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http://www.ncbi.nlm.nih.gov/pubmed/25784211 | 1. J Mol Biol. 2015 Aug 14;427(16):2599-609. doi: 10.1016/j.jmb.2015.03.006. Epub
2015 Mar 14.
Mitochondrial Genome Maintenance 1 (Mgm1) Protein Alters Membrane Topology and
Promotes Local Membrane Bending.
Rujiviphat J(1), Wong MK(2), Won A(2), Shih YL(3), Yip CM(4), McQuibban GA(5).
Author information:
(1)Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
M5S 1A8.
(2)Institute of Biomaterials and Biomedical Engineering, University of Toronto,
Toronto, Ontario, Canada M5S 3G9.
(3)Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
(4)Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
M5S 1A8; Institute of Biomaterials and Biomedical Engineering, University of
Toronto, Toronto, Ontario, Canada M5S 3G9; Department of Chemical Engineering
and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3E5.
(5)Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
M5S 1A8. Electronic address: [email protected].
Comment in
J Mol Biol. 2015 Aug 14;427(16):2595-8. doi: 10.1016/j.jmb.2015.06.003.
Large GTPases of the dynamin superfamily promote membrane fusion and division,
processes that are crucial for intracellular trafficking and organellar
dynamics. To promote membrane scission, dynamin proteins polymerize, wrap
around, and constrict the membrane; however, the mechanism underlying their role
in membrane fusion remains unclear. We previously reported that the
mitochondrial dynamin-related protein mitochondrial genome maintenance 1 (Mgm1)
mediates fusion by first tethering opposing membranes and then undergoing a
nucleotide-dependent structural transition. However, it is still unclear how
Mgm1 directly affects the membrane to drive fusion of tethered membranes. Here,
we show that Mgm1 association with the membrane alters the topography of the
membrane, promoting local membrane bending. We also demonstrate that Mgm1
creates membrane ruffles resulting in the formation of tubular structures on
both supported lipid bilayers and liposomes. These data suggest that Mgm1
membrane interactions impose a mechanical force on the membrane to overcome the
hydrophilic repulsion of the phospholipid head groups and initiate the fusion
reaction. The work reported here provides new insights into a possible mechanism
of Mgm1-driven mitochondrial membrane fusion and sheds light into how members of
the dynamin superfamily function as fusion molecules.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2015.03.006
PMID: 25784211 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9875761 | 1. Ann Thorac Surg. 1998 Nov;66(5):1618-25. doi: 10.1016/s0003-4975(98)00764-4.
Triiodothyronine reverses depressed contractile performance after excessive
catecholamine stimulation.
Timek T(1), Vahl CF, Bonz A, Schäffer L, Rosenberg M, Hagl S.
Author information:
(1)Department of Cardiac Surgery, University of Heidelberg, Germany.
BACKGROUND: Conflicting results have been reported regarding the acute effects
of triiodothyronine (T3) on myocardial contractile performance. The present
study analyzes the role of T3 in reversing the depressant effect of excessive
catecholamine stimulation in isolated porcine left ventricular myocardium.
METHODS: Thirty-six left ventricular trabeculae (0.4 x 6.0 mm) obtained from 6
pigs were used for measurements of isometric force development, isotonic
shortening, and intracellular calcium in three experimental series (measurement
conditions: 37 degrees C; optimal length; supramaximal electrical stimulation, 1
Hz; calcium measurement, fura-2 ratio method; frequency, 225 Hz). In series 1,
isometric force development was measured before and after a 60-minute incubation
with 10(-7) mol/L epinephrine in preparations with (n = 6) and without (n = 6)
preceding fura-2 loading for calcium measurements. In series 2, the acute
effects of a 30-minute administration of T3 (10(-9) mol/L) on isometric force
and intracellular calcium were analyzed (n = 6). In series 3, after simultaneous
fura-2 loading and a 6-hour 10(-7) mol/L epinephrine exposure the effects of T3
(10(-9) mol/L, 30 minutes) on force development, shortening, and intracellular
calcium transient were analyzed.
RESULTS: Long-term and high-dose epinephrine exposure induced a severe
contractile depression with a significant reduction of isometric force
development (p < 0.05) and increased diastolic (p < 0.001) and systolic calcium
(p < 0.001). In normal porcine myocardium T3 had no effect on the extent of
isometric force generation but accelerated the time course of force development
(p < 0.05) and increased the calcium transient (p < 0.001). After induction of
myocardial depression by epinephrine exposure T3 accelerated the intracellular
calcium transients and reduced diastolic calcium. Triiodothyronine increased the
shortening amplitude and the force amplitude (p < 0.01).
CONCLUSIONS: Triiodothyronine reverses depressed contractile performance after
preceding high-dose epinephrine exposure in isolated porcine myocardium.
Increased force amplitudes and unaltered or even reduced intracellular calcium
transients argue in favor of a resensitization of the contractile apparatus for
calcium by T3. The study supports a potential role for T3 treatment in depressed
myocardium after previous excessive catecholamine exposure (eg, brain death,
catecholamine treatment, ischemia).
DOI: 10.1016/s0003-4975(98)00764-4
PMID: 9875761 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15975558 | 1. Biochem Biophys Res Commun. 2005 Aug 5;333(3):954-60. doi:
10.1016/j.bbrc.2005.05.188.
Calpain cleavage regulates the protein stability of p73.
Munarriz E(1), Bano D, Sayan AE, Rossi M, Melino G, Nicotera P.
Author information:
(1)Medical Research Council, Toxicology Unit, University of Leicester, Leicester
LE1 9HN, UK.
The function of p73, a transcription factor belonging to the p53 family, is
finely regulated by its steady-state protein stability. p73 protein
degradation/stabilization can be regulated by mechanisms in part dependent on
the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii)
NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but
ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can
cleave p73 at two distinct sites: the first proline-rich region and within the
oligomerization domain. Consequently, different p73 isoforms can be degraded by
calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the
C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the
specific endogenous calpain inhibitor, calpastatin, in cultured cells increased
the steady-state p73 level. This suggests that calpains may play a physiological
role in the regulation of p73 protein stability.
DOI: 10.1016/j.bbrc.2005.05.188
PMID: 15975558 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21779495 | 1. Genes Cancer. 2011 Mar;2(3):216-31. doi: 10.1177/1947601911408081.
Functional specificity of ras isoforms: so similar but so different.
Castellano E(1), Santos E.
Author information:
(1)Signal Transduction Laboratory, Cancer Research UK London Research Institute,
London, UK.
H-ras, N-ras, and K-ras are canonical ras gene family members frequently
activated by point mutation in human cancers and coding for 4 different, highly
related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). Their expression
is nearly ubiquitous and broadly conserved across eukaryotic species, although
there are quantitative and qualitative differences of expression depending on
the tissue and/or developmental stage under consideration. Extensive functional
studies have determined during the last quarter century that these Ras gene
products are critical components of signaling pathways that control eukaryotic
cell proliferation, survival, and differentiation. However, because of their
homology and frequent coexpression in various cellular contexts, it remained
unclear whether the different Ras proteins play specific or overlapping
functional roles in physiological and pathological processes. Initially, their
high degree of sequence homology and the observation that all Ras isoforms share
common sets of downstream effectors and upstream activators suggested that they
were mostly redundant functionally. In contrast, the notion of functional
specificity for each of the different Ras isoforms is supported at present by an
increasing body of experimental observations, including 1) the fact that
different ras isoforms are preferentially mutated in specific types of tumors or
developmental disorders; 2) the different transforming potential of transfected
ras genes in different cell contexts; 3) the distinct sensitivities exhibited by
the various Ras family members for modulation by different GAPs or GEFs; 4) the
demonstration that different Ras isoforms follow distinct intracellular
processing pathways and localize to different membrane microdomains or
subcellular compartments; 5) the different phenotypes displayed by genetically
modified animal strains for each of the 3 ras loci; and 6) the specific
transcriptional networks controlled by each isoform in different cellular
settings.
DOI: 10.1177/1947601911408081
PMCID: PMC3128637
PMID: 21779495
Conflict of interest statement: The author(s) declared no potential conflicts of
interest with respect to the research, authorship, and/or publication of this
article. |
http://www.ncbi.nlm.nih.gov/pubmed/22648805 | 1. Electrophoresis. 2012 May;33(9-10):1385-96. doi: 10.1002/elps.201100606.
Functional specific roles of H-ras and N-ras. A proteomic approach using
knockout cell lines.
Ferreira L(1), Fuentes-Calvo I, Muñoz-Félix JM, Muñiz-Martín C, Sánchez-Juanes
F, Raposo C, González-Buitrago JM, López-Novoa JM, Martínez-Salgado C.
Author information:
(1)Unidad de Investigación, Hospital Universitario de Salamanca, Spain.
