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http://www.ncbi.nlm.nih.gov/pubmed/22367627 | 1. J Headache Pain. 2012 Jun;13(4):299-302. doi: 10.1007/s10194-012-0426-9. Epub
2012 Feb 25.
Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary
experience.
Donnini I(1), Nannucci S, Valenti R, Pescini F, Bianchi S, Inzitari D, Pantoni
L.
Author information:
(1)Department of Neurological and Psychiatric Sciences, University of Florence,
Largo Brambilla 3, Florence, Italy.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by NOTCH3
mutations. It is characterized by migraine, with or without aura, ischemic
events, psychiatric and cognitive disturbances. There is no approved treatment
for migraine prophylaxis in CADASIL, but acetazolamide has been anecdotally
reported to be effective. We retrospectively reviewed our database of patients
with a genetic diagnosis of CADASIL to identify how many of them were treated
with acetazolamide for the prophylaxis of migraine. The efficacy and the
tolerability of this treatment were checked looking at the clinic reports.
Acetazolamide was prescribed in seven patients; the mean duration of treatment
was 6 months, and the daily dose ranged from 125 to 500 mg. Three patients had a
total and sustained remission, while in two patients a reduction in attacks and
an improvement of the headache intensity were recorded. In one of these,
acetazolamide was deliberately taken only during the migraine attack and the
beneficial effect started 1 h after administration. In two patients, the drug
did not produce any beneficial effect. Mild side effects were recorded in two
patients. Our preliminary experience expands previous reports and confirms the
possible efficacy of acetazolamide in CADASIL migraine. Based on these data, a
randomized controlled trial seems worthy to be carried out to test the efficacy
and safety of this drug.
DOI: 10.1007/s10194-012-0426-9
PMCID: PMC3356473
PMID: 22367627 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22190405 | 1. Oncotarget. 2011 Dec;2(12):1127-33. doi: 10.18632/oncotarget.385.
Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased
human height.
Tatton-Brown K(1), Hanks S, Ruark E, Zachariou A, Duarte Sdel V, Ramsay E, Snape
K, Murray A, Perdeaux ER, Seal S, Loveday C, Banka S, Clericuzio C, Flinter F,
Magee A, McConnell V, Patton M, Raith W, Rankin J, Splitt M, Strenger V, Taylor
C, Wheeler P, Temple KI, Cole T; Childhood Overgrowth Collaboration; Douglas J,
Rahman N.
Collaborators: Amor D, Andries S, Archer H, Armstrong R, Ashton-Prolla P,
Baralle D, Barnicoat A, Barrow M, Beales P, Becker K, Beckh-Arnold E, Berg J,
Bernhard B, Bhat M, Birch J, Bitner M, Blair E, Bliek J, Blyth M, Brady A, Brice
G, Brueton L, Burn J, Canham N, Castle B, Cecconi M, Chandler K, Chandrasena R,
Cilliers D, Clarke A, Clayton-Smith J, Clericuzio C, Cole T, Colley A, Collins
A, Connell F, Cook J, Crow Y, Dabir T, Dalton A, Danda S, Davies S, Day R,
Dennis N, Deshpande C, Desouza B, Devlin L, Differ AM, Dinwiddie R, Dobbie A,
Donnai D, Ellis I, Elmslie F, Firth H, Fisher R, Fitzpatrick D, Flinter F, Foley
P, Foulds N, Fryer A, Gallagher A, Garcia S, Gardiner C, Gibbons R, Gillerot Y,
Goudie D, Gowrishanker K, Graham C, Gregersen N, Harper J, Hughes H, Henderson
A, Hennekam R, Hobson E, Holder S, Homfray T, Huma Z, Hurst J, Irving M, Izatt
L, Jagadeeth S, Jessen C, Johnson D, Josifova D, Joss S, Kerr B, Liebelt J, Kini
U, Krause A, Kumar A, Kumar D, Lam W, Lapunzina P, Lees M, Leonard N, Livesey A,
Longman C, Lucassen A, Lunt P, Lynch S, MacDonnell J, Magee A, Maher E, Male A,
Mansour S, McConnell V, McEntagart M, McKee S, McKeown C, Mehta S, Metcalfe K,
Mohammed S, Monaghan G, Montgomery T, Morgan A, Morrison P, Morton J, Mudgal R,
Murday V, Nampoothiri S, Nemeth A, Newbury-Ecob R, Oley C, Owen C, Park SM,
Parker M, Patel C, Patton M, Pilz D, Pinkney M, Pocha M, Pottinger C, Prescott
K, Price S, Proctor A, Quarrell O, Rankin J, Raymond L, Rea G, Reardon W, Reid
E, Robards M, Roposch A, Rosser E, Rourke D, Ruddy D, Saggar A, Sampson J,
Sandford R, Sarkar A, Scott R, Semple R, Sharif S, Shaw A, Shaw-Smith C, Shears
D, Shelagh J, Smith G, Smithson S, Splitt M, Stevens M, Stewart F, Stewart H,
Stopps K, Suri M, Sweeney E, Tanateles G, Taylor C, Temple K, Tischowitz M,
Tolmie J, Tomkins S, Turnpenny P, Van-Haelst M, Van Maldergem L, Vandersteen A,
Vasudevan P, Wakeling E, Walker L, Williams D, Wilson L, Woods G, Wright M,
Zankl A.
Author information:
(1)Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton,
UK.
Erratum in
Oncotarget. 2018 Nov 30;9(94):36719. doi: 10.18632/oncotarget.26429.
Comment in
Oncotarget. 2012 Jan;3(1):1-2. doi: 10.18632/oncotarget.435.
Oncotarget. 2012 Jan;3(1):3-4. doi: 10.18632/oncotarget.436.
The biological processes controlling human growth are diverse, complex and
poorly understood. Genetic factors are important and human height has been shown
to be a highly polygenic trait to which common and rare genetic variation
contributes. Weaver syndrome is a human overgrowth condition characterised by
tall stature, dysmorphic facial features, learning disability and variable
additional features. We performed exome sequencing in four individuals with
Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2,
in each case. Sequencing of EZH2 in additional individuals with overgrowth
identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome
shows considerable overlap with the inactivating somatic EZH2 mutations recently
reported in myeloid malignancies. Our data establish EZH2 mutations as the cause
of Weaver syndrome and provide further links between histone modifications and
regulation of human growth.
DOI: 10.18632/oncotarget.385
PMCID: PMC3282071
PMID: 22190405 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18710532 | 1. BMC Res Notes. 2008 May 30;1:16. doi: 10.1186/1756-0500-1-16.
Absence of mtDNA mutations in leukocytes of CADASIL patients.
Abu-Amero KK(1), Hellani A, Bohlega S.
Author information:
(1)Mitochondrial Research Laboratory, Department of Genetics, King Faisal
Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
[email protected]
BACKGROUND: Ultrastructural and biochemical abnormalities of mitochondria have
been reported in skeletal muscle biopsies of CADASIL patients with mutations in
the NOTCH3 nuclear gene. Additionally, it was proposed that NOTCH3 gene
mutations may predispose the mitochondrial DNA (mtDNA) to mutations.
METHODS: We sequenced the entire mitochondrial genome in five Arab patients
affected by CADASIL.
RESULTS: The mean number of mtDNA sequence variants (synonymous and
nonsynonymous) in CADASIL patients was not statistically significantly different
from that in controls (p = 0.378). After excluding haplogroup specific single
nucleotide polymorphisms (SNPs) and proved silent polymorphisms, no known or
novel pathologic mtDNA mutation(s) could be detected in any patient.
Additionally, there was no difference in the prevalence of different
mitochondrial haplogroups between patients and controls.
CONCLUSION: Our study group is too small for any valid conclusion to be made.
However, if our observation is confirmed in larger study group, then mtDNA
mutations or mitochondrial haplogroups may not be important in the pathogenesis
of CADASIL.
DOI: 10.1186/1756-0500-1-16
PMCID: PMC2518270
PMID: 18710532 |
http://www.ncbi.nlm.nih.gov/pubmed/22763387 | 1. Leukemia. 2013 Feb;27(2):430-40. doi: 10.1038/leu.2012.183. Epub 2012 Jul 5.
The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable
oprozomib have anti-resorptive and bone-anabolic activity in addition to
anti-myeloma effects.
Hurchla MA(1), Garcia-Gomez A, Hornick MC, Ocio EM, Li A, Blanco JF, Collins L,
Kirk CJ, Piwnica-Worms D, Vij R, Tomasson MH, Pandiella A, San Miguel JF,
Garayoa M, Weilbaecher KN.
Author information:
(1)Department of Medicine, Division of Oncology, Washington University School of
Medicine, St Louis, MO, USA.
Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone
therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting
pathologic bone destruction. In clinical trials, carfilzomib, a next generation
epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy
and decreased side effects compared with bortezomib. Carfilzomib and its orally
bioavailable analog oprozomib, effectively decreased MM cell viability following
continual or transient treatment mimicking in vivo pharmacokinetics.
Interactions between myeloma cells and the bone marrow (BM) microenvironment
augment the number and activity of bone-resorbing osteoclasts (OCs) while
inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth
and osteolytic lesions. At clinically relevant concentrations, carfilzomib and
oprozomib directly inhibited OC formation and bone resorption in vitro, while
enhancing osteogenic differentiation and matrix mineralization. Accordingly,
carfilzomib and oprozomib increased trabecular bone volume, decreased bone
resorption and enhanced bone formation in non-tumor bearing mice. Finally, in
mouse models of disseminated MM, the epoxyketone-based PIs decreased murine
5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data
demonstrate that, in addition to anti-myeloma properties, carfilzomib and
oprozomib effectively shift the bone microenvironment from a catabolic to an
anabolic state and, similar to bortezomib, may decrease skeletal complications
of MM.
DOI: 10.1038/leu.2012.183
PMCID: PMC3771507
PMID: 22763387 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST CJK is an employee of Onyx
Pharmaceuticals. All other authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24915039 | 1. Cancer Biol Ther. 2014 Sep;15(9):1142-52. doi: 10.4161/cbt.29452. Epub 2014
Jun 10.
Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head
and neck squamous cell carcinoma models of acquired resistance to proteasome
inhibitors.
Zang Y(1), Kirk CJ(2), Johnson DE(3).
Author information:
(1)Department of Medicine; University of Pittsburgh and the University of
Pittsburgh Cancer Institute; Pittsburgh, PA USA.
(2)Research; Onyx Pharmaceuticals, Inc.; South San Francisco, CA USA.
(3)Department of Medicine; University of Pittsburgh and the University of
Pittsburgh Cancer Institute; Pittsburgh, PA USA; Department of Pharmacology and
Chemical Biology; University of Pittsburgh; Pittsburgh, PA USA.
Acquired resistance to proteasome inhibitors represents a considerable
impediment to their effective clinical application. Carfilzomib and its orally
bioavailable structural analog oprozomib are second-generation,
highly-selective, proteasome inhibitors. However, the mechanisms of acquired
resistance to carfilzomib and oprozomib are incompletely understood, and
effective strategies for overcoming this resistance are needed. Here, we
developed models of acquired resistance to carfilzomib in two head and neck
squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure
to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33
demonstrated 205- and 64-fold resistance, respectively, relative to the parental
lines. Similarly, a high level of cross-resistance to oprozomib, as well as
paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to
29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen.
Synergistic induction of apoptosis signaling and cell death, and inhibition of
colony formation followed co-treatment of acquired resistance models with
carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism
was also seen with other combinations, including oprozomib plus vorinostat, or
carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation
of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired
resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of
MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in
R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining
carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful
strategy for overcoming acquired resistance to these proteasome inhibitors.
DOI: 10.4161/cbt.29452
PMCID: PMC4128857
PMID: 24915039 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8058745 | 1. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):7975-9. doi:
10.1073/pnas.91.17.7975.
Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells.
Youssoufian H(1).
Author information:
(1)Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Features of chromosomal aberrations, hypersensitivity to DNA crosslinking
agents, and predisposition to malignancy have suggested a fundamental anomaly of
DNA repair in Fanconi anemia. The function of the recently isolated FACC
(Fanconi anemia group C complementing) gene for a subset of this disorder is not
yet known. The notion that FACC plays a direct role in DNA repair would predict
that the polypeptide should reside in the nucleus. In this study, a polyclonal
antiserum raised against FACC was used to determine the subcellular location of
the polypeptide. Immunofluorescence and subcellular fractionation studies of
human cell lines as well as COS-7 cells transiently expressing human FACC showed
that the protein was localized primarily to the cytoplasm under steady-state
conditions, transit through the cell cycle, and exposure to crosslinking or
cytotoxic agents. However, placement of a nuclear localization signal from the
simian virus 40 large tumor antigen at the amino terminus of FACC directed the
hybrid protein to the nuclei of transfected COS-7 cells. These observations
suggest an indirect role for FACC in regulating DNA repair in this group of
Fanconi anemia.
DOI: 10.1073/pnas.91.17.7975
PMCID: PMC44527
PMID: 8058745 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24760151 | 1. J Immunol. 2014 Jun 1;192(11):5012-22. doi: 10.4049/jimmunol.1302943. Epub
2014 Apr 23.
Ezh2 regulates transcriptional and posttranslational expression of T-bet and
promotes Th1 cell responses mediating aplastic anemia in mice.
Tong Q(1), He S(2), Xie F(3), Mochizuki K(3), Liu Y(2), Mochizuki I(3), Meng
L(4), Sun H(5), Zhang Y(5), Guo Y(6), Hexner E(7), Zhang Y(8).
Author information:
(1)International Joint Cancer Institute, Second Military Medical University,
Shanghai 200433, China; Department of Internal Medicine, University of Michigan
Medical School, Ann Arbor, MI, 48109;
(2)Department of Internal Medicine, University of Michigan Medical School, Ann
Arbor, MI, 48109; Department of Microbiology and Immunology, Fels Institute for
Cancer Research and Molecular Biology, Temple University, Philadelphia, PA
19140;
(3)Department of Internal Medicine, University of Michigan Medical School, Ann
Arbor, MI, 48109;
(4)Department of Microbiology and Immunology, Fels Institute for Cancer Research
and Molecular Biology, Temple University, Philadelphia, PA 19140; Institute of
Health Sciences, Shanghai Institutes for Biological Sciences Chinese Academy of
Sciences, Shanghai 200433, China; and.
(5)Institute of Health Sciences, Shanghai Institutes for Biological Sciences
Chinese Academy of Sciences, Shanghai 200433, China; and.
(6)International Joint Cancer Institute, Second Military Medical University,
Shanghai 200433, China;
(7)Department of Medicine and Abramson Cancer Center, University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA 19104.
(8)Department of Internal Medicine, University of Michigan Medical School, Ann
Arbor, MI, 48109; Department of Microbiology and Immunology, Fels Institute for
Cancer Research and Molecular Biology, Temple University, Philadelphia, PA
19140; [email protected].
Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure
syndrome. IFN-γ-producing Th1 CD4(+) T cells mediate the immune destruction of
hematopoietic cells, and they are central to the pathogenesis. However, the
molecular events that control the development of BM-destructive Th1 cells remain
largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple
cellular processes primarily by silencing gene expression. We recently reported
that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM
transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in
AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the
effects of Ezh2 inhibition in CD4(+) T cells using a mouse model of human AA.
Conditionally deleting Ezh2 in mature T cells dramatically reduced the
production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1
cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant
decrease in the expression of Tbx21 and Stat4, which encode transcription
factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into
Ezh2-deficient T cells fully rescued their differentiation into Th1 cells
mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly
activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent
proteasome-mediated degradation of T-bet protein in Th1 cells. Our results
demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells
through a mechanism of transcriptional and posttranscriptional regulation of
T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition
in reducing AA and other autoimmune diseases.
Copyright © 2014 by The American Association of Immunologists, Inc.
DOI: 10.4049/jimmunol.1302943
PMCID: PMC4075972
PMID: 24760151 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18434402 | 1. J Virol. 2008 Jul;82(13):6409-18. doi: 10.1128/JVI.00490-08. Epub 2008 Apr 23.
Nuclear marginalization of host cell chromatin associated with expansion of two
discrete virus-induced subnuclear compartments during baculovirus infection.
Nagamine T(1), Kawasaki Y, Abe A, Matsumoto S.
Author information:
(1)Laboratory of Molecular Entomology, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama
351-0198, Japan. [email protected]
Chromatin structure is strictly regulated during the cell cycle. DNA viruses
occasionally disturb the spatial organization of the host cell chromatin due to
formation of the viral DNA replication compartment. To examine chromatin
behavior in baculovirus-infected cells, we constructed recombinant plasmids
expressing fluorescent protein-tagged histone H4 molecules and visualized the
intracellular localization of chromatin by their transient expression in live
infected cells. Similar to other DNA viruses, the baculovirus Bombyx mori
nucleopolyhedrovirus induced marginal relocation of chromatin within the nuclei
of BmN cells, simultaneously with expansion of the viral DNA replication
compartment, the virogenic stroma (VS). In the late stage of infection, however,
the peristromal region (PR), another virus-induced subnuclear compartment, was
also excluded from the chromatin-localizing area. Provided that late-gene
products such as PR proteins (e.g., envelope proteins of the occlusion-derived
virus) were expressed, blockage of viral DNA synthesis failed to inhibit
chromatin relocation, despite abrogation of VS expansion. Instead, chromatin
became marginalized concomitantly with PR expansion, suggesting that the PR
contributes directly to chromatin replacement. In addition, chromatin was
excluded from relatively large subnuclear structures that were induced in
uninfected cells by cotransfection with four baculovirus genes, ie1, lef3, p143,
and hr. Omission of any of the four genes, however, failed to result in
formation of the large structures or chromatin exclusion. This correlation
between compartmentalization and chromatin exclusion suggests the possibility
that a chromatin-exclusive property of viral molecules, at least in part,
supports nuclear compartmentalization of virus-infected cells.
DOI: 10.1128/JVI.00490-08
PMCID: PMC2447088
PMID: 18434402 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25409831 | 1. Nature. 2014 Nov 20;515(7527):402-5. doi: 10.1038/nature13986.
Topologically associating domains are stable units of replication-timing
regulation.
Pope BD(1), Ryba T(2), Dileep V(1), Yue F(3), Wu W(4), Denas O(5), Vera DL(1),
Wang Y(6), Hansen RS(7), Canfield TK(8), Thurman RE(8), Cheng Y(9), Gülsoy
G(10), Dennis JH(1), Snyder MP(9), Stamatoyannopoulos JA(8), Taylor J(5),
Hardison RC(4), Kahveci T(10), Ren B(11), Gilbert DM(1).
Author information:
(1)Department of Biological Science, 319 Stadium Drive, Florida State
University, Tallahassee, Florida 32306, USA.
(2)Division of Natural Sciences, 5800 Bay Shore Road, New College of Florida,
Sarasota, Florida 34243, USA.
(3)1] Department of Biochemistry and Molecular Biology, School of Medicine, The
Pennsylvania State University, Hershey, Pennsylvania 17033, USA [2]
Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The
Pennsylvania State University, University Park, Pennsylvania 16802, USA.
(4)Center for Comparative Genomics and Bioinformatics, Huck Institutes of the
Life Sciences, The Pennsylvania State University, University Park, Pennsylvania
16802, USA.
(5)Departments of Biology and Mathematics and Computer Science, Emory
University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta,
Georgia 30322, USA.
(6)Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences,
The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
(7)Department of Medicine, Division of Medical Genetics, University of
Washington, Seattle, Washington 98195, USA.
(8)Department of Genome Sciences, University of Washington, Seattle, Washington
98195, USA.
(9)Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477
Stanford, California 94305, USA.
(10)Computer and Information Sciences and Engineering, University of Florida,
Gainesville, Florida 32611, USA.
(11)Ludwig Institute for Cancer Research and University of California, San Diego
School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA.
Eukaryotic chromosomes replicate in a temporal order known as the
replication-timing program. In mammals, replication timing is cell-type-specific
with at least half the genome switching replication timing during development,
primarily in units of 400-800 kilobases ('replication domains'), whose positions
are preserved in different cell types, conserved between species, and appear to
confine long-range effects of chromosome rearrangements. Early and late
replication correlate, respectively, with open and closed three-dimensional
chromatin compartments identified by high-resolution chromosome conformation
capture (Hi-C), and, to a lesser extent, late replication correlates with
lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure
within chromatin compartments called topologically associating domains (TADs)
that are largely conserved in their positions between cell types and are similar
in size to replication domains. However, TADs can be further sub-stratified into
smaller domains, challenging the significance of structures at any particular
scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data
have not revealed a common, underlying domain structure. Here we localize
boundaries of replication domains to the early-replicating border of
replication-timing transitions and map their positions in 18 human and 13 mouse
cell types. We demonstrate that, collectively, replication domain boundaries
share a near one-to-one correlation with TAD boundaries, whereas within a cell
type, adjacent TADs that replicate at similar times obscure replication domain
boundaries, largely accounting for the previously reported lack of alignment.
Moreover, cell-type-specific replication timing of TADs partitions the genome
into two large-scale sub-nuclear compartments revealing that replication-timing
transitions are indistinguishable from late-replicating regions in chromatin
composition and lamina association and accounting for the reduced correlation of
replication timing to LADs and heterochromatin. Our results reconcile
cell-type-specific sub-nuclear compartmentalization and replication timing with
developmentally stable structural domains and offer a unified model for
large-scale chromosome structure and function.
DOI: 10.1038/nature13986
PMCID: PMC4251741
PMID: 25409831 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/11186332 | 1. Crit Rev Eukaryot Gene Expr. 2000;10(2):179-212.
Chromosome territories, interchromatin domain compartment, and nuclear matrix:
an integrated view of the functional nuclear architecture.
Cremer T(1), Kreth G, Koester H, Fink RH, Heintzmann R, Cremer M, Solovei I,
Zink D, Cremer C.
Author information:
(1)Institute of Anthropology and Human Genetics, Ludwig Maximilians University,
Munich, Germany.
