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http://www.ncbi.nlm.nih.gov/pubmed/20921030 | 1. Clin Rehabil. 2011 Mar;25(3):256-63. doi: 10.1177/0269215510380828. Epub 2010
Oct 4.
The relationship between objectively and subjectively measured activity levels
in people with chronic low back pain.
van Weering MG(1), Vollenbroek-Hutten MM, Hermens HJ.
Author information:
(1)Roessingh Research and Development, University of Twente, Enschede, The
Netherlands. [email protected]
OBJECTIVE: To compare self-report measures of daily activities with objective
activity data to determine whether patients with chronic lower back pain report
their activity levels as accurately as controls do.
DESIGN: A cross-sectional study was performed in patients and controls.
SETTING: The study was carried out in the daily environment of the subjects.
SUBJECTS: Thirty-two chronic lower back pain patients with symptoms more than
three months and 20 healthy controls from the Netherlands, aged 18-65 years.
MAIN MEASURES: A tri-axial accelerometer was worn for five weekdays and the
Baecke Physical Activity Questionnaire was filled in. Pearson's correlation was
calculated to get insight in the awareness of patients and controls. Comparisons
of the relationship between the objective and subjective scores of each
individual patient with those of the group of controls were used to allocate
each patient into subgroups: overestimators, underestimators and aware patients.
Physical and psychological characteristics of these groups were explored.
RESULTS: Patients showed weak correlations between the objective and subjective
scores of physical activity and appear to have problems in estimating their
activity levels (r = -0.27), in contrast to controls who showed strong
correlations between the objective and subjective scores (r = 0.66). Comparison
of the individual relationships of patients with those of controls showed that
44% of the patients were not aware of their activity level. There were
relatively more underestimators (30%) than overestimators (14%). Physical
characteristics between the three groups tended to be different.
CONCLUSIONS: Patient self-reports about their activity level are relatively
inaccurate when compared to objective measurements.
DOI: 10.1177/0269215510380828
PMID: 20921030 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25685152 | 1. Case Rep Med. 2015;2015:450937. doi: 10.1155/2015/450937. Epub 2015 Jan 21.
A Case of IFAP Syndrome with Severe Atopic Dermatitis.
Araújo C(1), Gonçalves-Rocha M(2), Resende C(1), Vieira AP(1), Brito C(1).
Author information:
(1)Dermatology Department, Hospital de Braga, Sete Fontes, São Victor, 4710-243
Braga, Portugal.
(2)Medical Genetics Unit, Hospital de Braga, Sete Fontes, São Victor, 4710-243
Braga, Portugal.
Introduction. The IFAP syndrome is a rare X-linked genetic disorder
characterized by the triad of follicular ichthyosis, atrichia, and photophobia.
Case Report. A three-month-old Caucasian, male patient was observed with
noncicatricial universal alopecia and persistent eczema from birth. He had
dystrophic nails, spiky follicular hyperkeratosis, and photophobia which became
apparent at the first year of life. Short stature and psychomotor developmental
delay were also noticed. Histopathological examination of skin biopsy on left
thigh showed epidermis with irregular acanthosis, lamellar orthokeratotic
hyperkeratosis, and hair follicles fulfilled by parakeratotic hyperkeratosis.
The chromosomal study showed a karyotype 46, XY. Total IgE was 374 IU/mL. One
missense mutation c.1360G>C (p.Ala454Pro) in hemizygosity was detected on the
MBTPS2 gene thus confirming the diagnosis of IFAP syndrome. Conclusions. We
describe a boy with a typical clinical presentation of IFAP syndrome and severe
atopic manifestations. A novel missense mutation c.1360G>C (p.Ala454Pro) in
MBTPS2 gene was observed. The phenotypic expression of disease is quantitatively
related to a reduced function of a key cellular regulatory system affecting
cholesterol and endoplasmic reticulum homeostasis. It can cause epithelial
disturbance with failure in differentiation of epidermal structures and abnormal
skin permeability barrier. However, no correlation phenotype/genotype could be
established.
DOI: 10.1155/2015/450937
PMCID: PMC4320795
PMID: 25685152 |
http://www.ncbi.nlm.nih.gov/pubmed/14708109 | 1. Am J Med Genet A. 2004 Jan 30;124A(3):323-7. doi: 10.1002/ajmg.a.20352.
Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: report of a
new family with additional features and review.
Mégarbané H(1), Zablit C, Waked N, Lefranc G, Tomb R, Mégarbané A.
Author information:
(1)Service de Dermatologie, Hôtel-Dieu de France, Beirut, Lebanon.
[email protected]
Comment in
Am J Med Genet A. 2004 Jan 30;124A(3):328. doi: 10.1002/ajmg.a.20353.
Two brothers with ichthyosis follicularis, noncicatricial universal alopecia,
photophobia, hyerkeratotic psoriasis-like lesions, nails dystrophy, inguineal
herniae, cryptorchidism, short stature, seizures, and psychomotor developmental
delay are described. These features correspond to the ichthyosis follicularis,
alopecia, photophobia (IFAP) syndrome. The youngest brother had in addition a
bilateral absence of 4th fingers and camptodactyly, features never reported in
patients with IFAP syndromes.
Copyright 2003 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.20352
PMID: 14708109 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19689518 | 1. Pediatr Dermatol. 2009 Jul-Aug;26(4):427-31. doi:
10.1111/j.1525-1470.2009.00946.x.
Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome due to
mutation of the gene MBTPS2 in a large Australian kindred.
Ming A(1), Happle R, Grzeschik KH, Fischer G.
Author information:
(1)Department of Dermatology, Prince of Wales Hospital, Sydney, Australia.
[email protected]
Ichthyosis follicularis, alopecia and photophobia (IFAP) is a rare
genodermatosis. Most patients have been men without significant family history.
We present the largest kindred of IFAP reported to date in the medical
literature clearly demonstrating X-linked inheritance. The gene defect has
recently been mapped to Xp22.11-p22.13. Missense mutations of the gene, MBTPS2,
which codes for an intramembrane zinc metalloprotease essential for cholesterol
homeostasis and endoplasmic reticulum stress response, are associated with the
IFAP phenotype in this kindred. We describe the clinical features and discuss
the differential diagnosis of IFAP. Our proband has benefited from treatment
with acitretin.
DOI: 10.1111/j.1525-1470.2009.00946.x
PMID: 19689518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26194676 | 1. Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):986-992. doi:
10.1016/j.ijrobp.2015.04.038. Epub 2015 Apr 30.
A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone
Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.
Krauze AV(1), Myrehaug SD(2), Chang MG(3), Holdford DJ(3), Smith S(1), Shih
J(1), Tofilon PJ(1), Fine HA(4), Camphausen K(5).
Author information:
(1)Radiation Oncology Branch, National Cancer Institute/National Institutes of
Health, Bethesda, Maryland.
(2)Department of Radiation Oncology, Lakeridge Health Durham Regional Cancer
Centre, Oshawa, Ontario, Canada.
(3)Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia.
(4)New York University Langone Medical Center, New York, New York.
(5)Radiation Oncology Branch, National Cancer Institute/National Institutes of
Health, Bethesda, Maryland. Electronic address: [email protected].
PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase
inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to
radiation in preclinical models. We evaluated the addition of VPA to standard
radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed
GBM.
METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were
enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg
orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of
VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and
subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA-
and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria
version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and
Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event
reporting (Radiation Therapy Oncology Group/European Organization for Research
and Treatment).
RESULTS: A total of 81% of patients took VPA according to protocol. Median
overall survival (OS) was 29.6 months (range: 21-63.8 months), and median
progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at
6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and
24 months was 70%, 43%, and 38% respectively. The most common grade 3/4
toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow
toxicity (32%), neurological toxicity (11%), and metabolic and laboratory
toxicity (8%). Younger age and class V recursive partitioning analysis (RPA)
results were significant for both OS and PFS. VPA levels were not correlated
with grade 3 or 4 toxicity levels.
CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly
diagnosed GBM was well tolerated. Additionally, VPA may result in improved
outcomes compared to historical data and merits further study.
Published by Elsevier Inc.
DOI: 10.1016/j.ijrobp.2015.04.038
PMCID: PMC4510472
PMID: 26194676 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: none. |
http://www.ncbi.nlm.nih.gov/pubmed/20826260 | 1. Am Heart J. 2010 Sep;160(3):506-12. doi: 10.1016/j.ahj.2010.06.039.
Protective effect of the CYP2C19 *17 polymorphism with increased activation of
clopidogrel on cardiovascular events.
Tiroch KA(1), Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schömig A, Kastrati
A.
Author information:
(1)Deutsches Herzzentrum München, Rechts der Isar, Technische Universität,
Germany. [email protected]
BACKGROUND: The prodrug clopidogrel requires activation by cytochrome P-450
(CYP) enzymes for its antiplatelet effect. The genes encoding enzymes for
clopidogrel activation are polymorphic, leading to reduced or increased
function, depending on the respective genotype. Reduced-function alleles have
been associated with an increase in cardiovascular events.
METHODS: We tested the association of the presence of the ABCB1 (C/T) T-allele,
CYP2C19*2 (G/A) A-allele, or CYP2C19*17 (C/T) T-allele with the primary end
point of the need of clinically-driven target lesion revascularization (TLR) and
the secondary end points of major adverse cardiovascular events (MACE; including
death, myocardial infarction [MI], and TLR) at 1 year in a high-risk population
of 928 patients with acute MI.
RESULTS: Carriers of the CYP2C19*17 T-allele, with increased clopidogrel
activation, had a 37% relative reduction in the TLR incidence, the primary end
point (14.0% vs 22.3%, P = .002), and a 22% relative reduction of the secondary
end point MACE (22.0% vs 28.1%, P = .04) compared with noncarriers,
respectively. The association of the T-allele with TLR remained significant in
the multivariate analysis (P = .001). The ABCB1 (C/T) and the CYP2C19*2 (G/A)
polymorphisms were not associated with the incidence of TLR or MACE.
CONCLUSIONS: Based on the genetic analysis in a high-risk population of acute MI
patients with interventional treatment and continuous clopidogrel therapy, our
study found a protective effect for carriers of an increased-function CYP2C19*17
T-allele with significantly lower rates of TLR and MACE. T-allele carriers with
acute MI and increased clopidogrel activation had significantly reduced clinical
event rates.
2010 Mosby, Inc. All rights reserved.
DOI: 10.1016/j.ahj.2010.06.039
PMID: 20826260 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21617040 | 1. Science. 2011 Jun 17;332(6036):1429-33. doi: 10.1126/science.1204592. Epub
2011 May 26.
TFEB links autophagy to lysosomal biogenesis.
Settembre C(1), Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S,
Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A.
Author information:
(1)Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino
111, 80131 Naples, Italy.
Comment in
Nat Rev Mol Cell Biol. 2011 Jun 08;12(7):404. doi: 10.1038/nrm3139.
Science. 2011 Jun 17;332(6036):1392-3. doi: 10.1126/science.1208607.
Hepatology. 2012 May;55(5):1632-4. doi: 10.1002/hep.25619.
Autophagy is a cellular catabolic process that relies on the cooperation of
autophagosomes and lysosomes. During starvation, the cell expands both
compartments to enhance degradation processes. We found that starvation
activates a transcriptional program that controls major steps of the autophagic
pathway, including autophagosome formation, autophagosome-lysosome fusion, and
substrate degradation. The transcription factor EB (TFEB), a master gene for
lysosomal biogenesis, coordinated this program by driving expression of
autophagy and lysosomal genes. Nuclear localization and activity of TFEB were
regulated by serine phosphorylation mediated by the extracellular
signal-regulated kinase 2, whose activity was tuned by the levels of
extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent
mechanism regulates autophagy by controlling the biogenesis and partnership of
two distinct cellular organelles.
DOI: 10.1126/science.1204592
PMCID: PMC3638014
PMID: 21617040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24874578 | 1. J Mol Neurosci. 2015 Jan;55(1):7-20. doi: 10.1007/s12031-014-0329-0. Epub 2014
May 30.
The effects of histone deacetylase inhibitors on glioblastoma-derived stem
cells.
Alvarez AA(1), Field M(1), Bushnev S(1), Longo MS(1), Sugaya K(2).
Author information:
(1)University of Central Florida, Orlando, FL, USA.
(2)University of Central Florida, Orlando, FL, USA. [email protected].
Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited
effective treatment options. Cancer stem cells (CSCs), a subpopulation of cancer
cells with stem cell properties found in GBMs, have been shown to be extremely
resistant to radiation and chemotherapeutic agents and have the ability to
readily reform tumors. Therefore, the development of therapeutic agents
targeting CSCs is extremely important. In this study, we isolated
glioblastoma-derived stem cells (GDSCs) from GBM tissue removed from patients
during surgery and analyzed their gene expression using quantitative real-time
PCR and immunocytochemistry. We examined the effects of histone deacetylase
inhibitors trichostatin A (TSA) and valproic acid (VPA) on the proliferation and
gene expression profiles of GDSCs. The GDSCs expressed significantly higher
levels of both neural and embryonic stem cell markers compared to GBM cells
expanded in conventional monolayer cultures. Treatment of GDSCs with histone
deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates
of the cells and expression of the stem cell markers, indicating differentiation
of the cells. Since differentiation into GBM makes them susceptible to the
conventional cancer treatments, we posit that use of histone deacetylase
inhibitors may increase efficacy of the conventional cancer treatments for
eliminating GDSCs.
DOI: 10.1007/s12031-014-0329-0
PMID: 24874578 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22343943 | 1. EMBO J. 2012 Mar 7;31(5):1095-108. doi: 10.1038/emboj.2012.32. Epub 2012 Feb
17.
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via
mTOR and TFEB.
Settembre C(1), Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron
M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A.
Author information:
(1)Telethon Institute of Genetics and Medicine, Naples, Italy.
The lysosome plays a key role in cellular homeostasis by controlling both
cellular clearance and energy production to respond to environmental cues.
However, the mechanisms mediating lysosomal adaptation are largely unknown.
Here, we show that the Transcription Factor EB (TFEB), a master regulator of
lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1
(mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation
of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition
of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by
promoting its nuclear translocation. In addition, the transcriptional response
of lysosomal and autophagic genes to either lysosomal dysfunction or
pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells.
Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and
activates mTORC1, is both necessary and sufficient to regulate starvation- and
stress-induced nuclear translocation of TFEB. These data indicate that the
lysosome senses its content and regulates its own biogenesis by a
lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.
DOI: 10.1038/emboj.2012.32
PMCID: PMC3298007
PMID: 22343943 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24899645 | 1. Oncologist. 2014 Jul;19(7):751-9. doi: 10.1634/theoncologist.2014-0060. Epub
2014 Jun 4.
Seizure prognosis in brain tumors: new insights and evidence-based management.
Vecht CJ(1), Kerkhof M(2), Duran-Pena A(2).
Author information:
(1)Service Neurologie Mazarin, GH Pitié-Salpêtrière, Paris, France; Department
of Neurology, Medical Center The Hague, The Netherlands [email protected].
(2)Service Neurologie Mazarin, GH Pitié-Salpêtrière, Paris, France; Department
of Neurology, Medical Center The Hague, The Netherlands.
Brain tumor-related epilepsy (BTE) is common in low- and high-grade gliomas. The
risk of seizures varies between 60% and 100% among low-grade gliomas and between
40% and 60% in glioblastomas. The presence of seizures in patients with brain
tumors implies favorable and unfavorable factors. New-onset seizures represent
an early warning sign for the presence of a brain tumor and count as a good
prognostic factor for survival. Recurrence or worsening of seizures during the
course of disease may signal tumor progression. Each of the modalities for tumor
control (i.e., surgery, radiotherapy, chemotherapy) contributes to seizure
control. Nevertheless, one third of BTE shows pharmacoresistance to
antiepileptic drugs (AEDs) and may severely impair the burden of living with a
brain tumor. For symptomatic therapy of BTE, seizure type and individual patient
factors determine the appropriate AED. Randomized controlled trials in partial
epilepsy in adults to which type BTE belongs and additional studies in gliomas
indicate that levetiracetam is the agent of choice, followed by valproic acid
(VPA). In the case of recurring seizures, combining these two drugs
(polytherapy) seems effective and possibly synergistic. If either one is not
effective or not well tolerated, lacosamide, lamotrigine, or zonisamide are
additional options. A new and exciting insight is the potential contribution of
VPA to prolonged survival, particularly in glioblastomas. A practice guideline
on symptomatic medical management including dose schedules of AEDs is supplied.
©AlphaMed Press.
DOI: 10.1634/theoncologist.2014-0060
PMCID: PMC4077452
PMID: 24899645 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures of potential conflicts of interest
may be found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/21806387 | 1. Pharmacogenomics. 2011 Sep;12(9):1269-80. doi: 10.2217/pgs.11.73. Epub 2011
Aug 1.
Impact of genetic variants on post-clopidogrel platelet reactivity in patients
after elective percutaneous coronary intervention.
Rideg O(1), Komócsi A, Magyarlaki T, Tokés-Füzesi M, Miseta A, Kovács GL, Aradi
D.
Author information:
(1)Institute of Laboratory Medicine, University of Pécs, 13 Ifjúság Street,
H-7624 Pecs, Hungary.
AIM: To determine the effect of various SNPs on post-clopidogrel platelet
reactivity and clinical outcome.
MATERIALS & METHODS: Cytochrome 2C19 (CYP2C19) loss-of-function (LOF; *2, *3)
and gain-of-function (GOF; *17) allelic variants, together with ABCB1 (3435 C→T
and 2677 G→T/A) and paraoxonase-1 (PON-1; 192 Q→R) SNPs were analyzed in 189
patients after elective stent implantation who participated in a randomized,
placebo-controlled trial (NCT00638326). Platelet reactivity was determined with
light transmission aggregometry and vasodilator stimulated phosphoprotein
phosphorylation (VASP-PRI) 12-24 h after 600 mg clopidogrel. High on-treatment
platelet reactivity (HTPR) was defined according to the consensus definition
(ADP 5 µM >46%; VASP-PRI>50%).
RESULTS: In the case of CYP2C19 genotypes, a gene-dose effect was observed in
ADP reactivity with the lowest values in GOF homozygotes and the highest degree
in patients carrying two LOF alleles. The odds for HTPR also increased with the
number of LOF alleles. There were no significant differences in platelet
reactivity according to PON-1 or ABCB1 genotypes. In multivariate analysis, the
presence of a CYP2C19 LOF allele turned out to be the independent determinant of
HTPR. Although the study was not powered to clinical outcome (not LOF
heterozygotes), only patients with two LOF alleles had a significantly higher
risk for cardiovascular death, myocardial infarction or unplanned target vessel
revascularization at 1 year compared with non-LOF carriers.
CONCLUSION: Genetic variants in CYP2C19 have a gene-dose effect on
post-clopidogrel platelet reactivity, with homozygote LOF carriers having the
highest risk for HTPR and for adverse ischemic events. Neither ABCB1 nor PON-1
genotypes significantly influenced platelet reactivity or outcome.
DOI: 10.2217/pgs.11.73
PMID: 21806387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21880994 | 1. Neurology. 2011 Sep 20;77(12):1156-64. doi: 10.1212/WNL.0b013e31822f02e1. Epub
2011 Aug 31.
Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial
for glioblastoma.
Weller M(1), Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K,
Brandes AA, Bogdahn U, Macdonald DR, Forsyth P, Rossetti AO, Lacombe D,
Mirimanoff RO, Vecht CJ, Stupp R.
Author information:
(1)Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26,
CH-8091 Zurich, Switzerland. [email protected]
Comment in
Neurology. 77:1114.
OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs
(AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients
with newly diagnosed glioblastoma.
METHODS: The European Organization for Research and Treatment of Cancer (EORTC)
26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial
database of radiotherapy (RT) with or without temozolomide (TMZ) for newly
diagnosed glioblastoma was examined to assess the impact of the interaction
between AED use and chemoradiotherapy on survival. Data were adjusted for known
prognostic factors.
RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%)
were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any
non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4
thrombopenia and leukopenia than patients without an AED or patients taking an
EIAED only. The overall survival (OS) of patients who were receiving an AED at
baseline vs not receiving any AED was similar. Patients receiving VPA alone (97
[16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR]
0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED
only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED
(HR 0.67, 95% CI 0.49-0.93).
CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma
who require an AED during TMZ-based chemoradiotherapy. Future studies are needed
to determine whether VPA increases TMZ bioavailability or acts as an inhibitor
of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.
DOI: 10.1212/WNL.0b013e31822f02e1
PMCID: PMC3265044
PMID: 21880994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24194598 | 1. Nucleic Acids Res. 2014 Jan;42(Database issue):D142-7. doi:
10.1093/nar/gkt997. Epub 2013 Nov 4.
JASPAR 2014: an extensively expanded and updated open-access database of
transcription factor binding profiles.
Mathelier A(1), Zhao X, Zhang AW, Parcy F, Worsley-Hunt R, Arenillas DJ, Buchman
S, Chen CY, Chou A, Ienasescu H, Lim J, Shyr C, Tan G, Zhou M, Lenhard B,
Sandelin A, Wasserman WW.
Author information:
(1)Department of Medical Genetics, Centre for Molecular Medicine and
Therapeutics at the Child and Family Research Institute, University of British
Columbia, Vancouver, BC, Canada, Department of Biology and Biotech Research and
Innovation Centre, The Bioinformatics Centre, Copenhagen University, Ole Maaloes
Vej 5, DK-2200, Denmark, Lineberger Comprehensive Cancer Center, University of
North Carolina, Chapel Hill, NC 27599, USA, Laboratoire Physiologie Cellulaire &
Végétale, Université Grenoble Alpes, CNRS, CEA, iRTSV, INRA, 38054 Grenoble,
France, Computational Regulatory Genomics, MRC Clinical Sciences Centre,
Imperial College London, Du Cane Road, London W12 0NN, UK, and Department of
Informatics, University of Bergen, Thormøhlensgate 55, N-5008 Bergen, Norway.