Ras small GTPases function as transducers of extracellular signals regulating
cell survival, growth and differentiation. There are three major ras isoforms:
H-, N- and K-Ras. To improve the understanding of H- and N-Ras protein
signalling networks, we compared total proteome changes in mouse embryonic
fibroblasts knock out for H-ras and/or N-ras, using proteomics tools combining
2DE, semi-quantitative image analysis, in-gel trypsin digestion and mass
spectrometry. There are four up-regulated proteins due to the loss of expression
of H-Ras (including cyclin-dependent kinase inhibitor 2A) and eight
down-regulated (including stress-70 protein, dihydropyrimidinase-related-protein
3, heat shock cognate 71 kDa protein, tropomyosin beta chain, Rho
GDP-dissociation inhibitor 1) and six up-regulated proteins (e.g. leukocyte
elastase inhibitor A, L-lactate dehydrogenase B chain, c-Myc-responsive protein
Rcl, interleukin-1 receptor antagonist protein) due to the loss of expression of
both N- and H-Ras. Most of these proteins are related to Ras signalling in one
way or another. Changes in expression of some of these proteins were further
confirmed by Western blot. This proteomic comparative analysis from loss of
function of H- and N-Ras knockout fibroblasts yields interpretable data to
elucidate the differential protein expression, and contributes to evaluate the
possibilities for physiological and therapeutic targets.
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/elps.201100606
PMID: 22648805 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22388545 | 1. Aging (Albany NY). 2012 Mar;4(3):202-5. doi: 10.18632/aging.100441.
Relative expression of TAp73 and ΔNp73 isoforms.
Conforti F(1), Yang AL, Agostini M, Rufini A, Tucci P, Nicklison-Chirou MV,
Grespi F, Velletri T, Knight RA, Melino G, Sayan BS.
Author information:
(1)University of Southampton, Cancer Sciences Unit, Somers Cancer Research
Building, Southampton, UK.
The transcription factor p73 belongs to the p53 family of tumour suppressors and
similar to other family members, transcribed as different isoforms with opposing
pro- and anti-apoptotic functions. Unlike p53, p73 mutations are extremely rare
in cancers. Instead, the pro-apoptotic activities of transcriptionally active
p73 isoforms are commonly inhibited by over-expression of the dominant negative
p73 isoforms. Therefore the relative ratio of different p73 isoforms is critical
for the cellular response to a chemotherapeutic agent. Here, we analysed the
expression of N-terminal p73 isoforms in cell lines and mouse tissues. Our data
showed that the transcriptionally competent TAp73 isoform is abundantly
expressed in cancer cell lines compared to the dominant negative ΔNp73 isoform.
Interestingly, we detected higher levels of ΔNp73 in some mouse tissues,
suggesting that ΔNp73 may have a physiological role in these tissues.
DOI: 10.18632/aging.100441
PMCID: PMC3348480
PMID: 22388545 [Indexed for MEDLINE]
Conflict of interest statement: The authors of this manuscript have no conflict
of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/15610529 | 1. J Invest Dermatol. 2004 Dec;123(6):1162-8. doi:
10.1111/j.0022-202X.2004.23498.x.
The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid
tazarotene.
Papoutsaki M(1), Lanza M, Marinari B, Nisticò S, Moretti F, Levrero M, Chimenti
S, Costanzo A.
Author information:
(1)Department of Dermatology, University of Rome Tor Vergata, Rome, Italy.
Comment in
J Invest Dermatol. 2004 Dec;123(6):xx-xxi. doi:
10.1111/j.0022-202X.2004.23533.x.
Tazarotene, a member of the new class of acetylenic retinoids, has been shown to
be effective in the treatment of several hyperproliferative skin diseases,
including non-melanoma skin cancer. Its effectiveness is thought to rely on the
ability to activate retinoic acid receptors beta and gamma and to induce a
number of downstream anti-proliferative genes. Here, we show that the
p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the
expression of the p73 gene in immortalized keratinocyte cell lines by inducing
the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the
anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the
transcriptional level through a coordinated action on P1p73 and P2p73 promoters
that control the expression of TA and DeltaN isoforms, respectively. The
selective downregulation of DeltaNp73 expression by small interfering RNA led to
an enhancement of tazarotene-induced bax activation and apoptosis, whereas the
downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated
apoptosis. These results indicate the relevance of p73 gene products in
tazarotene-induced growth inhibition and effectiveness in the treatment of skin
tumors.
DOI: 10.1111/j.0022-202X.2004.23498.x
PMID: 15610529 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16083956 | 1. Leuk Res. 2006 Feb;30(2):170-7. doi: 10.1016/j.leukres.2005.06.024. Epub 2005
Aug 3.
Allelic expression and quantitative RT-PCR study of TAp73 and DeltaNp73 in
non-Hodgkin's lymphomas.
Cuadros M(1), Ribas G, Fernández V, Rivas C, Benitez J, Martinez-Delgado B.
Author information:
(1)Human Genetics Department, Spanish National Cancer Centre (CNIO), Melchor
Fernandez Almagro 3, 28029 Madrid, Spain.
p73 shares structural and functional homology to p53. p73 generates different
proteins using alternative promoters and splicing which have different
biological characteristics. We investigated the pattern (monoallelic or
biallelic) of expression of TAp73 and DeltaNp73 in normal lymphocytes and
lymphomas using two p73 polymorphisms. We found monoallelic expression of TAp73
in normal lymphocytes and tumors, and a selective expression of AT allele in all
cases. Moreover, the quantitative expression analysis revealed DeltaNp73
over-expression in both B- and T-cell lymphomas comparing with normal lymphoid
cells, suggesting a role in tumorigenesis. Finally, we have confirmed that
although DeltaNp73 over-expression could be an alternative mechanism of p53
inactivation, both alterations may appear together.
DOI: 10.1016/j.leukres.2005.06.024
PMID: 16083956 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16322298 | 1. Clin Cancer Res. 2005 Dec 1;11(23):8372-83. doi:
10.1158/1078-0432.CCR-05-0899.
Clinical relevance of dominant-negative p73 isoforms for responsiveness to
chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73
cross-talk in vivo.
Concin N(1), Hofstetter G, Berger A, Gehmacher A, Reimer D, Watrowski R, Tong D,
Schuster E, Hefler L, Heim K, Mueller-Holzner E, Marth C, Moll UM, Zeimet AG,
Zeillinger R.
Author information:
(1)Department of Obstetrics and Gynecology, Innsbruck Medical University,
Innsbruck, Austria. [email protected]
PURPOSE: We aimed to determine the clinical role of the p53 family members p53
and p73 in the responsiveness to platinum-based chemotherapy and survival in
ovarian cancer, considering their cross-talk and the p53 polymorphism at codon
72.
EXPERIMENTAL DESIGN: A detailed analysis of p53 and p73 in a series of 122
ovarian cancers was done. We used a functional yeast-based assay to determine
the p53 mutational status. Red yeast colonies, indicating mutant p53, were
subsequently sequenced to determine the specific p53 alteration. p53 mutations
were divided into two groups according to their previous characterization in the
literature: those that efficiently inhibit transcriptionally active TAp73
function and those that do not. A p53 polymorphism at codon 72 was determined in
corresponding normal tissue or blood of ovarian cancer patients.
Isoform-specific p73 expression analysis using real-time reverse
transcription-PCR has previously been done in the majority of ovarian cancers
included in this study. In a retrospective chart review, responsiveness to
chemotherapy was assessed, and survival data with long follow-up times were
collected.
RESULTS: Eighty of 122 (65.6%) of ovarian cancers harbored p53 mutations. p53
mutational status was an important determinant of responsiveness to
platinum-based chemotherapy in all patients with a residual tumor of <2 cm in
diameter after initial surgery (wild-type versus mutant, P = 0.029). In
addition, p53 mutational status was a strong prognosticator for recurrence-free
and overall survival (P < 0.0001 and P = 0.003, respectively) in univariate
analyses. High expression levels of dominant-negative p73 isoforms (DeltaNp73
and DeltaN'p73) significantly correlated with chemotherapeutic failure (P =
0.048) and with worse recurrence-free and overall survival in patients with p53
mutant cancers (P = 0.048 and P = 0.005, respectively). Eight p53 mutations,
present in 19 cases, were found that efficiently inhibit TAp73 (i.e., 175H,
220C, 245S, 245D, 248W, 248Q, 266E, and 273H). Patients with p53 mutations that
efficiently inhibit TAp73 function had a significantly shorter overall survival
than patients with p53 mutations of unknown effect on TAp73 (P = 0.044). The p53
polymorphism at codon 72 had no influence on responsiveness to chemotherapy or
survival.
CONCLUSION: We provide the first clinical evidence that dominant-negative p73
isoforms contribute to drug resistance in vivo, underscoring the importance of a
p53-p73 cross-talk. NH2-terminally truncated p73 isoforms were of significant
clinical effect by providing an additional unfavorable factor for response to
platinum-based chemotherapy and survival in p53 mutant ovarian cancers.
DOI: 10.1158/1078-0432.CCR-05-0899
PMID: 16322298 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19777343 | 1. Breast Cancer Res Treat. 2010 Jul;122(1):159-68. doi:
10.1007/s10549-009-0542-7. Epub 2009 Sep 24.
Induction of the small heat shock protein alphaB-crystallin by genotoxic stress
is mediated by p53 and p73.
Evans JR(1), Bosman JD, Brown-Endres L, Yehiely F, Cryns VL.
Author information:
(1)Cell Death Regulation Lab, Departments of Medicine and Cell and Molecular
Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of
Medicine, Northwestern University, Lurie 4-113, 303 East Superior Street,
Chicago, IL 60611, USA.