Advances in the specific fluorescent labeling of chromatin in fixed and living
human cells in combination with three-dimensional (3D) and 4D (space plus time)
fluorescence microscopy and image analysis have opened the way for detailed
studies of the dynamic, higher-order architecture of chromatin in the human cell
nucleus and its potential role in gene regulation. Several features of this
architecture are now well established: 1. Chromosomes occupy distinct
territories in the cell nucleus with preferred nuclear locations, although there
is no evidence of a rigid suprachromosomal order. 2. Chromosome territories
(CTs) in turn contain distinct chromosome arm domains and smaller chromatin foci
or domains with diameters of some 300 to 800 nm and a DNA content in the order
of 1 Mbp. 3. Gene-dense, early-replicating and gene-poor,
middle-to-late-replicating chromatin domains exhibit different higher-order
nuclear patterns that persist through all stages of interphase. In mitotic
chromosomes early replicating chromatin domains give rise to Giemsa light bands,
whereas middle-to-late-replicating domains form Giemsa dark bands and C-bands.
In an attempt to integrate these experimental data into a unified view of the
functional nuclear architecture, we present a model of a modular and dynamic
chromosome territory (CT) organization. We propose that basically three nuclear
compartments exist, an "open" higher-order chromatin compartment with chromatin
domains containing active genes, a "closed" chromatin compartment comprising
inactive genes, and an interchromatin domain (ICD) compartment (Cremer et al.,
1993; Zirbel et al., 1993) that contains macromolecular complexes for
transcription, splicing, DNA replication, and repair. Genes in "open," but not
in "closed" higher-order chromatin compartments have access to transcription and
splicing complexes located in the ICD compartment. Chromatin domains that build
the "open" chromatin compartment are organized in a way that allows the direct
contact of genes and nascent RNA to transcription and splicing complexes,
respectively, preformed in the ICD compartment. In contrast, chromatin domains
that belong to the "closed" compartment are topologically arranged and compacted
in a way that precludes the accessibility of genes to transcription complexes.
We argue that the content of the ICD compartment is highly enriched in DNA
depleted biochemical matrix preparations. The ICD compartment may be considered
as the structural and functional equivalent of the in vivo nuclear matrix. A
matrix in this functional sense is compatible with but does not necessitate the
concept of a 3D nuclear skeleton existing of long, extensively arborized
filaments. In the absence of unequivocal evidence for such a structural matrix
in the nucleus of living cells we keep an agnostic attitude about its existence
and possible properties in maintaining the higher-order nuclear architecture.
Quantitative modeling of the 3D and 4D human genome architecture in situ shows
that such an assumption is not necessary to explain presently known aspects of
the higher-order nuclear architecture. We expect that the interplay of
quantitative modeling and experimental tests will result in a better
understanding of the compartmentalized nuclear architecture and its functional
consequences.
PMID: 11186332 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12520035 | 1. Nucleic Acids Res. 2003 Jan 1;31(1):406-9. doi: 10.1093/nar/gkg020.
TMPDB: a database of experimentally-characterized transmembrane topologies.
Ikeda M(1), Arai M, Okuno T, Shimizu T.
Author information:
(1)Department of Electronic Information System Engineering, Faculty of Science
and Technology, Hirosaki University, Hirosaki 036-8561, Japan.
TMPDB is a database of experimentally-characterized transmembrane (TM)
topologies. TMPDB release 6.2 contains a total of 302 TM protein sequences, in
which 276 are alpha-helical sequences, 17 beta-stranded, and 9 alpha-helical
sequences with short pore-forming helices buried in the membrane. The TM
topologies in TMPDB were determined experimentally by means of X-ray
crystallography, NMR, gene fusion technique, substituted cysteine accessibility
method, N-linked glycosylation experiment and other biochemical methods. TMPDB
would be useful as a test and/or training dataset in improving the proposed TM
topology prediction methods or developing novel methods with higher performance,
and as a guide for both the bioinformaticians and biologists to better
understand TM proteins. TMPDB and its subsets are freely available at the
following web site: http://bioinfo.si.hirosaki-u.ac.jp/~TMPDB/.
DOI: 10.1093/nar/gkg020
PMCID: PMC165467
PMID: 12520035 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25340765 | 1. PLoS Genet. 2014 Oct 23;10(10):e1004646. doi: 10.1371/journal.pgen.1004646.
eCollection 2014 Oct.
Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells
but not cancer cells.
McCole RB(1), Fonseka CY(2), Koren A(3), Wu CT(1).
Author information:
(1)Department of Genetics, Harvard Medical School, Boston, Massachusetts, United
States of America.
(2)Department of Genetics, Harvard Medical School, Boston, Massachusetts, United
States of America; Biological and Biomedical Sciences PhD program, Harvard
Medical School, Boston, Massachusetts, United States of America.
(3)Department of Genetics, Harvard Medical School, Boston, Massachusetts, United
States of America; Program in Medical and Population Genetics, Broad Institute
of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Ultraconserved elements (UCEs) are strongly depleted from segmental duplications
and copy number variations (CNVs) in the human genome, suggesting that deletion
or duplication of a UCE can be deleterious to the mammalian cell. Here we
address the process by which CNVs become depleted of UCEs. We begin by showing
that depletion for UCEs characterizes the most recent large-scale human CNV
datasets and then find that even newly formed de novo CNVs, which have passed
through meiosis at most once, are significantly depleted for UCEs. In striking
contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted
for UCEs and can even become significantly enriched. This observation raises the
possibility that CNVs that arise somatically and are relatively newly formed are
less likely to have established a CNV profile that is depleted for UCEs.
Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the
diseased state. In support of this latter explanation, somatic CNVs that are not
associated with disease are depleted for UCEs. Finally, we show that it is
possible to observe the CNVs of induced pluripotent stem (iPS) cells become
depleted of UCEs over time, suggesting that depletion may be established through
selection against UCE-disrupting CNVs without the requirement for meiotic
divisions.
DOI: 10.1371/journal.pgen.1004646
PMCID: PMC4207606
PMID: 25340765 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22929803 | 1. Clin Cancer Res. 2012 Oct 15;18(20):5639-49. doi:
10.1158/1078-0432.CCR-12-1213. Epub 2012 Aug 28.
Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck
cancer and their activities are enhanced by suppression of Mcl-1 or autophagy.
Zang Y(1), Thomas SM, Chan ET, Kirk CJ, Freilino ML, DeLancey HM, Grandis JR, Li
C, Johnson DE.
Author information:
(1)Department of Medicine, University of Pittsburgh, University of Pittsburgh
Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
PURPOSE: Carfilzomib is a selective, irreversible inhibitor of the
chymotrypsin-like activity of the proteasome and is undergoing clinical
evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable
derivative. The activities of carfilzomib and ONX 0912 against solid tumor
malignancies are less well understood. We investigated the impact and mechanisms
of action of carfilzomib and ONX 0912 in preclinical models of head and neck
squamous cell carcinoma (HNSCC).
EXPERIMENTAL DESIGN: The effects of carfilzomib and ONX 0912 on HNSCC cell
survival and xenograft tumor growth were evaluated. The impact and mechanisms of
both agents on apoptosis and autophagy induction were also investigated. The
contribution of the unfolded protein response (UPR) to autophagy induction and
the role of autophagy in attenuating HNSCC cell death were determined.
RESULTS: Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines
via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents
served to dampen their efficacies. Carfilzomib and ONX 0912 also induced
autophagy, mediated, in part, by activation of the UPR pathway involving
upregulation of ATF4 transcription factor. Autophagy induction served a
prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC
xenograft tumors in a dose-dependent manner.
CONCLUSIONS: These results show that carfilzomib and ONX 0912 are potently
active against HNSCC cells, and the activities of these agents can be enhanced
via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in
vivo activity against HNSCC tumors and may represent a useful therapeutic agent
for this malignancy.
©2012 AACR
DOI: 10.1158/1078-0432.CCR-12-1213
PMCID: PMC3473099
PMID: 22929803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24712303 | 1. J Cell Mol Med. 2014 Jun;18(6):947-61. doi: 10.1111/jcmm.12279. Epub 2014 Apr
8.
Proteasome inhibitors - molecular basis and current perspectives in multiple
myeloma.
Kubiczkova L(1), Pour L, Sedlarikova L, Hajek R, Sevcikova S.
Author information:
(1)Babak Myeloma Group, Department of Pathological Physiology, Faculty of
Medicine, Masaryk University, Brno, Czech Republic; Department of Clinical
Hematology, University Hospital Brno, Brno, Czech Republic.
Inhibition of proteasome, a proteolytic complex responsible for the degradation
of ubiquitinated proteins, has emerged as a powerful strategy for treatment of
multiple myeloma (MM), a plasma cell malignancy. First-in-class agent,
bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in
pre-clinical and in clinical studies. However, despite its high efficiency, a
large proportion of patients do not achieve sufficient clinical response.
Therefore, the development of a second-generation of proteasome inhibitors (PIs)
with improved pharmacological properties was needed. Recently, several of these
new agents have been introduced into clinics including carfilzomib, marizomib
and ixazomib. Further, new orally administered second-generation PI oprozomib is
being investigated. This review provides an overview of main mechanisms of
action of PIs in MM, focusing on the ongoing development and progress of novel
anti-proteasome therapeutics.
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John
Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
DOI: 10.1111/jcmm.12279
PMCID: PMC4508135
PMID: 24712303 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20601677 | 1. Bioinformatics. 2010 Oct 1;26(19):2490-2. doi: 10.1093/bioinformatics/btq362.
Epub 2010 Jul 3.
ExTopoDB: a database of experimentally derived topological models of
transmembrane proteins.
Tsaousis GN(1), Tsirigos KD, Andrianou XD, Liakopoulos TD, Bagos PG, Hamodrakas
SJ.
Author information:
(1)Department of Cell Biology and Biophysics, Faculty of Biology, University of
Athens, Panepistimiopolis Athens, Greece.
ExTopoDB is a publicly accessible database of experimentally derived topological
models of transmembrane proteins. It contains information collected from studies
in the literature that report the use of biochemical methods for the
determination of the topology of α-helical transmembrane proteins. Transmembrane
protein topology is highly important in order to understand their function and
ExTopoDB provides an up to date, complete and comprehensive dataset of
experimentally determined topologies of α-helical transmembrane proteins.
Topological information is combined with transmembrane topology prediction
resulting in more reliable topological models.
AVAILABILITY: http://bioinformatics.biol.uoa.gr/ExTopoDB.
DOI: 10.1093/bioinformatics/btq362
PMID: 20601677 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24471924 | 1. Expert Rev Hematol. 2014 Feb;7(1):97-111. doi: 10.1586/17474086.2014.882764.
Epub 2014 Jan 29.
Current strategies for treatment of relapsed/refractory multiple myeloma.
Laubach JP(1), Voorhees PM, Hassoun H, Jakubowiak A, Lonial S, Richardson PG.
Author information:
(1)Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute, Boston, MA, USA.
In spite of significant advances in the management of multiple myeloma (MM), the
disease remains incurable and nearly all patients ultimately relapse and require
salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a
critical area of research pertaining to biological mechanisms of progression and
chemotherapy resistance, as well as to the development of new pharmacologic
agents and immunologic approaches for the disease. The immunomodulatory agents
and proteasome inhibitors represent the cornerstone of treatment in this
setting, with combination regimens incorporating these drugs demonstrating
encouraging rates and duration of response, including the newer agents,
pomalidomide and carfilzomib. In addition, novel drug classes have shown
promising activity in RR MM, including the orally-administered proteasome
inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1
monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab;
and histone deacetylase inhibitors such as panobinostat and rocilinostat.
DOI: 10.1586/17474086.2014.882764
PMID: 24471924 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16115458 | 1. Med Sci (Paris). 2005 Aug-Sep;21(8-9):730-6. doi: 10.1051/medsci/2005218-9730.
[Fanconi anemia: genes and function(s) revisited].
[Article in French]
Papadopoulo D(1), Moustacchi E.
Author information:
(1)Institut Curie, Section de recherche, UMR 218 CNRS, 26 rue d'Ulm, 75248 Paris
Cedex 05, France. [email protected]
Fanconi anemia (FA), a rare inherited disorder, exhibits a complex phenotype
including progressive bone marrow failure, congenital malformations and
increased risk of cancers, mainly acute myeloid leukaemia. At the cellular
level, FA is characterized by hypersensitivity to DNA cross-linking agents and
by high frequencies of induced chromosomal aberrations, a property used for
diagnosis. FA results from mutations in one of the eleven FANC (FANCA to FANCJ)
genes. Nine of them have been identified. In addition, FANCD1 gene has been
shown to be identical to BRCA2, one of the two breast cancer susceptibility
genes. Seven of the FANC proteins form a complex, which exists in four different
forms depending of its subcellular localisation. Four FANC proteins (D1(BRCA2),
D2, I and J) are not associated to the complex. The presence of the nuclear form
of the FA core complex is necessary for the mono-ubiquitinylation of FANCD2
protein, a modification required for its re-localization to nuclear foci, likely
to be sites of DNA repair. A clue towards understanding the molecular function
of the FANC genes comes from the recently identified connection of FANC to the
BRCA1, ATM, NBS1 and ATR genes. Two of the FANC proteins (A and D2) directly
interact with BRCA1, which in turn interacts with the MRE11/RAD50/NBS1 complex,
which is one of the key components in the mechanisms involved in the cellular
response to DNA double strand breaks (DSB). Moreover, ATM, a protein kinase that
plays a central role in the network of DSB signalling, phosphorylates in vitro
and in vivo FANCD2 in response to ionising radiations. Moreover, the NBS1
protein and the monoubiquitinated form of FANCD2 seem to act together in
response to DNA crosslinking agents. Taken together with the previously reported
impaired DSB and DNA interstrand crosslinks repair in FA cells, the connection
of FANC genes to the ATM, ATR, NBS1 and BRCA1 links the FANC genes function to
the finely orchestrated network involved in the sensing, signalling and repair
of DNA replication-blocking lesions.
DOI: 10.1051/medsci/2005218-9730
PMID: 16115458 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16571130 | 1. BMC Bioinformatics. 2006 Mar 29;7:177. doi: 10.1186/1471-2105-7-177.
Identifying metabolic enzymes with multiple types of association evidence.
Kharchenko P(1), Chen L, Freund Y, Vitkup D, Church GM.
Author information:
(1)Department of Genetics, New Research Building (NRB) Room 238, 77 Ave, Louis
Pasteur, Harvard Medical School, Boston, MA 02115, USA.
[email protected]
BACKGROUND: Existing large-scale metabolic models of sequenced organisms
commonly include enzymatic functions which can not be attributed to any gene in
that organism. Existing computational strategies for identifying such missing
genes rely primarily on sequence homology to known enzyme-encoding genes.
RESULTS: We present a novel method for identifying genes encoding for a specific
metabolic function based on a local structure of metabolic network and multiple
types of functional association evidence, including clustering of genes on the
chromosome, similarity of phylogenetic profiles, gene expression, protein fusion
events and others. Using E. coli and S. cerevisiae metabolic networks, we
illustrate predictive ability of each individual type of association evidence
and show that significantly better predictions can be obtained based on the
combination of all data. In this way our method is able to predict 60% of
enzyme-encoding genes of E. coli metabolism within the top 10 (out of 3551)
candidates for their enzymatic function, and as a top candidate within 43% of
the cases.
CONCLUSION: We illustrate that a combination of genome context and other
functional association evidence is effective in predicting genes encoding
metabolic enzymes. Our approach does not rely on direct sequence homology to
known enzyme-encoding genes, and can be used in conjunction with traditional
homology-based metabolic reconstruction methods. The method can also be used to
target orphan metabolic activities.
DOI: 10.1186/1471-2105-7-177
PMCID: PMC1450304
PMID: 16571130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11438739 | 1. Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7940-5. doi:
10.1073/pnas.141236298.
Genes linked by fusion events are generally of the same functional category: a
systematic analysis of 30 microbial genomes.
Yanai I(1), Derti A, DeLisi C.
Author information:
(1)Bioinformatics Graduate Program and Department of Biomedical Engineering,
Boston University, Boston, MA 02215, USA.
Recent work in computational genomics has shown that a functional association
between two genes can be derived from the existence of a fusion of the two as
one continuous sequence in another genome. For each of 30 completely sequenced
microbial genomes, we established all such fusion links among its genes and
determined the distribution of links within and among 15 broad functional
categories. We found that 72% of all fusion links related genes of the same
functional category. A comparison of the distribution of links to simulations on
the basis of a random model further confirmed the significance of intracategory
fusion links. Where a gene of annotated function is linked to an unclassified
gene, the fusion link suggests that the two genes belong to the same functional
category. The predictions based on fusion links are shown here for
Methanobacterium thermoautotrophicum, and another 661 predictions are available
at http://fusion.bu.edu.
DOI: 10.1073/pnas.141236298
PMCID: PMC35447
PMID: 11438739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15215406 | 1. Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W336-9. doi:
10.1093/nar/gkh365.
Phydbac2: improved inference of gene function using interactive phylogenomic
profiling and chromosomal location analysis.
Enault F(1), Suhre K, Poirot O, Abergel C, Claverie JM.
Author information:
(1)Information Génomique & Structurale (UPR CNRS 2589), Institut de Biologie
Structurale et Microbiologie, 31, chemin Joseph Aiguier, 13402 Marseille Cedex
20, France. [email protected]
Phydbac (phylogenomic display of bacterial genes) implemented a method of
phylogenomic profiling using a distance measure based on normalized BLAST
scores. This method was able to increase the predictive power of phylogenomic
profiling by about 25% when compared to the classical approach based on Hamming
distances. Here we present a major extension of Phydbac (named here Phydbac2),
that extends both the concept and the functionality of the original web-service.
While phylogenomic profiles remain the central focus of Phydbac2, it now
integrates chromosomal proximity and gene fusion analyses as two additional
non-similarity-based indicators for inferring pairwise gene functional
relationships. Moreover, all presently available (January 2004) fully sequenced
bacterial genomes and those of three lower eukaryotes are now included in the
profiling process, thus increasing the initial number of reference genomes (71
in Phydbac) to 150 in Phydbac2. Using the KEGG metabolic pathway database as a
benchmark, we show that the predictive power of Phydbac2 is improved by 27% over
the previous version. This gain is accounted for on one hand, by the increased
number of reference genomes (11%) and on the other hand, as a result of
including chromosomal proximity into the distance measure (16%). The expanded
functionality of Phydbac2 now allows the user to query more than 50 different
genomes, including at least one member of each major bacterial group, most major
pathogens and potential bio-terrorism agents. The search for co-evolving genes
based on consensus profiles from multiple organisms, the display of Phydbac2
profiles side by side with COG information, the inclusion of KEGG metabolic
pathway maps the production of chromosomal proximity maps, and the possibility
of collecting and processing results from different Phydbac queries in a common
shopping cart are the main new features of Phydbac2. The Phydbac2 web server is
available at http://igs-server.cnrs-mrs.fr/phydbac/.
DOI: 10.1093/nar/gkh365
PMCID: PMC441503
PMID: 15215406 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9773867 | 1. J Heart Lung Transplant. 1998 Sep;17(9):931-40.
The effect of triiodothyronine on myocardial contractile performance after
epinephrine exposure: implications for donor heart management.
Timek T(1), Bonz A, Dillmann R, Vahl CF, Hagl S.
Author information:
(1)Department of Cardiac Surgery, University of Heidelberg, Germany.
BACKGROUND: This study analyzes in the experimental model of isolated human
atrial myocardium whether the myocardial contractile depression occurring after
high-dose/long-term catecholamine exposure (as typically occurring in brain-dead
organ donors) can be reversed by thyroid hormone administration.
METHODS: Isolated trabeculae were prepared from atrial myocardium from patients
undergoing coronary artery bypass (n = 15). Initial measurements of isometric
force were carried out (measurement conditions of 37 degrees C, Krebs Henseleit
solution, supramaximal electrical stimulation, 1 Hz, at optimal length). Then
the trabeculae were incubated for 6 hours at 26 degrees C in a Krebs Henseleit
solution containing epinephrine 10(-7) mol/L and the fluorescent dye FURA-2/AM
for calcium measurements. At the end of the incubation period, isometric force,
isotonic shortening, and intracellular calcium transient (FURA-2 "ratio method")
were measured. After 30 minutes administration of triiodothyronine (5 x 10(-9)
mol/L), the measurements were repeated. Control groups included 6 hours
incubation in 4 degrees C Krebs Henseleit solution (n = 5); 6 hours incubation
in 26 degrees C FURA-2/AM (n = 5); and 6 hours incubation in epinephrine 10(-7)
mol/L (n = 5).
RESULTS: After 6 hours catecholamine exposure isometric force declined
significantly to 56.8% (p < .0001) and isotonic shortening to 54% of its initial
value (p < .01). Administration of triiodothyronine was associated with a
significant recovery of the isotonic shortening amplitude (p < .005), of
isometric force development (p < .01), an increased velocity of force
development (p < .0001), and of diastolic force decay (p < .005). At the same
time the shape of the intracellular calcium transient became smaller as a result
of an accelerated diastolic decay. The amplitude of the calcium transient
remained unaltered, whereas the calcium time integral was reduced (p < .05).
CONCLUSION: In the model of isolated human myocardium, experimental depression
of the contractile performance resulting from long-term catecholamine exposure
could be reversed by a 30-minute triiodothyronine incubation. The experimental
data showing increased force amplitudes at unaltered amplitudes of the
intracellular calcium transient and an even-reduced calcium time integral
provide strong evidence for a sensitization of the contractile apparatus for
calcium by triiodothyronine. The data provide additional knowledge to explain
the successful administration of triiodothyronine in donor heart management.
PMID: 9773867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15701682 | 1. Bioinformatics. 2005 May 15;21(10):2558-9. doi: 10.1093/bioinformatics/bti313.
Epub 2005 Feb 8.
Protein function prediction using the Protein Link EXplorer (PLEX).
Date SV(1), Marcotte EM.
Author information:
(1)Center for Systems and Synthetic Biology, Institute for Cellular and
Molecular Biology, 1 University Station, A4800, Austin, TX 78712-1064, USA.
We introduce the Protein Link EXplorer (PLEX), a web-based environment that
allows the construction of a phylogenetic profile for any given amino acid
sequence, and its comparison with profiles of approximately 350,000 predicted
genes from 89 genomes, as a means of interactively identifying functionally
linked genes and predicting protein function. PLEX can be searched iteratively
and also enables searches for chromosomal gene neighbors and Rosetta Stone
linkages. PLEX search results are accompanied by quantitative estimates of
linkage confidence, enabling users to take advantage of coinheritance, operon
and gene fusion-based methods for inferring gene function and reconstructing
cellular systems and pathways.
