proteins are characterized by the presence of
mannose-6-phosphate, they were purified on an affinity support bearing
mannose-6-phosphate receptor. Analysis of the purified fraction led to the
preliminary identification of fifteen proteins, among which twelve are
well-known lysosomal hydrolases, one is assumed to be lysosomal on the basis of
sequence homology to cysteine proteinases of the papain family, and two
(leukocystatin and the human cellular repressor of E1A-stimulated genes) are
described here for the first time as mannose-6-phosphate-containing proteins.
DOI: 10.1002/1522-2683(20001001)21:16<3411::AID-ELPS3411>3.0.CO;2-M
PMID: 11079561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20132422 | 1. J Cutan Pathol. 2010 Aug;37(8):886-90. doi: 10.1111/j.1600-0560.2010.01511.x.
Epub 2010 Feb 4.
Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD
gene and different types of somatic mutations in benign and malignant tumors.
Kazakov DV(1), Schaller J, Vanecek T, Kacerovska D, Michal M.
Author information:
(1)Sikl's Department of Pathology, Charles University, Medical Faculty Hospital,
Pilsen, Czech Republic. [email protected]
The authors report a case of Brooke-Spiegler syndrome (BSS) with a novel
germline CYLD mutation and various somatic mutations identified in the lesional
tissues. The patient was a 46-year-old man with multiple lesions on the face.
The available histopathological material included 24 trichoepitheliomas, 2 large
nodular basal cell carcinomas (BCCs), 2 spiradenomas, 1 spiradenocylindroma and
1 trichoblastoma composed of large and small nodules with prominent clear cell
differentiation. Whereas one of the two BCCs manifested a conventional
morphology, the second neoplasm additionally showed foci with high grade
cytological features characterized by marked pleomorphism and numerous mitotic
figures. There were also numerous signet ring cells and cells containing
intracytoplasmic eosinophilic inclusions. The germline mutation was a
substitution mutation c.1684 + 1G> A. Somatic mutations were investigated in
eight tissue blocks from which high quality genomic DNA had been successfully
extracted. Somatic mutations included loss of heterozygosity (LOH) in four
lesions and a single sequence mutation, namely a single base deletion c.
2322delA causing a frameshift mutation E774DfsX2. LOH occurred in both BCCs, one
trichoepithelioma and one spiradenoma. In the remaining three lesions, the
somatic event remained undetected.
DOI: 10.1111/j.1600-0560.2010.01511.x
PMID: 20132422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12190880 | 1. J Invest Dermatol. 2002 Aug;119(2):527-31. doi:
10.1046/j.1523-1747.2002.01839.x.
Phenotype diversity in familial cylindromatosis: a frameshift mutation in the
tumor suppressor gene CYLD underlies different tumors of skin appendages.
Poblete Gutiérrez P(1), Eggermann T, Höller D, Jugert FK, Beermann T,
Grussendorf-Conen EI, Zerres K, Merk HF, Frank J.
Author information:
(1)Departments of Dermatology and Human Genetics and Interdisciplinary Center
for Clinical Research (IZKF), University Clinic of the RWTH Aachen, Germany.
Familial cylindromatosis (turban tumor syndrome; Brooke-Spiegler syndrome) (OMIM
numbers 123850, 132700, 313100, and 605041) is a rare autosomal dominantly
inherited tumor syndrome. The disorder can present with cutaneous adnexal tumors
such as cylindromas, trichoepitheliomas, and spiradenomas, and tumors preferably
develop in hairy areas of the body such as head and neck. In affected families,
mutations have been demonstrated in the CYLD gene located on chromosome 16q12-13
and reveal the characteristic attributes of a tumor suppressor. Here, we studied
familial cylindromatosis in a multigeneration family of German origin.
Clinically, some individuals only revealed discrete small skin-colored tumors
localized in the nasolabial region whereas one family member showed expansion of
multiple big tumors on the trunk and in a turban-like fashion on the scalp.
Histologically, cylindromas as well as epithelioma adenoides cysticum were
found. We detected a frameshift mutation in the CYLD gene, designated 2253delG,
underlying the disorder and were able to show that a single mutation can result
in distinct clinical and histologic expression in familial cylindromatosis. The
reasons for different expression patterns of the same genetic defect in this
disease remain elusive, however. Identification of mutations in the CYLD gene
enable us to rapidly confirm putative diagnoses on the genetic level and to
provide affected families with genetic counseling.
DOI: 10.1046/j.1523-1747.2002.01839.x
PMID: 12190880 [Indexed for MEDLINE] |