JASPAR (http://jaspar.genereg.net) is the largest open-access database of
matrix-based nucleotide profiles describing the binding preference of
transcription factors from multiple species. The fifth major release greatly
expands the heart of JASPAR-the JASPAR CORE subcollection, which contains
curated, non-redundant profiles-with 135 new curated profiles (74 in
vertebrates, 8 in Drosophila melanogaster, 10 in Caenorhabditis elegans and 43
in Arabidopsis thaliana; a 30% increase in total) and 43 older updated profiles
(36 in vertebrates, 3 in D. melanogaster and 4 in A. thaliana; a 9% update in
total). The new and updated profiles are mainly derived from published chromatin
immunoprecipitation-seq experimental datasets. In addition, the web interface
has been enhanced with advanced capabilities in browsing, searching and
subsetting. Finally, the new JASPAR release is accompanied by a new BioPython
package, a new R tool package and a new R/Bioconductor data package to
facilitate access for both manual and automated methods.
DOI: 10.1093/nar/gkt997
PMCID: PMC3965086
PMID: 24194598 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19906716 | 1. Nucleic Acids Res. 2010 Jan;38(Database issue):D105-10. doi:
10.1093/nar/gkp950. Epub 2009 Nov 11.
JASPAR 2010: the greatly expanded open-access database of transcription factor
binding profiles.
Portales-Casamar E(1), Thongjuea S, Kwon AT, Arenillas D, Zhao X, Valen E, Yusuf
D, Lenhard B, Wasserman WW, Sandelin A.
Author information:
(1)Department of Medical Genetics, Centre for Molecular Medicine and
Therapeutics, Child and Family Research Institute, University of British
Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
JASPAR (http://jaspar.genereg.net) is the leading open-access database of matrix
profiles describing the DNA-binding patterns of transcription factors (TFs) and
other proteins interacting with DNA in a sequence-specific manner. Its fourth
major release is the largest expansion of the core database to date: the
database now holds 457 non-redundant, curated profiles. The new entries include
the first batch of profiles derived from ChIP-seq and ChIP-chip whole-genome
binding experiments, and 177 yeast TF binding profiles. The introduction of a
yeast division brings the convenience of JASPAR to an active research community.
As binding models are refined by newer data, the JASPAR database now uses
versioning of matrices: in this release, 12% of the older models were updated to
improved versions. Classification of TF families has been improved by adopting a
new DNA-binding domain nomenclature. A curated catalog of mammalian TFs is
provided, extending the use of the JASPAR profiles to additional TFs belonging
to the same structural family. The changes in the database set the system ready
for more rapid acquisition of new high-throughput data sources. Additionally,
three new special collections provide matrix profile data produced by recent
alternative high-throughput approaches.
DOI: 10.1093/nar/gkp950
PMCID: PMC2808906
PMID: 19906716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25060788 | 1. Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1942-1952. doi:
10.1161/ATVBAHA.114.303342. Epub 2014 Jul 24.
Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue
lipid-induced lysosomal dysfunction and downstream sequelae.
Emanuel R(#)(1), Sergin I(#)(1), Bhattacharya S(1), Turner J(1), Epelman S(1),
Settembre C(1), Diwan A(1), Ballabio A(1), Razani B(1).
Author information:
(1)Cardiovascular Division, Department of Medicine, Washington University School
of Medicine, St. Louis, MO (R.E., I.S., S.B., S.E., A.D., B.R.) and Department
of Pathology and Immunology, Washington University School of Medicine, St.
Louis, MO (J.T., B.R.); John Cochran VA Medical Center, St. Louis, MO (A.D.);
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy (C.S., A.B.);
and Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX (C.S., A.B.).
(#)Contributed equally
OBJECTIVE: Recent reports of a proatherogenic phenotype in mice with
macrophage-specific autophagy deficiency have renewed interest in the role of
the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique
ability to process both exogenous material, including lipids and
autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to
understand the effects of an atherogenic lipid environment on macrophage
lysosomes and to evaluate novel ways to modulate this system.
APPROACH AND RESULTS: Using a variety of complementary techniques, we show that
oxidized low-density lipoproteins and cholesterol crystals, commonly encountered
lipid species in atherosclerosis, lead to profound lysosomal dysfunction in
cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity,
membrane integrity, and morphology are readily seen. Using flow cytometry, we
find that macrophages isolated from atherosclerotic plaques also display
features of lysosome dysfunction. We then investigated whether enhancing
lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only
known transcription factor that is a master regulator of lysosomal biogenesis
although its role in macrophages has not been studied. Lysosomal stress induced
by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and
activation of lysosomal and autophagy genes. TFEB overexpression in macrophages
further augments this prodegradative response and rescues several deleterious
effects seen with atherogenic lipid loading as evidenced by blunted lysosomal
dysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β,
enhanced cholesterol efflux, and decreased polyubiquitinated protein
aggregation.
CONCLUSIONS: Taken together, these data demonstrate that lysosomal function is
markedly impaired in atherosclerosis and suggest that induction of a lysosomal
biogenesis program in macrophages has antiatherogenic effects.
© 2014 American Heart Association, Inc.
DOI: 10.1161/ATVBAHA.114.303342
PMCID: PMC4140993
PMID: 25060788 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1915513 | 1. Eur J Pediatr. 1991 Jul;150(9):627-9. doi: 10.1007/BF02072621.
Further delineation of the ichthyosis follicularis, atrichia, and photophobia
syndrome.
Hamm H(1), Meinecke P, Traupe H.
Author information:
(1)Department of Dermatology, University of Münster, Federal Republic of
Germany.
We describe an 18-month-old male infant suffering from the ichthyosis
follicularis, atrichia, and photophobia (IFAP) syndrome and further delineate
the clinical phenotype. Severe retardation of growth and psychomotor
development, chill-like seizures, bronchial asthma, urticaria, a proneness to
skin infections and transient nail dystrophy observed in our patient are
non-obligatory manifestations of this disorder. Histological examination of the
atrichia revealed poorly developed, shortened hair follicles and a complete
absence of sebaceous glands. The sex ratio of published cases suggests an
X-linked recessive inheritance. The marked clinical variability of the IFAP
syndrome might be the expression of a contiguous gene defect.
DOI: 10.1007/BF02072621
PMID: 1915513 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21091161 | 1. Crit Rev Biotechnol. 2011 Dec;31(4):295-336. doi:
10.3109/07388551.2010.525498. Epub 2010 Nov 22.
Peptidoglycan biosynthesis machinery: a rich source of drug targets.
Gautam A(1), Vyas R, Tewari R.
Author information:
(1)Department of Biotechnology, Panjab University, Chandigarh, India.
The range of antibiotic therapy for the control of bacterial infections is
becoming increasingly limited because of the rapid rise in multidrug resistance
in clinical bacterial isolates. A few diseases, such as tuberculosis, which were
once thought to be under control, have re-emerged as serious health threats.
These problems have resulted in intensified research to look for new inhibitors
for bacterial pathogens. Of late, the peptidoglycan (PG) layer, the most
important component of the bacterial cell wall has been the subject of drug
targeting because, first, it is essential for the survivability of eubacteria
and secondly, it is absent in humans. The last decade has seen tremendous inputs
in deciphering the 3-D structures of the PG biosynthetic enzymes. Many
inhibitors against these enzymes have been developed using virtual and high
throughput screening techniques. This review discusses the mechanistic and
structural properties of the PG biosynthetic enzymes and inhibitors developed in
the last decade.
DOI: 10.3109/07388551.2010.525498
PMID: 21091161 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9210483 | 1. Eur J Biochem. 1997 May 15;246(1):193-9. doi:
10.1111/j.1432-1033.1997.t01-1-00193.x.
The lantibiotic mersacidin inhibits peptidoglycan biosynthesis at the level of
transglycosylation.
Brötz H(1), Bierbaum G, Reynolds PE, Sahl HG.
Author information:
(1)Institut für Medizinische Mikrobiologie und Immunologie, Universität Bonn,
Germany.
The lantibiotic mersacidin has been previously reported to interfere with
bacterial peptidoglycan biosynthesis, [Brötz, H., Bierbaum, G., Markus, A.,
Molitor, E. & Sahl, H.-G. (1995) Antimicrob. Agents Chemother. 39, 714-719].
Here, we focus on the target reaction and describe a mersacidin-induced
accumulation of UDP-N-acetylmuramoyl-pentapeptide, indicating that inhibition of
peptidoglycan synthesis occurs after the formation of cytoplasmic precursors. In
vitro studies involving a wall-membrane particulate fraction of Bacillus
megaterium KM demonstrated that mersacidin did not prevent the synthesis of
lipid II [undecaprenyl-diphosphoryl-N-acetylmuramoyl-(pentapeptide)-N-ac ety
lglucosamine] but specifically the subsequent conversion of this intermediate
into polymeric nascent glycan strands by transglycosylation. Comparison with
other inhibitors of transglycosylation shows that the effective concentration of
mersacidin in vitro is in the range of that of the glycopeptide antibiotic
vancomycin but 2-3 orders of magnitude higher than that of the competitive
enzyme inhibitor moenomycin. The analogy to the glycopeptides may hint at an
interaction of mersacidin with the peptidoglycan precursor rather than with the
enzyme. Unlike vancomycin however, mersacidin inhibits peptidoglycan formation
from UDP-N-acetylmuramoyl-tripeptide and is active against Enterococcus faecium
expressing the vanA resistance gene cluster. This indicates that the molecular
target site of mersacidin differs from that of vancomycin and that no
cross-resistance exists between the two antibiotics.
DOI: 10.1111/j.1432-1033.1997.t01-1-00193.x
PMID: 9210483 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12197711 | 1. J Am Chem Soc. 2002 Sep 4;124(35):10260-1. doi: 10.1021/ja017748h.
Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors.
McDonald LA(1), Barbieri LR, Carter GT, Lenoy E, Lotvin J, Petersen PJ, Siegel
MM, Singh G, Williamson RT.
Author information:
(1)Wyeth-Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
[email protected]
The muraymycins, a family of nucleoside-lipopeptide antibiotics, were purified
from the extract of Streptomyces sp. LL-AA896. The antibiotics were purified by
chromatographic methods and characterized by NMR spectroscopy, degradation
studies, and mass spectrometry. The structures of 19 compounds were established.
The muraymycins constitute a new antibiotic family whose core structure contains
a glycosylated uronic acid derivative joined by an aminopropane group to a
hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing
dipeptide that is further extended by a urea-valine moiety. Members of this
family show broad-spectrum in vitro antimicrobial activity against a variety of
clinical isolates (MIC 2 to >64 mug/mL). The muraymycins inhibited peptidoglycan
biosynthesis. The fatty acid substituent and the presence or absence of the
amino sugar play important roles in biological activity. One of the most active
compounds, muraymycin A1, demonstrated protection in vivo against Staphylococcus
aureus infection in mice (ED50 1.1 mg/kg).
DOI: 10.1021/ja017748h
PMID: 12197711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25066904 | 1. Seizure. 2014 Nov;23(10):830-5. doi: 10.1016/j.seizure.2014.06.015. Epub 2014
Jul 8.
Survival analysis for valproic acid use in adult glioblastoma multiforme: a
meta-analysis of individual patient data and a systematic review.
Yuan Y(1), Xiang W(2), Qing M(3), Yanhui L(4), Jiewen L(5), Yunhe M(6).
Author information:
(1)Department of Neurosurgery, West China Hospital, Si Chuan University, Chengdu
610041, China. Electronic address: [email protected].
(2)Department of Neurosurgery, West China Hospital, Si Chuan University, Chengdu
610041, China. Electronic address: [email protected].
(3)Department of Neurosurgery, West China Hospital, Si Chuan University, Chengdu
610041, China. Electronic address: [email protected].
(4)Department of Neurosurgery, West China Hospital, Si Chuan University, Chengdu
610041, China. Electronic address: [email protected].
(5)Department of Neurosurgery, West China Hospital, Si Chuan University, Chengdu
610041, China. Electronic address: [email protected].
(6)West China Medical School of Si Chuan University, Chengdu 610041, China.
Electronic address: [email protected].
PURPOSE: Glioblastoma multiforme (GBM) is the most lethal type of primary brain
tumor, and patients that undergo the maximum tumor resection that is safely
possible and standard radiochemotherapy only achieve a median survival time of
14.6 months. Several clinical studies have reported that valproic acid could
prolong survival of GBM patients. However, the results of these studies are
inconsistent. We examined relevant studies and conducted a meta-analysis to
assess the effects of VPA on survival times and recurrence.
METHODS: A bibliographic search was performed in the EMBASE, MEDLINE,
ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials
databases to identify potentially relevant articles or conference abstracts that
investigated the effects of VPA on the outcome of glioma patients. Five
observational studies were included.
RESULTS: Pooled estimates of the hazard ratio (HR) and 95% confidence intervals
(CI) were calculated. Our meta-analysis confirmed the benefit of using VPA (HR,
0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with
VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs.
patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence
interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. No
heterogeneity was observed in the subset analysis.
CONCLUSION: The results of our study suggest that glioblastoma patients may
experience prolonged survival due to VPA administration. Sub-analysis confirmed
the benefit of VPA use compared to a non-AEDs group and an other-AEDs group.
Further RCTs of this subject should be performed.
Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All
rights reserved.
DOI: 10.1016/j.seizure.2014.06.015
PMID: 25066904 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22280885 | 1. Curr Opin Microbiol. 2012 Apr;15(2):194-203. doi: 10.1016/j.mib.2011.12.013.
Epub 2012 Jan 24.
Recent advances in pneumococcal peptidoglycan biosynthesis suggest new vaccine
and antimicrobial targets.
Sham LT(1), Tsui HC, Land AD, Barendt SM, Winkler ME.
Author information:
(1)Department of Biology, Indiana University Bloomington, Bloomington, IN 47405,
United States.
Streptococcus pneumoniae is a serious human respiratory pathogen that has the
capacity to evade capsule-based vaccines and to develop multidrug antibiotic
resistance. This review summarizes recent advances in understanding the
mechanisms and regulation of peptidoglycan (PG) biosynthesis that result in
ellipsoid-shaped, ovococcus Streptococcus cells. New results support a two-state
model for septal and peripheral PG synthesis at mid-cell, involvement of
essential cell division proteins in PG remodeling, and mid-cell localization of
proteins that organize PG biosynthesis and that form the protein translocation
apparatus. PG biosynthesis proteins have already turned up as promising vaccine
candidates and targets of antibiotics. Properties of several recently
characterized proteins that mediate or regulate PG biosynthesis suggest a source
of additional targets for therapies against pneumococcus.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.mib.2011.12.013
PMCID: PMC3322672
PMID: 22280885 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21752829 | 1. Hum Mol Genet. 2011 Oct 1;20(19):3852-66. doi: 10.1093/hmg/ddr306. Epub 2011
Jul 13.
Characterization of the CLEAR network reveals an integrated control of cellular
clearance pathways.
Palmieri M(1), Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A.
Author information:
(1)Department of Molecular and Human Genetics, Baylor College of Medicine, Jan
and Dan Duncan Neurological Research Institute at Texas Children's Hospital,
Houston, TX, USA.
In metazoans, lysosomes are the center for the degradation of macromolecules and
play a key role in a variety of cellular processes, such as autophagy,
exocytosis and membrane repair. Defects of lysosomal pathways are associated
with lysosomal storage disorders and with several late onset neurodegenerative
diseases. We recently discovered the CLEAR (Coordinated Lysosomal Expression and
Regulation) gene network and its master gene transcription factor EB (TFEB),
which regulates lysosomal biogenesis and function. Here, we used a combination
of genomic approaches, including ChIP-seq (sequencing of chromatin
immunoprecipitate) analysis, profiling of TFEB-mediated transcriptional
induction, genome-wide mapping of TFEB target sites and recursive expression
meta-analysis of TFEB targets, to identify 471 TFEB direct targets that
represent essential components of the CLEAR network. This analysis revealed a
comprehensive system regulating the expression, import and activity of lysosomal
enzymes that control the degradation of proteins, glycosaminoglycans,
sphingolipids and glycogen. Interestingly, the CLEAR network appears to be
involved in the regulation of additional lysosome-associated processes,
including autophagy, exo- and endocytosis, phagocytosis and immune response.
Furthermore, non-lysosomal enzymes involved in the degradation of essential
proteins such as hemoglobin and chitin are also part of the CLEAR network.
Finally, we identified nine novel lysosomal proteins by using the CLEAR network
as a tool for prioritizing candidates. This study provides potential therapeutic
targets to modulate cellular clearance in a variety of disease conditions.
DOI: 10.1093/hmg/ddr306
PMID: 21752829 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12440876 | 1. J Am Chem Soc. 2002 Nov 27;124(47):13970-1. doi: 10.1021/ja021097n.
Rethinking ramoplanin: the role of substrate binding in inhibition of
peptidoglycan biosynthesis.
Helm JS(1), Chen L, Walker S.
Author information:
(1)Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Ramoplanin is a cyclicdepsipeptide antibiotic that inhibits peptidoglycan
biosynthesis. It was proposed in 1990 to block the MurG step of peptidoglycan
synthesis by binding to the substrate of MurG, Lipid I. The proposed mechanism
of MurG inhibition has become widely accepted even though it was never directly
tested. In this paper, we disprove the accepted mechanism for how ramoplanin
functions, and we present an alternative mechanism. This work has implications
for the design of ramoplanin derivatives and may influence how other proposed
substrate binding antibiotics are studied.
DOI: 10.1021/ja021097n
PMID: 12440876 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23609508 | 1. Nat Rev Mol Cell Biol. 2013 May;14(5):283-96. doi: 10.1038/nrm3565.
Signals from the lysosome: a control centre for cellular clearance and energy
metabolism.
Settembre C(1), Fraldi A, Medina DL, Ballabio A.
Author information:
(1)Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino
111, 80131, Naples, Italy.
For a long time, lysosomes were considered merely to be cellular 'incinerators'
involved in the degradation and recycling of cellular waste. However, now there
is compelling evidence indicating that lysosomes have a much broader function
and that they are involved in fundamental processes such as secretion, plasma
membrane repair, signalling and energy metabolism. Furthermore, the essential
role of lysosomes in autophagic pathways puts these organelles at the crossroads
of several cellular processes, with significant implications for health and
disease. The identification of a master regulator, transcription factor EB
(TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the
lysosome adapts to environmental cues, such as starvation, and targeting TFEB
may provide a novel therapeutic strategy for modulating lysosomal function in
human disease.
DOI: 10.1038/nrm3565
PMCID: PMC4387238
PMID: 23609508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23393155 | 1. Hum Mol Genet. 2013 May 15;22(10):1994-2009. doi: 10.1093/hmg/ddt052. Epub
2013 Feb 7.
TFEB regulates lysosomal proteostasis.
Song W(1), Wang F, Savini M, Ake A, di Ronza A, Sardiello M, Segatori L.
Author information:
(1)Department of Chemical and Biomolecular Engineering, Rice University,
Houston, TX 77005, USA.
Loss-of-function diseases are often caused by destabilizing mutations that lead
to protein misfolding and degradation. Modulating the innate protein homeostasis
(proteostasis) capacity may lead to rescue of native folding of the mutated
variants, thereby ameliorating the disease phenotype. In lysosomal storage
disorders (LSDs), a number of highly prevalent alleles have missense mutations
that do not impair the enzyme's catalytic activity but destabilize its native
structure, resulting in the degradation of the misfolded protein. Enhancing the
cellular folding capacity enables rescuing the native, biologically functional
structure of these unstable mutated enzymes. However, proteostasis modulators
specific for the lysosomal system are currently unknown. Here, we investigate
the role of the transcription factor EB (TFEB), a master regulator of lysosomal
biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show
that TFEB activation results in enhanced folding, trafficking and lysosomal
activity of a severely destabilized glucocerebrosidase (GC) variant associated
with the development of Gaucher disease (GD), the most common LSD. TFEB
specifically induces the expression of GC and of key genes involved in folding
and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and
its processing through the secretory pathway. TFEB activation also rescues the
activity of a β-hexosaminidase mutant associated with the development of another
LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated
proteostasis modulation to rescue destabilizing mutations in LSDs. In summary,
our findings identify TFEB as a specific regulator of lysosomal proteostasis and
suggest that TFEB may be used as a therapeutic target to rescue enzyme
homeostasis in LSDs.
DOI: 10.1093/hmg/ddt052
PMID: 23393155 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10801476 | 1. Chem Biol. 2000 May;7(5):R109-19. doi: 10.1016/s1074-5521(00)00116-2.
Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Ala ligases
in bacterial peptidoglycan biosynthesis.
Healy VL(1), Lessard IA, Roper DI, Knox JR, Walsh CT.
Author information:
(1)Department of Biological Chemistry and Molecular Pharmacology, Harvard
Medical School, Boston, MA 02115, USA.
Vancomycin binds to bacterial cell-wall intermediates to achieve its antibiotic
effect. Infections of vancomycin-resistant enterococci are, however, becoming an
increasing problem; the bacteria are resistant because they synthesize different
cell-wall intermediates. The enzymes involved in cell-wall biosynthesis,
therefore, are potential targets for combating this resistance. Recent
biochemical and crystallographic results are providing mechanistic and
structural details about some of these targets.
DOI: 10.1016/s1074-5521(00)00116-2
PMID: 10801476 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21986722 | 1. J Neurooncol. 2012 Mar;107(1):155-64. doi: 10.1007/s11060-011-0722-2. Epub
2011 Oct 11.
Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab
naïve, recurrent glioblastoma.
Reardon DA(1), Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE,
Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS.
Author information:
(1)Department of Surgery, The Preston Robert Tisch Brain Tumor Center at Duke,
Duke University Medical Center, Box 3624, Durham, NC 27710, USA.