AVAILABILITY: http://bioinformatics.icmb.utexas.edu/plex
DOI: 10.1093/bioinformatics/bti313
PMID: 15701682 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24023653 | 1. PLoS One. 2013 Aug 30;8(8):e72894. doi: 10.1371/journal.pone.0072894.
eCollection 2013.
Caveolae regulation of mechanosensitive channel function in myotubes.
Huang H(1), Bae C, Sachs F, Suchyna TM.
Author information:
(1)Capital Medical University, Department of Physiology, Beijing, China.
Mutations that lead to muscular dystrophy often create deficiencies in
cytoskeletal support of the muscle sarcolemma causing hyperactive
mechanosensitive cation channel (MSC) activity and elevated intracellular
Ca(2+). Caveolae are cholesterol-rich microdomains that form mechanically
deformable invaginations of the sarcolemma. Mutations to caveolin-3, the main
scaffolding protein of caveolae in muscle, cause Limbe-Girdle muscular
dystrophy. Using genetic and acute chemical perturbations of developing myotubes
we investigated whether caveolae are functionally linked to MSCs. MSC
sensitivity was assayed using suction application to patches and probe-induced
indentation during whole-cell recordings. Membrane mechanical stress in patches
was monitored using patch capacitance/impedance. Cholesterol depletion disrupted
caveolae and caused a large increase in MSC current. It also decreased the
membrane mechanical relaxation time, likely reflecting cytoskeleton dissociation
from the bilayer. Reduction of Cav3 expression with miRNA also increased MSC
current and decreased patch relaxation time. In contrast Cav3 overexpression
produced a small decrease in MSC currents. To acutely and specifically inhibit
Cav3 interactions, we made a chimeric peptide containing the antennapedia
membrane translocation domain and the Cav3 scaffolding domain (A-CSD3). A-CSD3
action was time dependent initially producing a mild Ca(2+) leak and increased
MSC current, while longer exposures decreased MSC currents coinciding with
increased patch stiffening. Images of GFP labeled Cav3 in patches showed that
Cav3 doesn't enter the pipette, showing patch composition differed from the cell
surface. However, disruption via cholesterol depletion caused Cav3 to become
uniformly distributed over the sarcolemma and Cav3 appearance in the patch dome.
The whole-cell indentation currents elicited under the different caveolae
modifying conditions mirror the patch response supporting the role of caveolae
in MSC function. These studies show that normal expression levels of Cav3 are
mechanoprotective to the sarcolemma through multiple mechanisms, and Cav3
upregulation observed in some dystrophies may compensate for other mechanical
deficiencies.
DOI: 10.1371/journal.pone.0072894
PMCID: PMC3758351
PMID: 24023653 [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/24103732 | 1. Transpl Immunol. 2013 Dec;29(1-4):1-6. doi: 10.1016/j.trim.2013.09.011. Epub
2013 Oct 5.
Effect of novel proteasome and immunoproteasome inhibitors on dendritic cell
maturation, function, and expression of IκB and NFκB.
Al-Homsi AS(1), Lai Z, Roy TS, Kouttab N.
Author information:
(1)Division of Adult Blood and Marrow Transplantation, Spectrum Health, Michigan
State College of Human Medicine, Grand Rapids, MI, USA. Electronic address:
[email protected].
Dendritic cells (DC) play a central role in the pathophysiology of graft versus
host disease (GvHD). Their antigen presenting capacity is nuclear factor κB-
(NF-κB) dependent. Consequently, DC have emerged as a potential target for the
prevention of GvHD and clinical trials with bortezomib are underway. We explored
the activity of novel proteasome and immunoproteasome inhibitors on healthy
volunteer peripheral blood DC. After incubation with the drug or drug
combination, DC were stimulated with lipopolysaccharide, stained for maturation
surface markers and then analyzed by flow cytometry. We found that the different
molecule(s) inhibited DC maturation marker expression to variable degrees, with
the constitutive proteasome-selective agent being the least active. In a DC and
allogeneic CD4+ mixed lymphocyte reaction, DC incubation with the studied
proteasome and immunoproteasome inhibitor(s), impeded T cell proliferation as
measured by BrDU incorporation. Finally, we found that DC incubation with the
drug(s) enhanced IκB expression and that oprozomib inhibited NF-κB expression.
We concluded that based on its activity and oral bioavailability, oprozomib
merits further investigation in an animal GvHD prevention model. We also suggest
that altering IκB and NF-κB expressions may, in DC, represent a new mechanism of
action of proteasome and immunoproteasome inhibitors.
© 2013. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.trim.2013.09.011
PMID: 24103732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2428004 | 1. Pflugers Arch. 1986 Aug;407(2):142-4. doi: 10.1007/BF00580665.
Influence of the thyroid state on the calcium transient in ventricular muscle.
MacKinnon R, Morgan JP.
The purpose of this study was to determine the influence of thyroid hormone on
tension development and the intracellular calcium transient in mammalian
ventricular muscle. A hyperthyroid (H) state was induced in ferrets by
subcutaneous injection of L-thyroxine, 0.3 mg/kg daily, for 2-3 weeks. One-half
of the age matched control group (C) were injected with vehicle. Aequorin was
loaded into the cells of ferret papillary muscles by a chemical procedure. The
muscles were stimulated at 0.33 Hz and isometric tension and the calcium
transient were simultaneously recorded at 30 degrees C. Peak isometric tension
in mN/mm2 (+/- SD) was 15.4 +/- 7.2 and 16.2 +/- 7.9 for C (n = 8) and H (n = 9)
respectively. The time to peak tension and time to 80% relaxation from peak of
tension were reduced by 22% and 28% respectively in H compared to C. After
stimulation, the calcium transient reached a maximum in 56 +/- 6 ms in C and in
47 +/- 5 ms in H. The time to 80% decay of the peak calcium transient was 95 +/-
8 ms and 68 +/- 5 ms for C and H respectively. The ratio of the aequorin
luminescence at the peak of the calcium transient over the calculated maximum
luminescence, Lmax, were compared and they were not different. At 22 degrees C
Log (L/Lmax) was -3.3 +/- 0.1 in C (n = 4) and -3.4 +/- 0.3 in H (n = 3). These
results indicate that the thyroid state influences the time course of the
calcium transient and are consistent with the abbreviation in the duration of
contraction that is observed in the hyperthyroid state.
DOI: 10.1007/BF00580665
PMID: 2428004 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23787000 | 1. Cardiovasc Res. 2013 Oct 1;100(1):151-9. doi: 10.1093/cvr/cvt157. Epub 2013
Jun 19.
Role of caveolae in shear stress-mediated endothelium-dependent dilation in
coronary arteries.
Chai Q(1), Wang XL, Zeldin DC, Lee HC.
Author information:
(1)Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo
Clinic, Rochester, MN 55905, USA.
AIMS: Caveolae are membrane microdomains where important signalling pathways are
assembled and molecular effects transduced. In this study, we hypothesized that
shear stress-mediated vasodilation (SSD) of mouse small coronary arteries (MCA)
is caveolae-dependent.
METHODS AND RESULTS: MCA (80-150 μm) isolated from wild-type (WT) and caveolin-1
null (Cav-1(-/-)) mice were subjected to physiological levels of shear stress
(1-25 dynes/cm(2)) with and without pre-incubation of inhibitors of nitric oxide
synthase (L-NAME), cyclooxygenase (indomethacin, INDO), or cytochrome P450
epoxygenase (SKF 525A). SSD was endothelium-dependent in WT and Cav-1(-/-)
coronaries but that in Cav-1(-/-) was significantly diminished compared with WT.
Pre-incubation with L-NAME, INDO, or SKF 525A significantly reduced SSD in WT
but not in Cav-1(-/-) mice. Vessels from the soluble epoxide hydrolase null
(Ephx2(-/-)) mice showed enhanced SSD, which was further augmented by the
presence of arachidonic acid. In donor-detector-coupled vessel experiments,
Cav-1(-/-) donor vessels produced diminished dilation in WT endothelium-denuded
detector vessels compared with WT donor vessels. Shear stress elicited a robust
intracellular Ca(2+) increase in vascular endothelial cells isolated from WT but
not those from Cav-1(-/-) mice.
CONCLUSION: Integrity of caveolae is critical for endothelium-dependent SSD in
MCA. Cav-1(-/-) endothelium is deficient in shear stress-mediated generation of
vasodilators including NO, prostaglandins, and epoxyeicosatrienoic acids.
Caveolae plays a critical role in endothelial signal transduction from shear
stress to vasodilator production and release.
DOI: 10.1093/cvr/cvt157
PMCID: PMC3778958
PMID: 23787000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23727353 | 1. Life Sci. 2013 Jul 19;93(1):1-6. doi: 10.1016/j.lfs.2013.05.016. Epub 2013 May
30.
Role of caveolin-1 and caveolae signaling in endotoxemia and sepsis.
Feng H(1), Guo W(2), Han J(1), Li XA(3).
Author information:
(1)Department of Tumor Research and Therapy Center, Provincial Hospital
Affiliated to Shandong University, Jinan, Shandong 250021, China.
(2)Taian Central Hospital, Taian, Shandong 271000, China.
(3)Department of Pediatrics, University of Kentucky College of Medicine,
Lexington, KY 40536, United States. Electronic address: [email protected].
Caveolae, plasma membrane invaginations of 60-80nm in diameter, are a subset of
lipid rafts enriched in cholesterol and sphingolipids. Caveolae are expressed in
various tissues and cell types, such as endothelial cells, macrophages,
neutrophils and adipocytes. The functions of caveolae are diverse and include
endocytosis, transcytosis, potocytosis, calcium signaling, and regulation of
various signaling events. Although growing evidence has increased our
understanding of caveolae function, the role of caveolae in sepsis is still a
controversial issue. In this review, we present a number of studies addressing
caveolae and sepsis and describe the signaling pathways involved, including the
LPS-eNOS-TLR4-NFκB, MKK3/p38 MAPK, cPLA2/p38 MAPK, STAT3/NFκB and IL-1β-IL-1R1
pathways. Different studies using endotoxemia and bacteremia animal models have
provided distinct conclusions about the function of caveolae, and we discuss
these inconsistencies. Taken together, the current data suggest that the
function of caveolae in sepsis, which involves a number of signaling pathways,
is complex and warrants further studies.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.lfs.2013.05.016
PMCID: PMC3733535
PMID: 23727353 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19298522 | 1. J Cell Mol Med. 2009 Sep;13(9B):3082-90. doi:
10.1111/j.1582-4934.2009.00728.x. Epub 2009 Feb 27.
Modulation of cardiac ionic homeostasis by 3-iodothyronamine.
Ghelardoni S(1), Suffredini S, Frascarelli S, Brogioni S, Chiellini G,
Ronca-Testoni S, Grandy DK, Scanlan TS, Cerbai E, Zucchi R.
Author information:
(1)Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa,
Italy.
3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone,
able to interact with trace amine-associated receptors, a class of plasma
membrane G protein-coupled receptors, and to produce a negative inotropic and
chronotropic effect. In the isolated rat heart 20-25 microM T(1)AM decreased
cardiac contractility, but oxygen consumption and glucose uptake were either
unchanged or disproportionately high when compared to mechanical work. In adult
rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude
and duration of the calcium transient. In patch clamped cardiomyocytes
sarcolemmal calcium current density was unchanged while current facilitation by
membrane depolarization was abolished consistent with reduced sarcoplasmic
reticulum (SR) calcium release. In addition, T(1)AM decreased transient outward
current (I(to)) and I(K1) background current. SR studies involving 20 microM
T(1)AM revealed a significant decrease in ryanodine binding due to reduced
B(max), no significant change in the rate constant of calcium-induced calcium
release, a significant increase in calcium leak measured under conditions
promoting channel closure, and no effect on oxalate-supported calcium uptake.
Based on these observations we conclude T(1)AM affects calcium and potassium
homeostasis and suggest its negative inotropic action is due to a diminished
pool of SR calcium as a result of increased diastolic leak through the ryanodine
receptor, while increased action potential duration is accounted for by
inhibition of I(to) and I(K1) currents.
DOI: 10.1111/j.1582-4934.2009.00728.x
PMCID: PMC4516467
PMID: 19298522 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12095249 | 1. J Mol Biol. 2002 Jul 19;320(4):713-9. doi: 10.1016/s0022-2836(02)00467-9.
Proteins with class alpha/beta fold have high-level participation in fusion
events.
Hua S(1), Guo T, Gough J, Sun Z.
Author information:
(1)Institute of Bioinformatics, Department of Biological Sciences and
Biotechnology, Tsinghua University, Beijing 100084, People's Republic of China.
Now that complete genome sequences are available for a variety of organisms, the
elucidation of potential gene products function is a central goal in the
post-genome era. Domain fusion analysis has been proposed recently to infer the
functional association of the component proteins. Here, we took a new approach
to the analysis of the structural features of the proteins involved in fusion
events. An exhaustive survey of fusion events within 30 completely sequenced
genomes and subsequent structure annotations to the component proteins at a SCOP
superfamily level with hidden Markov models was carried out. A domain fusion map
was then constructed. The results revealed that proteins with the class
alpha/beta fold are frequently involved in fusion events, around 86% of the
total 676 assigned single-domain fusion pairs including at least one component
protein belonging to the alpha/beta fold class. Moreover, the domain fusion map
in our work may offer an attractive framework for designing chimeric enzymes
following Nature's lead, and may give useful hints for exploring the
evolutionary history of proteins. (c) 2002 Elsevier Science Ltd.
DOI: 10.1016/s0022-2836(02)00467-9
PMID: 12095249 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15960802 | 1. Genome Biol. 2005;6(6):R50. doi: 10.1186/gb-2005-6-6-r50. Epub 2005 May 9.
The rarity of gene shuffling in conserved genes.
Conant GC(1), Wagner A.
Author information:
(1)Department of Genetics, Smurfit Institute, University of Dublin, Trinity
College, Dublin 2, Ireland. [email protected]
BACKGROUND: Among three sources of evolutionary innovation in gene function -
point mutations, gene duplications, and gene shuffling (recombination between
dissimilar genes) - gene shuffling is the most potent one. However, surprisingly
little is known about its incidence on a genome-wide scale.
RESULTS: We have studied shuffling in genes that are conserved between distantly
related species. Specifically, we estimated the incidence of gene shuffling in
ten organisms from the three domains of life: eukaryotes, eubacteria, and
archaea, considering only genes showing significant sequence similarity in
pairwise genome comparisons. We found that successful gene shuffling is very
rare among such conserved genes. For example, we could detect only 48 successful
gene-shuffling events in the genome of the fruit fly Drosophila melanogaster
which have occurred since its common ancestor with the worm Caenorhabditis
elegans more than half a billion years ago.
CONCLUSION: The incidence of gene shuffling is roughly an order of magnitude
smaller than the incidence of single-gene duplication in eukaryotes, but it can
approach or even exceed the gene-duplication rate in prokaryotes. If true in
general, this pattern suggests that gene shuffling may not be a major force in
reshaping the core genomes of eukaryotes. Our results also cast doubt on the
notion that introns facilitate gene shuffling, both because prokaryotes show an
appreciable incidence of gene shuffling despite their lack of introns and
because we find no statistical association between exon-intron boundaries and
recombined domains in the two multicellular genomes we studied.
DOI: 10.1186/gb-2005-6-6-r50
PMCID: PMC1175970
PMID: 15960802 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22925561 | 1. BMC Genomics. 2012 Aug 28;13:429. doi: 10.1186/1471-2164-13-429.
Identification and analysis of pig chimeric mRNAs using RNA sequencing data.
Ma L(1), Yang S, Zhao W, Tang Z, Zhang T, Li K.
Author information:
(1)The Key Laboratory for Domestic Animal Genetic Resources and Breeding of
Ministry of Agriculture of China, Institute of Animal Science, Chinese Academy
of Agricultural Sciences, Beijing, 100193, P R China.
BACKGROUND: Gene fusion is ubiquitous over the course of evolution. It is
expected to increase the diversity and complexity of transcriptomes and
proteomes through chimeric sequence segments or altered regulation. However,
chimeric mRNAs in pigs remain unclear. Here we identified some chimeric mRNAs in
pigs and analyzed the expression of them across individuals and breeds using
RNA-sequencing data.
RESULTS: The present study identified 669 putative chimeric mRNAs in pigs, of
which 251 chimeric candidates were detected in a set of RNA-sequencing data. The
618 candidates had clear trans-splicing sites, 537 of which obeyed the canonical
GU-AG splice rule. Only two putative pig chimera variants whose fusion junction
was overlapped with that of a known human chimeric mRNA were found. A set of
unique chimeric events were considered middle variances in the expression across
individuals and breeds, and revealed non-significant variance between sexes.
Furthermore, the genomic region of the 5' partner gene shares a similar DNA
sequence with that of the 3' partner gene for 458 putative chimeric mRNAs. The
81 of those shared DNA sequences significantly matched the known DNA-binding
motifs in the JASPAR CORE database. Four DNA motifs shared in parental genomic
regions had significant similarity with known human CTCF binding sites.
CONCLUSIONS: The present study provided detailed information on some pig
chimeric mRNAs. We proposed a model that trans-acting factors, such as CTCF,
induced the spatial organisation of parental genes to the same transcriptional
factory so that parental genes were coordinatively transcribed to give birth to
chimeric mRNAs.
DOI: 10.1186/1471-2164-13-429
PMCID: PMC3531304
PMID: 22925561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22872646 | 1. J Biol Chem. 2012 Sep 28;287(40):33523-32. doi: 10.1074/jbc.M112.370551. Epub
2012 Aug 7.
TRIM50 protein regulates vesicular trafficking for acid secretion in gastric
parietal cells.
Nishi M(1), Aoyama F, Kisa F, Zhu H, Sun M, Lin P, Ohta H, Van B, Yamamoto S,
Kakizawa S, Sakai H, Ma J, Sawaguchi A, Takeshima H.
Author information:
(1)Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Of the TRIM/RBCC family proteins taking part in a variety of cellular processes,
TRIM50 is a stomach-specific member with no defined biological function. Our
biochemical data demonstrated that TRIM50 is specifically expressed in gastric
parietal cells and is predominantly localized in the tubulovesicular and
canalicular membranes. In cultured cells ectopically expressing GFP-TRIM50,
confocal microscopic imaging revealed dynamic movement of TRIM50-associated
vesicles in a phosphoinositide 3-kinase-dependent manner. A protein overlay
assay detected preferential binding of the PRY-SPRY domain from the TRIM50
C-terminal region to phosphatidylinositol species, suggesting that TRIM50 is
involved in vesicular dynamics by sensing the phosphorylated state of
phosphoinositol lipids. Trim50 knock-out mice retained normal histology in the
gastric mucosa but exhibited impaired secretion of gastric acid. In response to
histamine, Trim50 knock-out parietal cells generated deranged canaliculi,
swollen microvilli lacking actin filaments, and excess multilamellar membrane
complexes. Therefore, TRIM50 seems to play an essential role in tubulovesicular
dynamics, promoting the formation of sophisticated canaliculi and microvilli
during acid secretion in parietal cells.
DOI: 10.1074/jbc.M112.370551
PMCID: PMC3460453
PMID: 22872646 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23886867 | 1. J Mol Biol. 2013 Dec 13;425(24):5032-44. doi: 10.1016/j.jmb.2013.07.025. Epub
2013 Jul 23.
Rhesus monkey TRIM5α SPRY domain recognizes multiple epitopes that span several
capsid monomers on the surface of the HIV-1 mature viral core.
Biris N(1), Tomashevski A, Bhattacharya A, Diaz-Griffero F, Ivanov DN.
Author information:
(1)Department of Biochemistry and Cancer Therapy and Research Center, University
of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San
Antonio, TX 78229, USA.
The restriction factor TRIM5α binds to the capsid protein of the retroviral core
and blocks retroviral replication. The affinity of TRIM5α for the capsid is a
major host tropism determinant of HIV and other primate immunodeficiency
viruses, but the molecular interface involved in this host-pathogen interaction
remains poorly characterized. Here we use NMR spectroscopy to investigate
binding of the rhesus TRIM5α SPRY domain to a selection of HIV capsid
constructs. The data are consistent with a model in which one SPRY domain
interacts with more than one capsid monomer within the assembled retroviral
core. The highly mobile SPRY v1 loop appears to span the gap between neighboring
capsid hexamers making interhexamer contacts critical for restriction. The
interaction interface is extensive, involves mobile loops and multiple epitopes,
and lacks interaction hot spots. These properties, which may enhance resistance
of TRIM5α to capsid mutations, result in relatively low affinity of the
individual SPRY domains for the capsid, and the TRIM5α-mediated restriction
depends on the avidity effect arising from the oligomerization of TRIM5α.
© 2013.
DOI: 10.1016/j.jmb.2013.07.025
PMCID: PMC4116666
PMID: 23886867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17431422 | 1. Cell Death Differ. 2007 Aug;14(8):1457-66. doi: 10.1038/sj.cdd.4402142. Epub
2007 Apr 13.
The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients,
interacts with inflammasome components and inhibits proIL-1beta processing.
Papin S(1), Cuenin S, Agostini L, Martinon F, Werner S, Beer HD, Grütter C,
Grütter M, Tschopp J.
Author information:
(1)Department of Biochemistry, University of Lausanne, Chemin des Boveresses
155, CH-1066 Epalinges, Switzerland.
The autoinflammatory disorders Muckle-Wells syndrome, familial cold urtecaria
and chronic infantile neurological cutaneous and articular syndrome are
associated with mutations in the NALP3 (Cryopyrin) gene, which is the central
platform of the proinflammatory caspase-1 activating complex, named the
inflammasome. In patients with another autoinflammatory disorder, familial
Mediterranean fever (FMF), mutations in the SPRY domain of the Pyrin protein are
frequently found. Recent evidence suggests that Pyrin associates with ASC, an
inflammasome component, via its Pyrin domain, thereby halting the inflammatory
response. This interaction, however, does not explain the effects of mutations
of the SPRY domain found in FMF patients. Here we show that the Pyrin SPRY
domain not only interacts with NALP3, but also with caspase-1 and its substrate
pro-interleukin(IL)-1beta. Whereas a Pyrin knockdown results in increased
caspase-1 activation and IL-1beta secretion, overexpression of the SPRY domain
alone blocks these processes. Thus Pyrin binds to several inflammasome
components thereby modulating their activity.