The small heat shock protein alphaB-crystallin is a molecular chaperone that is
induced by stress and protects cells by inhibiting protein aggregation and
apoptosis. To identify novel transcriptional regulators of the alphaB-crystallin
gene, we examined the alphaB-crystallin promoter for conserved transcription
factor DNA-binding elements and identified a putative response element for the
p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced
alphaB-crystallin mRNA and protein with delayed kinetics compared to p21.
Additionally, the induction of alphaB-crystallin by genotoxic stress was
inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of
an alphaB-crystallin promoter luciferase reporter required the putative p53RE,
chromatin immunoprecipitation failed to detect p53 binding to the
alphaB-crystallin promoter. These results suggested an indirect mechanism of
transactivation involving p53 family members p63 or p73. DeltaNp73 was
dramatically induced by p53 in a TAp73-dependent manner, and silencing p73
suppressed the transcriptional activation of alphaB-crystallin by p53. Moreover,
ectopic expression of DeltaNp73alpha (but not other p73 isoforms) increased
alphaB-crystallin mRNA levels in the absence of p53. Collectively, our results
link the molecular chaperone alphaB-crystallin to the cellular genotoxic stress
response via a novel mechanism of transcriptional regulation by p53 and p73.
DOI: 10.1007/s10549-009-0542-7
PMCID: PMC2883682
PMID: 19777343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12920125 | 1. J Biol Chem. 2003 Dec 5;278(49):49196-202. doi: 10.1074/jbc.M304921200. Epub
2003 Aug 13.
p73 is regulated by phosphorylation at the G2/M transition.
Fulco M(1), Costanzo A, Merlo P, Mangiacasale R, Strano S, Blandino G, Balsano
C, Lavia P, Levrero M.
Author information:
(1)Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of
Rome "La Sapienza," 00161 Rome, Italy.
p73 is a p53 paralog that encodes proapoptotic (transactivation-competent (TA))
and antiapoptotic (dominant negative) isoforms. TAp73 transcription factors
mediate cell cycle arrest and/or apoptosis in response to DNA damage and are
involved in developmental processes in the central nervous system and the immune
system. p73 proteins may also play a role in the regulation of cell growth.
Indeed, p73 expression is itself modulated during the cell cycle and TAp73
proteins accumulate in S phase cells. In addition, the function of p73 proteins
is also regulated by post-translational modifications and protein-protein
interactions in different cellular and pathophysiological contexts. Here we show
that p73 is a physiological target of the p34cdc2-cyclin B mitotic kinase
complex in vivo. Both p73beta and p73alpha isoforms are hyperphosphorylated in
normal mitotic cells and during mitotic arrest induced by microtubule-targeting
drugs. p34cdc2-cyclin B phosphorylates and associates with p73 in vivo, which
results in a decreased ability of p73 to both bind DNA and activate
transcription in mitotic cells. Indeed, p73 is excluded from condensed
chromosomes in meta- and anaphase, redistributes throughout the mitotic
cytoplasm, and unlike p53, shows no association with centrosomes. Together these
results indicate that M phase-specific phosphorylation of p73 by p34cdc2-cyclin
B is associated with negative regulation of its transcriptional activating
function.
DOI: 10.1074/jbc.M304921200
PMID: 12920125 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15635412 | 1. Nature. 2005 Jan 6;433(7021):73-7. doi: 10.1038/nature03180.
Beta-lactam antibiotics offer neuroprotection by increasing glutamate
transporter expression.
Rothstein JD(1), Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L,
Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher
PB.
Author information:
(1)Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287,
USA. [email protected]
Glutamate is the principal excitatory neurotransmitter in the nervous system.
Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1
(also known as EAAT2; refs 1, 2), the physiologically dominant astroglial
protein. In spite of its critical importance in normal and abnormal synaptic
activity, no practical pharmaceutical can positively modulate this protein.
Animal studies show that the protein is important for normal excitatory synaptic
transmission, while its dysfunction is implicated in acute and chronic
neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke,
brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs
and nutritionals, we discovered that many beta-lactam antibiotics are potent
stimulators of GLT1 expression. Furthermore, this action appears to be mediated
through increased transcription of the GLT1 gene. beta-Lactams and various
semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial
synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone
increased both brain expression of GLT1 and its biochemical and functional
activity. Glutamate transporters are important in preventing glutamate
neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of
ischaemic injury and motor neuron degeneration, both based in part on glutamate
toxicity. When used in an animal model of the fatal disease ALS, the drug
delayed loss of neurons and muscle strength, and increased mouse survival. Thus
these studies provide a class of potential neurotherapeutics that act to
modulate the expression of glutamate neurotransmitter transporters via gene
activation.
DOI: 10.1038/nature03180
PMID: 15635412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22184102 | 1. Birth Defects Res A Clin Mol Teratol. 2012 Feb;94(2):91-5. doi:
10.1002/bdra.22866. Epub 2011 Dec 20.
SEMA3A rs7804122 polymorphism is associated with Hirschsprung disease in the
Northeastern region of China.
Wang LL(1), Zhang Y, Fan Y, Li H, Zhou FH, Miao JN, Gu H, Huang TC, Yuan ZW.
Author information:
(1)Key Laboratory of Health Ministry for Congenital Malformation, Shengjing
Hospital, China Medical University, Shenyang 110004, People's Republic of China.
BACKGROUND: Hirschsprung disease (HSCR) is a congenital disorder characterized
by an absence of intrinsic ganglion cells in the nerve plexuses of the lower
colon. Our previous results showed increased semaphorin 3A (SEMA3A) expression
may be the risk factor for HSCR pathology in a subset of patients. Therefore,
the association between polymorphisms in SEMA3A and the risk of HSCR was
examined.
METHODS: The genotypes of two SNPs (rs7804122 and rs797821) in the SEMA3A gene
in 119 patients with HSCR and 93 controls were examined using PCR-sequencing to
determine the contribution of SEMA3A to the HSCR phenotype. PCR reaction with
cDNA template was also used to find out whether a novel mutation
(Chr7:83634610A→T) influences the SEMA3A pre-mRNA splicing.
RESULTS: Genotypes comprising allele G of rs7804122 (GG or AG) were
over-represented in patients (48.74 vs. 24.8%; p = 0.0013) which indicated that
the risk of HSCR was significantly higher among subjects with the GG or AG
genotype than among the subjects with the AA genotype. No statistically
significant associations were found for SNP rs797821 at the allele or genotype
levels. The differences in genotypes and allele distributions of rs7804122 and
rs797821 between various clinical classifications were not statistically
significant. The novel heterozygous mutation (Chr7:83634610A→T) 30bp away from
an intron/exon boundary, had no detectable effect on splicing efficiency.
CONCLUSION: Our results for rs7804122 provided preliminary evidence that the
SEMA3A gene is involved in the susceptibility to HSCR in the Northeastern
Chinese population.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/bdra.22866
PMID: 22184102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8624684 | 1. Brain. 1996 Feb;119 ( Pt 1):225-37. doi: 10.1093/brain/119.1.225.
Transient increase in symptoms associated with cytokine release in patients with
multiple sclerosis.
Moreau T(1), Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A.
Author information:
(1)University of Cambridge Neurology Unit, Addenbrooke's Hospital, UK.
Fourteen patients with multiple sclerosis were treated with the humanized
monoclonal antibody CAMPATH-1H which targets the CD52 antigen present on all
lymphocytes and some monocytes; four also received anti-CD4 antibody.
Lymphopaenia developed rapidly and was sustained for at least 1 year. In 12
patients, the first infusion of antibody was characterized by significant
exacerbation or re- awakening of pre-existing symptoms lasting several hours.
These clinical effects of antibody treatment correlated with increased levels of
circulating cytokines. Peak levels of tumour necrosis factor (TNF)-alpha and
interferon (IFN)-gamma occurred at 2 h, whereas the rise in interleukin-6 (IL-6)
was significantly delayed and peaked at 4 h after starting antibody treatment.
There was a decline in CH50, indicating complement activation. The neurological
symptoms could not be attributed directly to pyrexia and were not provoked (in
one patient) by an artificial rise in temperature. In the remaining two
patients, a single pre-treatment with intravenous methylprednisolone (500 mg)
prevented both the transient increase in neurological symptoms and the cytokine
release. Our results, involving 14 intensively studied patients treated with
humanized monoclonal antibodies, suggested that soluble immune mediators
contribute to symptom production in multiple sclerosis; the mechanism remains
uncertain but, on the available evidence, we favour the interpretation that
cytokines directly affect conduction through partially demyelinated pathways.
DOI: 10.1093/brain/119.1.225
PMID: 8624684 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22902450 | 1. Gan To Kagaku Ryoho. 2012 Aug;39(8):1243-5.
[A case of metastatic pancreatic cancer which trastuzumab+capecitabine
combination therapy was effective].
[Article in Japanese]
Nakatsukasa K(1), Koyama H, Tokugawa T, Inaba S.
Author information:
(1)Breast Center, Nara City Hospital, Japan.