[email protected]
We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among
bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2,
open-label, single arm trial. Forty eligible patients received carboplatin (area
under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10
mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing
anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were
administered on days 1 and 14 of every 28-day cycle. Patients were evaluated
after each of the first two cycles and then after every other cycle. Treatment
continued until progressive disease, unacceptable toxicity, non-compliance, or
voluntary withdrawal. The primary endpoint was progression-free survival at 6
months (PFS-6) and secondary endpoints included safety and median overall
survival (OS). All patients had progression after standard therapy. The median
age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%)
were at first progression. The median time from original diagnosis was 11.4
months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3
months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were
primarily hematologic and included neutropenia and thrombocytopenia in 20 and
10%, respectively. The most common grade 3 events were neutropenia,
thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively.
Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients
(43%) required dose modification. One patient died due to treatment-related
intestinal perforation. The addition of carboplatin and irinotecan to
bevacizumab significantly increases toxicity but does not improve anti-tumor
activity to that achieved historically with single-agent bevacizumab among
bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number
NCT00953121).
DOI: 10.1007/s11060-011-0722-2
PMCID: PMC3616617
PMID: 21986722 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22090453 | 1. Neuro Oncol. 2012 Feb;14(2):215-21. doi: 10.1093/neuonc/nor198. Epub 2011 Nov
16.
Phase II trial of vorinostat in combination with bortezomib in recurrent
glioblastoma: a north central cancer treatment group study.
Friday BB(1), Anderson SK, Buckner J, Yu C, Giannini C, Geoffroy F, Schwerkoske
J, Mazurczak M, Gross H, Pajon E, Jaeckle K, Galanis E.
Author information:
(1)Essentia Health-Duluth Clinic Cancer Center, Duluth, Minnesota, USA.
Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of
single-agent activity in glioblastoma (GBM), and in preclinical studies, we have
demonstrated significant synergistic cytotoxicity between HDAC inhibitors and
proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial
to evaluate the efficacy of vorinostat in combination with the proteasome
inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered
at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was
administered at a dose of 1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of
the cycle. A total of 37 patients were treated, and treatment was well
tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and
consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic
toxicity occurred in 37% of patients and consisted of thrombocytopenia (30%),
lymphopenia (4%), and neutropenia (4%). The trial was closed at the
predetermined interim analysis, with 0 of 34 patients being progression-free at
6 months. One patient achieved a partial response according to the Macdonald
criteria. The median time to progression for all patients was 1.5 months (range,
0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who
had received prior bevacizumab therapy had a shorter time to progression and OS,
compared with those who had not. On the basis of the results of this phase II
study, further evaluation of the vorinostat-bortezomib combination in GBM
patients in this dose and schedule is not recommended.
DOI: 10.1093/neuonc/nor198
PMCID: PMC3266383
PMID: 22090453 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22815801 | 1. PLoS One. 2012;7(7):e40734. doi: 10.1371/journal.pone.0040734. Epub 2012 Jul
17.
Treatment with antibiotics that interfere with peptidoglycan biosynthesis
inhibits chloroplast division in the desmid Closterium.
Matsumoto H(1), Takechi K, Sato H, Takio S, Takano H.
Author information:
(1)Faculty of Science, Kumamoto University, Kurokami, Kumamoto, Japan.
Charophytes is a green algal group closely related to land plants. We
investigated the effects of antibiotics that interfere with peptidoglycan
biosynthesis on chloroplast division in the desmid Closterium
peracerosum-strigosum-littorale complex. To detect cells just after division, we
used colchicine, which inhibits Closterium cell elongation after division.
Although normal Closterium cells had two chloroplasts before and after cell
division, cells treated with ampicillin, D-cycloserine, or fosfomycin had only
one chloroplast after cell division, suggesting that the cells divided without
chloroplast division. The antibiotics bacitracin and vancomycin showed no
obvious effect. Electron microscopic observation showed that irregular-shaped
chloroplasts existed in ampicillin-treated Closterium cells. Because antibiotic
treatments resulted in the appearance of long cells with irregular chloroplasts
and cell death, we counted cell types in the culture. The results suggested that
cells with one chloroplast appeared first and then a huge chloroplast was
generated that inhibited cell division, causing elongation followed by cell
death.
DOI: 10.1371/journal.pone.0040734
PMCID: PMC3398972
PMID: 22815801 [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/22832897 | 1. J Neurooncol. 2012 Oct;110(1):111-8. doi: 10.1007/s11060-012-0943-z. Epub 2012
Jul 26.
A prospective phase II single-institution trial of sunitinib for recurrent
malignant glioma.
Pan E(1), Yu D, Yue B, Potthast L, Chowdhary S, Smith P, Chamberlain M.
Author information:
(1)Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, FL 33612-9416, USA. [email protected]
Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine
kinase receptors, was evaluated for treatment of patients with recurrent
glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16 GB
patients, all previously treated with surgery, radiotherapy, and temozolomide,
were enrolled in a prospective phase II study at either first or second relapse.
Patients were treated with daily sunitinib for 4 consecutive weeks, followed by
a 2-week break. For AA patients, the most common side effects were fatigue (86
%), diarrhea (43 %), hand-foot syndrome (36 %), neutropenia (36 %),
thrombocytopenia (36 %), and nausea (29 %). In the GB cohort, the most common
side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and
thrombocytopenia (25 %). Six of 14 (43 %) AA and 5 of 16 (31 %) GB patients
experienced grade 3 or greater toxicities. Five patients discontinued study due
to drug toxicities. There were no partial or complete responses in either
cohort; 8/14 (57 %) AA and 5/16 (31 %) GB patients had stable disease at the
first planned assessment. Progression-free survival at 6 months was 21.5 % (AA)
and 16.7 % (GB). Median overall survival was 12.1 months (AA) and 12.6 months
(GB). These results are comparable to those reported in the literature in
patients treated with standard cytotoxic therapies. This is the largest reported
trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as
contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate
significant anti-glioma activity in patients with recurrent malignant astrocytic
gliomas.
DOI: 10.1007/s11060-012-0943-z
PMCID: PMC5735835
PMID: 22832897 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/3008359 | 1. Strahlenther Onkol. 1986 Mar;162(3):145-51.
[Comparison of the computed tomographic changes and the clinical course
following the irradiation of intracranial tumors and metastases].
[Article in German]
Fiegler W, Langer M, Hedde JP, Scheer M, Felix R, Kazner E.
The authors compared the clinical courses and the CT courses recorded at the
same time in patients with primary or secondary cerebral tumors. 69 patients
improved their neurologic state under external radiotherapy, 35 patients
remained unchanged, and 8 patients had a deteriorated condition. The changes in
computed tomography and the modifications of the clinical state of patients
corresponded only in 55% of all cases. The reasons are discussed. Some patients
suffered from fatigue and weak concentration about three months after the end of
radiotherapy, in some cases even the neurologic state was deteriorated. These
manifestations known as "early delayed reaction" were reversible.
PMID: 3008359 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2168357 | 1. Int J Radiat Oncol Biol Phys. 1990 Aug;19(2):421-8. doi:
10.1016/0360-3016(90)90552-u.
Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas.
Hegarty TJ(1), Thornton AF, Diaz RF, Chandler WF, Ensminger WD, Junck L, Page
MA, Gebarski SS, Hood TW, Stetson PL, et al.
Author information:
(1)Department of Radiation Oncology, University of Michigan Medical Center, Ann
Arbor 48109.
In the 1950's it was first observed that mammalian cells exposed to the
halogenated deoxyuridines were more sensitive to ultraviolet light and radiation
than untreated cells. This prompted early clinical trials with bromodeoxyuridine
(BUdR) which showed mixed results. More recently, several Phase I studies, while
establishing the feasibility of continuous intravenous (IV) infusion of BUdR,
have reported significant dose limiting skin and bone marrow toxicities and have
questioned the optimal method of BUdR delivery. To exploit the high mitotic
activity of malignant gliomas relative to surrounding normal brain tissue, we
have developed a permanently implantable infusion pump system for safe,
continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985,
23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been
treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2
weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2
weeks). Following initial biopsy/surgery the infusion pump system was implanted;
BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week
course of radiotherapy. There have been no vascular complications. Side-effects
in all patients have included varying degrees of anorexia, fatigue, ipsilateral
forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring
dose reduction occurred in one patient. An overall Kaplan-Meier estimated median
survival of 20 months has been achieved. As in larger controlled series,
histologic grade and age are prognostically significant. We have shown in a
Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to
improved survival, and appears to be an efficacious primary treatment of
malignant gliomas.
DOI: 10.1016/0360-3016(90)90552-u
PMID: 2168357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19904263 | 1. Br J Cancer. 2009 Dec 15;101(12):1995-2004. doi: 10.1038/sj.bjc.6605411. Epub
2009 Nov 10.
Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients
with progressive glioblastoma.
Reardon DA(1), Dresemann G, Taillibert S, Campone M, van den Bent M, Clement P,
Blomquist E, Gordower L, Schultz H, Raizer J, Hau P, Easaw J, Gil M, Tonn J,
Gijtenbeek A, Schlegel U, Bergstrom P, Green S, Weir A, Nikolova Z.
Author information:
(1)The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center,
Box 3624, Durham, NC 27710, USA. [email protected]
BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to
hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or
not on enzyme-inducing anti-epileptic drugs (EIAEDs).
METHODS: A total of 231 patients with GBM at first recurrence from 21
institutions in 10 countries were enrolled. All patients received 500 mg of
hydroxyurea twice a day. Imatinib was administered at 600 mg per day for
patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end
point was radiographic response rate and secondary end points were safety,
progression-free survival at 6 months (PFS-6), and overall survival (OS).
RESULTS: The radiographic response rate after centralised review was 3.4%.
Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks,
respectively. Outcome did not appear to differ based on EIAED status. The most
common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%),
and thrombocytopaenia (7%).
CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among
patients with recurrent GBM but did not show clinically meaningful anti-tumour
activity.
DOI: 10.1038/sj.bjc.6605411
PMCID: PMC2795431
PMID: 19904263 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19701833 | 1. Endocr Res. 2009;34(3):80-9. doi: 10.1080/07435800903156340.
Efficacy of combined levothyroxine and liothyronine as compared with
levothyroxine monotherapy in primary hypothyroidism: a randomized controlled
trial.
Valizadeh M(1), Seyyed-Majidi MR, Hajibeigloo H, Momtazi S, Musavinasab N,
Hayatbakhsh MR.
Author information:
(1)Department of Internal Medicine, Zanjan Faculty of Medicine, Zanjan
University of Medical Science, Zanjan, Islamic Republic of Iran.
OBJECTIVES: To examine the efficacy of combination therapy with levothyroxine
and liothyronine in improvement of general health, psychological problems, and
metabolic status in primary hypothyroidism.
METHODS: Seventy-one patients diagnosed with primary hypothyroidism were
randomly allocated into two study groups: the first group received usual dose of
levothyroxine and the second group received combination of levothyroxine and
liothyronine for at least 4 months. The main outcomes were psychosocial problems
(Goldberg's General Health Questionnaire, GHQ-28), bodyweight, heart rate, blood
pressure, and serum lipid levels.
RESULTS: In both groups serum thyroid-stimulating hormone levels remained
unchanged compared with baseline. Psychosocial scores, body weight, heart rate,
blood pressure, and lipid profile in the two groups remained constant. The only
exception was a small but significant reduction in anxiety/insomnia in combined
treatment group as compared with monotherapy.
CONCLUSIONS: The data do not support the hypothesis that combined therapy
improves the well-being and general health of patients.
DOI: 10.1080/07435800903156340
PMID: 19701833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11751110 | 1. Antimicrob Agents Chemother. 2002 Jan;46(1):47-54. doi:
10.1128/AAC.46.2.47-54.2002.
Mycobacterium smegmatis D-Alanine Racemase Mutants Are Not Dependent on
D-Alanine for Growth.
Chacon O(1), Feng Z, Harris NB, Cáceres NE, Adams LG, Barletta RG.
Author information:
(1)Department of Veterinary and Biomedical Sciences, University of Nebraska,
Lincoln, Nebraska 68583-0905, USA.
Mycobacterium smegmatis is a fast-growing nonpathogenic species particularly
useful in studying basic cellular processes of relevance to pathogenic
mycobacteria. This study focused on the D-alanine racemase gene (alrA), which is
involved in the synthesis of D-alanine, a basic component of peptidoglycan that
forms the backbone of the cell wall. M. smegmatis alrA null mutants were
generated by homologous recombination using a kanamycin resistance marker for
insertional inactivation. Mutants were selected on Middlebrook medium
supplemented with 50 mM D-alanine and 20 microg of kanamycin per ml. These
mutants were also able to grow in standard and minimal media without D-alanine,
giving rise to colonies with a drier appearance and more-raised borders than the
wild-type strain. The viability of the mutants and independence of D-alanine for
growth indicate that inactivation of alrA does not impose an auxotrophic
requirement for D-alanine, suggesting the existence of a new pathway of
D-alanine biosynthesis in M. smegmatis. Biochemical analysis demonstrated the
absence of any detectable D-alanine racemase activity in the mutant strains. In
addition, the alrA mutants displayed hypersusceptibility to the
antimycobacterial agent D-cycloserine. The MIC of D-cycloserine for the mutant
strain was 2.56 microg/ml, 30-fold less than that for the wild-type strain.
Furthermore, this hypersusceptibility was confirmed by the bactericidal action
of D-cycloserine on broth cultures. The kinetic of killing for the mutant strain
followed the same pattern as that for the wild-type strain, but at a
30-fold-lower drug concentration. This effect does not involve a change in the
permeability of the cell wall by this drug and is consistent with the
identification of D-alanine racemase as a target of D-cycloserine. This outcome
is of importance for the design of novel antituberculosis drugs targeting
peptidoglycan biosynthesis in mycobacteria.
DOI: 10.1128/AAC.46.2.47-54.2002
PMCID: PMC126997
PMID: 11751110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16832063 | 1. Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11033-8. doi:
10.1073/pnas.0600829103. Epub 2006 Jul 10.
Imaging peptidoglycan biosynthesis in Bacillus subtilis with fluorescent
antibiotics.
Tiyanont K(1), Doan T, Lazarus MB, Fang X, Rudner DZ, Walker S.
Author information:
(1)Department of Microbiology and Molecular Genetics, Harvard Medical School,
Boston, MA 02115, USA.
The peptidoglycan (PG) layers surrounding bacterial cells play an important role
in determining cell shape. The machinery controlling when and where new PG is
made is not understood, but is proposed to involve interactions between
bacterial actin homologs such as Mbl, which forms helical cables within cells,
and extracellular multiprotein complexes that include penicillin-binding
proteins. It has been suggested that labeled antibiotics that bind to PG
precursors may be useful for imaging PG to help determine the genes that control
the biosynthesis of this polymer. Here, we compare the staining patterns
observed in Bacillus subtilis using fluorescent derivatives of two PG-binding
antibiotics, vancomycin and ramoplanin. The staining patterns for both probes
exhibit a strong dependence on probe concentration, suggesting
antibiotic-induced perturbations in PG synthesis. Ramoplanin probes may be
better imaging agents than vancomycin probes because they yield clear staining
patterns at concentrations well below their minimum inhibitory concentrations.
Under some conditions, both ramoplanin and vancomycin probes produce helicoid
staining patterns along the cylindrical walls of B. subtilis cells. This
sidewall staining is observed in the absence of the cytoskeletal protein Mbl.
Although Mbl plays an important role in cell shape determination, our data
indicate that other proteins control the spatial localization of the
biosynthetic complexes responsible for new PG synthesis along the walls of B.
subtilis cells.
DOI: 10.1073/pnas.0600829103
PMCID: PMC1544169
PMID: 16832063 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: No conflicts
declared. |
http://www.ncbi.nlm.nih.gov/pubmed/23036591 | 1. Arthritis Res Ther. 2012 Oct 4;14(5):R208. doi: 10.1186/ar4046.
Dendritic cells provide a potential link between smoking and inflammation in
rheumatoid arthritis.
Kazantseva MG, Highton J, Stamp LK, Hessian PA.
INTRODUCTION: Smoking increases the risk of developing rheumatoid arthritis (RA)
and affects the severity of established RA. Smoking can impact on Th17
lymphocyte differentiation and function through activation of the aryl
hydrocarbon receptor (AHR), a process with implications for the pathogenic
mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective
of this study was to establish any effect of smoking on the inflammatory tissue
lesions of rheumatoid arthritis via the AHR and IL-17A.
METHODS: Twenty synovial and eighteen subcutaneous nodule tissue samples from 31
patients with RA were studied. Patient smoking status at the time of tissue
collection was established. Expression of AHR, CYP1A1, AHRR, IL6, IL17A, IL17F,
IL22, IL23, IL23R, IFNG, TBX21, IDO1 and FOXP3 genes were assessed in tissues
and cultured cells using real-time PCR. Two-colour immunofluorescence was used
to co-localise AHR and CYP1A1 protein in synovial tissues. The response of
monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist,
benzo(a)pyrene (BaP) was compared in vitro.
RESULTS: AHR gene expression was demonstrated in rheumatoid synovial tissues and
nodules with significantly greater expression in synovia. Expression was not
influenced by smoking in either tissue. Evidence of AHR activation, indicated by
CYP1A1 and AHRR gene expression, was found only in synovia from patients who
smoked. However, IL17A gene expression was lower in synovia from smokers. TBX21
and FOXP3 expression was not affected by smoking. Within the synovial tissues of
smokers the principal cell type with evidence of AHR activation was a subset of
synovial DCs. This observation was consistent with the sensitivity of human
mo-DCs to BaP stimulation demonstrated in vitro. Exposure to BaP affected mo-DC
function as demonstrated by decreased IL6 expression induced by PolyI:C, without
affecting indoleamine 2,3 dioxygenase (IDO)1 expression.
CONCLUSION: Our findings show that one effect of smoking on inflamed rheumatoid
synovial tissue involves activation of the AHR pathway. A subset of synovial DCs
is important in the response to cigarette smoke. The potential for smoking to
affect DC behaviour in joint tissues has relevance to both early and late phases
of RA pathogenesis and warrants further investigation.
DOI: 10.1186/ar4046
PMCID: PMC3580520
PMID: 23036591 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18758912 | 1. J Neurooncol. 2009 Jan;91(1):95-100. doi: 10.1007/s11060-008-9689-z. Epub 2008
Aug 29.
Hypofractionated radiotherapy followed by adjuvant chemotherapy with
temozolomide in elderly patients with glioblastoma.
Minniti G(1), De Sanctis V, Muni R, Rasio D, Lanzetta G, Bozzao A, Osti MF,
Salvati M, Valeriani M, Cantore GP, Maurizi Enrici R.
Author information:
(1)Department of Radiotherapy Oncology, Sant' Andrea Hospital, University "La
Sapienza", Via di Grottarossa 1035, 00189, Rome, Italy.
[email protected]
OBJECTIVES: The optimal treatment for elderly patients (age >70 years) with
glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43
consecutive elderly patients with GBM treated with hypofractionated radiotherapy
(RT) followed by adjuvant temozolomide.
PATIENTS AND METHODS: Forty-three patients 70 years of age or older with a newly
diagnosed GBM and a Karnofsky performance status (KPS) > or = 60 were treated
with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2
weeks) followed by up to 12 cycles of adjuvant temozolomide (150-200 mg/m(2) for
5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality
of Life Questionnaire C30. The primary endpoint was overall survival (OS).
Secondary endpoints included progression free survival (PFS), toxicity and
quality of life.
RESULTS: The median OS was 9.3 months and the median PFS was 6.3 months. The 6
and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month
PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the
only significant independent predictive factor of survival (P = 0.008).
Neurological deterioration occurred during or after RT in 16% of patients and
was resolved in most cases with the use of steroids. Grade 3-4 hematologic
toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment
with temozolomide. The treatment had no negative effect on HRQOL, however,
fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time.
CONCLUSIONS: Hypofractionated RT followed by temozolomide may provide survival
benefit maintaining a good quality of life in elderly patients with GBM. It may
represent a reasonable therapeutic approach especially in patients with less
favourably prognostic factors.
DOI: 10.1007/s11060-008-9689-z
PMID: 18758912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6538137 | 1. Eur J Pediatr. 1984 Jan;141(3):147-52. doi: 10.1007/BF00443212.
The Tay syndrome (congenital ichthyosis with trichothiodystrophy).
Happle R, Traupe H, Gröbe H, Bonsmann G.
We report a 5-year-old boy affected with the Tay syndrome, and give a review of
12 pertinent cases previously reported under various designations. The Tay
syndrome is a distinct type of congenital ichthyosis characterized by a peculiar
anomaly of hair growth which has been termed trichothiodystrophy. The hair
shafts are extremely brittle, and they show alternating light and dark banding
when examined microscopically between polarizing filters. Other features of this
syndrome are low birth weight, short stature, mental retardation, delayed
neuromuscular development and other CNS anomalies, dysplasia of nails,
hypoplasia of subcutaneous fatty tissue, prematurely aged facial appearance,
hypogonadism, cataracts, osteosclerosis, dysphonia, and increased susceptibility
to infections. The syndrome is inherited as an autosomal recessive trait. We
delineate the criteria for distinguishing this gene defect from other types of
congenital ichthyosis associated with disturbed hair growth, as well as from
other types of trichothiodystrophy which are not associated with ichthyosis.
DOI: 10.1007/BF00443212
PMID: 6538137 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20519953 | 1. Cell Cycle. 2010 Jun 15;9(12):2286-91. doi: 10.4161/cc.9.12.11907. Epub 2010
Jun 15.
Migratory potential of rheumatoid arthritis synovial fibroblasts: additional
perspectives.