DOI: 10.1038/sj.cdd.4402142
PMID: 17431422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22337885 | 1. J Biol Chem. 2012 Apr 6;287(15):12050-9. doi: 10.1074/jbc.M111.307678. Epub
2012 Feb 15.
TRIM67 protein negatively regulates Ras activity through degradation of 80K-H
and induces neuritogenesis.
Yaguchi H(1), Okumura F, Takahashi H, Kano T, Kameda H, Uchigashima M, Tanaka S,
Watanabe M, Sasaki H, Hatakeyama S.
Author information:
(1)Department of Biochemistry, Hokkaido University Graduate School of Medicine,
Sapporo, Hokkaido 060-8638, Japan.
Tripartite motif (TRIM)-containing proteins, which are defined by the presence
of a common domain structure composed of a RING finger, one or two B-box motifs
and a coiled-coil motif, are involved in many biological processes including
innate immunity, viral infection, carcinogenesis, and development. Here we show
that TRIM67, which has a TRIM motif, an FN3 domain and a SPRY domain, is highly
expressed in the cerebellum and that TRIM67 interacts with PRG-1 and 80K-H,
which is involved in the Ras-mediated signaling pathway. Ectopic expression of
TRIM67 results in degradation of endogenous 80K-H and attenuation of cell
proliferation and enhances neuritogenesis in the neuroblastoma cell line
N1E-115. Furthermore, morphological and biological changes caused by knockdown
of 80K-H are similar to those observed by overexpression of TRIM67. These
findings suggest that TRIM67 regulates Ras signaling via degradation of 80K-H,
leading to neural differentiation including neuritogenesis.
DOI: 10.1074/jbc.M111.307678
PMCID: PMC3320951
PMID: 22337885 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22267904 | 1. Evol Bioinform Online. 2012;8:47-60. doi: 10.4137/EBO.S8018. Epub 2011 Dec 18.
SAFE Software and FED Database to Uncover Protein-Protein Interactions using
Gene Fusion Analysis.
Tsagrasoulis D(1), Danos V, Kissa M, Trimpalis P, Koumandou VL, Karagouni AD,
Tsakalidis A, Kossida S.
Author information:
(1)Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Domain Fusion Analysis takes advantage of the fact that certain proteins in a
given proteome A, are found to have statistically significant similarity with
two separate proteins in another proteome B. In other words, the result of a
fusion event between two separate proteins in proteome B is a specific
full-length protein in proteome A. In such a case, it can be safely concluded
that the protein pair has a common biological function or even interacts
physically. In this paper, we present the Fusion Events Database (FED), a
database for the maintenance and retrieval of fusion data both in prokaryotic
and eukaryotic organisms and the Software for the Analysis of Fusion Events
(SAFE), a computational platform implemented for the automated detection,
filtering and visualization of fusion events (both available at:
http://www.bioacademy.gr/bioinformatics/projects/ProteinFusion/index.htm).
Finally, we analyze the proteomes of three microorganisms using these tools in
order to demonstrate their functionality.
DOI: 10.4137/EBO.S8018
PMCID: PMC3256994
PMID: 22267904 |
http://www.ncbi.nlm.nih.gov/pubmed/18655028 | 1. Proteomics. 2008 Jul;8(14):2907-10. doi: 10.1002/pmic.200800083.
Proteomic identification of a PSF/p54nrb heterodimer as RNF43
oncoprotein-interacting proteins.
Miyamoto K(1), Sakurai H, Sugiura T.
Author information:
(1)Discovery Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceutical Co.,
Ltd., Daiichi-Sankyo group, Tokyo, Japan.
RNF43 is an oncogenic RING finger protein overexpressed in colorectal cancer. To
dissect its biological functions, we explored RNF43-interacting proteins by
pull-down assay and MS. We identified a heterodimer, p54nrb and PSF, as RNF43's
binding partners and confirmed their physical interaction in vivo by the
co-immunoprecipitation experiment. Immunofluorescence analysis revealed that
co-expression of PSF relocates RNF43 from the nuclear periphery to the
nucleoplasm. Thus, proteomic identification of RNF43-associated proteins sheds
light on its dynamic interaction network in nuclear events.
DOI: 10.1002/pmic.200800083
PMID: 18655028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16381848 | 1. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D21-4. doi:
10.1093/nar/gkj019.
ChimerDB--a knowledgebase for fusion sequences.
Kim N(1), Kim P, Nam S, Shin S, Lee S.
Author information:
(1)Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750,
Korea.
Chromosome translocation and gene fusion are frequent events in the human genome
and are often the cause of many types of tumor. ChimerDB is the database of
fusion sequences encompassing bioinformatics analysis of mRNA and expressed
sequence tag (EST) sequences in the GenBank, manual collection of literature
data and integration with other known database such as OMIM. Our bioinformatics
analysis identifies the fusion transcripts that have non-overlapping alignments
at multiple genomic loci. Fusion events at exon-exon borders are selected to
filter out the cloning artifacts in cDNA library preparation. The result is
classified into two groups--genuine chromosome translocation and fusion between
neighboring genes owing to intergenic splicing. We also integrated manually
collected literature and OMIM data for chromosome translocation as an aid to
assess the validity of each fusion event. The database is available at
http://genome.ewha.ac.kr/ChimerDB/ for human, mouse and rat genomes.
DOI: 10.1093/nar/gkj019
PMCID: PMC1347382
PMID: 16381848 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18081932 | 1. BMC Genomics. 2007 Dec 14;8:460. doi: 10.1186/1471-2164-8-460.
Denoising inferred functional association networks obtained by gene fusion
analysis.
Kamburov A(1), Goldovsky L, Freilich S, Kapazoglou A, Kunin V, Enright AJ,
Tsaftaris A, Ouzounis CA.
Author information:
(1)Computational Genomics Group, The European Bioinformatics Institute, EMBL
Cambridge Outstation, Cambridge CB10 1SD, UK. [email protected]
BACKGROUND: Gene fusion detection - also known as the 'Rosetta Stone' method -
involves the identification of fused composite genes in a set of reference
genomes, which indicates potential interactions between its un-fused counterpart
genes in query genomes. The precision of this method typically improves with an
ever-increasing number of reference genomes.
RESULTS: In order to explore the usefulness and scope of this approach for
protein interaction prediction and generate a high-quality, non-redundant set of
interacting pairs of proteins across a wide taxonomic range, we have
exhaustively performed gene fusion analysis for 184 genomes using an efficient
variant of a previously developed protocol. By analyzing interaction graphs and
applying a threshold that limits the maximum number of possible interactions
within the largest graph components, we show that we can reduce the number of
implausible interactions due to the detection of promiscuous domains. With this
generally applicable approach, we generate a robust set of over 2 million
distinct and testable interactions encompassing 696,894 proteins in 184 species
or strains, most of which have never been the subject of high-throughput
experimental proteomics. We investigate the cumulative effect of increasing
numbers of genomes on the fidelity and quantity of predictions, and show that,
for large numbers of genomes, predictions do not become saturated but continue
to grow linearly, for the majority of the species. We also examine the
percentage of component (and composite) proteins with relation to the number of
genes and further validate the functional categories that are highly represented
in this robust set of detected genome-wide interactions.
CONCLUSION: We illustrate the phylogenetic and functional diversity of gene
fusion events across genomes, and their usefulness for accurate prediction of
protein interaction and function.
DOI: 10.1186/1471-2164-8-460
PMCID: PMC2248599
PMID: 18081932 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22101825 | 1. Acta Crystallogr D Biol Crystallogr. 2011 Nov;67(Pt 11):981-7. doi:
10.1107/S0907444911039606. Epub 2011 Oct 19.
Construct optimization for studying protein complexes: obtaining
diffraction-quality crystals of the pseudosymmetric PSPC1-NONO heterodimer.
Lee M(1), Passon DM, Hennig S, Fox AH, Bond CS.
Author information:
(1)School of Biomedical, Biomolecular and Chemical Sciences, University of
Western Australia, Crawley, WA 6009, Australia.
The methodology of protein crystallography provides a number of potential
bottlenecks. Here, an approach to successful structure solution of a difficult
heterodimeric complex of two human proteins, paraspeckle component 1 (PSPC1) and
non-POU domain-containing octamer-binding protein (NONO), that are involved in
gene regulation and the structural integrity of nuclear bodies termed
paraspeckles is described. With the aid of bioinformatic predictions and
systematic screening of a panel of constructs, bottlenecks of protein
solubility, crystallization, crystal quality and crystallographic pseudosymmetry
were overcome in order to produce crystals that ultimately revealed the
structure.
© 2011 International Union of Crystallography. Printed in Singapore – all rights
reserved.
DOI: 10.1107/S0907444911039606
PMID: 22101825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23334284 | 1. Chromosoma. 2013 Mar;122(1-2):121-34. doi: 10.1007/s00412-013-0396-y. Epub
2013 Jan 20.
An Eco1-independent sister chromatid cohesion establishment pathway in S.
cerevisiae.
Borges V(1), Smith DJ, Whitehouse I, Uhlmann F.
Author information:
(1)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cohesion between sister chromatids, mediated by the chromosomal cohesin complex,
is a prerequisite for their alignment on the spindle apparatus and segregation
in mitosis. Budding yeast cohesin first associates with chromosomes in G1. Then,
during DNA replication in S-phase, the replication fork-associated
acetyltransferase Eco1 acetylates the cohesin subunit Smc3 to make cohesin's DNA
binding resistant to destabilization by the Wapl protein. Whether stabilization
of cohesin molecules that happen to link sister chromatids is sufficient to
build sister chromatid cohesion, or whether additional reactions are required to
establish these links, is not known. In addition to Eco1, several other factors
contribute to cohesion establishment, including Ctf4, Ctf18, Tof1, Csm3, Chl1
and Mrc1, but little is known about their roles. Here, we show that each of
these factors facilitates cohesin acetylation. Moreover, the absence of Ctf4 and
Chl1, but not of the other factors, causes a synthetic growth defect in cells
lacking Eco1. Distinct from acetylation defects, sister chromatid cohesion in
ctf4Δ and chl1Δ cells is not improved by removing Wapl. Unlike previously
thought, we do not find evidence for a role of Ctf4 and Chl1 in Okazaki fragment
processing, or of Okazaki fragment processing in sister chromatid cohesion.
Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that
might hold important clues as to the mechanism of sister chromatid cohesion
establishment.
DOI: 10.1007/s00412-013-0396-y
PMCID: PMC3608886
PMID: 23334284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19430531 | 1. PLoS One. 2009;4(5):e5497. doi: 10.1371/journal.pone.0005497. Epub 2009 May
11.
The ELG1 clamp loader plays a role in sister chromatid cohesion.
Parnas O(1), Zipin-Roitman A, Mazor Y, Liefshitz B, Ben-Aroya S, Kupiec M.
Author information:
(1)Department of Molecular Microbiology and Biotechnology, Tel Aviv University,
Ramat Aviv, Israel.
Mutations in the ELG1 gene of yeast lead to genomic instability, manifested in
high levels of genetic recombination, chromosome loss, and gross chromosomal
rearrangements. Elg1 shows similarity to the large subunit of the Replication
Factor C clamp loader, and forms a RFC-like (RLC) complex in conjunction with
the 4 small RFC subunits. Two additional RLCs exist in yeast: in one of them the
large subunit is Ctf18, and in the other, Rad24. Ctf18 has been characterized as
the RLC that functions in sister chromatid cohesion. Here we present evidence
that the Elg1 RLC (but not Rad24) also plays an important role in this process.
A genetic screen identified the cohesin subunit Mcd1/Scc1 and its loader Scc2 as
suppressors of the synthetic lethality between elg1 and ctf4. We describe
genetic interactions between ELG1 and genes encoding cohesin subunits and their
accessory proteins. We also show that defects in Elg1 lead to higher precocious
sister chromatid separation, and that Ctf18 and Elg1 affect cohesion via a joint
pathway. Finally, we localize both Ctf18 and Elg1 to chromatin and show that
Elg1 plays a role in the recruitment of Ctf18. Our results suggest that Elg1,
Ctf4, and Ctf18 may coordinate the relative movement of the replication fork
with respect to the cohesin ring.
DOI: 10.1371/journal.pone.0005497
PMCID: PMC2676507
PMID: 19430531 [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/11864366 | 1. Genome Biol. 2002;3(2):INTERACTIONS1001. doi:
10.1186/gb-2002-3-2-interactions1001. Epub 2002 Jan 8.
Rosetta Stone proteins: "chance and necessity"?
Veitia RA.
Comment on
Genome Biol. 2001;2(9):RESEARCH0034. doi: 10.1186/gb-2001-2-9-research0034.
A response to Functional associations of proteins in entire genomes by means of
exhaustive detection of gene fusions by AJ Enright, CA Ouzounis. Genome Biology
2000, 2:research0034.1-0034.7
DOI: 10.1186/gb-2002-3-2-interactions1001
PMCID: PMC139009
PMID: 11864366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16148043 | 1. Mol Biol Cell. 2005 Nov;16(11):5304-15. doi: 10.1091/mbc.e05-06-0587. Epub
2005 Sep 7.
P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an
RNA-dependent manner.
Fox AH(1), Bond CS, Lamond AI.
Author information:
(1)Division of Gene Regulation and Expression, Wellcome Trust Biocentre,
University of Dundee, Dundee DD1 5EH, United Kingdom.
P54nrb is a protein implicated in multiple nuclear processes whose specific
functions may correlate with its presence at different nuclear locations. Here
we characterize paraspeckles, a subnuclear domain containing p54nrb and other
RNA-binding proteins including PSP1, a protein with sequence similarity to
p54nrb that acts as a marker for paraspeckles. We show that PSP1 interacts in
vivo with a subset of the total cellular pool of p54nrb. We map the domain
within PSP1 that is mediating this interaction and show it is required for the
correct localization of PSP1 to paraspeckles. This interaction is necessary but
not sufficient for paraspeckle targeting by PSP1, which also requires an RRM
capable of RNA binding. Blocking the reinitiation of RNA Pol II transcription at
the end of mitosis with DRB prevents paraspeckle formation, which recommences
after removal of DRB, indicating that paraspeckle formation is dependent on RNA
Polymerase II transcription. Thus paraspeckles are the sites where a subset of
the total cellular pool of p54nrb is targeted in a RNA Polymerase II-dependent
manner.
DOI: 10.1091/mbc.e05-06-0587
PMCID: PMC1266428
PMID: 16148043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22102035 | 1. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Oct 1;67(Pt 10):1231-4.
doi: 10.1107/S1744309111026212. Epub 2011 Sep 29.
Crystallization of a paraspeckle protein PSPC1-NONO heterodimer.
Passon DM(1), Lee M, Fox AH, Bond CS.
Author information:
(1)School of Biomedical, Biomolecular and Chemical Sciences, University of
Western Australia, Crawley, WA 6009, Australia.
The paraspeckle component 1 (PSPC1) and non-POU-domain-containing
octamer-binding protein (NONO) heterodimer is an essential structural component
of paraspeckles, ribonucleoprotein bodies found in the interchromatin space of
mammalian cell nuclei. PSPC1 and NONO both belong to the Drosophila behaviour
and human splicing (DBHS) protein family, which has been implicated in many
aspects of RNA processing. A heterodimer of the core DBHS conserved region of
PSPC1 and NONO comprising two tandemly arranged RNA-recognition motifs (RRMs), a
NONA/paraspeckle (NOPS) domain and part of a predicted coiled-coil domain has
been crystallized in space group C2, with unit-cell parameters a = 90.90, b =
67.18, c = 94.08 Å, β = 99.96°. The crystal contained one heterodimer in the
asymmetric unit and diffracted to 1.9 Å resolution using synchrotron radiation.
© 2011 International Union of Crystallography. All rights reserved.
DOI: 10.1107/S1744309111026212
PMCID: PMC3212370
PMID: 22102035 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16962805 | 1. Mol Cell. 2006 Sep 15;23(6):787-99. doi: 10.1016/j.molcel.2006.08.018. Epub
2006 Sep 7.
Establishment of sister chromatid cohesion at the S. cerevisiae replication
fork.
Lengronne A(1), McIntyre J, Katou Y, Kanoh Y, Hopfner KP, Shirahige K, Uhlmann
F.
Author information:
(1)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London
WC2A 3PX, United Kingdom.
Two identical sister copies of eukaryotic chromosomes are synthesized during S
phase. To facilitate their recognition as pairs for segregation in mitosis,
sister chromatids are held together from their synthesis onward by the
chromosomal cohesin complex. Replication fork progression is thought to be
coupled to establishment of sister chromatid cohesion, facilitating
identification of replication products, but evidence for this has remained
circumstantial. Here we show that three proteins required for sister chromatid
cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along
chromosomes with, replication forks. The ring-shaped cohesin complex is loaded
onto chromosomes before S phase in an ATP hydrolysis-dependent reaction.
Cohesion establishment during DNA replication follows without further cohesin
recruitment and without need for cohesin to re-engage an ATP hydrolysis motif
that is critical for its initial DNA binding. This provides evidence for
cohesion establishment in the context of replication forks and imposes
constraints on the mechanism involved.
DOI: 10.1016/j.molcel.2006.08.018
PMID: 16962805 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22416126 | 1. Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4846-50. doi:
10.1073/pnas.1120792109. Epub 2012 Mar 13.
Structure of the heterodimer of human NONO and paraspeckle protein component 1
and analysis of its role in subnuclear body formation.
Passon DM(1), Lee M, Rackham O, Stanley WA, Sadowska A, Filipovska A, Fox AH,
Bond CS.
Author information:
(1)School of Chemistry and Biochemistry, University of Western Australia,
Crawley, Western Australia 6009, Australia.
Proteins of the Drosophila behavior/human splicing (DBHS) family include
mammalian SFPQ (PSF), NONO (p54nrb), PSPC1, and invertebrate NONA and Hrp65.
DBHS proteins are predominately nuclear, and are involved in transcriptional and
posttranscriptional gene regulatory functions as well as DNA repair. DBHS
proteins influence a wide gamut of biological processes, including the
regulation of circadian rhythm, carcinogenesis, and progression of cancer.
Additionally, mammalian DBHS proteins associate with the architectural long
noncoding RNA NEAT1 (Menε/β) to form paraspeckles, subnuclear bodies that alter
gene expression via the nuclear retention of RNA. Here we describe the crystal
structure of the heterodimer of the multidomain conserved region of the DBHS
proteins, PSPC1 and NONO. These proteins form an extensively intertwined dimer,
consistent with the observation that the different DBHS proteins are typically
copurified from mammalian cells, and suggesting that they act as obligate
heterodimers. The PSPC1/NONO heterodimer has a right-handed antiparallel
coiled-coil that positions two of four RNA recognition motif domains in an
unprecedented arrangement on either side of a 20-Å channel. This configuration
is supported by a protein:protein interaction involving the NONA/paraspeckle
domain, which is characteristic of the DBHS family. By examining various mutants
and truncations in cell culture, we find that DBHS proteins require an
additional antiparallel coiled-coil emanating from either end of the dimer for
paraspeckle subnuclear body formation. These results suggest that paraspeckles
may potentially form through self-association of DBHS dimers into higher-order
structures.
DOI: 10.1073/pnas.1120792109
PMCID: PMC3324020
PMID: 22416126 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/14742714 | 1. Mol Biol Cell. 2004 Apr;15(4):1736-45. doi: 10.1091/mbc.e03-08-0619. Epub 2004
Jan 23.
Identification of protein complexes required for efficient sister chromatid
cohesion.
Mayer ML(1), Pot I, Chang M, Xu H, Aneliunas V, Kwok T, Newitt R, Aebersold R,
Boone C, Brown GW, Hieter P.
Author information:
(1)Centre for Molecular Medicine and Therapeutics, University of British
Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Ctf8p is a component of Ctf18-RFC, an alternative replication factor C-like
complex required for efficient sister chromatid cohesion in Saccharomyces
cerevisiae. We performed synthetic genetic array (SGA) analysis with a ctf8
deletion strain as a primary screen to identify other nonessential genes
required for efficient sister chromatid cohesion. We then assessed proficiency
of cohesion at three chromosomal loci in strains containing deletions of the
genes identified in the ctf8 SGA screen. Deletion of seven genes (CHL1, CSM3,
BIM1, KAR3, TOF1, CTF4, and VIK1) resulted in defective sister chromatid
cohesion. Mass spectrometric analysis of immunoprecipitated complexes identified
a physical association between Kar3p and Vik1p and an interaction between Csm3p
and Tof1p that we confirmed by coimmunoprecipitation from cell extracts. These
data indicate that synthetic genetic array analysis coupled with specific
secondary screens can effectively identify protein complexes functionally
related to a reference gene. Furthermore, we find that genes involved in mitotic
spindle integrity and positioning have a previously unrecognized role in sister
chromatid cohesion.
DOI: 10.1091/mbc.e03-08-0619
PMCID: PMC379271
PMID: 14742714 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15226378 | 1. J Cell Sci. 2004 Jul 15;117(Pt 16):3547-59. doi: 10.1242/jcs.01231. Epub 2004
Jun 29.
Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the
helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for
chromatid disjunction during meiosis II.
Petronczki M(1), Chwalla B, Siomos MF, Yokobayashi S, Helmhart W, Deutschbauer
AM, Davis RW, Watanabe Y, Nasmyth K.
Author information:
(1)Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna,
Austria.
Cohesion between sister chromatids mediated by a multisubunit complex called
cohesin is established during DNA replication and is essential for the orderly
segregation of chromatids during anaphase. In budding yeast, a specialized
replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the
DNA-polymerase-alpha-associated protein Ctf4 are required to maintain
sister-chromatid cohesion in cells arrested for long periods in mitosis. We show
here that CTF8, CTF4 and a helicase encoded by CHL1 are required for efficient
sister chromatid cohesion in unperturbed mitotic cells, and provide evidence
that Chl1 functions during S-phase. We also show that, in contrast to mitosis,
RF-C(Ctf18/Dcc1/Cft8), Ctf4 and Chl1 are essential for chromosome segregation
during meiosis and for the viability of meiotic products. Our finding that cells
deleted for CTF8, CTF4 or CHL1 undergo massive meiosis II non-disjunction
suggests that the second meiotic division is particularly sensitive to cohesion
defects. Using a functional as well as a cytological assay, we demonstrate that
CTF8, CHL1 and CTF4 are essential for cohesion between sister centromeres during
meiosis but dispensable for cohesin's association with centromeric DNA. Our
finding that mutants in fission yeast ctf18 and dcc1 have similar defects
suggests that the involvement of the alternative RF-C(Ctf18/Dcc1/Ctf8) complex
in sister chromatid cohesion might be highly conserved.