A 61-year-old woman presented with carcinoma of the left breast(T2N1M0, stage II
B), which enforced left Bt+R1. In May 2008, the patient underwent preoperative
chemotherapy consisting of 4 courses of FEC 75(fluororracil, epirubicin, and
cyclophosphamide). Pathological examination revealed that the lesion was a
papillotubular carcinoma,(ER-, PgR-, HER2 3+). In September, 2009, CT scans
revealed metastases of the cervical lymph nodes and pancreas. Examination of
biopsy specimens from the left cervical lymph nodes revealed that the metastases
were from breast cancer(ER-, PgR-, HER2 3+). To treat the recurrences,
combination therapy with trastuzumab+capecitabine was introduced in October,
2009. CT scans obtained in May 2010 revealed complete response of the metastases
of the lymph nodes and pancreas. It is difficult to distinguish a metastases
from a primary pancreatic cancer, but the present case was considered to be one
of metastic pancreatic cancer because the findings were in agreement with the
expression time of lymph node metastasis. Follow-up CT scans revealed that CR
was maintained by the combination therapy of trastuzumab+capecitabine.
PMID: 22902450 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18546269 | 1. Int J Cancer. 2008 Sep 1;123(5):1060-7. doi: 10.1002/ijc.23619.
p73 Isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal
tumors: VEGF165b downregulation as a marker of poor prognosis.
Díaz R(1), Peña C, Silva J, Lorenzo Y, García V, García JM, Sánchez A, Espinosa
P, Yuste R, Bonilla F, Domínguez G.
Author information:
(1)Department of Medical Oncology, Hospital Universitario Puerta de Hierro,
28035 Madrid, Spain.
The secreted mitogen vascular endothelial growth factor, VEGF, plays a pivotal
role in angiogenesis. Hypoxia, inactivation of p53 and oncogenic K-Ras induce
VEGF expression. Other factors such as p73 may also affect VEGF levels.
Curiously, p73 may also regulate angiogenesis by affecting the expression of the
pigment epithelium-derived factor, PEDF. Additionally, VEGF might harbor
additional functions through the activation of E2F transcription factors.
Recently, a new VEGF variant formed by alternative splicing, VEGF(165)b, has
been described as exerting anti-angiogenic activity. We study here whether p73
isoforms levels -TAp73 and DeltaTAp73- and p53 and K-Ras status affect the
expression of the above-mentioned angiogenesis-related genes (through the
correlation between their expressions), the prognostic value of VEGF(165)b and
PEDF and the correlation between VEGF and E2F-1 levels. Tumor and normal tissue
of 112 colorectal cancer patients was analyzed to evaluate: (i) levels of TAp73,
DeltaTAp73, VEGF, VEGF(165)b, PEDF and E2F-1 by quantitative real-time RT-PCR,
(ii) p53 status by immunohistochemistry and (iii) mutations in the first exon of
K-Ras by PCR-SSCP. Tumor characteristics were examined in each patient.
Associations were observed between: (i) specific p73 isoforms and VEGF and
VEGF(165)b expression; (ii) DeltaEx2p73 variant and downregulation of PEDF;
(iii) VEGF and PEDF expression; (iv) inactive p53 and VEGF(165)b levels; (v)
oncogenic K-Ras and PEDF downregulation; (vi) E2F-1 and VEGF expressions; (vii)
VEGF(165)b downregulation and poor prognosis parameters of tumors. We conclude
that the levels of p73 isoforms could affect the expression of VEGF, VEGF(165)b
and PEDF. This scenario becomes complicated because a feedback between VEGF and
PEDF may exist. VEGF may activate the E2F-1 factor. Mutations in K-Ras could
negatively regulate PEDF expression. p53 inactivation might result in
compensatory mechanisms such as over-expression of VEGF(165)b. Our data support
the role of VEGF(165)b as a tumor suppressor factor in colorectal carcinogenesis
and its possible prognosis value.
DOI: 10.1002/ijc.23619
PMID: 18546269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23233647 | 1. Hematology Am Soc Hematol Educ Program. 2012;2012:645-51. doi:
10.1182/asheducation-2012.1.645.
B- and T-cell prolymphocytic leukemia: antibody approaches.
Dearden C(1).
Author information:
(1)Department of Haemato-Oncology, The Royal Marsden Hospital and The Institute
of Cancer Research, London, United Kingdom. [email protected]
B- and T-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive
lymphoid malignancies with characteristic morphologic, immunophenotypic,
cytogenetic, and molecular features. Prognosis for these patients remains poor,
with short survival times and no curative therapy. The advent of mAbs has
improved treatment options. In B-PLL, rituximab-based combination
chemoimmunotherapy is effective in fitter patients. TP53 abnormalities are
common and, as for chronic lymphocytic leukemia, these patients should generally
be managed using an alemtuzumab-based therapy. Currently, the best treatment for
T-PLL is IV alemtuzumab, which has resulted in very high response rates of more
than 90% when given as frontline treatment and a significant improvement in
survival. Consolidation of remissions with autologous or allogeneic stem cell
transplantation further prolongs survival times, and the latter may offer
potential cure. The role of allogeneic transplantation with nonmyeloablative
conditioning needs to be explored further in both T- and B-PLL to broaden the
patient eligibility for what may be a curative treatment.
DOI: 10.1182/asheducation-2012.1.645
PMID: 23233647 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24247240 | 1. J Biol Chem. 2013 Dec 27;288(52):36856-62. doi: 10.1074/jbc.C113.525691. Epub
2013 Nov 18.
Differences in the regulation of K-Ras and H-Ras isoforms by monoubiquitination.
Baker R(1), Wilkerson EM, Sumita K, Isom DG, Sasaki AT, Dohlman HG, Campbell SL.
Author information:
(1)From the Departments of Biochemistry and Biophysics and.
Ras GTPases are signaling switches that control critical cellular processes
including gene expression, differentiation, and apoptosis. The major Ras
isoforms (K, H, and N) contain a conserved core GTPase domain, but have distinct
biological functions. Among the three Ras isoforms there are clear differences
in post-translational regulation, which contribute to differences in
localization and signaling output. Modification by ubiquitination was recently
reported to activate Ras signaling in cells, but the mechanisms of activation
are not well understood. Here, we show that H-Ras is activated by
monoubiquitination and that ubiquitination at Lys-117 accelerates intrinsic
nucleotide exchange, thereby promoting GTP loading. This mechanism of Ras
activation is distinct from K-Ras monoubiquitination at Lys-147, which leads to
impaired regulator-mediated GTP hydrolysis. These findings reveal that different
Ras isoforms are monoubiquitinated at distinct sites, with distinct mechanisms
of action, but with a common ability to chronically activate the protein in the
absence of a receptor signal or oncogenic mutation.
DOI: 10.1074/jbc.C113.525691
PMCID: PMC3873545
PMID: 24247240 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21550857 | 1. Clin Immunol. 2012 Jan;142(1):25-30. doi: 10.1016/j.clim.2011.04.006. Epub
2011 Apr 15.
Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on
alemtuzumab.
Klotz L(1), Meuth SG, Wiendl H.
Author information:
(1)University of Muenster, Clinic for Neurology—Inflammatory disorders of the
central nervous system and neurooncology, Muenster, Germany.
Alemtuzumab is a humanized monoclonal antibody targeting CD52, a broadly
expressed cell surface molecule on immune cells. Application results in a rapid
and long-lasting removal of lymphocyte populations from the circulation.
Alemtuzumab-treatment of MS patients with relapsing-remitting forms of the
disease significantly reduced the risk of relapse and accumulation of disability
compared to interferon β-1a treatment in a phase II trial. Interestingly,
further analysis together with parallel experimental studies suggested that
alemtuzumab not only reduces disease activity due to its immune cell-depleting
effect, but also confers neuroprotective effects, presumably by inducing
production of neurotrophic factors in autoreactive T cells. However,
alemtuzumab-treated MS patients experienced increased rates of novel
autoimmunity and a slight increase in infections, demonstrating that
alemtuzumab-mediated skewing of the immune cell compartment has a broad
influence on immune functions. This review discusses the current concepts about
the underlying mechanisms causing these altered immune responses in
alemtuzumab-treated MS patients.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.clim.2011.04.006
PMID: 21550857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22649104 | 1. Blood. 2012 Jul 19;120(3):538-51. doi: 10.1182/blood-2012-01-380139. Epub 2012
May 30.
How I treat prolymphocytic leukemia.
Dearden C(1).
Author information:
(1)Department of Haemato-Oncology, Royal Marsden Hospital and Institute of
Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
[email protected]
T- and B-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive
lymphoid malignancies with characteristic morphologic, immunophenotypic,
cytogenetic, and molecular features. Recent studies have highlighted the role of
specific oncogenes, such as TCL-1, MTCP-1, and ATM in the case of T-cell and
TP53 mutations in the case of B-cell prolymphocytic leukemia. Despite the
advances in the understanding of the biology of these conditions, the prognosis
for these patients remains poor with short survival and no curative therapy. The
advent of monoclonal antibodies has improved treatment options. Currently, the
best treatment for T-PLL is intravenous alemtuzumab, which has resulted in very
high response rates of more than 90% when given as first-line treatment and a
significant improvement in survival. Consolidation of remissions with autologous
or allogeneic stem cell transplantation further prolongs survival, and the
latter may offer potential cure. In B-PLL, rituximab-based combination
chemo-immunotherapy is effective in fitter patients. TP53 abnormalities are
common and, as for chronic lymphocytic leukemia, these patients should be
managed using an alemtuzumab-based therapy. The role of allogeneic transplant
with nonmyeloablative conditioning needs to be explored further in both T- and
B-cell PLL to broaden the patient eligibility for what may be a curative
treatment.