Neumann E(1), Lefèvre S, Zimmermann B, Geyer M, Lehr A, Umscheid T, Schönburg M,
Rehart S, Müller-Ladner U.
Author information:
(1)Department of Internal Medicine and Rheumatology, Justus-Liebig-University
Giessen, Kerckhoff-Klinik; Bad Nauheim, Germany. [email protected]
Cell migration is a central part of physiological and pathophysiological
processes including wound healing, immune defense, matrix remodeling and organ
homeostasis. Different cell types have migratory potential including cells of
the immune system and cells required in wound healing and tissue repair. These
cells migrate locally through the tissue to the site of damage. The fibroblast
is a central cell type of wound healing. In rheumatoid arthritis (RA), activated
synovial fibroblasts (SFs) have the ability to invade joint cartilage, actively
contributing to joint destruction in RA. Recently, RASFs have been shown to be
able to migrate to non-affected areas and joints through the blood stream and to
invade distant cartilage. RASFs most likely use similar mechanisms comparable to
lymphocytes and tumor cells for long-distance and vascular trans-migration.
Future experiments will address the goal to keep the transformed-appearing
fibroblasts in the affected joints using therapeutical strategies that inhibit
the pathophysiological changes of transformed-appearing RASFs but do not
interfere with the physiological processes of 'normal' fibroblasts.
DOI: 10.4161/cc.9.12.11907
PMID: 20519953 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23184145 | 1. J Neurooncol. 2013 Jan;111(2):205-12. doi: 10.1007/s11060-012-1009-y. Epub
2012 Nov 27.
Phase II open-label study of nintedanib in patients with recurrent glioblastoma
multiforme.
Muhic A(1), Poulsen HS, Sorensen M, Grunnet K, Lassen U.
Author information:
(1)Department of Oncology 5073, Section for Neuro-oncology and Phase I Unit,
Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase
inhibitor in phase III development (various indications) that targets VEGFR 1-3,
FGFR 1-3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed
the efficacy and safety of nintedanib in patients with recurrent glioblastoma
multiforme (GBM) who had previously failed radiotherapy plus temozolomide as
first-line therapy (STUPP), or the same regimen with subsequent
bevacizumab-based therapy as second-line treatment (BEV). Patients with a
performance status of 0-1, histologically proven GBM, and measurable disease (by
RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily
(bid), with magnetic resonance imaging undertaken every 8 weeks. The primary
endpoint was objective response rate. The study was stopped prematurely
following a preplanned futility analysis after inclusion of 13 patients in the
STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three
patients (12 %); all other patients progressed within the first four 28-day
cycles. One patient in the BEV arm has had SD for 17+ months. Median
progression-free survival was 1 month and median overall survival was 6 months.
Nintedanib had an acceptable safety profile, with no CTCAE grade 3-4 adverse
events. Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite,
diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited,
but clinically non-relevant antitumor activity in patients with recurrent GBM
who had failed 1-2 prior lines of therapy.
DOI: 10.1007/s11060-012-1009-y
PMID: 23184145 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20687499 | 1. Adv Exp Med Biol. 2010;685:106-10. doi: 10.1007/978-1-4419-6448-9_10.
Trichothiodystrophy: Photosensitive, TTD-P, TTD, Tay syndrome.
Lambert WC(1), Gagna CE, Lambert MW.
Author information:
(1)Department of Pathology and Laboratory Medicine, Room C520, Medical Science
Building, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, New
Jersey 07103, USA. [email protected]
Although the term, "trichothiodystrophy" (TTD) refers to the hair anomalies in
this group of patients, this is a heterogeneous, multisystem disease in which
any or every organ in the body may be affected. Neuroectodermal derived tissues
are particularly likely to be involved. This term was introduced by Price et
alin 1980 to designate patients with sulfur-deficient brittle hair, which they
recognized as a marker for this complex disease and designated it as a
"neuroectodermal symptom complex". Patients with TTD have brittle hair and nails
(associated with reduced content ofcysteine-rich matrix proteins), ichthyotic
skin and physical and mental growth retardation. Ichthyosis is usually apparent
at birth but much less so after the first few weeks of life. Other frequently
associated features include ocular cataracts, infections and maternal
complications related to pregnancy. Atrophy of subcutaneous fat may also be
present. TTD occurs in a pattern of inheritance consistent with an autosomal
recessive condition. The disease is extremely heterogeneous in severity and
extent, with some patients showing no neurological deficiency. Others show
severe, multisystem disease. Many patients die at a young age, most commonly due
to infectious disease. TTD is part of a more broadly defined group of diseases
identified as IBIDS (ichthyosis, brittle hair, impaired intelligence, decreased
fertility and short stature). Photosensitive cases are also identified as PIBIDS
(photosensitivity with IBIDS). Cases without manifest ichthyosis are also
identified as PBIDS. These syndromes defy rigorous definition because of
clinical variation between patients. The original two cases were described by
Tay in oriental siblings, whose parents were first cousins; thus the disease is
also known as Tay syndrome. The hairs in patients with TTD have a distinctive,
diagnostically useful appearance on polarized light microscopy consisting of
alternating light and dark bands known as the "tiger tail" anomaly. Diagnosis
may be confirmed by sulfur content analysis ofhair shafts, which shows decreased
sulfur and cysteine content. Approximately half of patients with TTD have
photosensitivity, which correlates with a nudeotide excision repair (NER)
defect. These patients are designated as having
trichothiodystrophy-photosensitive (TTDP). Non-photosensitivepatients are
designated as having trichothiodystrophy-nonphotosensitive (TTDN). Skin cancer
is very rare in sun-sensitive TTD.
DOI: 10.1007/978-1-4419-6448-9_10
PMID: 20687499 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20665891 | 1. Cancer. 2010 Nov 15;116(22):5297-305. doi: 10.1002/cncr.25462.
A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule
for patients with recurrent high-grade gliomas.
Raizer JJ(1), Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, Dubner
S, Rademaker AW, Renfrow J, Bredel M.
Author information:
(1)Department of Neurology, Northwestern University, Chicago, IL, USA.
[email protected]
BACKGROUND: The authors evaluated a 3-week schedule of bevacizumab in patients
with recurrent high-grade glioma (HGG).
METHODS: Patients received bevacizumab 15 mg/kg every 3 weeks and were evaluated
every 6 weeks until tumor progression. Tissue correlates were used to quantify
tumor content of vascular endothelial growth factor A (VEGFA) and vascular
endothelial growth factor receptor-2 (VEGFR2).
RESULTS: Of 61 patients who were treated (35 men and 26 women; median age, 52
years; age range, 21-78 years), 50 patients had glioblastoma multiforme (GBM),
and 11 patients had anaplastic glioma (AG). The median number of previous
chemotherapies was 2 (range, 1-5 previous chemotherapies), and 16 patients had
received ≥3 previous chemotherapies. The median number of bevacizumab doses was
4 (range, 1-20 doses), and 45% of patients received >5 doses. The toxicities
observed were primarily grade 1 and 2, and the most common were fatigue,
hypertension, and headache. One grade 2 intratumoral bleed and 1 bowel
perforation were reported. For patients with GBM, the 6-month progression-free
survival rate was 25%, the median time to tumor progression was 10.8 weeks, and
the median overall survival was 25.6 weeks. The best response included a partial
response in 15 patients (24.5%) and stable disease in 31 patients (50.8%)
patients; radiographic recurrence patterns included increased changes in fluid
attenuation inversion recovery (24%) and multifocal recurrence (20%). The median
survival after bevacizumab failure was 10 weeks. The ratio of tumor VEGFA/VEGFR2
was increased in patients aged >55 years; an increased VEGFA/VEGFR2 ratio was
correlated nonsignificantly with decreased survival (P = .052).
CONCLUSIONS: An every-3-week schedule of bevacizumab had antitumor activity and
was relatively nontoxic for patients with recurrent HGG. The predictive value of
VEGFA/VEGFR2 in tumor will require validation in a larger patient cohort.
Copyright © 2010 American Cancer Society.
DOI: 10.1002/cncr.25462
PMID: 20665891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19593660 | 1. J Neurooncol. 2010 Jan;96(2):259-69. doi: 10.1007/s11060-009-9957-6. Epub 2009
Jul 11.
Salvage therapy with single agent bevacizumab for recurrent glioblastoma.
Chamberlain MC(1), Johnston SK.
Author information:
(1)Department of Neurology and Neurosurgery, University of Washington, Fred
Hutchinson Cancer Research Center, Seattle, WA 98109-1023, USA.
[email protected]
A retrospective evaluation of single agent bevacizumab in adults with recurrent
glioblastoma (GBM) with an objective of determining progression free survival
(PFS). There is no standard therapy for recurrent GBM after failure of
alkylator-based chemotherapy. A total of 50 adults, ages 36-70 years (median
64), with recurrent GBM were treated. All patients had previously been treated
with surgery, concurrent radiotherapy and temozolomide, post-radiotherapy
temozolomide and in 34 patients, one salvage regimen (PCV: 21, cyclophosphamide:
13). A total of 13 patients underwent repeat surgery. Patients were treated at
first or second recurrence with bevacizumab, once every 2 weeks, defined as a
single cycle. Neurological evaluation was performed every 2 weeks and
neuroradiographic assessment following the initial 2 cycles of bevacizumab and
subsequently after every 4 cycles of bevacizumab. A total of 468 cycles of
bevacizumab (median 2 cycles; range 1-30) was administered. Bevacizumab-related
toxicity included fatigue (16 patients; 4 grade 3), leukopenia (9; 1 grade 3),
anemia (5; 0 grade 3), hypertension (7; 1 grade 3), deep vein thrombosis (4; 1
grade 3) and wound dehiscence (2; 1 grade 3). 21 patients (42%) demonstrated a
partial radiographic response and 29 (58%) progressive disease following 1-2
cycles of bevacizumab. Time to tumor progression ranged from 0.5 to 15 months
(median: 1.0 months). Survival ranged from 2 to 17 months (median: 8.5 months).
6-month and 12-month PFS were 42% and 22% respectively. Single agent bevacizumab
demonstrated efficacy and acceptable toxicity in this cohort of adults with
recurrent alkylator-refractory GBM.
DOI: 10.1007/s11060-009-9957-6
PMID: 19593660 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20510539 | 1. Int J Radiat Oncol Biol Phys. 2011 Jun 1;80(2):347-53. doi:
10.1016/j.ijrobp.2010.01.070. Epub 2010 May 25.
Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4
astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074.
Uhm JH(1), Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, James CD,
Scheithauer BW, Behrens RJ, Flynn PJ, Schaefer PL, Dakhill SR, Jaeckle KA.
Author information:
(1)Division of Neuro-Oncology, Department of Neurology, Mayo Clinic Rochester,
Rochester, MN 55905, USA. [email protected]
PURPOSE: Amplification of the epidermal growth factor receptor (EGFR) gene
represents one of the most frequent gene alterations in glioblastoma (GBM). In
the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the
treatment of adults with newly diagnosed GBM.
METHODS AND MATERIALS: Ninety-eight patients (96 evaluable) were accrued between
May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were
clinically and radiographically stable/improved after radiation treatment
(enrollment within 5 weeks of radiation completion). No prior chemotherapy was
permitted. EGFR amplification/mutation, as assessed by fluorescence in situ
hybridization and immunohistochemistry, was not required for treatment with
gefitinib but was studied when tissues were available. Gefitinib was
administered at 500 mg each day; for patients receiving dexamethasone or
enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD.
Treatment cycles were repeated at 4-week intervals with brain magnetic resonance
imaging at 8-week intervals.
RESULTS: Overall survival (OS; calculated from time of initial surgery) at 1
year (primary end point) with gefitinib was 54.2%, which was not statistically
different compared with that of historical control population (48.9%, data from
three previous Phase III North Central Cancer Treatment Group studies of newly
diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT
(16.7%) was also not significantly different to that of historical controls
(30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII
mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the
most frequent adverse events, the majority of these being limited to Grade 1/2.
Of note, the occurrence of drug-related adverse effects, such as loose stools
was associated with improved OS.
CONCLUSIONS: In our evaluation of nearly 100 patients with newly diagnosed GBM,
treatment with adjuvant gefitinib post-radiation was not associated with
significant improvement in OS or PFS. However, patients who experienced
gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved
OS.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ijrobp.2010.01.070
PMCID: PMC5753591
PMID: 20510539 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Statement: None of the
authors have any conflicts of interests to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/18376101 | 1. Indian J Pediatr. 2008 Mar;75(3):288-90. doi: 10.1007/s12098-008-0062-1.
Tay syndrome.
Jambhekar SD(1), Dhongade AR.
Author information:
(1)Grant Medical College and Sir JJ Group of Hospitals ST Georges Hospital,
Mumbai, Maharashtra, India. [email protected]
Tay syndrome or IBIDS is a rare autosomal recessive genetic disorder
characterized by congenital ichthyosis and abnormal brittle hair
(trichothiodystrophy). Other features include photosensitivity, abnormal nails
and multiple developmental defects affecting organs mainly derived from
neuroectoderm. The exact prevalence of this condition is not known, but up to
1991, clinical data of 15 cases with IBIDS were published .We report a case of
Tay syndrome with additional features of Duane's retraction syndrome and Perthes
disease, which have not yet been reported in literature.
DOI: 10.1007/s12098-008-0062-1
PMID: 18376101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10679843 | 1. Int J Geriatr Psychiatry. 2000 Feb;15(2):120-4. doi:
10.1002/(sici)1099-1166(200002)15:2<120::aid-gps84>3.0.co;2-7.
Do personality traits predict the occurrence of Alzheimer's disease?
Meins W(1), Dammast J.
Author information:
(1)Memory Clinic, Department of Geriatric Medicine, Albertinen Hospital,
Hamburg, Germany. [email protected]
OBJECTIVE: To identify specific premorbid personality traits in patients with
Alzheimer's disease (AD).
DESIGN: A prospective case-control study.
SETTING: A memory clinic of a department of geriatric medicine in a teaching
hospital.
PATIENTS: Fifty-six consecutive patients with probable AD. Sixty-five controls
with Parkinson's disease (PD).
MEASURES: Premorbid personality traits were assessed using the relative rating
version of the Munich Personality Test (MPT).
RESULTS: The AD patients showed higher neuroticism than the controls with PD
(p=0.013). In comparison with MPT normative values for psychiatric inpatients,
the AD patients scored significantly (p<0.05) lower on neuroticism and higher on
frustration tolerance and rigidity.
CONCLUSION: Our results support the assumption of specific premorbid
characteristics in AD patients, ie increased neuroticism and rigidity. More
research is needed to confirm the existence of typical premorbid personality
traits in AD.
Copyright 2000 John Wiley & Sons, Ltd.
DOI: 10.1002/(sici)1099-1166(200002)15:2<120::aid-gps84>3.0.co;2-7
PMID: 10679843 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9050052 | 1. Neuropediatrics. 1996 Dec;27(6):326-30. doi: 10.1055/s-2007-973803.
The central nervous system in Tay syndrome.
Ostergaard JR(1), Christensen T.
Author information:
(1)Department of Pediatrics A, University Hospital of Aarhus, Denmark.
Trichothiodystrophy (brittle sulfur-deficient hair) is a marker for several
autosomal recessive neurocutaneous syndromes with neurological manifestations
and mental retardation. In Tay syndrome, the trichothiodystrophy is accompanied
by congenital ichthyosis, short stature, delayed physical and mental development
and pyramidal tract signs with increase in muscular tone and brisk tendon
reflexes. The pathogenesis of these neurological manifestations is not fully
elucidated. We present a case of Tay syndrome in which a cranial MRI revealed an
almost total lack of myelin within the cerebral hemispheres and a patchy
hypomyelination of the cerebellum. In accordance, a strongly prolonged visual
evoked response pointed to a dysfunction of the white matter in Tay syndrome.
DOI: 10.1055/s-2007-973803
PMID: 9050052 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12767492 | 1. J Neurol Sci. 2003 Jul 15;211(1-2):15-22. doi: 10.1016/s0022-510x(03)00032-7.
Brain aging in normal Egyptians: cognition, education, personality, genetic and
immunological study.
Elwan O(1), Madkour O, Elwan F, Mostafa M, Abbas Helmy A, Abdel-Naseer M, Abdel
Shafy S, El Faiuomy N.
Author information:
(1)Department of Neurology, Cairo University, Cairo, Egypt.
[email protected]
Studying the cognitive and immunological changes that occur in old age as well
as genetic function have been considered an important subject to differentiate
between normal brain aging and early dementia especially Alzheimer's disease.
The aim of this study is to stress on age-related neuropsychological and
electrophysiological (P(300)) changes in normal Egyptian subjects, to throw
light on the value of genetic (Apo-E(4) genotype) and immunological markers
[interleukin-6 (IL-6) and intercellular adhesion molecules (ICAM-1) in the
serum] as tools used in early detection of cognitive decline in cerebral aging.
Ninety-four normal Egyptian subjects (below and above 60 years) were submitted
to the following: (1) neuropsychological tests for testing memory, perception,
psychomotor performance and attention, (2) Eysenck Personality Questionnaire
(EPQ) for personality traits, (3) event-related potential study (P(300), latency
and amplitude), (4) genetic test for detection of Apolipoprotein E genotype and
(5) immunological studies including detection of the level of IL-6 and ICAM-1 in
serum. There was a significant impairment of memory, psychomotor performance and
perception in elderly subjects particularly males and subjects with low level of
education. Regarding personality, significantly high scores were obtained in
neuroticism scale of EPQ in elderly subjects. Apo-E(3)/E(3) was the most common
genotype encountered in Egyptian subjects (49.1%). It was found that subjects
with Apo-E(4) genotype did significantly worse in scores of intentional memory
test (sensory memory) when compared with other genotypes. Statistically
significant impairment in attention and sensory memory was found in subjects
with high IL-6 level. This could not be detected in subjects with high ICAM-1
level. In conclusion, advancing age and lower levels of education are considered
risk factors for cognitive decline in normal brain aging. Neuropsychological
tests remain as the highly sensitive tools for detection of early cognitive
impairment. Neurotic traits are more encountered in old age. Apo-E(4) genotype
is associated with significant sensory (intentional) memory impairment. High
IL-6 level in the serum is accompanied by significant impairment in attention
and sensory (intentional) memory.
DOI: 10.1016/s0022-510x(03)00032-7
PMID: 12767492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10718200 | 1. Alzheimer Dis Assoc Disord. 2000 Jan-Mar;14(1):11-9. doi:
10.1097/00002093-200001000-00002.
Premorbid personality predicts level of rated personality change in patients
with Alzheimer disease.
Dawson DV(1), Welsh-Bohmer KA, Siegler IC.
Author information:
(1)Department of Epidemiology and Biostatistics, Case Western Reserve University
and MetroHealth Medical Center, Cleveland, Ohio 44109-1998, USA.
Multiple studies of individuals with Alzheimer disease have substantiated
significant levels of informant-rated change in several domains and facets of
the Neuroticism-Extraversion-Openness Personality Inventory, including increases
in Neuroticism and decreases in Extraversion and Conscientiousness relative to
premorbid personality traits. Decline in Openness was cited in some reports, and
replicable changes were identified in several facets. Current and premorbid
personality of 50 patients with Alzheimer disease were rated by informants using
the Neuroticism-Extraversion-Openness Personality Inventory. Multiple regression
analysis was used to assess possible relationships of levels of reported change
with covariates, including premorbid rating, education, duration of dementia,
age, gender, and Mini-Mental State Examination score. Premorbid rating was the
only significant predictor of reported change for Neuroticism, Extraversion,
Conscientiousness, and the facets Anxiety (N1), Assertiveness (E3), and Activity
(E4). Rated change in Depression was also found to be related to duration of
dementia, change in Vulnerability was influenced by gender, and reported change
in both Openness and Ideas showed a relationship to level of education.
DOI: 10.1097/00002093-200001000-00002
PMID: 10718200 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2087835 | 1. Z Hautkr. 1990 Dec;65(12):1085-91.
[What is new in genetically-induced hair diseases?].
[Article in German]
Traupe H(1), Hamm H.
Author information:
(1)Department of Human Genetics, University Hospital, Nijmegen, The Netherlands.
A profound knowledge of specific genetically determined anomalies of the hair
may be of considerable value in the diagnosis of genetic syndromes. We give a
review of a few recent developments in the field of genetic hair diseases. For
example, the brittle hair due to sulphur deficiency (trichothiodystrophy) is
nowadays regarded as genetically heterogeneous; three different syndromes can be
distinguished: BIDS syndrome, Tay syndrome, and PIBIDS syndrome. Polarization
microscopy revealed a striking resemblance of the hair anomalies found in
trichothiodystrophy syndromes and those in acrodermatitis enteropathica. This
surprising result indicates similar pathophysiological mechanisms. The
Comèl-Netherton syndrome--long regarded as representing two different
diseases--has recently been recognized as a clinically variable, but genetically
homogeneous syndrome, which is most likely based on a single mutation
("lumping"). Minor's sweat test allows the recognition of women heterozygous for
X-linked hypohidrotic ectodermal dysplasia and may help to appreciate seemingly
non-specific hair findings, such as diffuse alopecia.
PMID: 2087835 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7493597 | 1. Exp Aging Res. 1995 Jul-Sep;21(3):295-314. doi: 10.1080/03610739508253986.
Personality change in dementia of the Alzheimer's type: relations to caregiver
personality and burden.
Welleford EA(1), Harkins SW, Taylor JR.
Author information:
(1)Department of Gerontology, MCV Station, Richmond 23298-0266, USA.
Using the NEO Personality Inventory (NEO-PI), we evaluated caregivers'
perceptions of personality prior to symptom onset and current personality in 36
individuals with a clinical diagnosis of dementia of the Alzheimer's type (DAT).