DOI: 10.1242/jcs.01231
PMID: 15226378 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19423654 | 1. Mol Endocrinol. 2009 Aug;23(8):1147-60. doi: 10.1210/me.2008-0357. Epub 2009
May 7.
p54nrb is a transcriptional corepressor of the progesterone receptor that
modulates transcription of the labor-associated gene, connexin 43 (Gja1).
Dong X(1), Yu C, Shynlova O, Challis JR, Rennie PS, Lye SJ.
Author information:
(1)Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of
Toronto, Toronto, Ontario, Canada M5G 1X5. [email protected]
The progesterone receptor (PR) plays important roles in the establishment and
maintenance of pregnancy. By dynamic interactions with coregulators, PR
represses the expression of genes that increase the contractile activity of
myometrium and contribute to the initiation of labor. We have previously shown
that PTB-associated RNA splicing factor (PSF) can function as a PR corepressor.
In this report, we demonstrated that the PSF heterodimer partner, p54nrb
(non-POU-domain-containing, octamer binding protein), can also function as a
transcription corepressor, independent of PSF. p54nrb Interacts directly with PR
independent of progesterone. In contrast to PSF, p54nrb neither enhances PR
protein degradation nor blocks PR binding to DNA. Rather, p54nrb recruits mSin3A
through its N terminus to the PR-DNA complex, resulting in an inhibition of
PR-mediated transactivation of the progesterone-response element-luciferase
reporter gene. PR also repressed transcription of the connexin 43 gene (Gja1),
an effect dependent on the presence of an activator protein 1 site within the
proximal Gja1 promoter. Mutation of this site abolished PR-mediated repression
and decreased the recruitment of PR and p54nrb onto the Gja1 promoter.
Furthermore, knockdown p54nrb expression by small interfering RNA alleviated
PR-mediated repression on Gja1 transcription, whereas overexpression of p54nrb
enhanced it. In the physiological context of pregnancy, p54nrb protein levels
decrease with the approach of labor in the rat myometrium. We conclude that
p54nrb is a transcriptional corepressor of PR. Decreased expression of p54nrb at
the time of labor may act to derepress PR-mediated inhibition on connexin 43
expression and contribute to the initiation of labor.
DOI: 10.1210/me.2008-0357
PMCID: PMC5419194
PMID: 19423654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7913092 | 1. J Clin Endocrinol Metab. 1994 Jul;79(1):323-6. doi: 10.1210/jcem.79.1.7913092.
Three new mutations of thyroid hormone receptor-beta associated with resistance
to thyroid hormone.
Bartolone L(1), Regalbuto C, Benvenga S, Filetti S, Trimarchi F, Pontecorvi A.
Author information:
(1)Institute of Endocrinology, University of Messina, Rome, Italy.
Three novel point mutations at nucleotides 1249, 1282, and 1614 (exons 9 and 10)
of the human thyroid hormone receptor-beta gene were observed in six individuals
affected by the syndrome of resistance to thyroid hormone. All three mutations
occurred in a heterozygous pattern and caused the following changes in the
mature form of the receptor protein: Asp322 to Asn, Glu333 to Gln, and Lys443 to
Asn, respectively. The first and third point mutations arose in two unrelated
families from eastern Sicily, whereas the second concerned an individual from
southern Calabria, apparently presenting a sporadic form of the resistance
syndrome. The clinical and biochemical features of resistance to thyroid
hormone, both before and after the administration of thyroid hormones, highlight
the striking intrafamilial heterogeneity in the phenotypical presentation of the
syndrome.
DOI: 10.1210/jcem.79.1.7913092
PMID: 7913092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25120693 | 1. Oncol Lett. 2014 Sep;8(3):1222-1228. doi: 10.3892/ol.2014.2236. Epub 2014 Jun
11.
XRCC2 rs3218536 polymorphism decreases the sensitivity of colorectal cancer
cells to poly(ADP-ribose) polymerase 1 inhibitor.
Xu K(1), Song X(1), Chen Z(1), Qin C(1), He Y(1).
Author information:
(1)Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated
Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Single nucleotide polymorphisms (SNPs) are associated with the development of
certain types of cancer. The present study aimed to investigate the association
between X-ray repair complementing defective repair in Chinese hamster cells 2
(XRCC2) SNPs and colorectal cancer (CRC) cell sensitivity to the
poly(ADP-ribose) polymerase (PARP) 1 inhibitor olaparib (AZD2281). SNaPshot®
analysis of XRCC2 SNPs was performed in five CRC cell lines. The
AZD2281-sensitivities of the CRC cells were also analyzed using MTT assays. The
effect of AZD2281 on XRCC2 and PARP1 expression was investigated in the five
cell lines using quantitative polymerase chain reaction and western blot
analyses. Parallel investigations were performed using a cisplatin (DDP) model
of DNA damage. The XRCC2 rs3218536 SNP was found to be associated with the LoVo
microsatellite instability CRC cell line. The relative rate of growth inhibition
was found to be lower in the LoVo cells following treatment with AZD2281
compared with the other four cell lines (P=0.002). Furthermore, the XRCC2 mRNA
level in the LoVo cells was observed to be significantly higher than that in the
other four cell lines (P<0.05). Similar results were found using the DDP model
of DNA damage (P<0.05). The present study indicated that the XRCC2 rs3218536
polymorphism decreases the sensitivity of CRC cells to AZD2281.
DOI: 10.3892/ol.2014.2236
PMCID: PMC4114618
PMID: 25120693 |
http://www.ncbi.nlm.nih.gov/pubmed/9092799 | 1. Mol Endocrinol. 1997 Apr;11(4):470-80. doi: 10.1210/mend.11.4.9914.
Thyroid hormone resistance syndrome manifests as an aberrant interaction between
mutant T3 receptors and transcriptional corepressors.
Yoh SM(1), Chatterjee VK, Privalsky ML.
Author information:
(1)Division of Biological Sciences, University of California at Davis, 95616,
USA.
Nuclear hormone receptors are hormone-regulated transcription factors that play
critical roles in chordate development and homeostasis. Aberrant nuclear hormone
receptors have been implicated as causal agents in a number of endocrine and
neoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a
human genetic disease characterized by an impaired physiological response to
thyroid hormone. RTH is associated with diverse mutations in the thyroid hormone
receptor beta-gene. The resulting mutant receptors function as dominant
negatives, interfering with the actions of normal thyroid hormone receptors
coexpressed in the same cells. We report here that RTH receptors interact
aberrantly with a newly recognized family of transcriptional corepressors
variously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor
interacting protein-13 (RIP-13), silencing mediator for retinoid and thyroid
hormone receptors (SMRT), and thyroid hormone receptor-associating cofactor
(TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from
corepressors in the presence of thyroid hormone. Two of the RTH mutations
uncouple corepressor dissociation from hormone binding; two additional RTH
mutants exhibit an unusually strong interaction with corepressor under all
hormone conditions tested. Finally, artificial mutants that abolish corepressor
binding abrogate the dominant negative activity of RTH mutants. We suggest that
an altered corepressor interaction is likely to play a critical role in the
dominant negative potency of RTH mutants and may contribute to the variable
phenotype in this disorder.
DOI: 10.1210/mend.11.4.9914
PMCID: PMC2725002
PMID: 9092799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25221646 | 1. Genes Cancer. 2014 Jul;5(7-8):285-92. doi: 10.18632/genesandcancer.26.
Impact of DNA repair pathways on the cytotoxicity of piperlongumine in chicken
DT40 cell-lines.
Okamoto S(1), Narita T(2), Sasanuma H(2), Takeda S(2), Masunaga S(1), Bessho
T(3), Tano K(1).
Author information:
(1)Division of Radiation Life Science, Research Reactor Institute, Kyoto
University, Kumatori, Osaka 590-0494, Japan.
(2)Department of Radiation Genetics, Graduate School of Medicine, Kyoto
University, Sakyo-Ku, Kyoto 606-8501, Japan.
(3)Eppley Institute for Research in Cancer and Allied Diseases, University of
Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Piperlongumine is a naturally-occurring small molecule with various biological
activities. Recent studies demonstrate that piperlongumine selectively kills
various types of transformed cells with minimal toxicity to non-transformed
cells by inducing a high level of reactive oxygen species (ROS). ROS generates
various types of DNA lesions, including base modifications and single strand
breaks. In order to examine the contribution of ROS-induced DNA damage to the
cytotoxicity by piperlongumine, various DNA repair-deficient chicken DT40
cell-lines with a single DNA repair gene deletion were tested for cellular
sensitivity to piperlongumine. The results showed that cell lines defective in
homologous recombination (HR) display hyper-sensitivity to piperlongumine, while
other cell lines with a deficiency in non-homologous end joining (NHEJ), base
excision repair (BER), nucleotide excision repair (NER), Fanconi anemia (FA)
pathway, or translesion DNA synthesis (TLS) polymerases, show no sensitivity to
piperlongumine. The results strongly implicate that double strand breaks (DSBs)
generated by piperlongumine are major cytotoxic DNA lesions. Furthermore, a
deletion of 53BP1 or Ku70 in the BRCA1-deficient cell line restored cellular
resistance to piperlongumine. This strongly supports the idea that
piperlongumine induces DSB- mediated cell death. Interestingly, piperlongumine
makes the wild type DT40 cell line hypersensitive to a PARP-inhibitor, Olaparib.
The results implicate that piperlongumine inhibits HR. Further analysis with
cell-based HR assay and the kinetic study of Rad51 foci formation confirmed that
piperlongumine suppresses HR activity. Altogether, we revealed novel mechanisms
of piperlongumine-induced cytotoxicity.
DOI: 10.18632/genesandcancer.26
PMCID: PMC4162141
PMID: 25221646 |
http://www.ncbi.nlm.nih.gov/pubmed/20436461 | 1. Nat Biotechnol. 2010 May;28(5):495-501. doi: 10.1038/nbt.1630. Epub 2010 May
2.
GREAT improves functional interpretation of cis-regulatory regions.
McLean CY(1), Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM,
Bejerano G.
Author information:
(1)Department of Computer Science, Stanford University, Stanford, California,
USA.
We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to
analyze the functional significance of cis-regulatory regions identified by
localized measurements of DNA binding events across an entire genome. Whereas
previous methods took into account only binding proximal to genes, GREAT is able
to properly incorporate distal binding sites and control for false positives
using a binomial test over the input genomic regions. GREAT incorporates
annotations from 20 ontologies and is available as a web application. Applying
GREAT to data sets from chromatin immunoprecipitation coupled with massively
parallel sequencing (ChIP-seq) of multiple transcription-associated factors,
including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts,
we recover many functions of these factors that are missed by existing
gene-based tools, and we generate testable hypotheses. The utility of GREAT is
not limited to ChIP-seq, as it could also be applied to open chromatin,
localized epigenomic markers and similar functional data sets, as well as
comparative genomics sets.
DOI: 10.1038/nbt.1630
PMCID: PMC4840234
PMID: 20436461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23036200 | 1. Biochem Biophys Res Commun. 2012 Oct 26;427(3):682-6. doi:
10.1016/j.bbrc.2012.09.124. Epub 2012 Oct 1.
Rmi1 functions in S phase-mediated cohesion establishment via a pathway
involving the Ctf18-RFC complex and Mrc1.
Lai MS(1), Seki M, Tada S, Enomoto T.
Author information:
(1)Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
Saccharomyces cerevisiae RecQ helicase (Sgs1) combines with DNA topoisomerase
III (Top3) and RecQ-mediated genome instability 1 (Rmi1) to form an
evolutionarily conserved complex that is required for processing homologous
recombination intermediates and restarting collapsed replication forks. It was
previously reported that Rmi1 contributes to sister chromatid cohesion; however,
the underlying molecular mechanism has been unclear. In the present study, Rmi1
was found to be enriched at the region close to an early-firing replication
origin when replication forks were arrested near their origins in the presence
of hydroxyurea. Genetic analyses revealed that Rmi1 promoted sister chromatid
cohesion in a process that was distinct from both the cohesion establishment
pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation
of Smc3. On the other hand, Rmi1 seemed to function in a pathway involving the
Ctf18-RFC complex and Mrc1, which were previously predicted to regulate
leading-strand DNA replication.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2012.09.124
PMID: 23036200 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17040361 | 1. Intern Med J. 2006 Nov;36(11):738-41. doi: 10.1111/j.1445-5994.2006.01189.x.
Thyroid hormone resistance: the role of mutational analysis.
Florkowski CM(1), Brownlie BE, Croxson MS, Manning P, Farrand S, Smith G, Potter
HC, George PM.
Author information:
(1)Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New
Zealand. [email protected]
The finding of increased thyroxine (T4) and tri-iodothyronine (T3) levels in a
patient with normal or increased thyroid-stimulating hormone is unexpected and
presents a differential diagnosis between a thyroid-stimulating
hormone-secreting pituitary adenoma, generalized resistance to thyroid hormone
(RTH) and laboratory artefact. Without careful clinical and biochemical
evaluation, errors may occur in patient diagnosis and treatment. In the case of
RTH, mutation of the thyroid hormone receptor beta gene results in generalized
tissue resistance to thyroid hormone. As the pituitary gland shares in this
tissue resistance, euthyroidism with a normal thyroid-stimulating hormone is
usually maintained by increased thyroid hormones. To date, we have identified
eight pedigrees in New Zealand with mutations in the thyroid hormone receptor
beta gene, including two novel mutations. Mutational analysis of the thyroid
hormone receptor beta gene allows definitive diagnosis of RTH, potentially
avoiding the need for protracted and expensive pituitary function testing and
imaging. Mutational analysis also enables family screening and may help to avoid
potential misdiagnosis and inappropriate treatment.
DOI: 10.1111/j.1445-5994.2006.01189.x
PMID: 17040361 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20421735 | 1. Cell Cycle. 2010 Apr 15;9(8):1568-76. doi: 10.4161/cc.9.8.11298. Epub 2010 Apr
15.
Involvement of Matrin 3 and SFPQ/NONO in the DNA damage response.
Salton M(1), Lerenthal Y, Wang SY, Chen DJ, Shiloh Y.
Author information:
(1)Department of Human Molecular Genetics and Biochemistry, Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel.
The DNA damage response (DDR) is a complex signaling network that is induced by
DNA lesions and vigorously activated by double strand breaks (DSBs). The DSB
response is mobilized by the nuclear protein kinase ATM, which phosphorylates
key players in its various branches. SFPQ (PSF) and NONO (p54) are nuclear
proteins that interact with each other and have diverse roles in nucleic acids
metabolism. The SFPQ/NONO heterodimer was previously found to enhance DNA strand
break rejoining in vitro. Our attention was drawn to these two proteins as they
interact with the nuclear matrix protein Matrin 3 (MATR3), which we found to be
a novel ATM target. We asked whether SFPQ and NONO too are involved in the DSB
response. Proteins that function at the early phase of this response are often
recruited to the damaged sites. We observed rapid recruitment of SFPQ/NONO to
sites of DNA damage induced by laser microbeam. In MATR3 knockdown cells
SFPQ/NONO retention at DNA damage sites was prolonged. SFPQ and MATR3 depletion
led to abnormal accumulation of cells at the S-phase of the cell cycle following
treatment with the radiomimetic chemical neocarzinostatin. Notably, proteins
involved in DSB repair via nonhomologous end-joining co-immunoprecipitated with
NONO; SFPQ depletion delayed DSB repair. Collectively the data suggest that
SFPQ, NONO and MATR3 are involved in the early stage of the DSB response,
setting the scene for DSB repair.
DOI: 10.4161/cc.9.8.11298
PMID: 20421735 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25139258 | 1. Mol Oncol. 2015 Jan;9(1):78-92. doi: 10.1016/j.molonc.2014.07.022. Epub 2014
Aug 2.
PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in
vitro and in vivo model of anaplastic thyroid carcinoma.
Passaro C(1), Volpe M(1), Botta G(1), Scamardella E(1), Perruolo G(1), Gillespie
D(2), Libertini S(3), Portella G(4).
Author information:
(1)Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di
Napoli "Federico II", Napoli, Italy.
(2)The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow
G61 1BD, UK.
(3)Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di
Napoli "Federico II", Napoli, Italy; The Beatson Institute for Cancer Research,
Switchback Road, Bearsden, Glasgow G61 1BD, UK. Electronic address:
[email protected].
(4)Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di
Napoli "Federico II", Napoli, Italy. Electronic address: [email protected].
PARP inhibitors are mostly effective as anticancer drugs in association with DNA
damaging agents. We have previously shown that the oncolytic adenovirus
dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic
antitumoral effect of the PARP inhibitor olaparib in association with dl922-947.
Anaplastic thyroid carcinoma was chosen as model since it is a particularly
aggressive tumor and, because of its localized growth, it is suitable for
intratumoral treatment with oncolytic viruses. Here, we show that dl922-947
infection induces PARP activation, and we confirm in vitro and in vivo that PARP
inhibition increases dl922-947 replication and oncolytic activity. In vitro, the
combination with olaparib exacerbates the appearance of cell death markers, such
as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium
iodide permeability. In vivo, we also observed a better viral distribution upon
PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on
tumor vascularization and on the viral distribution within the tumor mass. The
observation that PARP inhibition enhances the effects of dl922-947 is highly
promising not only for the treatment of anaplastic thyroid carcinoma but, in
general, for the treatment of other tumors that could benefit from the use of
oncolytic viruses.
Copyright © 2014 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.molonc.2014.07.022
PMCID: PMC5528680
PMID: 25139258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25817014 | 1. Am J Hum Genet. 2015 Apr 2;96(4):623-30. doi: 10.1016/j.ajhg.2015.02.010. Epub
2015 Mar 26.
Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.
Bunn KJ(1), Daniel P(1), Rösken HS(1), O'Neill AC(1), Cameron-Christie SR(1),
Morgan T(1), Brunner HG(2), Lai A(3), Kunst HP(4), Markie DM(5), Robertson
SP(6).
Author information:
(1)Department of Women's and Children's Health, Dunedin School of Medicine,
University of Otago, Dunedin 9054, New Zealand.
(2)Department of Human Genetics, Radboud University Medical Center, Nijmegen
6525 GA, the Netherlands; Department of Clinical Genetics, Maastricht University
Medical Center, Maastricht 6200 MD, the Netherlands.
(3)Genetics Service, Department of Paediatrics, KK Women's and Children's
Hospital, Singapore 229899, Singapore.
(4)Department of Otorhinolaryngology and Radboud Institute for Health Sciences,
Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
(5)Department of Pathology, Dunedin School of Medicine, University of Otago,
Dunedin 9054, New Zealand.
(6)Department of Women's and Children's Health, Dunedin School of Medicine,
University of Otago, Dunedin 9054, New Zealand. Electronic address:
[email protected].
Robinow syndrome (RS) is a phenotypically and genetically heterogeneous
condition that can be caused by mutations in genes encoding components of the
non-canonical Wnt signaling pathway. In contrast, germline mutations that act to
increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes.
Here, we identified de novo frameshift mutations in DVL1, a mediator of both
canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype
involving osteosclerosis, in three unrelated individuals. The mutations all
delete the DVL1 C terminus and replace it, in each instance, with a novel,
highly basic sequence. We showed the presence of mutant transcript in
fibroblasts from one individual with RS-OS and demonstrated unimpaired protein
stability with transfected GFP-tagged constructs bearing a frameshift mutation.
In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic
phenotype, revealed that the mutant allele was less active than the wild-type
allele in the canonical Wnt signaling pathway. However, when the mutant and
wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher
than that in the wild-type construct alone. This work establishes that DVL1
mutations cause a specific RS subtype, RS-OS, and that the osteosclerosis
associated with this subtype might be the result of an interaction between the
wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2015.02.010
PMCID: PMC4385193
PMID: 25817014 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7711514 | 1. Thyroid. 1994 Winter;4(4):485-92. doi: 10.1089/thy.1994.4.485.
Mechanisms by which thyroid hormone receptor mutations cause clinical syndromes
of resistance to thyroid hormone.
Jameson JL(1).
Author information:
(1)Center for Endocrinology, Metabolism, and Molecular Medicine, Northwestern
University Medical School, Chicago, Illinois.
Resistance to thyroid hormone (RTH) is an autosomal dominant disorder that is
caused by mutations in the thyroid hormone receptor beta (TR beta) gene. The
thyroid hormone receptor is a nuclear receptor that acts by binding to DNA to
stimulate or repress gene transcription. Mutations that cause RTH are clustered
within two regions of the hormone binding domain of the receptor. These
mutations reduce thyroid hormone binding in most cases, but preserve the ability
of the receptor to dimerize and to bind to DNA. Consequently, the mutant
receptors are thought to occupy DNA target sites as inactive complexes that are
not capable of activation by hormone. Not only are RTH mutants inactive, but
they function in a dominant negative manner to block the access of normal
receptors to thyroid hormone responsive genes. The mechanism of dominant
negative activity and the relationship of genotype and phenotype remain active
areas of investigation.
DOI: 10.1089/thy.1994.4.485
PMID: 7711514 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12750454 | 1. Mol Endocrinol. 2003 Aug;17(8):1647-55. doi: 10.1210/me.2003-0114. Epub 2003
May 15.
Compensatory role of thyroid hormone receptor (TR) alpha 1 in resistance to
thyroid hormone: study in mice with a targeted mutation in the TR beta gene and
deficient in TR alpha 1.
Suzuki H(1), Cheng SY.