DOI: 10.1182/blood-2012-01-380139
PMID: 22649104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23103856 | 1. Cancer Discov. 2013 Jan;3(1):112-23. doi: 10.1158/2159-8290.CD-12-0231. Epub
2012 Oct 25.
Oncogenic and wild-type Ras play divergent roles in the regulation of
mitogen-activated protein kinase signaling.
Young A(1), Lou D, McCormick F.
Author information:
(1)Helen Diller Family Comprehensive Cancer Center, Department of Medicine,
University of California San Francisco, San Francisco, California 94143, USA.
Comment in
Cancer Discov. 2013 Jan;3(1):24-6. doi: 10.1158/2159-8290.CD-12-0521.
H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often
activated by somatic mutation in human tumors. Although oncogenic lesions occur
in a single Ras isoform within individual tumors, it is unclear whether the
remaining wild-type isoforms play supporting roles in tumor growth. Here, we
show that oncogenic and wild-type Ras isoforms play independent and nonredundant
roles within the cell. Oncogenic Ras regulates basal effector pathway signaling,
whereas wild-type Ras mediates signaling downstream of activated receptor
tyrosine kinases (RTK). We show that both are necessary for exponential growth
of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes
signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA
oligonucleotides relieves this negative feedback, leading to the hyperactivation
of EGFR and wild-type Ras signaling. Consistent with this model, combining
oncogenic Ras depletion with EGFR inhibition potently increases cell death.
SIGNIFICANCE: The results of this study highlight a novel role for wild-type Ras
signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these
findings reveal that therapeutically targeting oncogenic Ras signaling alone may
be ineffective owing to feedback activation of RTKs, and suggest that blocking
upstream RTKs in combination with downstream effector pathways may be beneficial
in the treatment of Ras-mutant tumors.
DOI: 10.1158/2159-8290.CD-12-0231
PMID: 23103856 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22038740 | 1. Cardiovasc Res. 2012 May 1;94(2):284-92. doi: 10.1093/cvr/cvr291. Epub 2011
Oct 28.
Role of microRNAs in the reperfused myocardium towards post-infarct remodelling.
Zhu H(1), Fan GC.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati
College of Medicine, Cincinnati, OH 45267-0575, USA.
Myocardial ischaemia/reperfusion (I/R)-induced remodelling generally includes
cell death (necrosis and apoptosis), myocyte hypertrophy, angiogenesis, cardiac
fibrosis, and myocardial dysfunction. It is becoming increasingly clear that
microRNAs (miRNAs or miRs), a group of highly conserved small (∼18-24
nucleotide) non-coding RNAs, fulfil specific functions in the reperfused
myocardium towards post-infarct remodelling. While miR-21, -133, -150, -195, and
-214 regulate cardiomyocyte hypertrophy, miR-1/-133 and miR-208 have been
elucidated to influence myocardial contractile function. In addition, miR-21,
-24, -133, -210, -494, and -499 appear to protect myocytes against I/R-induced
apoptosis, whereas miR-1, -29, -199a, and -320 promote apoptosis. Myocardial
fibrosis can be regulated by the miR-29 family and miR-21. Moreover, miR-126 and
miR-210 augment I/R-induced angiogenesis, but miR-24, -92a, and -320 suppress
post-infarct neoangiogenesis. In this review, we summarize the latest advances
in the identification of myocardial ischaemia-associated miRNAs and their
functional significance in the modulation of I/R-triggered remodelling.
Controversial effects of some miRNAs in post-infarct remodelling will be also
discussed.
DOI: 10.1093/cvr/cvr291
PMCID: PMC3331611
PMID: 22038740 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20929585 | 1. Mol Neurodegener. 2010 Oct 7;5:39. doi: 10.1186/1750-1326-5-39.
The biochemical aftermath of anti-amyloid immunotherapy.
Maarouf CL(1), Daugs ID, Kokjohn TA, Kalback WM, Patton RL, Luehrs DC, Masliah
E, Nicoll JA, Sabbagh MN, Beach TG, Castaño EM, Roher AE.
Author information:
(1)The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health
Research Institute, Sun City, AZ, USA. [email protected].
BACKGROUND: Active and passive immunotherapy in both amyloid-beta precursor
protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have
resulted in remarkable reductions in amyloid plaque accumulation, although the
degree of amyloid regression has been highly variable. Nine individuals with a
clinical diagnosis of AD dementia were actively immunized with the Aβ peptide
1-42 (AN-1792) and subjected to detailed postmortem biochemical analyses. These
patients were compared to 6 non-immunized AD cases and 5 non-demented control
(NDC) cases.
RESULTS: All patients were assessed for the presence of AD pathology including
amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort
revealed that two immunotherapy recipients had dementia as a consequence of
diseases other than AD. Direct neuropathological examination consistently
demonstrated small to extensive areas in which amyloid plaques apparently were
disrupted. Characterization of Aβ species remnants by ELISA suggested that total
Aβ levels may have been reduced, although because the amounts of Aβ peptides
among treated individuals were extremely variable, those data must be regarded
as tentative. Chromatographic analysis and Western blots revealed abundant
dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive
number of Aβ-related peptides, some of them with elongated C-terminal sequences.
Pro-inflammatory TNF-α levels were significantly increased in the gray matter of
immunized AD cases compared to the NDC and non-immunized AD groups.
CONCLUSIONS: Immunotherapy responses were characterized by extreme variability.
Considering the broad range of biological variation that characterizes aging and
complicates the recognition of reliable AD biomarkers, such disparities will
make the interpretation of outcomes derived from epidemiologic and therapeutic
investigations challenging. Although in some cases the apparent removal of
amyloid plaques by AN-1792 was impressive, proportionate alterations in the
clinical progression of AD were not evident. The fact that plaque elimination
did not alter the trajectory of decline into dementia suggests the likelihood
that these deposits alone are not the underlying cause of dementia.
DOI: 10.1186/1750-1326-5-39
PMCID: PMC2959013
PMID: 20929585 |
http://www.ncbi.nlm.nih.gov/pubmed/10573422 | 1. Nature. 1999 Nov 4;402(6757):86-90. doi: 10.1038/47056.
Protein interaction maps for complete genomes based on gene fusion events.
Enright AJ(1), Iliopoulos I, Kyrpides NC, Ouzounis CA.
Author information:
(1)Computational Genomics Group, Research Programme, The European Bioinformatics
Institute, EMBL Cambridge Outstation, UK.
Comment in
Nature. 1999 Nov 4;402(6757):23, 25-6. doi: 10.1038/46915.
A large-scale effort to measure, detect and analyse protein-protein interactions
using experimental methods is under way. These include biochemistry such as
co-immunoprecipitation or crosslinking, molecular biology such as the two-hybrid
system or phage display, and genetics such as unlinked noncomplementing mutant
detection. Using the two-hybrid system, an international effort to analyse the
complete yeast genome is in progress. Evidently, all these approaches are
tedious, labour intensive and inaccurate. From a computational perspective, the
question is how can we predict that two proteins interact from structure or
sequence alone. Here we present a method that identifies gene-fusion events in
complete genomes, solely based on sequence comparison. Because there must be
selective pressure for certain genes to be fused over the course of evolution,
we are able to predict functional associations of proteins. We show that 215
genes or proteins in the complete genomes of Escherichia coli, Haemophilus
influenzae and Methanococcus jannaschii are involved in 64 unique fusion events.
The approach is general, and can be applied even to genes of unknown function.
DOI: 10.1038/47056
PMID: 10573422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22357853 | 1. J Neurosci. 2012 Feb 22;32(8):2696-702. doi: 10.1523/JNEUROSCI.1676-11.2012.
Neutralization of soluble, synaptotoxic amyloid β species by antibodies is
epitope specific.
Zago W(1), Buttini M, Comery TA, Nishioka C, Gardai SJ, Seubert P, Games D, Bard
F, Schenk D, Kinney GG.
Author information:
(1)Janssen Alzheimer Immunotherapy Research & Development, South San Francisco,
CA 94080, USA. [email protected]
Several anti-amyloid β (Aβ) antibodies are under evaluation for the treatment of
Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aβ
antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals,
suggesting the reduction of Aβ plaques, and reduced levels of total and
phosphorylated tau protein in the CSF of treated AD patients. Preclinical
studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution
of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of
synaptic density in the transgenic APP mouse models. In contrast, few studies
have evaluated the direct interaction of this antibody with synaptotoxic soluble
Aβ species. In the current report, we demonstrated that 3D6 binds to soluble,
synaptotoxic assemblies of Aβ(1-42) and prevents multiple downstream functional
consequences in rat hippocampal neurons including changes in glutamate AMPA
receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines.