Caregivers also completed the self form of the NEO-PI and an index of objective
and subjective burden. Personality change in DAT was consistent with previous
reports of increased neuroticism, decreased extraversion, and decreased
conscientiousness, with smaller decreases in openness and agreeableness.
Significant relationships were found among perceived present patient
personality, caregiver personality, and caregiver burden. Regression analyses
indicated that present patient conscientiousness and caregiver neuroticism were
the best predictors of both objective and subjective burden, and these variables
were found to contribute independently to caregivers' reported level of burden.
To the extent that caregivers perceive specific behaviors and interferences
negatively, cognitive and supportive interventions are likely to prove extremely
beneficial.
DOI: 10.1080/03610739508253986
PMID: 7493597 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15358438 | 1. Psychoneuroendocrinology. 2005 Jan;30(1):11-7. doi:
10.1016/j.psyneuen.2004.04.005.
Distress proneness and cognitive decline in a population of older persons.
Wilson RS(1), Bennett DA, Mendes de Leon CF, Bienias JL, Morris MC, Evans DA.
Author information:
(1)Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush
University Medical Center, Chicago, IL 60612, USA. [email protected]
The association between distress proneness and cognitive decline was examined in
older residents of a biracial community in Chicago. At baseline, participants
completed four cognitive tests that yielded a global measure (baseline
mean=101.2; standard deviation (SD)=7.8), and a brief measure of the tendency to
experience negative emotions (mean=16.5; SD=6.7) based on the Neuroticism scale
of the NEO Five-Factor Inventory. Cognitive testing was repeated twice at
three-year intervals. In mixed models that controlled age, sex, race, and
education, for each point on the distress proneness scale, global cognitive
score was 0.12 unit lower at baseline (p<0.001) and annual rate of decline
increased by 0.01 unit (p=0.002), or about 2%. Thus, cognitive decline was about
30% faster in a person highly prone to distress (score=24, 90th percentile)
compared to the one low in distress proneness (score=9, 10th percentile). This
effect was unchanged after controlling for level of cognitive activity or
excluding people with cognitive impairment at baseline, but it was reduced to a
trend (p=0.059) after controlling for depressive symptoms. The results suggest
that the tendency to experience psychological distress is associated with
increased cognitive decline in old age.
DOI: 10.1016/j.psyneuen.2004.04.005
PMID: 15358438 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18694539 | 1. Psychol Med. 2009 Apr;39(4):665-73. doi: 10.1017/S003329170800408X. Epub 2008
Aug 12.
Midlife Neuroticism and the age of onset of Alzheimer's disease.
Archer N(1), Brown RG, Reeves S, Nicholas H, Boothby H, Lovestone S.
Author information:
(1)Medical Research Council (MRC) Centre for Neurodegeneration Research,
Institute of Psychiatry, King's College London, UK. [email protected]
BACKGROUND: There may be important public health implications of increasing our
knowledge of factors associated with age of dementia onset. The pre-morbid
personality domain of Neuroticism constituted an interesting and theoretically
plausible, yet uninvestigated, candidate for such an association. We aimed to
examine whether midlife Neuroticism was associated with earlier age of onset of
Alzheimer's disease (AD).
METHOD: This was a case-comparison study of 213 patients with probable AD.
Detailed clinical information was collected for all patients including age of
onset of dementia symptoms. One or two knowledgeable informants rated each
patient's midlife personality retrospectively using the Neuroticism,
Extraversion, Openness Five-Factor Inventory (NEO-FFI) questionnaire. The
relationship between midlife Neuroticism and age of dementia onset was evaluated
using both correlational analysis and backward linear regression analysis.
RESULTS: Midlife Neuroticism predicted younger age of dementia onset in females
but not in males. The association found in females was independent of pre-morbid
history of affective disorder.
CONCLUSIONS: This finding and its potential mechanism warrant further
investigation.
DOI: 10.1017/S003329170800408X
PMID: 18694539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18590355 | 1. Neuropsychology. 2008 Jul;22(4):432-41. doi: 10.1037/0894-4105.22.4.432.
Cortical atrophy and personality in multiple sclerosis.
Benedict RH(1), Hussein S, Englert J, Dwyer MG, Abdelrahman N, Cox JL,
Munschauer FE, Weinstock-Guttman B, Zivadinov R.
Author information:
(1)Department of Neurology, State University of New York at Buffalo, School of
Medicine, New York, USA. [email protected]
Although the cognitive disorder of multiple sclerosis (MS) is well
characterized, little is known about personality changes that may occur in this
disease. There are reliable personality tests available for research in
neurological disease, based on the well-known Five Factor Model. Preliminary
research suggests that cognitively impaired MS patients exhibit elevation in
Neuroticism, and diminution in Extraversion, Agreeableness, and
Conscientiousness, as do patients with Alzheimer's disease. We predicted that
these characteristics would be associated with lower neocortical volume. We
studied 44 patients using brain MRI and the NEO Five-Factor Inventory.
Regression models controlling for T2 lesion volume, depression, and cognitive
dysfunction revealed significant correlation between cortical atrophy and
reduction in Extraversion and Conscientiousness. Discrepancies between patient-
and informant-reports were found, and overreporting of high Openness and
Conscientiousness among patients was associated with lower neocortical volume. A
final regression model accounting for depression, cognitive function, and
personality accounted for 38% of the variance in neocortical volume. These
findings suggest that cortical atrophy in MS is associated with adverse impact
on personality, although longitudinal research is needed to test this
hypothesis.
PsycINFO Database Record (c) 2008 APA, all rights reserved.
DOI: 10.1037/0894-4105.22.4.432
PMID: 18590355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20729242 | 1. Neuro Oncol. 2010 Nov;12(11):1167-72. doi: 10.1093/neuonc/noq100. Epub 2010
Aug 20.
A phase I factorial design study of dose-dense temozolomide alone and in
combination with thalidomide, isotretinoin, and/or celecoxib as
postchemoradiation adjuvant therapy for newly diagnosed glioblastoma.
Gilbert MR(1), Gonzalez J, Hunter K, Hess K, Giglio P, Chang E, Puduvalli V,
Groves MD, Colman H, Conrad C, Levin V, Woo S, Mahajan A, de Groot J, Yung WK.
Author information:
(1)Department of Neuro-Oncology, The University of Texas MD Anderson Cancer
Center, Unit 431, 1515 Holcombe Blvd., Houston, TX 77030, USA.
[email protected]
External beam radiation therapy (XRT) with concomitant temozolomide and 6 cycles
of adjuvant temozolomide (5/28-day schedule) improves survival in patients with
newly diagnosed glioblastoma compared with XRT alone. Studies suggest that
dose-dense temozolomide schedules and addition of cytostatic agents may further
improve efficacy. This factorial design phase I/II protocol tested dose-dense
temozolomide alone and combined with cytostatic agents. Patients with newly
diagnosed glioblastoma received fractionated XRT to 60 Gy concomitant with
temozolomide (75 mg/m²)/day for 42 days). In the phase I portion, patients with
stable disease or radiologic response 1 month after chemoradiation were
randomized to adjuvant temozolomide alone (150 mg/m²/day, 7/14-day schedule) or
with doublet combinations of thalidomide (400 mg/day), isotretinoin (100
mg/m²/day), and/or celecoxib (400 mg twice daily), or all 3 agents. Toxicity was
assessed after 4 weeks. Among 54 patients enrolled (median age, 52 years; median
Karnofsky performance status, 90), adjuvant treatment was not administered to 12
(22%), primarily because of disease progression (n = 10). All combinations were
well tolerated. Grade 3/4 lymphopenia developed in 63% of patients, but no
related infections occurred. One patient treated with temozolomide plus
isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1
patient receiving all 4 agents had dose-limiting grade 4 neutropenia. Venous
thrombosis occurred in 7 patients, 4 of whom received thalidomide. From study
entry, median survival was 20 months and the 2-year survival rate was 40%.
Multiple cytostatic agents can be safely combined with dose-dense temozolomide.
The factorial-based phase II portion of this study is currently ongoing.
DOI: 10.1093/neuonc/noq100
PMCID: PMC3098026
PMID: 20729242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20856809 | 1. PLoS One. 2010 Sep 15;5(9):e12716. doi: 10.1371/journal.pone.0012716.
Fine-mapping resolves Eae23 into two QTLs and implicates ZEB1 as a candidate
gene regulating experimental neuroinflammation in rat.
Stridh P(1), Thessen Hedreul M, Beyeen AD, Adzemovic MZ, Laaksonen H, Gillett A,
Ockinger J, Marta M, Lassmann H, Becanovic K, Jagodic M, Olsson T.
Author information:
(1)Center for Molecular Medicine, Department of Clinical Neuroscience,
Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
[email protected]
BACKGROUND: To elucidate mechanisms involved in multiple sclerosis (MS), we
studied genetic regulation of experimental autoimmune encephalomyelitis (EAE) in
rats, assuming a conservation of pathogenic pathways. In this study, we focused
on Eae23, originally identified to regulate EAE in a (LEW.1AV1xPVG.1AV1)F2
cross. Our aim was to determine whether one or more genes within the 67 Mb
region regulate EAE and to define candidate risk genes.
METHODOLOGY/PRINCIPAL FINDINGS: We used high resolution quantitative trait loci
(QTL) analysis in the 10th generation (G10) of an advanced intercross line (AIL)
to resolve Eae23 into two QTLs that independently regulate EAE, namely Eae23a
and Eae23b. We established a congenic strain to validate the effect of this
region on disease. PVG alleles in Eae23 resulted in significant protection from
EAE and attenuated CNS inflammation/demyelination. Disease amelioration was
accompanied with increased levels of Foxp3(+) cells in the CNS of the congenic
strain compared to DA. We then focused on candidate gene investigation in
Eae23b, a 9 Mb region linked to all clinical phenotypes. Affymetrix exon arrays
were used to study expression of the genes in Eae23b in the parental strains,
where none showed differential expression. However, we found lower expression of
exon 4 of ZEB1, which is specific for splice-variant Zfhep1. ZEB1 is an
interleukin 2 (IL2) repressor involved in T cell development. The
splice-specific variance prompted us to next analyze the expression of ZEB1 and
its two splice variants, Zfhep1 and Zfhep2, in both lymph node and spleen. We
demonstrated that ZEB1 splice-variants are differentially expressed; severity of
EAE and higher IL2 levels were associated with down-regulation of Zfhep1 and
up-regulation of Zfhep2.
CONCLUSIONS/SIGNIFICANCE: We speculate that the balance between splice-variants
of ZEB1 could influence the regulation of EAE. Further functional studies of
ZEB1 and the splice-variants may unravel novel pathways contributing to MS
pathogenesis and inflammation in general.
DOI: 10.1371/journal.pone.0012716
PMCID: PMC2939884
PMID: 20856809 [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/17244848 | 1. Psychosom Med. 2007 Jan;69(1):47-53. doi: 10.1097/01.psy.0000250264.25017.21.
Chronic distress, age-related neuropathology, and late-life dementia.
Wilson RS(1), Arnold SE, Schneider JA, Li Y, Bennett DA.
Author information:
(1)Rush Alzheimer's Disease Center, Rush University Medical Center, 600 South
Paulina, Suite 1038, Chicago, IL 60612, USA. [email protected]
OBJECTIVE: The objective of this study was to test whether common age-related
neuropathology could account for the relation of chronic distress to dementia.
METHODS: In a selected cohort of more than 1000 older Catholic clergy members
undergoing annual clinical evaluations, 326 persons died, of whom 306 (94%)
underwent brain autopsy, the results of which were available in 219 (mean age at
death = 85.4, standard deviation [SD] = 6.6; mean postmortem interval = 7.6
hours, SD = 6.9). A composite measure of chronic distress was constructed from
standard measures of two traits, neuroticism and anxiety proneness, completed at
baseline, and of depressive symptoms, completed annually. Dementia was diagnosed
according to standard criteria and cognition was assessed with previously
established composite measures based on a uniform clinical evaluation that took
place a mean of 9.1 months before death (SD = 9.5). On postmortem examination,
levels of amyloid-beta and tau-positive neurofibrillary tangles and the presence
of Lewy bodies were quantified in six brain regions, and the number and location
of chronic cerebral infarctions were noted.
RESULTS: In analyses that controlled for age, sex, education, amyloid, tangles,
Lewy bodies, and cerebral infarction, higher level of chronic distress was
associated with a higher likelihood of dementia and lower level of cognition
proximate to death. Chronic distress was not correlated with any form of
neuropathology, including limbic, neocortical, and global indices, and did not
modify the association of pathology with cognition.
CONCLUSIONS: Chronic psychological distress is associated with late-life
dementia but not with its leading causes, suggesting that novel
neurodeteriorative mechanisms may be involved.
DOI: 10.1097/01.psy.0000250264.25017.21
PMID: 17244848 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16252381 | 1. Int Psychogeriatr. 2005 Sep;17(3):499-512. doi: 10.1017/s1041610205001638.
What do subjective cognitive complaints in persons with aging-associated
cognitive decline reflect?
Kliegel M(1), Zimprich D, Eschen A.
Author information:
(1)Institute of Psychology, Department of Gerontopsychology, University of
Zurich, Switzerland. [email protected]
BACKGROUND: Subjective cognitive complaints have been included in diagnostic
concepts such as Aging-Associated Cognitive Decline (AACD) aiming to identify
older adults with cognitive impairments at high risk of developing dementia.
Although several studies in normal aging have found that subjective cognitive
complaints are related to depressive affect and personality factors, little is
known as to whether this is also true for older adults with AACD.
METHODS: In 123 older adults diagnosed with AACD and 291 controls, the role of
actual cognitive performance, depressive affect, neuroticism and
conscientiousness in predicting subjective cognitive complaints was
investigated. In separate ordinary least squares regression analyses for both
groups with gender, age, years of schooling, cognitive performance, depressive
affect, neuroticism and conscientiousness as predicting variables, in the
control participants, gender, age, depressive affect and neuroticism were
related to subjective cognitive complaints, whereas in the AACD participants
only gender and neuroticism accounted for variance in subjective cognitive
complaints. Testing for group differences in predictive power, revealed
differential effects for gender, depressive affect and neuroticism.
CONCLUSIONS: As subjective cognitive complaints in the AACD group were related
to neuroticism and gender rather than to cognitive performance, their inclusion
in diagnostic concepts such as AACD should be revaluated. However, the nature of
subjective cognitive complaints might be qualitatively different in persons
diagnosed with AACD compared to those stated by normal older adults.
DOI: 10.1017/s1041610205001638
PMID: 16252381 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16314587 | 1. Psychosom Med. 2005 Nov-Dec;67(6):841-5. doi:
10.1097/01.psy.0000190615.20656.83.
Neuroticism, extraversion, and mortality in a defined population of older
persons.
Wilson RS(1), Krueger KR, Gu L, Bienias JL, Mendes de Leon CF, Evans DA.
Author information:
(1)Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL
60612, USA. [email protected]
Comment in
Psychosom Med. 2005 Nov-Dec;67(6):839-40. doi:
10.1097/01.psy.0000189130.15870.93.
OBJECTIVE: The objective of this study was to test the association of the
personality traits of neuroticism and extraversion with risk of death in old
age.
METHODS: A census was taken of a geographically defined urban community in
Chicago, and those aged 65 years or older were invited to participate in an
in-home interview; 6158 (79% of those eligible) did so. The interview included
brief measures of neuroticism and extraversion, medical history, and questions
about current participation in cognitive, social, and physical activities. Vital
status was subsequently monitored. The association of each trait with risk of
death was examined in a series of accelerated failure-time models that
controlled for age, sex, race, and education.
RESULTS: During a mean of more than 6 years of observation, 2430 persons (39.5%)
died. A high level of neuroticism (score = 27; 90th percentile) was associated
with a 33% increase in risk of death compared with a low level of neuroticism
(score = 9; 10th percentile). A high level of extraversion (score = 33; 90th
percentile) was associated with a 21% decrease in risk of death compared with a
low level (score = 18; 10th percentile). Adjustment for medical conditions and
health-related variables did not substantially affect results, but adjusting for
baseline levels of cognitive, social, and physical activity reduced the
association of both traits with mortality.
CONCLUSIONS: The results suggest that higher extraversion and lower neuroticism
are associated with reduced risk of mortality in old age and that these
associations are mediated in part by personality-related patterns of cognitive,
social, and physical activity.
DOI: 10.1097/01.psy.0000190615.20656.83
PMID: 16314587 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19153372 | 1. Neurology. 2009 Jan 20;72(3):253-9. doi: 10.1212/01.wnl.0000339485.39246.87.
Personality and lifestyle in relation to dementia incidence.
Wang HX(1), Karp A, Herlitz A, Crowe M, Kåreholt I, Winblad B, Fratiglioni L.
Author information:
(1)Aging Research Center, Dept. Neurobiology, Care Sciences and Society,
Karolinska Institutet, Gävlegatan 16, 113 30 Stockholm, Sweden.
[email protected]
OBJECTIVE: High neuroticism has been associated with a greater risk of dementia,
and an active/socially integrated lifestyle with a lower risk of dementia. The
aim of the current study was to explore the separate and combined effects of
neuroticism and extraversion on the risk of dementia, and to examine whether
lifestyle factors may modify this association.
METHODS: A population-based cohort of 506 older people with no dementia from the
Kungsholmen Project, Stockholm, Sweden, was followed up for an average of 6
years. Personality traits were assessed using the Eysenck Personality Inventory.
Dementia was diagnosed by specialists according to DSM-III-R criteria.
RESULTS: Neither high neuroticism nor low extraversion alone was related to
significantly higher incidence of dementia. However, among people with an
inactive or socially isolated lifestyle, low neuroticism was associated with a
decreased dementia risk (hazard ratio [HR] = 0.51, 95% confidence interval [CI]
= 0.27-0.96). When compared to persons with high neuroticism and high
extraversion, a decreased risk of dementia was detected in individuals with low
neuroticism and high extraversion (HR = 0.51, 95% CI = 0.28-0.94), but not among
persons with low neuroticism and low extraversion (HR = 0.95, 95% CI =
0.57-1.60), nor high neuroticism and low extraversion (HR = 0.97 95% CI =
0.57-1.65). Stratified analysis by lifestyle showed that the inverse association
of low neuroticism and high extraversion in combination was present only among
the inactive or socially isolated persons.
CONCLUSION: Low neuroticism in combination with high extraversion is the
personality trait associated with the lowest dementia risk; however, among
socially isolated individuals even low neuroticism alone seems to decrease
dementia risk.
DOI: 10.1212/01.wnl.0000339485.39246.87
PMID: 19153372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20973606 | 1. Psychol Aging. 2011 Jun;26(2):351-62. doi: 10.1037/a0021377.
Personality and risk for Alzheimer's disease in adults 72 years of age and
older: a 6-year follow-up.
Duberstein PR(1), Chapman BP, Tindle HA, Sink KM, Bamonti P, Robbins J, Jerant
AF, Franks P.
Author information:
(1)Laboratory of Personality and Development, Department of Psychiatry,
University of Rochester Medical Center, 300 Crittenden Boulevard, Rochester, NY
14642, USA. [email protected]
Erratum in
Psychol Aging. 2011 Jun;26(2):338.
[Correction Notice: An erratum for this article was reported in Vol 26(2) of
Psychology and Aging (see record 2011-05802-001). This article contains an error
in the Discussion, under the Implications, Caveats, Future Directions heading.
The third paragraph includes the sentences that should have been removed. The
corrected paragraph appears in the correction.] We conducted secondary analyses
to determine the relationship between longstanding personality traits and risk
for Alzheimer's disease (AD) among 767 participants 72 years of age or older who
were followed for more than 6 years. Personality was assessed with the NEO-FFI.
We hypothesized that elevated Neuroticism, lower Openness, and lower
Conscientiousness would be independently associated with risk of AD. Hypotheses
were supported. The finding that AD risk is associated with elevated Neuroticism
and lower Conscientiousness can be added to the accumulating literature
documenting the pathogenic effects of these two traits. The link between lower
Openness and AD risk is consistent with recent findings on cognitive activity
and AD risk. Findings have implications for prevention research and for the
conceptualization of the etiology of AD.
(c) 2011 APA, all rights reserved.
DOI: 10.1037/a0021377
PMCID: PMC3115437
PMID: 20973606 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23475435 | 1. Jpn J Clin Oncol. 2013 Apr;43(4):417-21. doi: 10.1093/jjco/hyt011. Epub 2013
Mar 8.
Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.
Hiramoto N(1), Kobayashi Y, Nomoto J, Maruyama D, Watanabe T, Tochigi N, Furuta
K, Takeda K, Chuman H, Yagyu S, Hosoi H, Tobinai K.
Author information:
(1)Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
We report the case of a patient in whom the diagnosis of Ewing sarcoma arising
from a soft tissue was made after successful treatment of diffuse large B-cell
lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left
scapular region 8 years after successful chemotherapy with the cyclophosphamide,
hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse
large B-cell lymphoma. Computed tomographic examination and magnetic resonance
imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size
in the left scapular region. Histopathological examination of an open biopsy
specimen revealed a small round cell tumour that showed positive staining for
CD99. Fluorescence in situ hybridization showed a split signal by a break-apart
probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase
chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on
these findings, the patient was diagnosed as having secondary Ewing sarcoma.
Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years
after the diagnosis of Ewing sarcoma. Therapy-related haematological
malignancies with balanced translocations have been reported previously. A
mechanism similar to that underlying the development of secondary malignancy
might explain the occurrence of this solid cancer.
DOI: 10.1093/jjco/hyt011
PMID: 23475435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23040035 | 1. Neurobiol Aging. 2013 Apr;34(4):1045-50. doi:
10.1016/j.neurobiolaging.2012.08.008. Epub 2012 Oct 2.
Personality and resilience to Alzheimer's disease neuropathology: a prospective
autopsy study.
Terracciano A(1), Iacono D, O'Brien RJ, Troncoso JC, An Y, Sutin AR, Ferrucci L,
Zonderman AB, Resnick SM.