Author information:
(1)Laboratory of Molecular Biology, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid
hormone receptor beta (TR beta) gene. Almost all RTH patients are heterozygous
with an autosomal dominant pattern of inheritance. That most are clinically
euthyroid suggests a compensatory role of the TR alpha1 isoform in maintaining
the normal functions of thyroid hormone (T3) in these patients. To understand
the role of TR alpha1 in the manifestation of RTH, we compared the phenotypes of
mice with a targeted dominantly negative mutant TR beta (TR betaPV) with or
without TR alpha1. TR betaPV mice faithfully recapitulate RTH in humans in that
these mice demonstrate abnormalities in the pituitary-thyroid axis and
impairment in growth. Here we show that the dysregulation of the
pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice,
and severe impairment of postnatal growth was manifested in TR betaPV mice
deficient in TR alpha1. Furthermore, abnormal expression patterns of T3-target
genes in TR betaPV mice were altered by the lack of TR alpha1. These results
demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in
TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating
the functions of T3 in heterozygous patients with RTH. This compensatory role
may be especially crucial for postnatal growth.
DOI: 10.1210/me.2003-0114
PMID: 12750454 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8068885 | 1. Semin Cell Biol. 1994 Apr;5(2):127-36. doi: 10.1006/scel.1994.1016.
Clinical syndromes of hormone receptor mutations: hormone resistance and
independence.
Auchus RJ(1), Fuqua SA.
Author information:
(1)Department of Endocrinology, Wilford Hall Medical Center, Lackland AFB, TX
78236.
Clinical syndromes of hormone resistance or independence have baffled clinicians
for decades. These syndromes sometimes result from mutations or deficiencies in
enzymes that activate prohormones or from alterations in signal transduction
proteins. The majority of these conditions, however, arise from abnormalities of
hormone receptors. We describe examples of syndromes that result from genetic
mutations or misexpression of steroid/thyroid hormone receptors, with a specific
emphasis on thyroid and androgen resistance syndromes, and estrogen independence
in breast cancer.
DOI: 10.1006/scel.1994.1016
PMID: 8068885 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24257692 | 1. Kidney Int. 2014 Oct;86(4):693-700. doi: 10.1038/ki.2013.451. Epub 2013 Nov
20.
Sodium-glucose linked transporter-2 inhibitors: potential for renoprotection
beyond blood glucose lowering?
Gilbert RE(1).
Author information:
(1)Division of Endocrinology, Department of Medicine, University of Toronto, St
Michael's Hospital, Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada.
Comment in
Kidney Int. 2014 May;85(5):1243-4. doi: 10.1038/ki.2014.43.
Kidney Int. 2014 Nov;86(5):1057-8. doi: 10.1038/ki.2014.246.
Kidney Int. 2014 Nov;86(5):1058-9. doi: 10.1038/ki.2014.252.
The proximal tubule's sodium-glucose linked transporter-2 (SGLT2) accounts for
the vast majority of glucose reabsorption by the kidney. Its selective
inhibition, accordingly, leads to substantial glycosuria, lowering blood
glucose, and facilitating weight loss in individuals with diabetes. During the
past year, two SGLT2 inhibitors, canagliflozin and dapagliflozin, have been
approved for the treatment of type 2 diabetes. Beyond their anti-hyperglycemic
properties, however, this new class of drugs has several other attributes that
provide a theoretical basis for kidney protection. Like agents that block the
renin-angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular
filtration rate (SNGFR) in the chronically diseased kidney, though by quite
different mechanisms. Additional potentially beneficial effects of SGLT2
inhibition include modest reductions in blood pressure and plasma uric acid.
Finally, cell culture studies indicate that glucose uptake from the tubular
lumen, as well as from the basolateral compartment, can contribute to proximal
tubular production of extracellular matrix proteins. Whether such attributes
will translate into reducing the progression of chronic kidney disease will
require the undertaking of long-term, dedicated studies.
DOI: 10.1038/ki.2013.451
PMID: 24257692 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23087012 | 1. BMJ Open. 2012 Oct 18;2(5):e001007. doi: 10.1136/bmjopen-2012-001007. Print
2012.
Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type
2 diabetes.
Clar C(1), Gill JA, Court R, Waugh N.
Author information:
(1)Systematic review, Berlin, Germany.
BACKGROUND: Despite the number of medications for type 2 diabetes, many people
with the condition do not achieve good glycaemic control. Some existing
glucose-lowering agents have adverse effects such as weight gain or
hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most
patients require treatment with combinations of glucose-lowering agents. The
sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of
glucose-lowering agents.
OBJECTIVE: To assess the clinical effectiveness and safety of the SGLT2 receptor
inhibitors in dual or triple therapy in type 2 diabetes.
DATA SOURCES: MEDLINE, Embase, Cochrane Library (all sections); Science Citation
Index; trial registries; conference abstracts; drug regulatory authorities;
bibliographies of retrieved papers.
INCLUSION CRITERIA: Randomised controlled trials of SGLT2 receptor inhibitors
compared with placebo or active comparator in type 2 diabetes in dual or
combination therapy.
METHODS: Systematic review. Quality assessment used the Cochrane risk of bias
score.
RESULTS: Seven trials, published in full, assessed dapagliflozin and one
assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced
HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40)
compared to placebo, but there was no difference compared to glipizide.
Canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs
sitagliptin). Both dapagliflozin and canagliflozin led to weight loss
(dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg
compared to placebo).
LIMITATIONS: Long-term trial extensions suggested that effects were maintained
over time. Data on canagliflozin are currently available from only one paper.
Costs of the drugs are not known so cost-effectiveness cannot be assessed. More
data on safety are needed, with the Food and Drug Administration having concerns
about breast and bladder cancers.
CONCLUSIONS: Dapagliflozin appears effective in reducing HbA1c and weight in
type 2 diabetes, although more safety data are needed.
DOI: 10.1136/bmjopen-2012-001007
PMCID: PMC3488745
PMID: 23087012 |
http://www.ncbi.nlm.nih.gov/pubmed/15913586 | 1. Clin Chim Acta. 2005 Aug;358(1-2):55-9. doi: 10.1016/j.cccn.2005.02.014.
DNA-based diagnosis of thyroid hormone resistance syndrome: a novel THRB
mutation associated with mild resistance to thyroid hormone.
Lam CW(1), On-Kei Chan A, Tong SF, Shek CC, Cheung Tiu S.
Author information:
(1)Department of Chemical Pathology, The Chinese University of Hong Kong, Prince
of Wales Hospital, Hong Kong, China. [email protected]
BACKGROUND: Thyroid hormones govern a wide range of metabolic processes in the
body via thyroid hormone receptors (TR). We report a patient with mild
resistance to thyroid hormone who was initially misdiagnosed and treated as
having thyrotoxicosis.
METHODS: We used direct DNA sequencing of the THRB gene.
RESULTS: We identified a novel missense mutation, I276L, located in exon 8 of
the gene. The mutation is located in cluster 3 of the ligand-binding domain, a
protein domain associated with resistance to thyroid hormone.
CONCLUSION: DNA-based diagnosis of thyroid hormone resistance syndrome is
simple, reliable, and economical compared to traditional biochemical tests. Once
the mutation is identified, targeted screening for the whole family can be
performed and the unnecessary use of anti-thyroid drugs or thyroidectomy can be
avoided.
DOI: 10.1016/j.cccn.2005.02.014
PMID: 15913586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25302833 | 1. Int J Cancer. 2015 May 1;136(9):2146-57. doi: 10.1002/ijc.29263. Epub 2014 Oct
24.
New therapeutic perspectives in CCDC6 deficient lung cancer cells.
Morra F(1), Luise C, Visconti R, Staibano S, Merolla F, Ilardi G, Guggino G,
Paladino S, Sarnataro D, Franco R, Monaco R, Zitomarino F, Pacelli R, Monaco G,
Rocco G, Cerrato A, Linardopoulos S, Muller MT, Celetti A.
Author information:
(1)Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore",
CNR, Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche,
Università Federico II, Napoli, Italy.
Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death
worldwide and new therapeutic strategies are urgently needed. In this study, we
have characterized a panel of NSC lung cancer cell lines for the expression of
coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in
apoptosis and DNA damage response. We show that low CCDC6 protein levels are
associated with a weak response to DNA damage and a low number of Rad51 positive
foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via
homologous recombination. In accordance with its role in the DNA damage
response, CCDC6 attenuation confers resistance to cisplatinum, the current
treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small
molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of
the two drugs is more effective than each agent individually, as demonstrated by
a combination index <1. Finally, CCDC6 is expressed at low levels in about 30%
of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein
staining is significatively correlated with the presence of lymph node
metastasis (p ≤ 0.02) and negatively correlated to the disease free survival
(p ≤ 0.01) and the overall survival (p ≤ 0.05). Collectively, the data indicate
that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a
predictive biomarker of resistance to conventional single mode therapy and yield
insight on tumor sensitivity to PARP inhibitors in NSCLC.
© 2014 UICC.
DOI: 10.1002/ijc.29263
PMID: 25302833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9685218 | 1. Mol Cell Endocrinol. 1998 Mar 16;138(1-2):95-104. doi:
10.1016/s0303-7207(98)00014-8.
Difference in dominant negative activities between mutant thyroid hormone
receptors alpha1 and beta1 with an identical truncation in the extreme
carboxyl-terminal tau4 domain.
Nishiyama K(1), Andoh S, Kitahara A, Natsume H, Mikami T, Genma R, Nakamura H.
Author information:
(1)Department of Internal Medicine, Hamamatsu University School of Medicine,
Japan.
Although different expression patterns of thyroid hormone receptor (TR) alpha1
and beta1 have been reported, no essential distinction has been established in
their functions. Unlike the TR beta gene, a mutation in the TR alpha1 gene has
never been found in patients with resistance to thyroid hormone (RTH).
Previously we found a mutant TR beta with an 11-carboxyl (C)-terminal amino acid
truncation (betaF451X) in a girl with severe RTH. BetaF451X is a natural mutant
with disruption of the transactivation domain, tau4, and it had very strong
dominant negative activities. Based on the fact that the 46 amino acid sequence
in the extreme C-terminal region is identical in TR alpha1 and TR beta, except
for a C-terminal three amino acid extension of TR alpha1, we constructed a
mutant TR alpha1 (alphaF397X) with the identical C-terminal truncation to
betaF451X, to study functional differences between TR alpha1 and beta1. Both
betaF451X and alphaF397X had negligible T3 binding and transcriptional
activities even with 1 microM T3. The dominant negative activities of the mutant
TRs were remarkable and T3 response element (TRE)-dependent. Co-expression of
betaF451X decreased the CAT activity of either wild-type TR alpha1 or beta1 at
100 nM T3 by approximately 90% on the TRE-pal2 and 70% on DR4. AlphaF397X
inhibited the transcriptional activities of both wild-type TR alpha1 and beta1
by approximately 50% on TRE-pal2 and by 60% on DR4. The dominant negative
potency of betaF451X was significantly stronger than that of alphaF397X on the
TRE-pal2, -DR4 and chicken lysozyme silencer F2, but similar on TRE-myosin heavy
chain alpha and malic enzyme. No partiality for the TR subtypes was found in the
dominant negative effects of betaF451X and alphaF397X. Co-expression with RXR
enhanced the dominant negative effects of alphaF397X, but not of betaF451X. The
results indicate that there are different dominant negative properties between
alphaF397X and betaF451X, which are TRE-dependent, despite their identical
C-terminal truncation. Deletion in the tau4 domain might affect the receptor
structures of TR alpha1 and beta1 differently.
DOI: 10.1016/s0303-7207(98)00014-8
PMID: 9685218 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15988389 | 1. Ann Endocrinol (Paris). 2005 Jun;66(3):264-9. doi:
10.1016/s0003-4266(05)81760-3.
Syndromes of thyroid hormone resistance.
Beck-Peccoz P(1), Mannavola D, Persani L.
Author information:
(1)Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore
IRCCS, Padiglione Granelli, 20122-Milano, Italy. [email protected]
Thyroid hormone resistance (RTH) is a rare autosomal dominant disorder,
characterized clinically by goiter and biochemically by elevated circulating
free thyroid hormone levels in the presence of measurable serum TSH
concentrations. About 85% of patients with RTH are harboring mutations in
thyroid hormone receptor beta (TRB). These mutations cluster in three different
"hot spot" in the T3 binding domain of the receptor. When mapped to their
homologous residues in the TR crystal structure, these three clusters of
mutations border the T3-binding pocket. As a consequence, most TRB mutations
impair the hormone binding to the receptor and interfere with the mechanism(s)
of corepressor release and the consequent recruitment of coactivators. Thus, the
remodeling of chromatin structure throughout the process of histone acetylation
is prevented and the transcriptional activity of the mutant receptor on both
positively and negatively regulated genes, severely disrupted. The lack of
interaction with coactivators appears to be an additional mechanism for the
dominant negative effects of mutant TRB on the transcriptional activity of the
normal receptor.
DOI: 10.1016/s0003-4266(05)81760-3
PMID: 15988389 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23563279 | 1. Pharmacol Ther. 2013 Jul;139(1):51-9. doi: 10.1016/j.pharmthera.2013.04.003.
Epub 2013 Apr 4.
Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the
treatment of type 2 diabetes: preclinical and clinical data.
Kurosaki E(1), Ogasawara H.
Author information:
(1)Astellas Pharma, Inc., Ibaraki, Japan. [email protected]
Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of
the kidneys and plays a key role in renal glucose reabsorption. A novel class of
antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic
control in diabetics by preventing glucose from being reabsorbed through SGLT2
and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3
clinical development for the treatment of type 2 diabetes mellitus (T2DM). In
this review, we summarize recent animal and human studies on ipragliflozin and
other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin,
tofogliflozin, and luseogliflozin. These agents all show potent and selective
SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both
diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several
advantages over other classes of hypoglycemic agents. Due to their
insulin-independent mode of action, SGLT2 inhibitors provide steady glucose
control without major risk for hypoglycemia and may also reverse β-cell
dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors
include a reduction in both body weight and blood pressure. SGLT2 inhibitors are
safe and well tolerated and can easily be combined with other classes of
antidiabetic medications to achieve tighter glycemic control. The long-term
safety and efficacy of these agents are under evaluation.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pharmthera.2013.04.003
PMID: 23563279 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23895803 | 1. Am Heart J. 2013 Aug;166(2):217-223.e11. doi: 10.1016/j.ahj.2013.05.007. Epub
2013 Jun 24.
Rationale, design, and baseline characteristics of the Canagliflozin
Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.
Neal B(1), Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M,
Shaw W, Jiang J, Vercruysse F, Meininger G, Matthews D.
Author information:
(1)The George Institute for Global Health and University of Sydney, Sydney, New
South Wales, Australia. [email protected]
Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type
2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor
canagliflozin lowered blood glucose, blood pressure, and body weight, with
increased risk of urogenital infections in Phase 2 studies. Effects on
macrovascular complications of diabetes remain to be determined. CANVAS is a
double-blind, placebo-controlled trial designed to evaluate the effects of
canagliflozin on the risk of cardiovascular disease and to assess safety and
tolerability in patients with inadequately controlled T2DM and increased
cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals
to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about
2 years to substantiate potential cardiovascular protection by assessing key
biomarkers and to achieve initial safety objectives. By the end of mid-September
2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age
was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma
glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are
female and 57% had a history of atherosclerotic vascular disease. Participants
will be followed up to achieve primary safety and tolerability objectives and to
investigate secondary outcomes. The planned second phase will not be undertaken.
CANVAS will define the effects of canagliflozin on biomarkers and provide data
on cardiovascular safety against established regulatory parameters.
Copyright © 2013 Mosby, Inc. All rights reserved.
DOI: 10.1016/j.ahj.2013.05.007
PMID: 23895803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19896475 | 1. Chem Biol Interact. 2010 Jan 5;183(1):172-80. doi: 10.1016/j.cbi.2009.10.018.
The suppressive effect of Rho kinase inhibitor, Y-27632, on oncogenic Ras/RhoA
induced invasion/migration of human bladder cancer TSGH cells.
Chang HR(1), Huang HP, Kao YL, Chen SL, Wu SW, Hung TW, Lian JD, Wang CJ.
Author information:
(1)Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan;
Department of Nephrology, Chung Shan Medical University Hospital, Taichung 402,
Taiwan.
Urothelial cell carcinoma is the most common type of malignancy found in
long-term dialysis patients and kidney transplant recipients in Taiwan. Surgical
specimens of tumorous and non-tumorous bladder tissues were collected from 12
patients with bladder cancer. Increased expressions of Ras, RhoA, Akt, PI-3K
were demonstrated in the tumors as compared to adjacent control tissues. To
understand the impact of Ras over-expression on bladder cancer progression,
human bladder cancer TSGH 8301 cells were transfected with Ras DNA. The
Ras-transfected cells were then treated with either a PI-3K inhibitor
(wortmannin) or Rho kinase inhibitor (Y-27632) and the expressions of Ras,
PI-3K, Akt, NF-kappaB, and RhoA were analyzed. Fluorescent phalloidin staining
demonstrated more intense F-actin staining in the Ras over-expressed cells than
in the control cells, and the intensity of F-actin was inhibited by Y-27632. A
gelatin zymography study demonstrated that the MMP-2 and MMP-9 expressions of
the Ras-transfected cells were enhanced, and Y-27632 treatment reduced the
levels of MMP-2 and MMP-9. Similarly, a wound healing assay revealed that the
ability of cell migration was markedly increased by Ras transfection and the
healing rate after treatment of Y-27632 was delayed. Our results provide
evidence that Ras-induced RhoA and NF-kappaB activation was involved in the
invasion/migration of bladder cancer. Through Ras and/or RhoA inhibition, there
might be an opportunity for new therapeutic interventions in bladder cancer.
DOI: 10.1016/j.cbi.2009.10.018
PMID: 19896475 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22547464 | 1. Orv Hetil. 2012 May 6;153(18):695-701. doi: 10.1556/OH.2012.29351.
[New possibility in the oral glucose lowering treatment of type 2 diabetes
mellitus: sodium-glucose co-transporter-2 inhibitors].
[Article in Hungarian]
Simonyi G(1).
Author information:
(1)Pest Megyei Flór Ferenc Kórház, Kardiometabolikus Centrum V.
Belgyógyászat-Lipidológiai Osztály, Regionális Zsíranyagcsere-központ és
Hypertonia Decentrum, Kistarcsa. [email protected]
Sodium-glucose co-transporters (SGLTs) have a key role in the re-absorption of
glucose in the kidneys. Therefore, inhibition of SGLTs may provide a novel
therapeutic strategy for diabetes mellitus. SGLT2 inhibitors enhance renal
glucose excretion by inhibiting renal glucose re-absorption and reduce plasma
glucose level, as well as they decrease the body weight. Their action is insulin
independent and they improve insulin resistance in diabetes mellitus. Numerous
SGLT2 inhibitors have been developed and evaluated in clinical trials. Phase III
trials are needed to assess the safety of SGLT2 inhibitors. Results suggest that
the beneficial effects of SGLT2 inhibition might be achieved without the
development of significant side effects.
DOI: 10.1556/OH.2012.29351
PMID: 22547464 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23555069 | 1. J Thyroid Res. 2013;2013:264387. doi: 10.1155/2013/264387. Epub 2013 Mar 10.
New insights into mechanisms of cardioprotection mediated by thyroid hormones.
Nicolini G(1), Pitto L, Kusmic C, Balzan S, Sabatino L, Iervasi G, Forini F.
Author information:
(1)Institute of Clinical Physiology, CNR, 56100 Pisa, Italy ; CNR, Tuscany
Region G. Monasterio Foundation, Pisa, Italy.
Heart failure represents the final common outcome in cardiovascular diseases.
Despite significant therapeutic advances, morbidity and mortality of heart
failure remain unacceptably high. Heart failure is preceded and sustained by a
process of structural remodeling of the entire cardiac tissue architecture.
Prevention or limitation of cardiac remodeling in the early stages of the
process is a crucial step in order to ameliorate patient prognosis. Acquisition
of novel pathophysiological mechanisms of cardiac remodeling is therefore
required to develop more efficacious therapeutic strategies. Among all
neuroendocrine systems, thyroid hormone seems to play a major homeostatic role
in cardiovascular system. In these years, accumulating evidence shows that the
"low triiodothyronine" syndrome is a strong prognostic, independent predictor of
death in patients affected by both acute and chronic heart disease. In
experimental models of cardiac hypertrophy or myocardial infarction, alterations
in the thyroid hormone signaling, concerning cardiac mitochondrion, cardiac
interstitium, and vasculature, have been suggested to be related to heart
dysfunction. The aim of this brief paper is to highlight new developments in
understanding the cardioprotective role of thyroid hormone in reverting
regulatory networks involved in adverse cardiac remodeling. Furthermore, new
recent advances on the role of specific miRNAs in thyroid hormone regulation at
mitochondrion and interstitial level are also discussed.
DOI: 10.1155/2013/264387
PMCID: PMC3608184
PMID: 23555069 |
http://www.ncbi.nlm.nih.gov/pubmed/17893267 | 1. Eur J Endocrinol. 2007 Oct;157(4):515-20. doi: 10.1530/EJE-07-0318.
Thyroid hormone is a critical determinant of myocardial performance in patients
with heart failure: potential therapeutic implications.
Pantos C(1), Dritsas A, Mourouzis I, Dimopoulos A, Karatasakis G,
Athanassopoulos G, Mavrogeni S, Manginas A, Cokkinos DV.
Author information:
(1)Department of Pharmacology, University of Athens, 75 Mikras Asias Avenue,
11527 Goudi, Athens, Greece. [email protected]
OBJECTIVE: Previous experimental studies have provided evidence showing that
changes in thyroid hormone signaling correspond to alterations in myocardial
function in animal models of heart failure. The present study further explores
whether thyroid hormone alterations are correlated with the functional status of
the myocardium in patients with heart failure.
METHODS: In this study, 37 patients with mean ejection fraction (EF%) of 26.2
(8.2) were included. Myocardial performance was assessed by echocardiography and
cardiopulmonary exercise testing. Total tri-iodothyronine (T3), thyroxine, and
TSH levels were measured in plasma.
RESULTS: Total T3 was strongly correlated with VO2max (r = 0.78, P = 2 x
10(-8)). Furthermore, multivariate analysis revealed that total T3 was an
independent predictor of VO2max (P = 0.000 005). A weaker but significant
correlation was also found between total T3 and EF% (r = 0.56, P = 0.0004),
systolic (r = 0.43, P = 0.009) and diastolic (r = 0.46, P = 0.004) blood
pressure.