In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely
reverses the behavioral deficit in the contextual fear conditioning task in
transgenic mouse models of AD, two endpoints thought to be linked to
synaptotoxic soluble Aβ moieties. Importantly C-terminal anti-Aβ antibodies were
ineffective on these endpoints. These results, taken with prior studies, suggest
that N-terminal anti-Aβ antibodies effectively interact with both soluble and
insoluble forms of Aβ and therefore appear particularly well suited for testing
the Aβ hypothesis of AD.
DOI: 10.1523/JNEUROSCI.1676-11.2012
PMCID: PMC6621896
PMID: 22357853 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22339463 | 1. Immunotherapy. 2012 Feb;4(2):213-38. doi: 10.2217/imt.11.170.
Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based
immunization strategies.
Panza F(1), Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A,
Greco A, Seripa D, Pilotto A.
Author information:
(1)Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa
Sollievo della Sofferenza, Foggia, Italy. [email protected].
The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown,
limiting the identification of effective disease-modifying therapies. The two
principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ),
peptide deposition (senile plaques) and intracellular neurofibrillary tangles
containing hyperphosphorylated tau protein. During the last decade, most of the
efforts of the pharmaceutical industry were directed against the production and
accumulation of Aβ. The most innovative of the pharmacological approaches was
the stimulation of Aβ clearance from the brain of AD patients via the
administration of Aβ antigens (active vaccination) or anti-Aβ antibodies
(passive vaccination). Several active and passive anti-Aβ vaccines are under
clinical investigation. Unfortunately, the first active vaccine (AN1792,
consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned
because it caused meningoencephalitis in approximately 6% of treated patients.
Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being
developed. The clinical results of the initial studies with bapineuzumab were
equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after
bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4
carriers), has raised concerns on the safety of these antibodies directed
against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ
monoclonal antibody directed against the midregion of the Aβ peptide, was shown
to neutralize soluble Aβ species. Phase II studies showed a good safety profile
of solanezumab, while studies on cerebrospinal and plasma biomarkers documented
good signals of pharmacodynamic activity. Although some studies suggested that
active immunization may be effective against tau in animal models of AD, very
few studies regarding passive immunization against tau protein are currently
available. The results of the large, ongoing Phase III trials with bapineuzumab
and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the
rate of deterioration of AD. Based on the new diagnostic criteria of AD and on
recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one
could argue that clinical trials on potential disease-modifying drugs, including
immunological approaches, should be performed in the early stages of AD.
DOI: 10.2217/imt.11.170
PMID: 22339463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18223678 | 1. Oncogene. 2008 Jun 12;27(26):3761-4. doi: 10.1038/sj.onc.1211038. Epub 2008
Jan 28.
BHLHB3: a candidate tumor suppressor in lung cancer.
Falvella FS(1), Colombo F, Spinola M, Campiglio M, Pastorino U, Dragani TA.
Author information:
(1)Department of Experimental Oncology and Laboratories, Fondazione IRCCS
Istituto Nazionale Tumori, Milan, Italy.
BHLHB3 is a basic helix-loop-helix (bHLH) domain-containing protein that acts as
a transcriptional repressor. We found that BHLHB3 transcript levels were low in
three human lung cancer cell lines and downregulated in human lung
adenocarcinomas as compared to normal lung tissue. BHLHB3 gene overexpression
inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. The
reduced colony growth was likely due to inhibition of cell proliferation as
suggested by the downregulation of cyclin D1 (CCND1) expression in NCI-H520
cells transfected to overexpress the BHLHB3 gene; no evidence of apoptosis was
observed. These results point to the potential role of the BHLHB3 protein as a
tumor suppressor for lung cancer.
DOI: 10.1038/sj.onc.1211038
PMID: 18223678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19727257 | 1. Psychiatry (Edgmont). 2008 Sep;5(9):24-33.
Functional neurosurgery in the treatment of severe obsessive compulsive disorder
and major depression: overview of disease circuits and therapeutic targeting for
the clinician.
Shah DB(1), Pesiridou A, Baltuch GH, Malone DA, O'Reardon JP.
Author information:
(1)Neuromodulation Treatment and Research Program, Department of Psychiatry,
University of Pennsylvania, Philadelphia, USA. [email protected]
Over the past 20 years, there has been a concerted effort to expand our
understanding of the neural circuitry involved in the pathogenesis of
psychiatric disorders. Distinct neuronal circuits and networks have been
implicated in obsessive compulsive disorder (OCD) and major depressive disorder
(MDD) involving feedback loops between the cortex, striatum, and thalamus. When
neurosurgery is used as a therapeutic tool in severe OCD and MDD, the goal is to
modulate specific targets or nodes within these networks in an effort to produce
symptom relief.Currently, four lesioning neurosurgical procedures are utilized
for treatment refractory OCD and MDD: cingulotomy, capsulotomy, subcaudate
tractotomy, and limbic leucotomy. Deep brain stimulation (DBS) is a novel
neurosurgical approach that has some distinct advantages over lesioning
procedures. With DBS, the desired clinical effect can be achieved by reversible,
high frequency stimulation in a nucleus or at a node in the circuit without the
need to produce an irreversible lesion. Recent trials of deep brain stimulation
in both OCD and MDD at several neuroanatomical targets have reported promising
early results in highly refractory patients and with a good safety profile.
Future definitive trials in MDD and OCD are envisaged.
PMCID: PMC2687086
PMID: 19727257 |
http://www.ncbi.nlm.nih.gov/pubmed/22587716 | 1. J Sports Sci. 1998 Jan;16 Suppl:S31-45. doi: 10.1080/026404198366957.
A natural history of athleticism, health and longevity.
Paffenbarger RS Jr(1), Lee IM.
Author information:
(1)Division of Epidemiology, Department of Health Research and Policy, Stanford
University School of Medicine, Stanford, CA 94305-5405, USA.
Longitudinal observations on the sports play, social habits and health status of
52,000 men who entered Harvard College or the University of Pennsylvania between
1916 and 1950 have afforded means of identifying causes of disease and death.
These observations were then translated into the eff ect of sports and physical
exercise on health and longevity. Student sports play in college predicted a
decreased risk of developing cardiovascular disease (CVD) at least up to age 50
years. Questionnaire surveys showed physical exercise (sports play, walking and
stair climbing) in middle age to be inversely related to the later development
of CVD and early death. In a 10-year follow-up between 1962 and 1972, alumni
aged 35-74 years who expended greater than or equal to ≥ 2000 kcal week(-1) (8.4
MJ week -1 ) in such activities had a 25% reduced risk of CVD and death compared
with less active men. But, the 'protective eff ect' of early athleticism waned
unless a physically active life was maintained. In contrast, sedentary students
who took up an active life were at a lower risk of CVD and death than former
student athletes who gave up or reduced their physical activities in middle age.
A total of 17,815 Harvard alumni aged 45-84 years were followed from a 1977
questionnaire survey through 1992, with 4399 deaths occurring. Death rates
declined with increased levels of total activity (estimated in kilocalories),
and declined also with increased intensity of effort measured as from none, to
light, to moderately vigorous or vigorous sports play. Death rates at any given
quantity of physical exercise were lower for men playing moderately intense
sports than for less vigorous men. Over the age range, in the 16-year follow-up,
Harvard alumni playing moderately vigorous or more intense sports gained 1.5
years by age 90 compared with less active men.
DOI: 10.1080/026404198366957
PMID: 22587716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23931438 | 1. Curr Top Med Chem. 2013;13(15):1853-63. doi: 10.2174/15680266113139990141.
Clinical pharmacology of novel anti-Alzheimer disease modifying medications.
Caraci F(1), Bosco P, Leggio GM, Malaguarnera M, Drago F, Bucolo C, Salomone S.
Author information:
(1)Department of Educational Sciences, University of Catania, Catania, Italy.
In recent years, efforts have been directed to develop "disease-modifying"
medications to treat Alzheimer's disease (AD), able to halt or slow the
pathological process. Because the earlier the treatment starts, the greater is
the possibility of efficacy, it is important to set up biomarkers for early
diagnosis of functional brain abnormalities, before the clinical manifestation
of the overt disease. Up to now, strategies to develop disease-modifying drugs
have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or
tau protein (phosphorylation and aggregation). Active and passive immunotherapy
is the main strategy aimed at increasing Aβ clearance. Unfortunately several
candidate diseasemodifying drugs have failed in phase III clinical trials
conducted in mild to moderate AD. More recently, in phase III studies,
bapineuzumab has been discontinued because it did not prove clinically effective
(despite its significant effect on biomarkers), while solaneuzumab has been
found effective in slowing AD progression. Several methological problems have
been recently pointed out to explain the lack of clinical efficacy of novel
disease-modifying drug-treatments; moreover, new insights in pathophysiology of
AD give the premise to develop novel drug targeting. Clinical trials recently
completed and/or still ongoing are discussed in the present review.
DOI: 10.2174/15680266113139990141
PMID: 23931438 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16231285 | 1. Eur J Immunol. 2005 Nov;35(11):3332-42. doi: 10.1002/eji.200535075.
Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple
sclerosis.
Cox AL(1), Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, Compston DA,
Coles AJ.
Author information:
(1)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
[email protected]
Comment in
Eur J Immunol. 2005 Nov;35(11):3099-102. doi: 10.1002/eji.200535385.
Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution
of lymphocytes. We prospectively studied this process in 16 patients for 1 year
after a single pulse of treatment with Campath-1H, a humanised anti-CD52
monoclonal antibody. We observed two phases of lymphocyte reconstitution. In the
first 6 months after treatment the precursor frequency and proliferation index
of the patients' autologous mixed lymphocyte reaction increased; the depleted T
cell pool was dominated by memory T cells, especially (CD4+)CD25high T cells, a
putative regulatory phenotype; and there was a non-significant rise in
peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive
cytokine mRNA expression. In the later phase, from 6-to-12 months after
Campath-1H, these changes reversed and there was a rise in ROG mRNA expression.
However, total CD4+ numbers remained below 50% of pre-treatment levels at 12
months, perhaps reflecting a failure in homeostasis. This was not due to an
impaired IL-7 response, as in rheumatoid arthritis, nor to a lack of IL-7
receptors, which are found on fewer human (CD4+)CD25high than naive cells. We
speculate that CCL21 and IL-15 responses to lymphopaenia may be suboptimal in
multiple sclerosis.
DOI: 10.1002/eji.200535075
PMID: 16231285 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23448220 | 1. Expert Rev Neurother. 2013 Mar;13(3):313-35. doi: 10.1586/ern.13.17.
Treating multiple sclerosis with monoclonal antibodies: a 2013 update.
Deiß A(1), Brecht I, Haarmann A, Buttmann M.
Author information:
(1)Department of Neurology, University of Würzburg, Josef-Schneider-Str 11,
Würzburg 97080, Germany.
The third part of this in-depth review series on the treatment of multiple
sclerosis (MS) with monoclonal antibodies covers the years 2010-2012. The
natalizumab section gives a progressive multifocal leukoencephalopathy update,
focusing on clinically relevant aspects. Furthermore, it outlines problems
around natalizumab cessation and current evidence on therapeutic strategies
thereafter. Finally, it reviews evidence on Janus-faced modes of natalizumab
action besides anti-inflammatory effects, including proinflammatory effects. The
section on alemtuzumab critically analyzes recent Phase III results and
discusses which patients might be best suited for alemtuzumab treatment, and
reviews the long-term immunological impact of this anti-CD52 antibody. The
daclizumab section critically summarizes results from the Phase IIb
SELECT/SELECTION trial and introduces the Phase III program. The section on
anti-CD20 antibodies reviews Phase II results on ocrelizumab and ofatumumab, and
discusses current perspectives of these antibodies for MS therapy. Promising
recent Phase II results on the anti-IL-17A antibody secukinumab (AIN457) are
outlined and a short update on tabalumab (LY2127399) is given. Other highlighted
antibodies currently being tested in MS patients include GNbAC1, BIIB033, MOR103
and MEDI-551. Finally, the authors give an update on the role monoclonal
antibodies could play in the therapeutic armamentarium for MS in the medium
term.
DOI: 10.1586/ern.13.17
PMID: 23448220 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18946064 | 1. N Engl J Med. 2008 Oct 23;359(17):1786-801. doi: 10.1056/NEJMoa0802670.
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.
CAMMS223 Trial Investigators; Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran
S, Margolin DH, Norris K, Tandon PK.
Collaborators: Panitch H, Anaissie E, Cines D, DeGroot L, Dorsey F, Phillips T,
Simon J, Brinar V, Demarin V, Janculjak D, Rudez J, Vladic A, Czlonkowska A,
Mirowska-Guzel D, Kozubski W, Kwiecinski H, Selmaj K, Stelmasiak Z, Szczudlik A,
Boyko A, Gusev EI, Skoromets A, Stolyarov I, Yakhno N, Zavalishin I, Coles AJ,
Compston DA, Shawcross J, Jones J, Cox AL, Bass A, Wenzel D, Biton V, Cascione
M, Cleeremans B, Cooper J, Coyle PK, Madigan D, Cutler B, Fox EJ, Mayer L, Tyer
R, Gazda S, Glyman S, Gupta A, Harney J, Hutton G, Jacobs D, Khan O, Lisak R,
Tselis A, Klapper J, Liss J, Meyer D, Rae-Grant A, Rossman H, Boudouris W,
Belkin M, Pierce R, Royal W, Shubin R, Sider D, Stein M, Steingo B, Sullivan H,
Twyman C, Webb R, Weinshenker B, Keegan BM, Rauchwarter D, Wingerchuk D, Carter
J, Wray S, Wynn D, Allen N, Nagar C, O'Brien D, Paskavitz J, Schaefer P, DeGroot
L, Valente W, Beardsley D, Bussel J, Cines D, Goldberg M, MacMillan R, Scadden
D, D'Agostino RB, Pencina M, Gonzales G, Waldmann H, Hale G.
Comment in
N Engl J Med. 2008 Oct 23;359(17):1838-41. doi: 10.1056/NEJMe0806738.
Curr Neurol Neurosci Rep. 2009 Sep;9(5):341-2. doi:
10.1007/s11910-009-0062-1.
Mult Scler Relat Disord. 2019 Feb;28:153-154. doi:
10.1016/j.msard.2018.12.020.
BACKGROUND: Alemtuzumab, a humanized monoclonal antibody that targets CD52 on
lymphocytes and monocytes, may be an effective treatment for early multiple
sclerosis.
METHODS: In this phase 2, randomized, blinded trial involving previously
untreated, early, relapsing-remitting multiple sclerosis, we assigned 334
patients with scores of 3.0 or less on the Expanded Disability Status Scale and
a disease duration of 3 years or less to receive either subcutaneous interferon
beta-1a (at a dose of 44 microg) three times per week or annual intravenous
cycles of alemtuzumab (at a dose of either 12 mg or 24 mg per day) for 36
months. In September 2005, alemtuzumab therapy was suspended after immune
thrombocytopenic purpura developed in three patients, one of whom died.
Treatment with interferon beta-1a continued throughout the study.
RESULTS: Alemtuzumab significantly reduced the rate of sustained accumulation of
disability, as compared with interferon beta-1a (9.0% vs. 26.2%; hazard ratio,
0.29; 95% confidence interval [CI], 0.16 to 0.54; P<0.001) and the annualized
rate of relapse (0.10 vs. 0.36; hazard ratio, 0.26; 95% CI, 0.16 to 0.41;
P<0.001). The mean disability score on a 10-point scale improved by 0.39 point
in the alemtuzumab group and worsened by 0.38 point in the interferon beta-1a
group (P<0.001). In the alemtuzumab group, the lesion burden (as seen on
T(2)-weighted magnetic resonance imaging) was reduced, as compared with that in
the interferon beta-1a group (P=0.005). From month 12 to month 36, brain volume
(as seen on T(1)-weighted magnetic resonance imaging) increased in the
alemtuzumab group but decreased in the interferon beta-1a group (P=0.02).
Adverse events in the alemtuzumab group, as compared with the interferon beta-1a
group, included autoimmunity (thyroid disorders [23% vs. 3%] and immune
thrombocytopenic purpura [3% vs. 1%]) and infections (66% vs. 47%). There were
no significant differences in outcomes between the 12-mg dose and the 24-mg dose
of alemtuzumab.
CONCLUSIONS: In patients with early, relapsing-remitting multiple sclerosis,
alemtuzumab was more effective than interferon beta-1a but was associated with
autoimmunity, most seriously manifesting as immune thrombocytopenic purpura. The
study was not powered to identify uncommon adverse events. (ClinicalTrials.gov
number, NCT00050778.)
2008 Massachusetts Medical Society
DOI: 10.1056/NEJMoa0802670
PMID: 18946064 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25759798 | 1. Eur Thyroid J. 2014 Dec;3(4):227-33. doi: 10.1159/000366274. Epub 2014 Oct 15.
Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the
Brain-Lung-Thyroid Syndrome.
de Filippis T(1), Marelli F(1), Vigone MC(2), Di Frenna M(2), Weber G(2),
Persani L(3).
Author information:
(1)Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico
Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS
Istituto Auxologico Italiano, Milan, Italy.
(2)Department of Pediatrics, Vita-Salute University, San Raffaele Scientific
Institute, Milan, Italy.
(3)Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico
Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS
Istituto Auxologico Italiano, Milan, Italy ; Department of Clinical Sciences and
Community Health, University of Milan, Milan, Italy.
OBJECTIVES: To verify the involvement of NKX2-1 gene in infants with
brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among
congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of
postnatal onset.
METHODS: The candidates were selected by a case-finding approach in 130 CH and
53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex
ligation-dependent probe amplification. The variants were studied in vitro, by
expression analyses and luciferase bioassay.
RESULTS: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were
identified. Two children were affected with respiratory distress and CH, but
wild-type NKX2-1 gene. The remaining two presented choreic movements and no
pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with
lingual ectopy and the other one IMH with gland in situ. They were carriers of
new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and
c.153_166del14). The c.177delG leads to a prematurely truncated protein
(p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to
the generation of an elongated aberrant protein (p.A52RfsX351) able to
translocate into the nucleus, but completely inactive on a responsive promoter.
CONCLUSIONS: Two novel heterozygous frameshift mutations of NKX2-1 were
identified in 2 cases selected on the basis of a BLT-like phenotype among 183
hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH
with lingual ectopy or IMH of postnatal onset) further expand the clinical
spectrum that can be associated with NKX2-1 mutations.