Author information:
(1)National Institute on Aging, National Institutes of Health, Baltimore, MD
21224,, USA. [email protected]
Alzheimer's disease (AD) neuropathology is found at autopsy in approximately 30%
of cognitively normal older individuals. We examined whether personality traits
are associated with such resilience to clinical dementia in individuals with AD
neuropathology. Broad factors and specific facets of personality were assessed
up to 28 years (mean 11 ± 7 years) before onset of dementia and up to 30 years
(mean 15 ± 7 years) before death in a cohort (n = 111) evaluated for AD
neuropathology at autopsy. Individuals with higher baseline scores on
vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0;
95% confidence interval, 1.2-3.5), or lower scores on order and competence
(conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less
likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism
(r = 0.26), low agreeableness (r = -0.34), and some facets were also
significantly associated with advanced stages of neurofibrillary tangles, but
the associations between personality traits and risk of clinical dementia were
mostly unchanged by controlling for the extent of neurofibrillary tangles and Aβ
neuritic plaques. In sum, a resilient personality profile is associated with
lower risk or delay of clinical dementia even in persons with AD neuropathology.
Published by Elsevier Inc.
DOI: 10.1016/j.neurobiolaging.2012.08.008
PMCID: PMC3541457
PMID: 23040035 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20231617 | 1. Am J Clin Pathol. 2010 Apr;133(4):633-45. doi: 10.1309/AJCPPJJ0PY4XZOEC.
Reverse transcriptase-polymerase chain reaction as an ancillary molecular
technique in the diagnosis of small blue round cell tumors by fine-needle
aspiration cytology.
Gautam U(1), Srinivasan R, Rajwanshi A, Bansal D, Marwaha RK, Vasishtha RK.
Author information:
(1)Dept of Cytology and Gynecological Pathology, Postgraduate Institute of
Medical Education and Research, Chandigarh, India.
We evaluated the feasibility and usefulness of reverse transcriptase-polymerase
chain reaction (RT-PCR) on fine-needle aspirates for categorization of small
blue round cell tumors (SBRCTs). A total of 51 cases, including 25 Ewing
sarcoma/peripheral primitive neuroectodermal tumors (PNETs), 11
rhabdomyosarcomas, 13 neuroblastomas, and 2 desmoplastic small round cell tumors
(DSRCTs) were analyzed. The detection of the EWS-FLI1 (20/25) and EWS-ERG (4/25)
fusion transcripts resolved 24 of 25 cases of Ewing sarcoma/PNET. The
PAX3/7-FKHR fusion transcript was detected in 2 of 4 cases of alveolar
rhabdomyosarcoma and the EWS-WT1 transcript in both cases of DSRCT. Tyrosine
hydroxylase and 3,4-dihydroxyphenylalanine (dopa) decarboxylase transcripts were
demonstrated in 10 of 13 cases of neuroblastoma. In comparison,
immunocytochemical analysis resolved 19 (76%) of 25 Ewing sarcomas, 9 (82%) of
11 rhabdomyosarcomas, 6 (46%) of 13 neuroblastomas, and 1 (50%) of 2 DSRCTs.
Overall, RT-PCR resolved 38 (86%) of 44 vs 35 (69%) of 51 cases by
immunocytochemical analysis. RT-PCR is easily applied to fine-needle aspirates
of SBRCT and greatly facilitates accurate tumor typing.
DOI: 10.1309/AJCPPJJ0PY4XZOEC
PMID: 20231617 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21427641 | 1. Am J Geriatr Psychiatry. 2011 Apr;19(4):327-34. doi:
10.1097/JGP.0b013e31820119da.
Vulnerability to stress, anxiety, and development of dementia in old age.
Wilson RS(1), Begeny CT, Boyle PA, Schneider JA, Bennett DA.
Author information:
(1)Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush
University Medical Center, Chicago, IL 60612, USA. [email protected]
OBJECTIVE: To identify the components of the neuroticism trait most responsible
for its association with cognitive decline and dementia in old age.
DESIGN: Longitudinal clinical-pathologic cohort study.
SETTING: Chicago metropolitan area.
PARTICIPANTS: A total of 785 older persons without dementia completed standard
self-report measures of six components of neuroticism and then had annual
clinical evaluations for a mean of 3.4 years and brain autopsy in the event of
death.
MEASUREMENTS: Incidence of clinically diagnosed Alzheimer disease (AD), change
in global and specific cognitive functions, and postmortem measures of plaques
and tangles, cerebral infarction, and Lewy bodies.
RESULTS: During follow-up, 94 individuals developed AD. Higher levels of anxiety
and vulnerability to stress were associated with increased risk of AD and more
rapid decline in global cognition, with no effects for the other four trait
components. In analyses of specific cognitive systems, neuroticism subscales
were related to decline in episodic memory, working memory, and perceptual
speed, but not in semantic memory or visuospatial ability. No component of
neuroticism was related to the neuropathologic lesions most commonly associated
with late-life dementia.
CONCLUSIONS: Neuroticism's association with late-life dementia mainly reflects
vulnerability to stress and anxiety and their correlation with decline in the
ability to process and retain new information.
DOI: 10.1097/JGP.0b013e31820119da
PMCID: PMC3078621
PMID: 21427641 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21905097 | 1. Int J Geriatr Psychiatry. 2011 Oct;26(10):1019-29. doi: 10.1002/gps.2655. Epub
2010 Nov 9.
Personality changes in Alzheimer's disease: a systematic review.
Robins Wahlin TB(1), Byrne GJ.
Author information:
(1)School of Medicine, The University of Queensland, Brisbane, Australia.
[email protected]
OBJECTIVE: People with Alzheimer's disease (AD) commonly exhibit changes in
personality that sometimes precede the other early clinical manifestations of
the condition, such as cognitive impairment and mood changes. Although these
personality changes reflect the impact of progressive brain damage, there are
several possible patterns of personality change with dementia. Early
identification of personality change might assist with the timely diagnosis of
AD. The objective of this study was to review studies of personality change in
AD.
METHODS: Systematic searches of the PubMed, Ovid Medline, EBSCOhost, PsychINFO
and CINAHL databases were undertaken from inception to November 2009. Published
studies of informant-rated personality traits in AD patients were identified.
Studies that mapped changes in traits from the five-factor model of personality
which includes factors for Neuroticism, Extraversion, Openness, Agreeableness
and Conscientiousness, were selected for analysis. The change in each of these
five traits was calculated as the mean difference in score before and after the
diagnosis of AD.
RESULTS: There was a mean increase in Neuroticism of 10-20 T scores (equivalent
to 1-2 SD), a decrease of the same magnitude in Extraversion, consistently
reduced Openness and Agreeableness, and a marked decrease in Conscientiousness
of about 20-30 T scores (equivalent to 2-3 SD). These changes were systematic
and consistent. Particularly striking was the similarity of both the magnitude
and direction of change in all studies reviewed.
CONCLUSIONS: Conscientiousness and Neuroticism are the personality traits that
exhibit the most change in dementia. These traits might be useful early markers
of dementia.
Copyright © 2010 John Wiley & Sons, Ltd.
DOI: 10.1002/gps.2655
PMID: 21905097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20384580 | 1. Curr Cancer Drug Targets. 2010 Aug;10(5):484-95. doi:
10.2174/156800910791517172.
The mTOR pathway: a new target in cancer therapy.
Ciuffreda L(1), Di Sanza C, Incani UC, Milella M.
Author information:
(1)Division of Medical Oncology A, Regina Elena National Cancer Institute, Via
Elio Chianesi n. 53, 00144 Rome, Italy.
Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal
transduction from various growth factors and upstream proteins to the level of
mRNA translation and ribosome biogenesis, with pivotal regulatory effects on
cell cycle progression, cellular proliferation and growth, autophagy and
angiogenesis. The mTOR pathway, and its upstream regulators in the PI3K/PTEN/AKT
cascade, are altered in a variety of experimental and human malignancies.This
has led to the prediction that mTOR inhibitors may be used as anticancer agents.
With the recent approval of two mTOR-targeted drugs (temsirolimus and
everolimus) for the treatment of renal cell carcinoma and mantle cell lymphoma,
this paradigm has been effectively translated into the clinical setting. In this
review, we discuss mTOR biology and regulation, the mode of action of mTOR
inhibitors as anti-cancer agents, and current clinical evidence supporting the
use of rapamycin-like mTOR inhibitors in cancer treatment.
DOI: 10.2174/156800910791517172
PMID: 20384580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24257606 | 1. J Virol. 2014 Feb;88(3):1703-13. doi: 10.1128/JVI.02209-13. Epub 2013 Nov 20.
Epigenetic deregulation of the LMP1/LMP2 locus of Epstein-Barr virus by mutation
of a single CTCF-cohesin binding site.
Chen HS(1), Martin KA, Lu F, Lupey LN, Mueller JM, Lieberman PM, Tempera I.
Author information:
(1)The Wistar Institute, Philadelphia, Pennsylvania, USA.
The chromatin regulatory factors CTCF and cohesin have been implicated in the
coordinated control of multiple gene loci in Epstein-Barr virus (EBV) latency.
We have found that CTCF and cohesin are highly enriched at the convergent and
partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not
yet known how CTCF and cohesin may coordinately regulate these transcripts. We
now show that genetic disruption of this CTCF binding site (EBVΔCTCF166) leads
to a deregulation of LMP1, LMP2A, and LMP2B transcription in EBV-immortalized B
lymphocytes. EBVΔCTCF166 virus-immortalized primary B lymphocytes showed a
decrease in LMP1 and LMP2A mRNA and a corresponding increase in LMP2B mRNA. The
reduction of LMP1 and LMP2A correlated with a loss of euchromatic histone
modification H3K9ac and a corresponding increase in heterochromatic histone
modification H3K9me3 at the LMP2A promoter region in EBVΔCTCF166. Chromosome
conformation capture (3C) revealed that DNA loop formation with the origin of
plasmid replication (OriP) enhancer was eliminated in EBVΔCTCF166. We also
observed that the EBV episome copy number was elevated in EBVΔCTCF166 and that
this was not due to increased lytic cycle activity. These findings suggest that
a single CTCF binding site controls LMP2A and LMP1 promoter selection, chromatin
boundary function, DNA loop formation, and episome copy number control during
EBV latency.
DOI: 10.1128/JVI.02209-13
PMCID: PMC3911611
PMID: 24257606 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9552022 | 1. J Clin Oncol. 1998 Apr;16(4):1248-55. doi: 10.1200/JCO.1998.16.4.1248.
EWS-FLI1 fusion transcript structure is an independent determinant of prognosis
in Ewing's sarcoma.
de Alava E(1), Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, Gerald WL,
Jhanwar SC, Argani P, Antonescu CR, Pardo-Mindan FJ, Ginsberg J, Womer R, Lawlor
ER, Wunder J, Andrulis I, Sorensen PH, Barr FG, Ladanyi M.
Author information:
(1)Clinica Universitaria de Navarra, Pamplona, Spain.
Erratum in
J Clin Oncol 1998 Aug;16(8):2895.
Comment in
J Clin Oncol. 1998 Apr;16(4):1241-3. doi: 10.1200/JCO.1998.16.4.1241.
PURPOSE: More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and
FLI1 genes, due to the t(11;22)(q24;q12) translocation. At the molecular level,
the EWS-FLI1 rearrangements show great diversity. Specifically, many different
combinations of exons from EWS and FLI1 encode in-frame fusion transcripts and
result in differences in the length and composition of the chimeric protein,
which functions as an oncogenic aberrant transcription factor. In the most
common fusion type (type 1), EWS exon 7 is linked in frame with exon 6 of FLI1.
As the fundamental pathogenetic lesion in ES, the molecular heterogeneity of
these fusion transcripts may have functional and clinical significance.
PATIENTS AND METHODS: We performed a clinical and pathologic analysis of 112
patients with ES in which EWS-FLI1 fusion transcripts were identified by
reverse-transcriptase polymerase chain reaction (RT-PCR). Adequate treatment and
follow-up data were available in 99 patients treated with curative intent.
Median follow-up in these 99 patients was 26 months (range, 1 to 140 months).
Univariate and multivariate survival analyses were performed that included other
prognostic factors, such as age, tumor location, size, and stage.
RESULTS: Among the 99 patients suitable for survival analysis, the tumors in 64
patients contained the type 1 fusion and in 35 patients contained less common
fusion types. Stage at presentation was localized in 74 patients and metastatic
in 25. Metastases (relative risk [RR] = 2.6; P = .008), and type 1 EWS-FLI1
fusion (RR = 0.37; P = .014) were, respectively, independent negative and
positive prognostic factors for overall survival by multivariate analysis. Among
74 patients with localized tumors, the type 1 EWS-FLI1 fusion was also a
significant positive predictor of overall survival (RR = 0.32; P = .034) by
multivariate analysis.
CONCLUSION: EWS-FLI1 fusion type appears to be prognostically relevant in ES,
independent of tumor site, stage, and size. Further studies are needed to
clarify the biologic basis of this phenomenon.
DOI: 10.1200/JCO.1998.16.4.1248
PMID: 9552022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24293381 | 1. Pathol Oncol Res. 2014 Jul;20(3):503-16. doi: 10.1007/s12253-013-9721-2. Epub
2013 Nov 30.
Clinicopathological and molecular spectrum of ewing sarcomas/PNETs, including
validation of EWSR1 rearrangement by conventional and array FISH technique in
certain cases.
Rekhi B(1), Vogel U, Basak R, Desai SB, Jambhekar NA.
Author information:
(1)Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, India,
[email protected].
Over the years, a wide clinicopathological spectrum has been identified within
Ewing family of tumors (EFTs). As these tumors are chemosensitive, their correct
and timely identification is necessary. The aims of this study were (1) to
present the diverse clinicopathological and molecular profile of EFTs in our
settings, (2) to identify a pragmatic approach for diagnosing EFTs, especially
for application of ancillary techniques, namely RT-PCR for specific transcripts
(EWS-FLI1, EWS-ERG) and FISH for EWSR1 gene rearrangement, in certain cases and
(3) to show the utility of tissue microarray in establishing a new FISH test.
Fifty-eight EFTs were identified in 38 males and 20 females within an age-range
of 1-65 years (median, 16), mostly in lower extremities (14) (24.1 %).
Therapeutically, most patients underwent neoadjuvant chemotherapy with
subsequent surgery. Histopathologically, diagnosis of EFTs was initially offered
in 41/58 (70.6 %) tumors. On review, 59 % tumors showed diffuse pattern, while
41 % displayed rosettes. Immunohistochemically, tumor cells were mostly
diffusely positive for CD99 (48/52) (92.3 %); FLI-1 (17/18) (94.4 %); variably
for BCL2 (16/18) (88.8 %), synaptophysin (6/20) (35 %), S100-P (2/7) (28.5 %),
CD56 (2/5) (40 %), NSE (2/5) (40 %), calponin (3/4) (75 %), EMA (5/24) (20.8 %)
and CK (3/24) (12.5 %), the latter two mostly focally. Fifty five tumors were
EWS-FLI1 positive, while a single tumor was EWS-ERG positive. Sensitivity for
PCR was 61 %. EWSR1 rearrangement was detected by FISH in 12/13 Ewing
sarcomas/PNETs. Sensitivity for EWSR1 test was 92.3 % and specificity was 100 %.
Thirty-eight tumors, including 14 molecular confirmed EFTs and 21 other tumors
were tested for EWSR1 rearrangement. Among 21 unrelated tumors, EWSR1
rearrangement was detected in few myoepithelial tumors, occasional desmoplastic
small round cell tumor and an extraskeletal myxoid chondrosarcoma. Further, a
tissue microarray with a separate set of 8 EFTs, confirmed at another laboratory
was analysed for validation of EWSR1 rearrangement test. 23/28 (82.1 %) tissue
cores of the tissue microarray, stained by FISH were interpretable, including
EWSR1 rearrangement, detected in 20/28 tissue cores; not detected in 3 liver
cores and uninterpretable in 5 (17.8 %) cores. Classical EFTs can be diagnosed
with diffuse, membranous CD99 positivity, intranuclear FLI1 positivity and LCA
negativity in malignant round cells. In unconventional cases, it is
indispensable to reveal the concomitant fusion m-RNA by RT-PCR. In case of
negative molecular results, it is necessary to prove EWSR1 rearrangement by
FISH. These tests should be interpreted with clinicopathological correlation.
Tissue microarrays for FISH are useful during validation of a new test,
especially when sarcomas like EFTs show less genetic heterogeneity within tumor
cells.
DOI: 10.1007/s12253-013-9721-2
PMID: 24293381 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23079898 | 1. Am J Geriatr Psychiatry. 2012 Dec;20(12):1026-35. doi:
10.1097/JGP.0b013e318267016b.
Personality factors moderate the associations between apolipoprotein genotype
and cognitive function as well as late onset Alzheimer disease.
Dar-Nimrod I(1), Chapman BP, Franks P, Robbins J, Porsteinsson A, Mapstone M,
Duberstein PR.
Author information:
(1)School of Psychology, University of Sydney, Australia.
[email protected]
OBJECTIVES: We tested the hypothesis that neuroticism moderates the association
between APOE (apolipoprotein E) genotype and two major outcomes, cognitive
function and Alzheimer disease. We also explored whether other personality
dimensions (extraversion, openness to experience, agreeableness, and
conscientiousness) moderate the associations of APOE with these outcomes.
DESIGN: Primary analyses of existing randomized clinical trial data.
SAMPLE: Six-hundred two older adults (mean age of 78 years at baseline).
MEASUREMENTS: APOE genotype, the NEO-Five Factor Inventory, the Alzheimer's
Disease Assessment Scale-Cognitive: measured every 6 months for 6.5 years) and
relevant covariates.
RESULTS: Fully adjusted multivariate analyses showed that the association
between the presence of APOE [Latin Small Letter Open E]-4 allele(s) and both
outcomes was evident among individuals with high levels of neuroticism and
extraversion but not among persons with low levels of these traits.
CONCLUSIONS: Phenotypic personality dimensions, primarily neuroticism and
extraversion, moderate the relationship between APOE [Latin Small Letter Open
E]-4 genotype and cognitive outcomes among older adults. Future research is
needed to elucidate the physiological processes involved in these particular
phenotype-genotype interactions.
DOI: 10.1097/JGP.0b013e318267016b
PMCID: PMC4184145
PMID: 23079898 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20133600 | 1. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3651-6. doi:
10.1073/pnas.0912087107. Epub 2010 Feb 2.
Cell type specificity of chromatin organization mediated by CTCF and cohesin.
Hou C(1), Dale R, Dean A.
Author information:
(1)Laboratory of Cellular and Developmental Biology, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892, USA.
CTCF sites are abundant in the genomes of diverse species but their function is
enigmatic. We used chromosome conformation capture to determine long-range
interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11
encompassing the beta-globin locus and flanking olfactory receptor genes.
Although CTCF occupies these sites in both erythroid K562 cells and fibroblast
293T cells, the long-range interaction frequencies among the sites are highly
cell type specific, revealing a more densely clustered organization in the
absence of globin gene activity. Both CTCF and cohesins are required for the
cell-type-specific chromatin conformation. Furthermore, loss of the
organizational loops in K562 cells through reduction of CTCF with shRNA results
in acquisition of repressive histone marks in the globin locus and reduces
globin gene expression whereas silent flanking olfactory receptor genes are
unaffected. These results support a genome-wide role for CTCF/cohesin sites
through loop formation that both influences transcription and contributes to
cell-type-specific chromatin organization and function.
DOI: 10.1073/pnas.0912087107
PMCID: PMC2840441
PMID: 20133600 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/21880767 | 1. J Virol. 2011 Nov;85(21):11159-69. doi: 10.1128/JVI.00720-11. Epub 2011 Aug
31.
Mechanism of glycyrrhizic acid inhibition of Kaposi's sarcoma-associated
herpesvirus: disruption of CTCF-cohesin-mediated RNA polymerase II pausing and
sister chromatid cohesion.
Kang H(1), Lieberman PM.
Author information:
(1)The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268, USA.
Glycyrrhizic acid (GA), a derivative of licorice, selectively inhibits the
growth of lymphocytes latently infected with Kaposi's sarcoma-associated
herpesvirus. The mechanism involves the deregulation of the multicistronic
latency transcript, including the failure to generate the mature forms of viral
mRNA encoding LANA. We show here that GA disrupts an RNA polymerase II (RNAPII)
complex that accumulates at the CTCF-cohesin binding site within the first
intron of the latency transcript. GA altered the enrichment of the RNAPII
pausing complex, along with pausing factors SPT5 and NELF-A, at the intragenic
CTCF-cohesin binding sites. GA blocked the interaction of cohesin subunit SMC3
with another cohesin subunit, RAD21, and reduced SPT5 interaction with RNAPII.
Covalent coupling of GA to a solid support revealed that GA interacts with
several cellular proteins, including SMC3 and SPT5, but not their respective
interaction partners RAD21 and RNAPII. GA treatment also inhibited the
transcription of some cellular genes, like c-myc, which contain a similar
CTCF-cohesin binding site within the first intron. We also found that GA leads
to a more general loss of sister chromatid cohesion for cellular chromosomes.
These findings suggest that RNAPII pauses at intragenic CTCF-cohesin binding
sites and that abrogation of this pausing by GA leads to loss of proper mRNA
production and defects in sister chromatid cohesion, a process important for
both viral and cellular chromosome stability.
DOI: 10.1128/JVI.00720-11
PMCID: PMC3194953
PMID: 21880767 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9924832 | 1. Int Psychogeriatr. 1998 Dec;10(4):369-78. doi: 10.1017/s1041610298005468.
Premorbid personality traits in Alzheimer's disease: do they predispose to
noncognitive behavioral symptoms?
Meins W(1), Frey A, Thiesemann R.