CONCLUSIONS: changes in thyroid hormone were closely correlated to myocardial
functional status in patients with heart failure. These data probably indicate a
possible role of thyroid hormone in the pathophysiology of heart failure and
confirm previous experimental reports.
DOI: 10.1530/EJE-07-0318
PMID: 17893267 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9489964 | 1. Am Heart J. 1998 Feb;135(2 Pt 1):187-96. doi: 10.1016/s0002-8703(98)70081-x.
Thyroid hormone and cardiovascular disease.
Gomberg-Maitland M(1), Frishman WH.
Author information:
(1)Department of Medicine, New York Hospital-Cornell Medical Center, NY, USA.
Thyroid hormone directly affects the heart and peripheral vascular system. The
hormone can increase myocardial inotropy and heart rate and dilate peripheral
arteries to increase cardiac output. An excessive deficiency of thyroid hormone
can cause cardiovascular disease and aggravate many preexisting conditions. In
severe systemic illness and after major surgical procedures changes in thyroid
function can occur, leading to the "euthyroid sick syndrome." Patients will have
normal or decreased levels of T4, decreased free and total T3, and usually
normal levels of thyroid stimulating hormone. This syndrome may be an adaptive
response to systemic illness that usually will revert to normal without hormone
supplementation as the illness subsides. Recently, however, many investigators
have explored the benefits of thyroid hormone supplementation in those diseases
associated with euthyroid sick syndrome. Thyroid hormone's effects on the
cardiovascular system make it an attractive therapy for those patients with
impaired hemodynamics and low T3. Thyroid hormone has also been considered a
treatment for patients with congestive heart failure, for patients undergoing
cardiopulmonary bypass and heart transplantation, and for patients with
hyperlipidemia. At present there is no evidence suggesting a favorable treatment
outcome using thyroid hormone supplementation for any systemic condition except
in those patients with documented hypothyroidism.
DOI: 10.1016/s0002-8703(98)70081-x
PMID: 9489964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12356724 | 1. EMBO J. 2002 Oct 1;21(19):5079-87. doi: 10.1093/emboj/cdf523.
Retardation of post-natal development caused by a negatively acting thyroid
hormone receptor alpha1.
Tinnikov A(1), Nordström K, Thorén P, Kindblom JM, Malin S, Rozell B, Adams M,
Rajanayagam O, Pettersson S, Ohlsson C, Chatterjee K, Vennström B.
Author information:
(1)Department of Cell and Molecular Biology, Department of Physiology and
Pharmacology, Microbiology and Tumour Biology Center, Karolinska Institute,
S-177 71 Stockholm, Sweden.
Most patients with the syndrome resistance to thyroid hormone (RTH) express a
mutant thyroid hormone receptor beta (TRbeta) with transdominant negative
transcriptional effects. Since no patient with a mutant TRalpha has been
identified, we introduced a point mutation into the mouse thyroid hormone
receptor (TRalpha1) locus originally found in the TRbeta gene, that reduces
ligand binding 10-fold. Heterozygous 2- to 3-week- old mice exhibit a severe
retardation of post-natal development and growth, but only a minor reduction in
serum thyroxine levels. Homozygous mice died before 3 weeks of age. Adult
heterozygotes overcome most of these defects except for cardiac function
abnormalities, suggesting that other factors compensate for the receptor defect.
However, the additional deletion of the TRbeta gene in this mouse strain caused
a 10-fold increase in serum thyroxine, restored hormonal regulation of target
genes for TRs, and rescued the growth retardation. The data demonstrate a novel
array of effects mediated by a dominant negative TRalpha1, and may provide
important clues for identification of a potentially unrecognized human disorder
and its treatment.
DOI: 10.1093/emboj/cdf523
PMCID: PMC129045
PMID: 12356724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10481836 | 1. Neuropsychopharmacology. 1999 Oct;21(4):519-29. doi:
10.1016/S0893-133X(99)00037-8.
Inhibition of the high affinity myo-inositol transport system: a common
mechanism of action of antibipolar drugs?
Lubrich B(1), van Calker D.
Author information:
(1)Department of Psychiatry, University of Freiburg, Germany.
The mechanism of action of antibipolar drugs like lithium, carbamazepine, and
valproate that are used in the treatment of manic-depressive illness, is
unknown. Lithium is believed to act through uncompetitive inhibition of
inositolmonophosphatase, which results in a depletion of neural cells of
inositol and a concomitant modulation of phosphoinositol signaling. Here, we
show that lithium ions, carbamazepine, and valproate, but not the tricyclic
antidepressant amitriptyline, inhibit at therapeutically relevant concentrations
and with a time course similar to their clinical actions the high affinity
myo-inositol transport in astrocyte-like cells and downregulate the level of the
respective mRNA. Inhibition of inositol uptake could thus represent an
additional pathway for inositol depletion, which might be relevant in the
mechanism of action of all three antibipolar drugs.
DOI: 10.1016/S0893-133X(99)00037-8
PMID: 10481836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8594618 | 1. Proc Soc Exp Biol Med. 1996 Jan;211(1):49-61. doi: 10.3181/00379727-211-43951.
Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.
Kopp P(1), Kitajima K, Jameson JL.
Author information:
(1)Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern
University Medical School, Chicago, Illinois 60611, USA.
Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear
thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are
transcription factors that act by altering patterns of gene expression.
Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in
the TR beta gene. Biochemically, the syndrome is defined by elevated circulating
levels of free thyroid hormones due to reduced target tissue responsiveness and
normal, or elevated, levels of thyroid-stimulating hormone (TSH). This
"inappropriate" TSH elevation contrasts with the situation in hyperthyroidism,
where the pituitary secretion of TSH is suppressed. Patients with RTH usually
present with goiter and an euthyroid or mildly hypothyroid metabolic state.
Thus, pituitary resistance results in hypersecretion of TSH, which compensates,
at least in part, for hormone resistance in peripheral tissues. Despite this
compensation, clinical effects of RTH can include short stature, delayed bone
maturation, hyperactivity, learning disabilities, and hearing defects, as well
as variable features of hyper- and hypothyroidism. With the exception of a
single sibship, which harbored a deletion of the entire coding sequence of the
TR beta gene and a recessive pattern of inheritance, all other cases of RTH have
been inherited in an autosomal dominant manner or have been de novo heterozygous
mutations of the TR beta gene. The dominant pattern of inheritance is explained
by the functional properties of the mutant receptors which act in a dominant
negative manner to block the activity of normal TR alpha and TR beta receptors.
Now that a large number of different RTH mutations have been identified, it is
striking that the mutations are clustered within restricted domains in the
carboxyterminal region of the receptor. Mutations in these regions have been
shown to preserve critical receptor functions such as dimerization and DNA
binding, while inactivating other activites such as T3 binding and
transcriptional activation. The examination of patients with RTH and their
mutated receptors has provided important insights into the mechanisms of thyroid
hormone action, the structure-function relationship of the receptors, and the
molecular mechanisms of dominant negative activity.
DOI: 10.3181/00379727-211-43951
PMID: 8594618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19006851 | 1. Curr Pharm Des. 2008;14(26):2686-92. doi: 10.2174/138161208786264142.
Prognostic role of sub-clinical hypothyroidism in chronic heart failure
outpatients.
Iacoviello M(1), Guida P, Guastamacchia E, Triggiani V, Forleo C, Catanzaro R,
Cicala M, Basile M, Sorrentino S, Favale S.
Author information:
(1)Cardiology Unit, Emergency and Organ Transplantation Department, University
of Bari, Bari, Italy. [email protected]
BACKGROUND: It has been suggested that low thyroid hormones levels may be
associated with increased mortality in patients with cardiovascular disease.
AIM: To evaluate the prognostic role of thyroid function deficiency in patients
with chronic heart failure (CHF).
METHODS: We evaluated 338 consecutive outpatients with stable CHF receiving
conventional therapy, all of whom underwent a physical examination,
electrocardiography and echocardiography. Blood samples were drawn to assess
renal function, and Na+, hemoglobin, NT-proBNPs, fT3, fT4 and TSH levels.
Patients with hyperthyroidism were excluded.
RESULTS: During the follow-up (15+/-8 months), heart failure progression was
observed in 79 patients (including 18 who died of heart failure after
hospitalisation and six who underwent transplantation). Univariate regression
analysis showed that TSH (p<0.0001), fT3 (p<0.0001), fT4 (p=0.016) and fT3/fT4
(p<0.0001) were associated with heart failure progression but multivariate
analysis showed that only TSH considered as a continuous variable (p = 0.001) as
well as subclinical hypothyroidism (TSH > 5.5 mUI/l; p=0.014) remained
significantly associated with the events.
CONCLUSIONS: In CHF patients TSH levels even slightly above normal range are
independently associated with a greater likelihood of heart failure progression.
This supports the need for prospective studies aimed at clarifying the most
appropriate therapeutic approach to sub-clinical hypothyroidism in such
patients.
DOI: 10.2174/138161208786264142
PMID: 19006851 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15860414 | 1. Trends Endocrinol Metab. 2005 May-Jun;16(4):176-82. doi:
10.1016/j.tem.2005.03.008.
Thyroid hormone receptor mutations and disease: beyond thyroid hormone
resistance.
Cheng SY(1).
Author information:
(1)Laboratory of Molecular Biology, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
[email protected]
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that
mediate the biological activities of thyroid hormone (T3). Two THR genes (A and
B), located on different chromosomes, yield four T3-binding isoforms with highly
conserved sequences in the DNA- and ligand-binding domains. Mutations of THRB
cause a human genetic disease, thyroid hormone resistance syndrome (RTH).
Comprehensive genomic profiling unveiled the contribution of novel
change-of-function mutations of TRbeta to the pathogenesis of RTH. In addition,
abnormalities associated with mutations of the THRA gene have been uncovered
recently. The phenotypic manifestations of mutated THRB and THRA genes are
distinct, indicating isoform-dependent actions of TR mutants in vivo. Therefore,
mutant TRs provide a new paradigm to understand the molecular basis of receptor
disease.
DOI: 10.1016/j.tem.2005.03.008
PMID: 15860414 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12855641 | 1. Clin Cancer Res. 2003 Jul;9(7):2632-41.
Significant association of Rho/ROCK pathway with invasion and metastasis of
bladder cancer.
Kamai T(1), Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H.
Author information:
(1)Department of Urology, Dokkyo University School of Medicine, Tochigi
321-0293, Japan. [email protected]
Comment in
Urol Oncol. 2017 Apr;35(4):155-156. doi: 10.1016/j.urolonc.2016.12.018.
PURPOSE: The small GTP-binding protein Rho and its best-characterized downstream
effector Rho-associated serine-threonine protein kinase, ROCK, participate in
actin cytoskeleton organization, and are linked to pathogenesis and progression
of several human tumors. We investigated the roles of Rho and ROCK in bladder
cancer.
EXPERIMENTAL DESIGN: Using Western blotting, we quantitated Rho and ROCK protein
expression in paired tumor and nontumor surgical samples from 107 consecutive
Japanese patients with bladder cancer.
RESULTS: RhoA, RhoC, and ROCK were more abundant in tumors and metastatic lymph
nodes than in nontumor bladder and uninvolved lymph nodes (P < 0.0001). Amounts
of RhoA and RhoC protein, and ROCK protein expression correlated positively with
one another (P < 0.0001). High RhoA, RhoC, and ROCK expression were related to
poor tumor differentiation (P < 0.05, P < 0.01, and P < 0.01, respectively),
muscle invasion (P < 0.001), and lymph node metastasis (P < 0.05). Kaplan-Meier
plots linked high RhoA, RhoC, and ROCK protein expression to shortened
disease-free and overall survival (P < 0.0001). By univariate analysis, high
RhoA, RhoC, and ROCK protein expression predicted shortened disease-free and
overall survival (P < 0.0001). By multivariate analysis, only RhoC was
independently influenced in disease-free survival (P < 0.05), and RhoA and RhoC
in overall survival (P < 0.001). In contrast, RhoB expression was inversely
related to the grade and stage (P < 0.05), and its higher expression is
associated with better overall survival (P < 0.05). In superficial tumors (Ta or
T1; 63 patients), RhoA, RhoC, and ROCK were unrelated with recurrence-free
survival. Overall survival in tumors invading muscle (T2 to T4; 44 patients) was
significantly influenced by RhoA, RhoC, and ROCK in a Kaplan-Meier analysis (P <
0.0001, P < 0.0001, and P < 0.01, respectively). Whereas RhoA, RhoC, and ROCK
independently predicted shortened overall survival in patients with invasive
tumor by univariate analysis (P < 0.0001, P < 0.0001, and P < 0.01,
respectively), only RhoC did so by multivariate analysis (P < 0.05).
CONCLUSION: Rho/ROCK pathway apparently involved in occurrence and progression
of bladder cancer may be valuable prognostic markers.
PMID: 12855641 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21080238 | 1. Mol Neurobiol. 2010 Dec;42(3):161-84. doi: 10.1007/s12035-010-8149-x. Epub
2010 Nov 16.
The biochemistry, ultrastructure, and subunit assembly mechanism of AMPA
receptors.
Nakagawa T(1).
Author information:
(1)Department of Chemistry and Biochemistry, University of California, San
Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. [email protected]
The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric
ligand-gated ion channels that play crucial roles in synaptic transmission and
plasticity. Our knowledge about the ultrastructure and subunit assembly
mechanisms of intact AMPA-Rs was very limited. However, the new studies using
single particle EM and X-ray crystallography are revealing important insights.
For example, the tetrameric crystal structure of the GluA2cryst construct
provided the atomic view of the intact receptor. In addition, the single
particle EM structures of the subunit assembly intermediates revealed the
conformational requirement for the dimer-to-tetramer transition during the
maturation of AMPA-Rs. These new data in the field provide new models and
interpretations. In the brain, the native AMPA-R complexes contain auxiliary
subunits that influence subunit assembly, gating, and trafficking of the
AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become
increasingly important to precisely describe the function of AMPA-Rs in the
brain. The AMPA-R proteomics studies continuously reveal a previously unexpected
degree of molecular heterogeneity of the complex. Because the AMPA-Rs are
important drug targets for treating various neurological and psychiatric
diseases, it is likely that these new native complexes will require detailed
mechanistic analysis in the future. The current ultrastructural data on the
receptors and the receptor-expressing stable cell lines that were developed
during the course of these studies are useful resources for high throughput drug
screening and further drug designing. Moreover, we are getting closer to
understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity.
DOI: 10.1007/s12035-010-8149-x
PMCID: PMC2992128
PMID: 21080238 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14599741 | 1. DNA Repair (Amst). 2003 Nov 21;2(11):1185-97. doi:
10.1016/j.dnarep.2003.07.002.
UV-induced de novo protein synthesis enhances nucleotide excision repair
efficiency in a transcription-dependent manner in S. cerevisiae.
Al-Moghrabi NM(1), Al-Sharif IS, Aboussekhra A.
Author information:
(1)Department of Biological and Medical Research, King Faisal Specialist
Hospital and Research Center, MBC #03, PO Box 3354, Riyadh 11211, Saudi Arabia.
DNA damage results in the up-regulation of several genes involved in different
cellular physiological processes, such as the nucleotide excision repair (NER)
mechanism that copes with a broad range of DNA alterations, including the
carcinogenic ultraviolet (UV) light-induced pyrimidine dimers (PDs). There are
two NER sub-pathways: transcription coupled repair (TCR) that is specific for
the transcribed strands (TS) of active genes and global genomic repair (GGR)
that repairs non-transcribed DNA sequences (NTD) and the non-transcribed strands
(NTS) of expressed genes. To elucidate the role of UV-dependent de novo protein
synthesis in nucleotide excision repair in the budding yeast, we investigated
the effect of the protein synthesis inhibitor, cycloheximide, on the removal of
PDs. Log phase as well as G(1)-synchronized cells were treated with the drug
shortly before UV irradiation and immediately thereafter, and the repair of
damaged DNA was assessed with the high resolution primer extension technique.
The results show that in both cellular conditions, the inhibition of
UV-dependent de novo protein synthesis by cycloheximide impairs the excision
repair of the transcriptionally active GAL10 and URA3 genes, with a greater
effect on the non-transcribed strands. This indicates that UV-mediated de novo
protein synthesis is required for efficient nucleotide excision repair, but not
for the preferential repair of the TSs. On the other hand, cycloheximide did not
affect the repair of either strand of the repressed GAL10 gene or the
non-transcribed promoter region of the URA3 gene, showing that UV-induced de
novo protein synthesis is not required for PD removal from transcriptionally
inactive DNA sequences. Together, these data show that despite the fact that NTD
and NTSs are normally repaired by the GGR sub-pathway, their requirement for
UV-dependent de novo protein synthesis is different, which may suggest a
difference in the processing of UV lesions in these non-transcribed sequences of
the genome.
DOI: 10.1016/j.dnarep.2003.07.002
PMID: 14599741 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14599769 | 1. Toxicology. 2003 Nov 15;193(1-2):79-90. doi: 10.1016/j.tox.2003.06.001.
Nucleotide excision repair and its interplay with transcription.
van Hoffen A(1), Balajee AS, van Zeeland AA, Mullenders LH.
Author information:
(1)MGC-Department of Toxicogenetics, Leiden University Medical Center,
Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Nucleotide excision repair (NER) is a multistep process capable to remove a
variety of DNA distorting lesions from prokaryotic and eukaryotic genomes. In
eukaryotic cells, the process requires more than 30 proteins to perform the
different steps, i.e. recognition of DNA damage, single strand incisions and
excision of the lesion-containing DNA fragment and DNA repair
synthesis/ligation. NER can operate via two subpathways: global genome repair
(GGR) and a specialized pathway coupled to active transcription
(transcription-coupled repair, TCR) and directed to DNA lesions in the
transcribed strand of active genes. Both in vivo as well as in cultured cells
the fast removal of transcription blocking lesions by TCR is crucial to escape
from lethal effects of inhibited transcription inhibition The most delicate step
in NER is the recognition of the DNA lesions in their different chromatin
context and the mechanism of damage recognition in GGR and TCR is principally
different and requires specific proteins. In GGR, the XPC-HR23B is essential for
the formation of the incision complex. In TCR the Cockayne syndrome (CS) gene
products are key players in the recognition of a stalled RNA polymerase the
presumed signaling structure for repair of transcribed strands. In this study,
we show that the extent of recovery of UV-inhibited transcription and TCR
strictly depends on the amount of CSB protein as well as the amount of DNA
damage present in the cell. This indicates that the ratio between DNA damage
frequency and CSB protein concentration in the cell is rather critical for acute
cellular response, i.e. recovery of inhibited transcription upon DNA damage
infliction, and hence cellular survival.
DOI: 10.1016/j.tox.2003.06.001
PMID: 14599769 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17655857 | 1. J Mol Cell Cardiol. 2007 Sep;43(3):337-43. doi: 10.1016/j.yjmcc.2007.06.009.
Epub 2007 Jun 30.
Genetic screening of calcium regulation genes in familial hypertrophic
cardiomyopathy.
Chiu C(1), Tebo M, Ingles J, Yeates L, Arthur JW, Lind JM, Semsarian C.
Author information:
(1)Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney
Australia.
Genes encoding Ca(2+) regulatory proteins responsible for Ca(2+) homeostasis
have been suggested as possible candidates for FHC. Mutations in sarcomere genes
account for approximately 50% of all FHC cases indicating other genes, including
those involved in Ca(2+) handling, may account for the remainder. The aim of
this study was to identify causative mutations in genes involved in Ca(2+)
regulation in patients with familial hypertrophic cardiomyopathy (FHC). An
Australian cohort of 252 unrelated familial hypertrophic cardiomyopathy patients
were screened for mutations in the Ca(2+) regulatory genes, sorcin (SRI),
calstabin (FKBP1B), calsequestrin (CASQ2), phospholamban (PLN), sarcolipin
(SLN), calreticulin (CALR3) and calmodulin (CALM). A total of 17 exonic DNA
variants were identified in the 7 Ca(2+) regulatory genes studied, of which 4
were considered of pathogenic significance. Two novel mutations in the CALR3
gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN
gene (Leu39Ter). A variant was also identified in the CASQ2 gene (Asp63Glu).
These four variants were all novel, resulted in changes in conserved amino acids
and were not identified in a normal population. In conclusion, mutations in
Ca(2+) handling genes are an infrequent but important cause of FHC. DNA variants
in Ca(2+) genes may also be involved as modifying factors in phenotype
development. Further evaluation of the role of defects in Ca(2+) regulation will
shed light on the molecular pathogenesis of FHC.
DOI: 10.1016/j.yjmcc.2007.06.009
PMID: 17655857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23729000 | 1. Drugs. 2013 Jun;73(9):979-88. doi: 10.1007/s40265-013-0064-9.
Canagliflozin: first global approval.
Elkinson S(1), Scott LJ.
Author information:
(1)Adis R&D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North
Shore 0754, Auckland, New Zealand. [email protected]
Erratum in
Drugs. 2013 Nov;73(16):1847.
Canagliflozin (Invokana™), an oral selective sodium-glucose co-transporter 2
(SGLT2) inhibitor, is under global development with Mitsubishi Tanabe Pharma and
Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, for the treatment
of type 2 diabetes mellitus. SGLT2 are mainly located in the proximal tubule of
the kidney and are involved in the reabsorption of filtered glucose from the
glomeruli into the body. Inhibition of SGLT2 lowers blood glucose in an insulin
independent manner as a consequence of blocking reabsorption of filtered glucose
in the glomeruli, thereby increasing urinary excretion of glucose and, in turn,
potentially reducing bodyweight. Canagliflozin is the first SGLT2 inhibitor to
be approved in the USA and is under regulatory review in the EU. This article
summarizes the milestones in the development of canagliflozin, leading to its
first approval for use in adults with type 2 diabetes.
DOI: 10.1007/s40265-013-0064-9
PMID: 23729000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22870736 | 1. Acta Cardiol. 2012 Jun;67(3):291-6. doi: 10.1080/ac.67.3.2160717.
The role of brain natriuretic peptide and serum triiodothyronine in the
diagnosis and prognosis of chronic heart failure.
Du JB(1), Da CH, Zhao Y, Guo Y, Guo G, Ju TF, Xu YP.
Author information:
(1)Affiliated Baiyin Hospital of Lanzhou University, Baiyin, China.