Author information:
(1)Department of Geriatric Medicine, Albertinen Hospital, Hamburg, Germany.
[email protected]
The purpose of this study was to examine whether premorbid personality traits
predispose to noncognitive symptoms in Alzheimer's disease (AD). The Munich
Personality Test was used to evaluate caregivers' perception of personality
prior to symptom onset in 56 outpatients with probable AD. Caregivers also
completed the "mood" and "disturbed behavior" scales of the Nurses' Observation
Scale for Geriatric Patients. A neuropsychiatrist rated depressive symptoms on
the Cornell Scale for Depression and the occurrence of personality change in
four domains according to ICD-10. Under statistical control of confounding
variables, results showed a moderate association between (high) premorbid
neuroticism, subsequent troublesome behavior, and personality change, on the one
hand, and (low) frustration tolerance and depression, on the other. Premorbid
personality traits may indeed predispose to subsequent noncognitive symptoms in
AD.
DOI: 10.1017/s1041610298005468
PMID: 9924832 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21106760 | 1. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21836-41. doi:
10.1073/pnas.1002130107. Epub 2010 Nov 24.
Nicotinamide adenine dinucleotide (NAD)-regulated DNA methylation alters
CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus.
Chang J(1), Zhang B, Heath H, Galjart N, Wang X, Milbrandt J.
Author information:
(1)Department of Genetics, and Hope Center for Neurological Disorders,
Washington University School of Medicine, St Louis, MO 63110, USA.
Cellular metabolism alters patterns of gene expression through a variety of
mechanisms, including alterations in histone modifications and transcription
factor activity. Nicotinamide adenine dinucleotide (NAD)-dependent proteins such
as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important
roles in this regulation, thus NAD provides a crucial link between metabolism
and these cellular signaling processes. Here, we found that lowering NAD levels
in mouse primary cortical neurons led to decreased activity-dependent BDNF
expression. The altered BDNF transcription occurred independently of Sirt or
Parp activities; instead, low NAD levels promoted increased DNA methylation of
the activity-dependent BDNF promoter. Increased methylation at this promoter
triggered the dissociation of the insulator protein CTCF as well as the
accompanying cohesin from the BDNF locus. The loss of these proteins resulted in
histone acetylation and methylation changes at this locus consistent with
chromatin compaction and gene silencing. Because BDNF is critical for neuronal
function, these results suggest that age- or nutrition-associated declines in
NAD levels as well as deficits in cohesin function associated with disease
modulate BDNF expression and could contribute to cognitive impairment.
DOI: 10.1073/pnas.1002130107
PMCID: PMC3003122
PMID: 21106760 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: The authors and
Washington University may derive benefit from a licensing agreement with Sirtris
Pharmaceuticals, which did not provide any support for this work. |
http://www.ncbi.nlm.nih.gov/pubmed/17890266 | 1. Nephrol Dial Transplant. 2007 Sep;22 Suppl 8:viii61-viii65. doi:
10.1093/ndt/gfm652.
Sirolimus in renal transplantation.
Morath C(1), Arns W, Schwenger V, Mehrabi A, Fonouni H, Schmidt J, Zeier M.
Author information:
(1)Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162,
69120 Heidelberg, Germany. [email protected]
Acute rejection episodes are now as low as 5-20% in the first year after renal
transplantation; however, graft half-life has remained almost unchanged in the
last decade. This statistic is mainly attributable to the side effects of
immunosuppression, with loss of allografts due to the chronic allograft
nephropathy that is a consequence of calcineurin inhibitor toxicity or
hypertension. Patient death due to cardiovascular events, infections and
malignancy also contribute to allograft loss. The introduction of the inhibitors
of the mammalian target of rapamycin sirolimus and everolimus in renal
transplantation has increased the repertoire of immunosuppressive protocols
substantially. They have a different mode of action and a different side effect
profile (i.e. lower nephrotoxicity, less hypertension and less neoplastic
potential) than the calcineurin inhibitors. The inhibitors of the mammalian
target of rapamycin therefore provide an especially promising alternative for
the maintenance immunosuppression after renal transplantation. This overview
provides a summary of the current literature on inhibitors of the mammalian
target of rapamycin, with a special focus on sirolimus.
DOI: 10.1093/ndt/gfm652
PMID: 17890266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17154184 | 1. Pediatr Blood Cancer. 2008 Mar;50(3):703-6. doi: 10.1002/pbc.21099.
SK-NEP-1 and Rh1 are Ewing family tumor lines.
Smith MA(1), Morton CL, Phelps D, Girtman K, Neale G, Houghton PJ.
Author information:
(1)Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda,
Maryland, USA. [email protected]
The utility of preclinical models of childhood cancers is contingent upon
reliably classifying them with their corresponding clinical counterparts.
Molecular tools such as gene expression profiling allow researchers to confirm
the similarity between clinical tumors and preclinical models. We describe the
use of gene expression profiling to show that SK-NEP-1, a cell line previously
thought to represent anaplastic Wilms tumor, is instead related to Ewing
sarcoma. RT-PCR confirmed that SK-NEP-1 expresses EWS-FLI1 gene fusion
transcripts characteristic of Ewing sarcoma, and DNA sequencing demonstrated the
joining of exon 7 of EWS with exon 5 of FLI1 for these transcripts. Rh1, which
was previously categorized as an alveolar rhabdomyosarcoma cell line, also has a
gene expression profile suggestive of Ewing sarcoma and expresses EWS-FLI1
fusion transcripts in which exon 7 of EWS is joined with exon 6 of FLI1. These
examples illustrate the importance of molecularly characterizing pediatric
preclinical models used for testing new agents.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/pbc.21099
PMID: 17154184 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16157025 | 1. Chin Med J (Engl). 2005 Aug 20;118(16):1323-9.
Molecular detection of EWS-Ets fusion transcripts and their clinicopathologic
significance in Ewing's sarcoma/peripheral primitive neuroectodermal tumor.
Wang H(1), Zheng J, Wang YP, Yang Y, You JF.
Author information:
(1)Department of Pathology, Peking University Health Science Center, Beijing
100083, China.
BACKGROUND: Ewing's sarcoma/peripheral primitive neuroectodermal tumor
(ES/pPNET) is often difficult to distinguish from other small round cell tumors.
The EWS-Ets gene fusions that result from chromosomal translocations in this
tumor provide potential molecular diagnostic markers. To apply these molecular
markers to commonly available archival materials, we evaluated the feasibility
of detecting EWS-Ets including EWS-Fli1 and EWS-ERG fusion transcripts in
paraffin-embedded tissues and its diagnostic value for detecting ES/pPNET.
METHODS: Thirteen paraffin-embedded samples of ES/pPNETs were retrieved from
archives. Thirteen cases of other tumors with small round cell features
(including rhabdomyosarcoma, neuroblastoma, lymphoma, small cell carcinoma, and
desmoplastic small round cell tumor) were used as negative controls. Beta-actin
and beta2-microglobulin were used as internal controls. A nested reverse
transcriptase-polymerase chain reaction (RT-PCR)-based assay was performed to
detect the EWS-Fli1 and EWS-ERG fusion transcripts.
RESULTS: Beta-actin and beta2-microglobulin were detected in 10/13 and 13/13
ES/pPNETs, respectively. EWS-Fli1 fusion transcripts were detected in 11 of 13
(85%) ES/pPNETs. Three chimeric transcripts, all EWS-Fli1, were detected in
ES/pPNET samples. Among 11 EWS-Fli1-positive cases, 7 cases had a type I fusion
transcript involving fusion of EWS exon 7 with Fli1 exon 6, 2 cases had a type
II fusion transcript involving EWS exon 7 with Fli1 exon 5, and 2 cases
expressed fusion transcripts involving EWS exon 7 and Fli1 exon 8. Type I
EWS-Fli1 fusion predominated over other types. Fusion types could not be
distinguished in the remaining 2 cases. Thirteen negative controls did not show
detectable chimeric messages. There was a significant relationship between
EWS-Fli1 fusion transcripts and CD99 expression.
CONCLUSIONS: Molecular detection of EWS-Fli1 fusion transcripts in
formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is
useful for the diagnosis and differential diagnosis of ES/pPNETs.
PMID: 16157025 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10379685 | 1. APMIS. 1999 Jun;107(6):577-84. doi: 10.1111/j.1699-0463.1999.tb01595.x.
Molecular detection of EWS-FLI1 chimeric transcripts in Ewing family tumors by
nested reverse transcription-polymerase chain reaction: application to archival
paraffin-embedded tumor tissues.
Hisaoka M(1), Tsuji S, Morimitsu Y, Hashimoto H, Shimajiri S, Komiya S, Ushijima
M.
Author information:
(1)Department of Pathology and Oncology, School of Medicine, University of
Occupational and Environmental Health, Kitakyushu, Japan.
Chromosomal translocations generating unique chimeric genes are highly
characteristic of specific sarcomas, and their use as diagnostic markers has
been suggested. From a diagnostic pathologic point of view, detection of such
cytogenetic or molecular aberrations applicable to routinely processed archival
tissue specimens is considered a powerful tool for tumor diagnosis. To assess
the feasibility and reliability of the molecular detection of the transcript
originating from the chimeric gene in paraffin-embedded tumor specimens, we
performed a nested reverse transcription-polymerase chain reaction
(RT-PCR)-based assay to detect the EWS-FLI1 chimeric message in a series of
Ewing family tumors. Of 24 paraffin-embedded tumor specimens from 23 cases
analyzed, the chimeric message was detectable in 20 (83%) specimens from 20
cases (87%) by this nested RT-PCR assay, whereas none of 7 small round cell
tumors not from this family (3 alveolar rhabdomyosarcomas, 2 neuroblastomas, 2
malignant lymphomas) showed detectable chimeric messages. In the sequence
analysis of the PCR products, the amplified chimeric messages contained the
junctions between exon 7 of the EWS gene and any one of exons 5, 6 and 8 of the
FLI1 gene. The detection process was usually completed within 3 days, except for
the subseqent sequence analysis. Our results endorse the use of this molecular
assay as an ancillary technique in the diagnosis of Ewing family tumors using
paraffin-embedded material.
DOI: 10.1111/j.1699-0463.1999.tb01595.x
PMID: 10379685 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15363317 | 1. Zhonghua Bing Li Xue Za Zhi. 2004 Aug;33(4):328-31.
[Detection of EWS-FLI1 fusion transcript in Ewing's sarcoma/peripheral primitive
neuroectodermal tumors by one-step RT-PCR using paraffin-embedded tissues].
[Article in Chinese]
Li F(1), Chang B, Li XX, Pang LJ, Lu HF, Wang J, Sun MH, Shi DR.
Author information:
(1)Department of Pathology, Shihezi University School of Medicine, Xinjiang
832002, China. [email protected]
OBJECTIVE: To investigate the expression of EWS-FLI1/ERG fusion transcript
resulting from t(11;12)(q24;12) in paraffin-embedded tissues and its diagnostic
implication for Ewing's sarcoma/peripheral primitive neuroectodermal tumors
(ES/pPNET).
METHODS: One-step reverse transcriptase-polymerase chain reaction (RT-PCR) was
employed to detect a characteristic EWS-FLI1/ERG fusion transcript in 25 cases
of ES/pPNET and 15 cases of other small round cell tumors (including 8 cases of
rhabdomyosarcoma, 4 cases of synovial sarcoma, 2 cases of neuroblastoma and 1
case of lymphoma) using formalin-fixed and paraffin-embedded tissues.
RESULTS: EWS-FLI1/ERG fusion transcript was detected in 20 of the 25 ES/pPNET
cases (80%). The 15 non-ES/pPNET control cases were negative for EWS-FLI1/ERG
fusion transcript.
CONCLUSIONS: Detection of EWS-FLI1/ERG fusion transcript is a reliable index for
molecular diagnosis of ES/pPNET. One-step RT-PCR is a practical method for such
analysis in routine paraffin-embedded tumor tissues.
PMID: 15363317 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15565546 | 1. Klin Padiatr. 2004 Nov-Dec;216(6):315-22. doi: 10.1055/s-2004-832338.
Identification of various exon combinations of the ews/fli1 translocation: an
optimized RT-PCR method for paraffin embedded tissue -- a report by the
CWS-study group.
Stegmaier S(1), Leuschner I, Aakcha-Rudel E, Münch P, Kazanowska B, Bekassy A,
Treuner J, Koscielniak E.
Author information:
(1)Olgahospital, Stuttgart, Germany. [email protected]
BACKGROUND: Chromosomal translocations t(11;22) (q24;q12) are characteristic of
about 80-90 % of Ewing's sarcoma family of tumors [bone and soft tissue Ewing's
sarcoma and peripheral neuroectodermal tumors (PNET)]. They generate ews/fli1
rearrangements showing great diversity in breakpoint exon combination. In about
5 % of Ewing's tumors, ews is fused to the erg gene at 21q22. The various
chimeric proteins encoded may function as aberrant oncogenic transcription
factors. These specific translocations can be used for exact molecular diagnosis
in these poorly differentiated small round-cell tumors. Moreover, the prognostic
relevance of different translocational variants has been previously suggested.
Furthermore, the sensitive molecular detection of minimal metastatic and
residual disease and its clinical significance can be evaluated. To address
these questions more definitively in the large number of patients registered in
multicenter studies, it is often necessary to access archival paraffin-embedded
tumor tissue if no fresh or frozen tumor material is available for analysis by
RT (reverse transcription)-PCR. Specific problems arise from formalin-fixed and
paraffin-embedded tissue due to the degradation of RNA and insufficient
extraction efficiency. Therefore, primer distance and product size are limited
for successful PCR amplification. This conflicts with the requirement for
identification of various possible exon combinations by PCR simultaneously using
one single primer pair with larger distance.
PATIENTS: We examined paraffin embedded soft part tumor tissue samples from 47
Ewing's tumor patients. Patients were treated according to either CWS
(Cooperative Weichteilsarkomstudie, CWS-91 or CWS-96) or Euro-E.W.I.N.G. 99
therapy protocols.
METHOD: We established a novel RT-PCR method, using 3 different exon specific
sets of PCR primer pairs, selected according to the coding ews and fli1
nucleotide sequences (NCBI database), suitable for RT-PCR identification of
variant ews/fli1 fusion transcripts in RNA isolated from formalin-fixed,
paraffin-embedded tissue. For use in combination with ews -primer, an erg
specific primer was selected to alternatively test for ews/erg fusion
transcripts. As positive control for the integrity of isolated mRNA, we used the
ubiquitously expressed gapdh transcript for RT-PCR amplification in each sample.
RESULTS: In 31 cases (= 66 %) of 47 paraffin samples of Ewing's tumors analysed,
gapdh control indicated adequate quality of RNA. In 16 cases no gapdh control
fragment was amplifiable, nevertheless in 2 of these 16 samples distinct ews
fusion products could be detected. In 23 cases we identified ews fusion
transcripts. Thereof in 65 % ews exon 7 being fused to fli1 exon 6 (fusion type
I), in 22 % to fli1 exon 5 (fusion type II). In 4 % each ews exon 10 being
juxtaposed to fli1 either exon 6 or exon 5, respectively. An ews/erg fusion was
detected in 4 % ( ews exon 7 fused to erg exon 6). In 10 samples, a gapdh
fragment was amplified, but no ews/fli1 or - erg fusion transcript could be
identified. The reference pathological review (I. L., Kiel, Germany) disproved
the primary histopathology in 5 cases.
CONCLUSIONS: Using our different sets of exon specific primer pairs, it was
possible to detect 4 different breakpoints of ews/fli1 fusion transcripts and
the ews/erg fusion by RT-PCR in RNA isolates from formalin-fixed,
paraffin-embedded Ewing's tumor tissue. This method can be a very useful
alternative in clinical situations (to ensure diagnosis and perform minimal
metastatic and residual disease investigations) and in order to assess
prognostic significance of translocation subtypes when no fresh tumor tissue is
available.
DOI: 10.1055/s-2004-832338
PMID: 15565546 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18155474 | 1. Methods Cell Biol. 2008;85:431-70. doi: 10.1016/S0091-679X(08)85019-4.
Bimolecular fluorescence complementation: visualization of molecular
interactions in living cells.
Kerppola TK(1).
Author information:
(1)Department of Biological Chemistry, Howard Hughes Medical Institute,
University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
A variety of experimental methods have been developed for the analysis of
protein interactions. The majority of these methods either require disruption of
the cells to detect molecular interactions or rely on indirect detection of the
protein interaction. The bimolecular fluorescence complementation (BiFC) assay
provides a direct approach for the visualization of molecular interactions in
living cells and organisms. The BiFC approach is based on the facilitated
association between two fragments of a fluorescent protein when the fragments
are brought together by an interaction between proteins fused to the fragments.
The BiFC approach has been used for visualization of interactions among a
variety of structurally diverse interaction partners in many different cell
types. It enables detection of transient complexes as well as complexes formed
by a subpopulation of the interaction partners. It is essential to include
negative controls in each experiment in which the interface between the
interaction partners has been mutated or deleted. The BiFC assay has been
adapted for simultaneous visualization of multiple protein complexes in the same
cell and the competition for shared interaction partners. A ubiquitin-mediated
fluorescence complementation assay has also been developed for visualization of
the covalent modification of proteins by ubiquitin family peptides. These
fluorescence complementation assays have a great potential to illuminate a
variety of biological interactions in the future.
DOI: 10.1016/S0091-679X(08)85019-4
PMCID: PMC2829325
PMID: 18155474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22780989 | 1. Genome Res. 2012 Nov;22(11):2163-75. doi: 10.1101/gr.136507.111. Epub 2012 Jul
10.
Cohesin regulates tissue-specific expression by stabilizing highly occupied
cis-regulatory modules.
Faure AJ(1), Schmidt D, Watt S, Schwalie PC, Wilson MD, Xu H, Ramsay RG, Odom
DT, Flicek P.
Author information:
(1)European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton,
Cambridge CB10 1SD, United Kingdom.
The cohesin protein complex contributes to transcriptional regulation in a
CTCF-independent manner by colocalizing with master regulators at
tissue-specific loci. The regulation of transcription involves the concerted
action of multiple transcription factors (TFs) and cohesin's role in this
context of combinatorial TF binding remains unexplored. To investigate
cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as
well as a collection of tissue-specific and ubiquitous transcriptional
regulators using ChIP-seq in primary mouse liver. We observe a positive
correlation between the number of distinct TFs bound and the presence of CNC
sites. In contrast to regions of the genome where cohesin and CTCF colocalize,
CNC sites coincide with the binding of master regulators and enhancer-markers
and are significantly associated with liver-specific expressed genes. We also
show that cohesin presence partially explains the commonly observed discrepancy
between TF motif score and ChIP signal. Evidence from these statistical analyses
in wild-type cells, and comparisons to maps of TF binding in Rad21-cohesin
haploinsufficient mouse liver, suggests that cohesin helps to stabilize large
protein-DNA complexes. Finally, we observe that the presence of mirrored CTCF
binding events at promoters and their nearby cohesin-bound enhancers is
associated with elevated expression levels.
DOI: 10.1101/gr.136507.111
PMCID: PMC3483546
PMID: 22780989 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23317900 | 1. Methods Cell Biol. 2013;113:107-21. doi: 10.1016/B978-0-12-407239-8.00006-9.
Bimolecular fluorescence complementation (BiFC) analysis of protein-protein
interaction: how to calculate signal-to-noise ratio.
Kodama Y(1), Hu CD.
Author information:
(1)Center for Bioscience Research and Education, Utsunomiya University,
Utsunomiya, Tochigi, Japan.
Bimolecular fluorescence complementation (BiFC) is a technique to visualize
protein-protein interactions in living cells, and has been widely used in
various model organisms. The principle of the BiFC assay is based on the
reconstitution of an intact fluorescent protein. The two non-fluorescent
fragments are fused to proteins of interest that may interact. If the two
proteins interact, the two non-fluorescent fragments are brought together to
reconstitute an intact fluorescent protein. The purpose of this protocol is to
calculate signal-to-noise (S/N) ratio in the bimolecular fluorescence
complementation (BiFC) assay and to provide a semi-quantitative analysis of
protein-protein interaction (PPI) in living cells.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-12-407239-8.00006-9
PMID: 23317900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25151172 | 1. Methods Mol Biol. 2014;1196:307-18. doi: 10.1007/978-1-4939-1242-1_19.
Bimolecular fluorescence complementation (BiFC) in live Drosophila embryos.
Duffraisse M(1), Hudry B, Merabet S.
Author information:
(1)Institut de Génomique Fonctionnelle de Lyon, ENS de Lyon - CNRS UMR5242, 46
Allée d'Italie, 69364, Lyon Cedex 07, France.
Bimolecular fluorescence complementation (BiFC) is a powerful method for
studying protein-protein interactions in different cell types and organisms.
This method was recently developed in the fruit fly Drosophila melanogaster,
allowing analyzing protein interaction properties in a physiologically relevant
developing context. Here we present a detailed protocol for performing BiFC with
the Venus fluorescent protein in live Drosophila embryos, taking the Hox-PBC
partnership as an illustrative test case. This protocol applies to any
transcription factor and split fluorescent protein in general.
DOI: 10.1007/978-1-4939-1242-1_19
PMID: 25151172 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22952237 | 1. J Biol Chem. 2012 Sep 7;287(37):30906-13. doi: 10.1074/jbc.R111.324962. Epub
2012 Sep 5.
Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight
into chromatin structure and regulation.
Lee BK(1), Iyer VR.
Author information:
(1)Center for Systems and Synthetic Biology, Institute for Cellular and
Molecular Biology, Section of Molecular Genetics and Microbiology, University of
Texas, Austin, Texas 78712, USA.