[email protected]
OBJECTIVE: The objective of this paper was to investigate the diagnostic and
prognostic value of plasma B type natriuretic peptide (BNP) and serum
triiodothyronine (T3) in chronic congestive heart failure (CHF).
METHODS: 156 cases of CHF patients and 75 cases of cardiac function I patients
hospitalized over the same period were utilized in this study. On admission, the
patient's BNP and T3 plasma concentrations were measured. The correlation
analysis of plasma BNP and T3 in CHF patients with cardiac function
classification was conducted.
RESULTS: According to the NYHA grading systems, the plasma BNP levels in
patients with II, III, and IV grade CHF were significantly higher than those
with cardiac function I (P < 0.05); BNP levels and NYHA grading of cardiac
function correlated positively. The BNP concentrations increased with CHF
progression (P < 0.01). The T3 level and NYHA grading of cardiac function
correlated negatively.TheT3 level decreased as the degree of heart failure
increased. Using CHF in combination with BNP to predict the occurrence of CHF
had a sensitivity value of 90.8% with 95.5% specificity, 86.3% accuracy, and a
negative predictive value of 87.7%.
CONCLUSIONS: Plasma BNP was more sensitive than T3 in the diagnosis of CHF. The
T3 was more meaningful than the BNP in the prognosis of CHF. The BNP and T3
combination detection was more valuable in determining the severity of CHF and
prognosis.
DOI: 10.1080/ac.67.3.2160717
PMID: 22870736 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9065408 | 1. J Biol Chem. 1997 Mar 21;272(12):7570-3. doi: 10.1074/jbc.272.12.7570.
Model for XPC-independent transcription-coupled repair of pyrimidine dimers in
humans.
Mu D(1), Sancar A.
Author information:
(1)Department of Biochemistry and Biophysics, School of Medicine, CB 7260,
University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.
In humans, DNA lesions such as pyrimidine dimers in the template strand of genes
transcribed by RNA polymerase II are repaired faster than those in the coding
strand and nontranscribed regions of the genome. This phenomenon, referred to as
transcription-coupled repair (i) requires active transcription, (ii) does not
require the XPC gene product which is essential for general/basal repair
reactions, and (iii) requires the CSA and CSB proteins. We have developed an in
vitro model system that consists of purified human excision repair factors and a
DNA substrate analogous to a transcription bubble terminating at a cyclobutane
thymine dimer. In this system the thymine dimer was excised independent of XPC.
Furthermore, the thymine dimer in the bubble-containing substrate was removed
approximately 3-fold faster by the excision repair nuclease reconstituted with
or without XPC, compared with the removal of thymine dimer from a base paired
duplex by the entire set of excision nuclease factors. These results provide
important insight into the mechanism of transcription-coupled repair in humans.
DOI: 10.1074/jbc.272.12.7570
PMID: 9065408 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12705874 | 1. Biochem Biophys Res Commun. 2003 Apr 25;304(1):1-4. doi:
10.1016/s0006-291x(03)00526-6.
Mutation of the phospholamban promoter associated with hypertrophic
cardiomyopathy.
Minamisawa S(1), Sato Y, Tatsuguchi Y, Fujino T, Imamura S, Uetsuka Y, Nakazawa
M, Matsuoka R.
Author information:
(1)Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo
Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, 162-8666, Tokyo, Japan.
[email protected] <[email protected]>
Phospholamban is an endogenous inhibitor of sarcoplasmic reticulum calcium
ATPase and plays a prime role in cardiac contractility and relaxation.
Phospholamban may be a candidate gene responsible for cardiomyopathy. We
investigated genome sequence of phospholamban in patients with cardiomyopathy.
PCR-based direct sequence was performed for the promoter region and the whole
coding region of phospholamban in 87 hypertrophic, 10 dilated, and 2 restricted
cardiomyopathic patients. We found a heterozygous single nucleotide transition
from A to G at -77-bp upstream of the transcription start site in the
phospholamban promoter region of one patient with familial hypertrophic
cardiomyopathy. This nucleotide change was not found in 296 control subjects.
Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the
phospholamban promoter activity. No nucleotide change in the phospholamban
coding region was found in 99 patients with cardiomyopathy. We suspect that the
mutation plays an important role in the development of hypertrophic
cardiomyopathy.
DOI: 10.1016/s0006-291x(03)00526-6
PMID: 12705874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18291710 | 1. Mutat Res. 2009 Jan-Feb;681(1):44-50. doi: 10.1016/j.mrrev.2007.12.003. Epub
2008 Jan 17.
New applications of the Comet assay: Comet-FISH and transcription-coupled DNA
repair.
Spivak G(1), Cox RA, Hanawalt PC.
Author information:
(1)Department of Biological Sciences, Stanford University, Stanford, CA
94305-5020, USA. [email protected]
Transcription-coupled repair (TCR) is a pathway dedicated to the removal of
damage from the template strands of actively transcribed genes. Although the
detailed mechanism of TCR is not yet understood, it is believed to be triggered
when a translocating RNA polymerase is arrested at a lesion or unusual structure
in the DNA. Conventional assays for TCR require high doses of DNA damage for the
statistical analysis of repair in the individual strands of DNA sequences
ranging in size from a few hundred bases to 30kb. The single cell gel
electrophoresis (Comet) assay allows detection of single- or double-strand
breaks at a 10-100-fold higher level of resolution. Fluorescence in situ
hybridization (FISH) combined with the Comet assay (Comet-FISH) affords a
heightened level of sensitivity for the assessment of repair in defined DNA
sequences of cells treated with physiologically relevant doses of genotoxins.
This approach also reveals localized susceptibility to chromosomal breakage in
cells from individuals with hypersensitivity to radiation or chemotherapy.
Several groups have reported preferential repair in transcriptionally active
genes or chromosomal domains using Comet-FISH. The prevailing interpretation of
the behavior of DNA in the Comet assay assumes that the DNA is arranged in loops
and matrix-attachment sites; that supercoiled, undamaged loops are contained
within the nuclear matrix and appear in Comet "heads", and that Comet "tails"
consist of relaxed DNA loops containing one or more breaks. According to this
model, localization of FISH probes in Comet heads signifies that loops
containing the targeted sequences are free of damage. This implies that
preferential repair as detected by Comet-FISH might encompass large chromosomal
domains containing both transcribed and non-transcribed sequences. We review the
existing evidence and discuss the implications in relation to current models for
the molecular mechanism of TCR.
DOI: 10.1016/j.mrrev.2007.12.003
PMCID: PMC2667151
PMID: 18291710 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8972850 | 1. Nucleic Acids Res. 1996 Dec 1;24(23):4653-9. doi: 10.1093/nar/24.23.4653.
The sensitivity of human fibroblasts to N-acetoxy-2-acetylaminofluorene is
determined by the extent of transcription-coupled repair, and/or their
capability to counteract RNA synthesis inhibition.
van Oosterwijk MF(1), Filon R, Kalle WH, Mullenders LH, van Zeeland AA.
Author information:
(1)MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden
University, The Netherlands.
Nucleotide excision repair (NER) mechanism is the major pathway responsible for
the removal of a large variety of bulky lesions from the genome. Two different
NER subpathways have been identified, i.e. the transcription-coupled and the
global genome repair pathways. For DNA-damage induced by ultraviolet light both
transcription-coupled repair and global genome repair are essential to confer
resistance to cytotoxic effects. To gain further insight into the contribution
of NER subpathways in the repair of bulky lesions and in their prevention of
biological effects we measured the rate of repair of dG-C8-AF in active and
inactive genes in normal human cells, XP-C cells (only transcription-coupled
repair) and XP-A cells (completely NER-deficient) exposed to NA-AAF. XP-C cells
are only slightly more sensitive to NA-AAF than normal cells and, like normal
cells, they are able to recover RNA synthesis repressed by the treatment. In
contrast, XP-A cells are sensitive to NA-AAF and unable to recover from RNA
synthesis inhibition. Repair of dG-C8-AF in the active ADA gene proceeds in a
biphasic way and without strand specificity, with a subclass of lesions quickly
repaired during the first 8 h after treatment. Repair in the inactive 754 gene
occurs more slowly than in the ADA gene. In XP-C cells, repair of dG-C8-AF in
the ADA gene is confined to the transcribed strand and occurs at about half the
rate of repair seen in normal cells. Repair in the inactive 754 gene in XP-C
cells is virtually absent. Consistent with these results we found that repair
replication in XP-C is drastically reduced when compared with normal cells and
abolished by alpha-amanitin indicating that the repair in XP-C cells is mediated
by transcription-coupled repair only. Our data suggest that dG-C8-AF is a target
for transcription-coupled repair and that this repair pathway is the main
pathway or recovery of RNA synthesis inhibition conferring resistance to
cytotoxic effects of NA-AAF. In spite of this, repair of dG-C8-AF in active
genes in normal cells by transcription-coupled repair and global genome repair
is not additive, but dominated by global genome repair. This indicates that the
subset of lesions which are capable of stalling RNA polymerase II, and are,
therefore, a substrate for TCR, are also the lesions which are very efficiently
recognized by the global genome repair system.
DOI: 10.1093/nar/24.23.4653
PMCID: PMC146299
PMID: 8972850 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9934845 | 1. Carcinogenesis. 1999 Jan;20(1):19-26. doi: 10.1093/carcin/20.1.19.
UV-enhanced reactivation of a UV-damaged reporter gene suggests
transcription-coupled repair is UV-inducible in human cells.
Francis MA(1), Rainbow AJ.
Author information:
(1)Department of Biology, McMaster University, Hamilton, Ontario, Canada.
The genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS)
exhibit deficiencies in the repair of UV-induced DNA damage. CS fibroblasts
retain proficient nucleotide excision repair (NER) of inactive (or bulk) DNA,
but are deficient in the transcription-coupled repair (TCR) of active genes. In
contrast, XP complementation group C (XP-C) fibroblasts retain proficient TCR,
but are deficient in bulk DNA repair. The remaining NER-deficient XP groups
exhibit deficiencies in both repair pathways. Ad5HCMVsp1lacZ is a recombinant
adenovirus vector that is unable to replicate in human fibroblasts, but can
efficiently infect and express the beta-galactosidase reporter gene in these
cells. We have examined the host cell reactivation (HCR) of beta-galactosidase
activity for UV-irradiated Ad5HCMVsp1lacZ in non-irradiated and UV-irradiated
normal, XP-B, XP-C, XP-D, XP-F, XP-G, CS-A and CS-B fibroblasts. HCR of
beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ was reduced in
non-irradiated cells from each of the repair-deficient groups examined
(including XP-C) relative to that in non-irradiated normal cells. Prior
irradiation of cells with low UV fluences resulted in an enhancement of HCR for
normal and XP-C strains, but not for the remaining XP and CS strains. HCR of the
UV-damaged reporter gene in UV-irradiated XP and CS strains was similar to
measurements of TCR reported previously for these cells. These results suggest
that UV treatment results in an induced repair of UV-damaged DNA in the
transcribed strand of an active gene in XP-C and normal cells through an
enhancement of TCR or a mechanism which involves the TCR pathway.
DOI: 10.1093/carcin/20.1.19
PMID: 9934845 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23369135 | 1. Endocr Metab Immune Disord Drug Targets. 2013 Mar;13(1):22-37. doi:
10.2174/1871530311313010005.
Thyroid disorders in chronic heart failure: from prognostic set-up to
therapeutic management.
Triggiani V(1), Iacoviello M.
Author information:
(1)Endocrinology and Metabolic Diseases, Interdisciplinary Department of
Medicine, University of Bari "Aldo Moro" School of Medicine, Policlinico, Bari,
Italy. [email protected]
Thyroid hormones have relevant activity at cardiac and vascular level, by
influencing heart rate, myocardial excitability as well as inotropic and
lusitropic status, systemic vascular resistance and blood pressure. Moreover,
they interact with neuro-hormonal systems such as sympathetic nervous system and
renin-angiotensin-aldosterone system thus also indirectly influencing
cardiovascular function. Due to these effects, both hypothyroidism and
hyperthyroidism, either in their overt or subclinical forms, can have an
unfavourable impact in the setting of cardiovascular diseases. The aim of this
review is to focus on the prognostic consequences of thyroid disorders in heart
failure patients. Moreover, the therapeutical approach and the possible
beneficial effects of restoring euthyroidism are reviewed.
DOI: 10.2174/1871530311313010005
PMID: 23369135 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20829081 | 1. Eur J Paediatr Neurol. 2011 Mar;15(2):138-45. doi: 10.1016/j.ejpn.2010.07.009.
Epub 2010 Sep 15.
3D gait analysis in patients with hereditary spastic paraparesis and spastic
diplegia: a kinematic, kinetic and EMG comparison.
Piccinini L(1), Cimolin V, D'Angelo MG, Turconi AC, Crivellini M, Galli M.
Author information:
(1)IRCCS "E. Medea", "La Nostra Famiglia" Association, Bosisio Parini, Lecco,
Italy.
The predominant clinical feature of patients with Hereditary Spastic Paraparesis
(HSP) is gait disturbance owing to spasticity and weakness of the lower limbs;
the spasticity in early-onset disease (infancy or childhood) often cannot be
distinguished from mild form of spastic diplegia (SD). The aim of this study was
to quantify the gait strategy in HSP and SD children, focusing on the
differences between groups as concerns functional limitation during gait. 9 HSP
and 16 SD children were evaluated using Gait Analysis; kinematic and kinetic
parameters and EMG pattern during walking were identified and calculated to
compare the two gait strategies. The results revealed that these two pathologies
are characterised by different gait strategies. In particular we found that knee
joint, in terms of kinematics and kinetics, and rectus femoris pattern represent
discriminatory aspects in order to compare and differentiate gait patterns of
HSP and SD children. The findings strongly support the issue that HSP and SD
patients need individualised therapeutical program, either neurosurgical or
pharmacological treatment, based on the quantification of gait deficiencies and
in order to address the peculiarity of their motor limitations and to prevent
the onset of compensatory strategies.
Copyright © 2010 European Paediatric Neurology Society. Published by Elsevier
Ltd. All rights reserved.
DOI: 10.1016/j.ejpn.2010.07.009
PMID: 20829081 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12549749 | 1. Dev Med Child Neurol. 2003 Jan;45(1):4-11.
Reliability and validity of the Observational Gait Scale in children with
spastic diplegia.
Mackey AH(1), Lobb GL, Walt SE, Stott NS.
Author information:
(1)University of Auckland Gait Laboratory, New Zealand.
The aim of this study was to establish the reliability and validity of visual
gait assessment in children with spastic diplegia, who were community or
household ambulators, using a modified version of the Physicians Rating Scale,
known as the Observational Gait Scale (OGS). Two clinicians viewed edited
split-screen video recordings of 20 children/adolescents (11 males, 9 females;
mean age 12 years, range 6 to 21 years) made at the time of three-dimensional
gait analysis (3-DGA). Walking ability in each child was scored at initial
assessment and reassessed from the same videos three months later using the
first seven sections of the OGS. Validity of the OGS score was determined by
comparison with 3-DGA. The OGS was found to have acceptable interrater and
intrarater reliability for knee and foot position in mid-stance, initial foot
contact, and heel rise with weighted kappas (wk) ranging from 0.53 to 0.91
(intrarater) and 0.43 to 0.86 (interrater). Comparison with 3-DGA suggests that
these sections might also have high validity(wk range 0.38-0.94). Base of
support and hind foot position had lower interrater and intrarater reliabilities
(wk 0.29 to 0.71 and wk 0.30 to 0.78 respectively) and were not easily validated
by 3-DGA.
PMID: 12549749 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11037190 | 1. Neuropathology. 2000 Sep;20 Suppl:S61-4. doi:
10.1046/j.1440-1789.2000.00300.x.
Moyamoya disease.
Fukui M(1), Kono S, Sueishi K, Ikezaki K.
Author information:
(1)Department of Neurosurgery, Neurological Institute, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan. [email protected]
Moyamoya disease is a specific chronic cerebrovascular occlusive disease first
reported by Japanese surgeons in 1957. The disease is characterized by stenosis
or occlusion of the terminal portions of the bilateral internal carotid arteries
and abnormal vascular network in the vicinity of the arterial occlusion. It may
cause ischemic attacks or cerebral infarction, which is more frequent in
children than in adults. In adults, cerebral hemorrhage may occur. The disease
is distributed in all age groups, but the highest peak is in childhood at less
than 10 years of age. The characteristic histopathologic features of the
steno-occlusive arteries are fibrocellular thickening of the intima containing
proliferated smooth muscle cells and prominently tortuous and often duplicated
internal elastic lamina. There is usually no atheromatous plaque in the arterial
wall. Etiology of the disease is still unknown; however, multifactorial
inheritance is considered possible because of a higher incidence of the disease
in Japanese and Koreans and approximately 10% of familial occurrence among the
Japanese. Recent genetic studies suggest some responsible genetic foci in
chromosomes 3, 6 and 17.
DOI: 10.1046/j.1440-1789.2000.00300.x
PMID: 11037190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19302042 | 1. Annu Rev Immunol. 2009;27:287-312. doi:
10.1146/annurev.immunol.25.022106.141532.
Aire.
Mathis D(1), Benoist C.
Author information:
(1)Section on Immunology and Immunogenetics, Joslin Diabetes Center; Department
of Medicine, Brigham and Women's Hospital; Harvard Medical School; and the
Harvard Stem Cell Institute, Boston, Massachusetts 02215, USA.
[email protected]
Mutations in the transcriptional regulator, Aire, cause APECED, a polyglandular
autoimmune disease with monogenic transmission. Animal models of APECED have
revealed that Aire plays an important role in T cell tolerance induction in the
thymus, mainly by promoting ectopic expression of a large repertoire of
transcripts encoding proteins normally restricted to differentiated organs
residing in the periphery. The absence of Aire results in impaired clonal
deletion of self-reactive thymocytes, which escape into the periphery and attack
a variety of organs. In addition, Aire is a proapoptotic factor, expressed at
the final maturation stage of thymic medullary epithelial cells, a function that
may promote cross-presentation of the antigens encoded by Aire-induced
transcripts in these cells. Transcriptional regulation by Aire is unusual in
being very broad, context-dependent, probabilistic, and noisy.
Structure/function analyses and identification of its interaction partners
suggest that Aire may impact transcription at several levels, including
nucleosome displacement during elongation and transcript splicing or other
aspects of maturation.
DOI: 10.1146/annurev.immunol.25.022106.141532
PMID: 19302042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24409030 | 1. J Phys Ther Sci. 2013 Dec;25(12):1605-8. doi: 10.1589/jpts.25.1605. Epub 2014
Jan 8.
Effects of vojta therapy on gait of children with spastic diplegia.
Lim H(1), Kim T(2).
Author information:
(1)Department of Physical Therapy, Dankook University, Republic of Korea.
(2)Department of Physical Therapy, Hanseo University, Republic of Korea.
[Purpose] This study aimed to investigate the effects of Vojta therapy on
spatiotemporal gait parameters in children with spastic diplegia. [Methods] The
study population consisted of 3 children diagnosed with spastic diplegia. The
subjects were treated with Vojta therapy for 8 weeks and followed up for 8 weeks
after completion of the therapy. Vicon motion analysis was used to determine the
subjects' spatiotemporal gait parameters. [Results] The following results were
noted in the changes of each joint angle in the sagittal plane after Vojta
therapy. Subject 1 remained in phase throughout the entire gait cycle and did
not show any noticeable improvement, even demonstrating a negative range of
motion when compared to the baseline. Subject 2 showed a normal anti-phase in
heel strike, and the mid-stance, and swing phases. Subject 3 showed a normal
anti-phase in heel strike and mid-stance, but the anti-phase during the swing
phase was not significantly different from the baseline. For subjects 2 and 3,
compared to the baseline, the range of motion of the hip and knee increased but
the range of motion of the ankle decreased. [Conclusion] The findings of this
study indicate that Vojta therapy can do a good role in improve the
spatiotemporal gait parameters of children with spastic diplegia.
DOI: 10.1589/jpts.25.1605
PMCID: PMC3885849
PMID: 24409030 |
http://www.ncbi.nlm.nih.gov/pubmed/23085499 | 1. Res Dev Disabil. 2013 Jan;34(1):495-504. doi: 10.1016/j.ridd.2012.09.005. Epub
2012 Oct 17.
Full body gait analysis may improve diagnostic discrimination between hereditary
spastic paraplegia and spastic diplegia: a preliminary study.
Bonnefoy-Mazure A(1), Turcot K, Kaelin A, De Coulon G, Armand S.
Author information:
(1)Willy Taillard Laboratory of Kinesiology, Geneva University Hospitals and
Geneva University, Geneva, Switzerland. [email protected]
Hereditary spastic paraplegia (HSP) and spastic diplegia (SD) patients share a
strong clinical resemblance. Thus, HSP patients are frequently misdiagnosed with
a mild form of SD. Clinical gait analysis (CGA) has been highlighted as a
possible tool to support the differential diagnosis of HSP and SD. Previous
analysis has focused on the lower-body but not the upper-body, where numerous
compensations during walking occur. The aim of this study was to compare the
full-body movements of HSP and SD groups and, in particular, the movement of the
upper limbs. Ten HSP and 12 SD patients were evaluated through a CGA (VICON 460
and Mx3+; ViconPeak(®), Oxford, UK) between 2008 and 2012. The kinematic
parameters were computed using the ViconPeak(®) software (Plug-In-Gait). In
addition, the mean amplitude of normalised (by the patient's height) arm swing
was calculated. All patients were asked to walk at a self-selected speed along a
10-m walkway. The mean kinematic parameters for the two populations were
analysed with Mann-Whitney comparison tests, with a significant P-value set at
0.05. The results demonstrated that HSP patients used more spine movement to
compensate for lower limb movement alterations, whereas SD patients used their
arms for compensation. SD patients had increased shoulder movements in the
sagittal plane (Flexion/extension angle) and frontal plane (elevation angle)
compared to HSP patients. These arm postures are similar to the description of
the guard position that toddlers exhibit during the first weeks of walking. To
increase speed, SD patients have larger arm swings in the sagittal, frontal and
transversal planes. Upper-body kinematics, and more specifically arm movements
and spine movements, may support the differential diagnosis of HSP and SD.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ridd.2012.09.005
PMID: 23085499 [Indexed for MEDLINE] |