Eukaryotic genomes are organized into higher order chromatin architectures by
protein-mediated long-range interactions in the nucleus. CCCTC-binding factor
(CTCF), a sequence-specific transcription factor, serves as a chromatin
organizer in building this complex chromatin structure by linking chromosomal
domains. Recent genome-wide studies mapping the binding sites of CTCF and its
interacting partner, cohesin, using chromatin immunoprecipitation coupled with
deep sequencing (ChIP-seq) revealded that CTCF globally co-localizes with
cohesin. This partnership between CTCF and cohesin is emerging as a novel and
perhaps pivotal aspect of gene regulatory mechanisms, in addition to playing a
role in the organization of higher order chromatin architecture.
DOI: 10.1074/jbc.R111.324962
PMCID: PMC3438923
PMID: 22952237 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17406412 | 1. Nat Protoc. 2006;1(3):1278-86. doi: 10.1038/nprot.2006.201.
Design and implementation of bimolecular fluorescence complementation (BiFC)
assays for the visualization of protein interactions in living cells.
Kerppola TK(1).
Author information:
(1)Howard Hughes Medical Institute and Department of Biological Chemistry,
University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
[email protected]
Bimolecular fluorescence complementation (BiFC) analysis enables direct
visualization of protein interactions in living cells. The BiFC assay is based
on the discoveries that two non-fluorescent fragments of a fluorescent protein
can form a fluorescent complex and that the association of the fragments can be
facilitated when they are fused to two proteins that interact with each other.
BiFC must be confirmed by parallel analysis of proteins in which the interaction
interface has been mutated. It is not necessary for the interaction partners to
juxtapose the fragments within a specific distance of each other because they
can associate when they are tethered to a complex with flexible linkers. It is
also not necessary for the interaction partners to form a complex with a long
half-life or a high occupancy since the fragments can associate in a transient
complex and un-associated fusion proteins do not interfere with detection of the
complex. Many interactions can be visualized when the fusion proteins are
expressed at levels comparable to their endogenous counterparts. The BiFC assay
has been used for the visualization of interactions between many types of
proteins in different subcellular locations and in different cell types and
organisms. It is technically straightforward and can be performed using a
regular fluorescence microscope and standard molecular biology and cell culture
reagents.
DOI: 10.1038/nprot.2006.201
PMCID: PMC2518326
PMID: 17406412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20684013 | 1. Am J Med Genet A. 2010 Sep;152A(9):2254-61. doi: 10.1002/ajmg.a.33598.
Inheritance and variable expression in Rubinstein-Taybi syndrome.
Bartsch O(1), Kress W, Kempf O, Lechno S, Haaf T, Zechner U.
Author information:
(1)Institut für Humangenetik, Universitätsmedizin der
Johannes-Gutenberg-Universität Mainz, Mainz, Germany.
[email protected]
Familial Rubinstein-Taybi syndrome (RTS) is very rare. Here we report on the 6th
and 7th case of inherited RTS. Family 1 presents with incomplete or mild RTS
over three generations; a 13-year-old girl (proband 1) with mild but typical
facial features and learning disabilities, her very mildly affected mother
(proband 2), and the maternal grandmother (proband 3). Family 2 includes three
females with classical RTS (probands 4-6) and their father (proband 7) with
broad thumbs and halluces. Proband 5 also had a brain tumor (ganglioglioma) at
the age of 3 years. In probands 1-3, direct sequencing identified a novel CREBBP
missense mutation, c.2728A > G (predicting p.Thr910Ala), that was absent in
non-affected family members. The p.Thr910Ala variant is outside the crucial
histone acetyltransferase domain, and this may explain the mild and variable
phenotype. In probands 4-7 we identified another novel CREBBP mutation, c.4134G
> T, which alters the consensus splice sequence at position 1 of exon 25. The
c.4134G > T mutation was transmitted from the very mildly affected father who
displayed somatic mosaicism (with 38% mutated alleles in blood and 31% in buccal
smear DNA) to his three daughters. Our findings emphasize that variable
expression (family 1) and somatic mosaicism (family 2) contribute to the
phenotypic variability of RTS. Somatic mosaicism may be more frequent in RTS
than previously assumed. Accumulating data suggest a recurrence risk of
approximately 0.5-1% for parents of a child with RTS, exceeding the so far
estimated risk of approximately 0.1% for siblings.
Copyright 2010 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.33598
PMID: 20684013 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21091444 | 1. Biotechniques. 2010 Nov;49(5):793-805. doi: 10.2144/000113519.
An improved bimolecular fluorescence complementation assay with a high
signal-to-noise ratio.
Kodama Y(1), Hu CD.
Author information:
(1)Department of Medicinal Chemistry and Molecular Pharmacology, Purdue
University, West Lafayette, IN 47907, USA. [email protected]
Protein-protein interactions (PPIs) play crucial roles in various biological
processes. Among biochemical, genetic, and imaging approaches that have been
used for the study of PPIs, visualization of PPIs in living cells is the key to
understanding their cellular functions. The bimolecular fluorescence
complementation (BiFC) assay represents one of these imaging tools for direct
visualization of PPIs in living cells. The BiFC assay is based on the structural
complementation of two nonfluorescent N- and C-terminal fragments of a
fluorescent protein when they are fused to a pair of interacting proteins.
Although over 10 different fluorescent proteins have been used for BiFC assays,
the two nonfluorescent fragments from all of these fluorescent proteins can
spontaneously self-assemble, which contributes to background fluorescence and
decreases the signal-to-noise (S/N) ratio in the BiFC assay. Here we report the
identification of a mutation, I152L, that can specifically reduce self-assembly
and decrease background fluorescence in a Venus-based BiFC system. This mutation
allows a 4-fold increase in the S/N ratio of the BiFC assay in living cells.
This improved Venus-based BiFC system will facilitate PPI studies in various
biological research fields.
DOI: 10.2144/000113519
PMID: 21091444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18573091 | 1. Annu Rev Biophys. 2008;37:465-87. doi:
10.1146/annurev.biophys.37.032807.125842.
Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein
interactions in living cells.
Kerppola TK(1).
Author information:
(1)Howard Hughes Medical Institute and Department of Biological Chemistry,
University of Michigan Medical School, Ann Arbor, Michigan 48109-0650, USA.
[email protected]
Protein interactions are a fundamental mechanism for the generation of
biological regulatory specificity. The study of protein interactions in living
cells is of particular significance because the interactions that occur in a
particular cell depend on the full complement of proteins present in the cell
and the external stimuli that influence the cell. Bimolecular fluorescence
complementation (BiFC) analysis enables direct visualization of protein
interactions in living cells. The BiFC assay is based on the association between
two nonfluorescent fragments of a fluorescent protein when they are brought in
proximity to each other by an interaction between proteins fused to the
fragments. Numerous protein interactions have been visualized using the BiFC
assay in many different cell types and organisms. The BiFC assay is technically
straightforward and can be performed using standard molecular biology and cell
culture reagents and a regular fluorescence microscope or flow cytometer.
DOI: 10.1146/annurev.biophys.37.032807.125842
PMCID: PMC2829326
PMID: 18573091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18773673 | 1. Turk J Pediatr. 2008 May-Jun;50(3):265-8.
Rubinstein-Taybi syndrome with normal FISH result and CREBBP gene analysis: a
case report.
Balci S(1), Ergün MA, Yüksel-Konuk EB, Bartsch O.
Author information:
(1)Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara,
Turkey.
We report on a six-year-old boy with typical Rubinstein-Taybi syndrome (RSTS)
phenotype. Clinical findings included mental and motor retardation, patent
ductus arteriosus (PDA), undescended testes, hirsutism, broad thumbs with radial
angulation and broad toes, and inguinal hernia. His karyotype was normal (46,
XY) and fluorescence in situ hybridization (FISH) showed no deletion of the
CREBBP [cAMP response element-binding (CREB) binding protein] gene on chromosome
16p13.3. CREBBP gene sequencing also revealed normal results. We wish to present
this case because this patient had typical RSTS phenotype, but normal FISH and
CREBBP gene sequencing results. It could be possible that genetic heterogeneity
is related with novel mutations in other genes. With the publication of such
cases, their significance will be brought to the attention of researchers in
this field.
PMID: 18773673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23945083 | 1. BMC Genomics. 2013 Aug 14;14:553. doi: 10.1186/1471-2164-14-553.
Characterization of constitutive CTCF/cohesin loci: a possible role in
establishing topological domains in mammalian genomes.
Li Y(1), Huang W, Niu L, Umbach DM, Covo S, Li L.
Author information:
(1)Biostatistics Branch, National Institute of Environmental Health Sciences,
Research Triangle Park, Durham, NC 27709, USA. [email protected].
BACKGROUND: Recent studies suggested that human/mammalian genomes are divided
into large, discrete domains that are units of chromosome organization. CTCF, a
CCCTC binding factor, has a diverse role in genome regulation including
transcriptional regulation, chromosome-boundary insulation, DNA replication, and
chromatin packaging. It remains unclear whether a subset of CTCF binding sites
plays a functional role in establishing/maintaining chromatin topological
domains.
RESULTS: We systematically analysed the genomic, transcriptomic and epigenetic
profiles of the CTCF binding sites in 56 human cell lines from ENCODE. We
identified ~24,000 CTCF sites (referred to as constitutive sites) that were
bound in more than 90% of the cell lines. Our analysis revealed: 1) constitutive
CTCF loci were located in constitutive open chromatin and often co-localized
with constitutive cohesin loci; 2) most constitutive CTCF loci were distant from
transcription start sites and lacked CpG islands but were enriched with the
full-spectrum CTCF motifs: a recently reported 33/34-mer and two other
potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci
were present in CTCF-mediated chromatin interactions detected by ChIA-PET and
these pair-wise interactions occurred predominantly within, but not between,
topological domains identified by Hi-C.
CONCLUSIONS: Our results suggest that the constitutive CTCF sites may play a
role in organizing/maintaining the recently identified topological domains that
are common across most human cells.
DOI: 10.1186/1471-2164-14-553
PMCID: PMC3765723
PMID: 23945083 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21948239 | 1. Mol Cell Biochem. 2012 Jan;360(1-2):243-51. doi: 10.1007/s11010-011-1063-3.
Epub 2011 Sep 23.
CTCF and cohesin cooperatively mediate the cell-type specific interchromatin
interaction between Bcl11b and Arhgap6 loci.
Ren L(1), Shi M, Wang Y, Yang Z, Wang X, Zhao Z.
Author information:
(1)State Key Laboratory of Bioreactor Engineering, East China University of
Science and Technology, Shanghai, China.
CCCTC-binding factor (CTCF) is a master organizer of genome spatial organization
and plays an important role in mediating extensive chromatin interactions.
Circular chromosome conformation capture (4C) is a high-throughput approach that
allows genome-wide screening for unknown potential interaction partners. Using a
conserved CTCF binding site on the Bcl11b locus as bait, an interaction partner
at the Arhgap6 locus on a different chromosome was identified by 4C. Additional
experiments verified that the interchromatin interaction between the Bcl11b and
Arhgap6 loci was cell-type specific, which was cooperatively mediated by CTCF
and cohesin. Functional analysis showed that the interchromatin interaction
partners were repressing regulatory elements. These results indicate that
interaction chromatin loops regulate the expression of the relevant genes.
DOI: 10.1007/s11010-011-1063-3
PMID: 21948239 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21276241 | 1. BMC Biol. 2011 Jan 28;9:5. doi: 10.1186/1741-7007-9-5.
Visualization of protein interactions in living Drosophila embryos by the
bimolecular fluorescence complementation assay.
Hudry B(1), Viala S, Graba Y, Merabet S.
Author information:
(1)Institut de Biologie du Développement de Marseille Luminy, IBDML, UMR 6216,
CNRS, Université de la méditerranée, Parc Scientifique de Luminy, Case 907,
13288, Marseille Cedex 09, France.
BACKGROUND: Protein interactions control the regulatory networks underlying
developmental processes. The understanding of developmental complexity will,
therefore, require the characterization of protein interactions within their
proper environment. The bimolecular fluorescence complementation (BiFC)
technology offers this possibility as it enables the direct visualization of
protein interactions in living cells. However, its potential has rarely been
applied in embryos of animal model organisms and was only performed under
transient protein expression levels.
RESULTS: Using a Hox protein partnership as a test case, we investigated the
suitability of BiFC for the study of protein interactions in the living
Drosophila embryo. Importantly, all BiFC parameters were established with
constructs that were stably expressed under the control of endogenous promoters.
Under these physiological conditions, we showed that BiFC is specific and
sensitive enough to analyse dynamic protein interactions. We next used BiFC in a
candidate interaction screen, which led to the identification of several Hox
protein partners.
CONCLUSION: Our results establish the general suitability of BiFC for revealing
and studying protein interactions in their physiological context during the
rapid course of Drosophila embryonic development.
DOI: 10.1186/1741-7007-9-5
PMCID: PMC3041725
PMID: 21276241 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20219941 | 1. Genome Res. 2010 May;20(5):578-88. doi: 10.1101/gr.100479.109. Epub 2010 Mar
10.
A CTCF-independent role for cohesin in tissue-specific transcription.
Schmidt D(1), Schwalie PC, Ross-Innes CS, Hurtado A, Brown GD, Carroll JS,
Flicek P, Odom DT.
Author information:
(1)Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre,
Cambridge CB2 0RE, United Kingdom.
The cohesin protein complex holds sister chromatids in dividing cells together
and is essential for chromosome segregation. Recently, cohesin has been
implicated in mediating transcriptional insulation, via its interactions with
CTCF. Here, we show in different cell types that cohesin functionally behaves as
a tissue-specific transcriptional regulator, independent of CTCF binding. By
performing matched genome-wide binding assays (ChIP-seq) in human breast cancer
cells (MCF-7), we discovered thousands of genomic sites that share cohesin and
estrogen receptor alpha (ER) yet lack CTCF binding. By use of human
hepatocellular carcinoma cells (HepG2), we found that liver-specific
transcription factors colocalize with cohesin independently of CTCF at
liver-specific targets that are distinct from those found in breast cancer
cells. Furthermore, estrogen-regulated genes are preferentially bound by both ER
and cohesin, and functionally, the silencing of cohesin caused aberrant re-entry
of breast cancer cells into cell cycle after hormone treatment. We combined
chromosomal interaction data in MCF-7 cells with our cohesin binding data to
show that cohesin is highly enriched at ER-bound regions that capture
inter-chromosomal loop anchors. Together, our data show that cohesin cobinds
across the genome with transcription factors independently of CTCF, plays a
functional role in estrogen-regulated transcription, and may help to mediate
tissue-specific transcriptional responses via long-range chromosomal
interactions.
DOI: 10.1101/gr.100479.109
PMCID: PMC2860160
PMID: 20219941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14974086 | 1. Hum Mutat. 2004 Mar;23(3):278-84. doi: 10.1002/humu.20001.
Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients
using real-time quantitative PCR.
Coupry I(1), Monnet L, Attia AA, Taine L, Lacombe D, Arveiler B.
Author information:
(1)Laboratoire de Génétique Humaine, Développement et Cancer, Université Victor
Segalen Bordeaux 2, Bordeaux, France. [email protected]
Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome characterized by
facial abnormalities, broad thumbs, broad big toes, and growth and mental
retardation as the main clinical features. RTS was shown to be associated with
disruption of the CREB-binding protein gene CBP (CREBBP), either by gross
chromosomal rearrangements or by point mutations. Translocations and inversions
involving chromosome band 16p13.3 form the minority of CBP mutations, whereas
microdeletions occur more frequently (about 10%). Most deletion studies in RTS
are performed by FISH analysis, and five cosmids must be used to cover the whole
of the CBP gene, which spreads over 150 kb. Here we report the design of gene
dosage assays by real-time quantitative PCR that are targeted on three exons
located respectively at the 5' end (exon 2), in the middle (exon 12), and at the
3' end (exon 30) of the CBP gene. This technique proved to be efficient and
powerful in finding deletions and complementary to the other available
techniques, since it allowed us to identify deletions at the 3' end of the gene
that had been missed by FISH analysis, and to refine some deletion breakpoints.
Our results therefore suggest that real-time quantitative PCR is a useful
technique to be included in the deletion search in RTS patients.
Copyright 2004 Wiley-Liss, Inc.
DOI: 10.1002/humu.20001
PMID: 14974086 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19771334 | 1. Chem Soc Rev. 2009 Oct;38(10):2876-86. doi: 10.1039/b909638h. Epub 2009 Sep 4.
Visualization of molecular interactions using bimolecular fluorescence
complementation analysis: characteristics of protein fragment complementation.
Kerppola TK(1).
Author information:
(1)Howard Hughes Medical Institute and Department of Biological Chemistry,
University of Michigan Medical School, Ann Arbor, MI 48109-0650, USA.
[email protected]
Investigations of the molecular processes that sustain life must include studies
of these processes in their normal cellular environment. The bimolecular
fluorescence complementation (BiFC) assay provides an approach for the
visualization of protein interactions and modifications in living cells. This
assay is based on the facilitated association of complementary fragments of a
fluorescent protein that are fused to interaction partners. Complex formation by
the interaction partners tethers the fluorescent protein fragments in proximity
to each other, which can facilitate their association. The BiFC assay enables
sensitive visualization of protein complexes with high spatial resolution. The
temporal resolution of BiFC analysis is limited by the time required for
fluorophore formation, as well as the stabilization of complexes by association
of the fluorescent protein fragments. Many modifications and enhancements to the
BiFC assay have been developed. The multicolor BiFC assay enables simultaneous
visualization of multiple protein complexes in the same cell, and can be used to
investigate competition among mutually exclusive interaction partners for
complex formation in cells. The ubiquitin-mediated fluorescence complementation
(UbFC) assay enables visualization of covalent ubiquitin family peptide
conjugation to substrate proteins in cells. The BiFC assay can also be used to
visualize protein binding to specific chromatin domains, as well as other
molecular scaffolds in cells. BiFC analysis therefore provides a powerful
approach for the visualization of a variety of processes that affect molecular
proximity in living cells. The visualization of macromolecular interactions and
modifications is of great importance owing to the central roles of proteins,
nucleic acids and other macromolecular complexes in the regulation of cellular
functions. This tutorial review describes the BiFC assay, and discusses the
advantages and disadvantages of this experimental approach. The review will be
of interest to scientists interested in the investigation of macromolecular
interactions or modifications who need exquisite sensitivity for the detection
of their complexes or conjugates of interest.
DOI: 10.1039/b909638h
PMCID: PMC2980501
PMID: 19771334 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21952165 | 1. Mol Ther. 2012 Jan;20(1):178-86. doi: 10.1038/mt.2011.192. Epub 2011 Sep 27.
Aire controls mesenchymal stem cell-mediated suppression in chronic colitis.
Parekkadan B(1), Fletcher AL, Li M, Tjota MY, Bellemare-Pelletier A, Milwid JM,
Lee JW, Yarmush ML, Turley SJ.
Author information:
(1)Department of Surgery, Center for Engineering in Medicine and Surgical
Services, Massachusetts General Hospital, Harvard Medical School and the
Shriners Hospitals for Children, Boston, Massachusetts, USA.
[email protected]
Mesenchymal stem cells (MSCs) are emerging as a promising immunotherapeutic,
based largely on their overt suppression of T lymphocytes under inflammatory and
autoimmune conditions. While paracrine cross-talk between MSCs and T cells has
been well-studied, an intrinsic transcriptional switch that programs MSCs for
immunomodulation has remained undefined. Here we show that bone marrow-derived
MSCs require the transcriptional regulator Aire to suppress T cell-mediated
pathogenesis in a mouse model of chronic colitis. Surprisingly, Aire did not
control MSC suppression of T cell proliferation in vitro. Instead, Aire reduced
T cell mitochondrial reductase by negatively regulating a proinflammatory
cytokine, early T cell activation factor (Eta)-1. Neutralization of Eta-1
enabled Aire(-/-) MSCs to ameliorate colitis, reducing the number of
infiltrating effector T cells in the colon, and normalizing T cell reductase
levels. We propose that Aire represents an early molecular switch imposing a
suppressive MSC phenotype via regulation of Eta-1. Monitoring Aire expression in
MSCs may thus be a critical parameter for clinical use.
DOI: 10.1038/mt.2011.192
PMCID: PMC3255580
PMID: 21952165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23259496 | 1. J Proteome Res. 2013 Jan 4;12(1):28-32. doi: 10.1021/pr300933p. Epub 2012 Dec
21.
The chromosome-centric human proteome project: a call to action.
Hühmer AF(1), Paulus A, Martin LB, Millis K, Agreste T, Saba J, Lill JR, Fischer
SM, Dracup W, Lavery P.
Author information:
(1)Thermo Fisher Scientific, Life Science Mass Spectrometry, San Jose,
California 95134, United States.
The grand vision of the human proteome project (HPP) is moving closer to reality
with the recent announcement by HUPO of the creation of the HPP consortium in
charge of the development of a two-part HPP, one focused on the description of
proteomes of biological samples or related to diseases (B/D-HPP) and the other
dedicated to a systematic description of proteins as gene products encoded in
the human genome (the C-HPP). This new initiative of HUPO seeks to identify and
characterize at least one representative protein from every gene, create a
protein distribution atlas and a protein pathway or network map. This vision for
proteomics can be the roadmap of biological and clinical research for years to
come if it delivers on its promises. The Industrial Advisory Board (IAB) to HUPO
shares the visions of C-HPP. The IAB will support and critically accompany the
overall project goals and the definitions of the critical milestones. The member
companies are in a unique position to develop hardware and software, reagents
and standards, procedures, and workflows to ensure a reliable source of tools
available to the proteomics community worldwide. In collaboration with academia,
the IAB member companies can and must develop the tools to reach the ambitious
project goals. We offer to partner with and challenge the academic groups
leading the C-HPP to define both ambitious and obtainable goals and milestones
to make the C-HPP a real and trusted resource for future biology.
DOI: 10.1021/pr300933p
PMID: 23259496 [Indexed for MEDLINE] |