DOI: 10.1159/000366274
PMCID: PMC4311306
PMID: 25759798 |
http://www.ncbi.nlm.nih.gov/pubmed/23861639 | 1. J Cent Nerv Syst Dis. 2011 May 8;3:67-73. doi: 10.4137/JCNSD.S5018. Print
2011.
Alzheimers disease: review of emerging treatment role for intravenous
immunoglobulins.
Kayed R(1), Jackson GR, Estes DM, Barrett AD.
Author information:
(1)Mitchell Center for Neurodegenerative Diseases, University of Texas Medical
Branch, Galveston, TX, USA. ; Department of Neurology, University of Texas
Medical Branch, Galveston, TX, USA. ; Sealy Center for Vaccine Development,
University of Texas Medical Branch, Galveston, TX, USA.
Alzheimer's disease (AD) is the most common neurodegenerative disorder.
Currently available therapies are symptomatic but do not alter underlying
disease progression. Immunotherapeutic approaches such as anti Aβ peptide active
vaccination trials have had limited success to date. Intravenous immunoblobulin
(IVIg) is widely used in immune-mediated neurological disorders such myasthenia
gravis and Guillain-Barre syndrome. These preparations have been obtained from
the pooled plasma of healthy human donors and contain natural anti-amyloid
antibodies and are well tolerated. A small pilot study of passive immunotherapy
using IVIg has suggested cognitive improvement. A multicenter phase III trial is
ongoing and will determine whether or not this treatment can ameliorate
cognitive deficits in mild-to-moderate AD. Here, we briefly review the
pathogenic role of amyloid and tau in AD, as well as immunotherapeutic efforts
to date. We also summarize what is known about naturally occurring anti-Aβ and
tau antibodies in IVIg with a view toward explaining potential mechanisms
underlying their therapeutic effects.
DOI: 10.4137/JCNSD.S5018
PMCID: PMC3663607
PMID: 23861639 |
http://www.ncbi.nlm.nih.gov/pubmed/21347466 | 1. Lab Chip. 2011 Apr 7;11(7):1256-61. doi: 10.1039/c0lc00613k. Epub 2011 Feb 23.
A first step towards practical single cell proteomics: a microfluidic antibody
capture chip with TIRF detection.
Salehi-Reyhani A(1), Kaplinsky J, Burgin E, Novakova M, deMello AJ, Templer RH,
Parker P, Neil MA, Ces O, French P, Willison KR, Klug D.
Author information:
(1)Single Cell Proteomics Project, Institute of Chemical Biology, Imperial
College London, Exhibition Road, London SW7 2AZ, UK.
[email protected]
We have developed a generic platform to undertake the analysis of protein copy
number from single cells. The approach described here is 'all-optical' whereby
single cells are manipulated into separate analysis chambers using an optical
trap; single cells are lysed by a shock wave caused by laser-induced
microcavitation, and the protein released from a single cell is measured by
total internal reflection microscopy as it is bound to micro-printed antibody
spots within the device. The platform was tested using GFP transfected cells and
the relative precision of the measurement method was determined to be 88%.
Single cell measurements were also made on a breast cancer cell line to measure
the relative levels of unlabelled human tumour suppressor protein p53 using a
chip incorporating an antibody sandwich assay format. These results suggest that
this is a viable method for measuring relative protein levels in single cells.
DOI: 10.1039/c0lc00613k
PMID: 21347466 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22228800 | 1. Syst Biol. 2012 Mar;61(2):337-45. doi: 10.1093/sysbio/syr129. Epub 2012 Jan 5.
Taxon influence index: assessing taxon-induced incongruities in phylogenetic
inference.
Mariadassou M(1), Bar-Hen A, Kishino H.
Author information:
(1)Department of Mathematics and Informatics, MAP5, Université Paris Descartes,
45 rue des Saints Pères, 75270 Paris Cedex 06, France.
[email protected]
Understanding the evolutionary history of species is at the core of molecular
evolution and is done using several inference methods. The critical issue is to
quantify the uncertainty of the inference. The posterior probabilities in
Bayesian phylogenetic inference and the bootstrap values in frequentist
approaches measure the variability of the estimates due to the sampling of sites
from genes and the sampling of genes from genomes. However, they do not measure
the uncertainty due to taxon sampling. Taxa that experienced molecular
homoplasy, recent selection, a spur of evolution, and so forth may disrupt the
inference and cause incongruences in the estimated phylogeny. We define a taxon
influence index to assess the influence of each taxon on the phylogeny. We found
that although most taxa have a weak influence on the phylogeny, a small fraction
of influential taxa strongly alter it even in clades only loosely related to
them. We conclude that highly influential taxa should be given special attention
and sampling them more thoroughly can lead to more dependable phylogenies.
DOI: 10.1093/sysbio/syr129
PMID: 22228800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23702791 | 1. Acta Neurochir (Wien). 2013 Aug;155(8):1525-30. doi:
10.1007/s00701-013-1740-y. Epub 2013 May 24.
Impact of the moon on cerebral aneurysm rupture.
Kamp MA(1), Dibué M, Slotty P Jr, Steiger HJ, Hänggi D.
Author information:
(1)Department for Neurosurgery, Medical Faculty, Heinrich Heine University,
Moorenstraße 5, 40225 Düsseldorf, Germany.
[email protected]
BACKGROUND: Several external and internal risk factors for cerebral aneurysm
rupture have been identified to date. Recently, it has been reported that moon
phases correlate with the incidence of aneurysmal subarachnoid hemorrhage (SAH),
however, another author found no such association. Therefore, the present study
investigates the influence of the lunar cycle on the incidence of aneurysmal
rupture, the initial clinical presentation, and the amount of subarachnoid
blood.
METHODS: Lunar phase and the particular day of the lunar cycle were correlated
to the date of aneurysm rupture, aneurysm location, initial clinical
presentation, and amount of subarachnoid blood assessed from CT scans of all
patients treated for basal SAH in our department from 2003 to 2010.
RESULTS: We found no correlation between incidence of aneurysmal SAH, location
of the aneurysm, initial clinical presentation, or amount of subarachnoid blood
and the lunar cycle.
CONCLUSIONS: The moon influences neither the incidence of aneurysmal SAH nor the
grade of initial neurological deterioration or amount of subarachnoid blood.
DOI: 10.1007/s00701-013-1740-y
PMID: 23702791 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23199982 | 1. Trends Cell Biol. 2013 Mar;23(3):103-11. doi: 10.1016/j.tcb.2012.10.010. Epub
2012 Nov 27.
Evolution of Bcl-2 homology motifs: homology versus homoplasy.
Aouacheria A(1), Rech de Laval V, Combet C, Hardwick JM.
Author information:
(1)Molecular Biology of the Cell Laboratory, Ecole Normale Supérieure de Lyon,
LBMC UMR 5239 CNRS - UCBL - ENS Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07,
France. [email protected]
Bcl-2 family proteins regulate apoptosis in animals. This protein family
includes several homologous proteins and a collection of other proteins lacking
sequence similarity except for a Bcl-2 homology (BH)3 motif. Thus, membership in
the Bcl-2 family requires only one of the four BH motifs. On this basis, a
growing number of diverse BH3-only proteins are being reported. Although
compelling cell biological and biophysical evidence validates many BH3-only
proteins, claims of significant BH3 sequence similarity are often unfounded.
Computational and phylogenetic analyses suggest that only some BH3 motifs arose
by divergent evolution from a common ancestor (homology), whereas others arose
by convergent evolution or random coincidence (homoplasy), challenging current
assumptions about which proteins constitute the extended Bcl-2 family.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2012.10.010
PMCID: PMC3582728
PMID: 23199982 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20154508 | 1. Aging Clin Exp Res. 2009 Dec;21(6):386-406. doi: 10.1007/BF03327445.
Beyond the neurotransmitter-focused approach in treating Alzheimer's disease:
drugs targeting beta-amyloid and tau protein.
Panza F(1), Solfrizzi V, Frisardi V, Imbimbo BP, Capurso C, D'Introno A,
Colacicco AM, Seripa D, Vendemiale G, Capurso A, Pilotto A.
Author information:
(1)Department of Geriatrics, Center for Aging Brain, Memory Unit, University of
Bari, 70124, Bari, Italy. [email protected]
Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic
value and do not affect the main neuropathological hallmarks of the disease,
i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly
formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles
are composed of paired helical filaments of hyperphosphorylated tau protein.
New, potentially disease-modifying, therapeutic approaches are targeting Abeta
and tau protein. Drugs directed against Abeta include active and passive
immunization, that have been found to accelerate Abeta clearance from the brain.
The most developmentally advanced monoclonal antibody directly targeting Abeta
is bapineuzumab, now being studied in a large Phase III clinical trial.
Compounds that interfere with proteases regulating Abeta formation from amyloid
precursor protein (APP) are also actively pursued. The discovery of inhibitors
of beta-secretase, the enzyme that regulates the first step of the amyloidogenic
metabolism of APP, has been revealed to be particularly difficult due to
inherent medicinal chemistry problems, and only one compound (CTS-21166) has
reached clinical testing. Conversely, several compounds that inhibit
gamma-secretase, the pivotal enzyme that generates Abeta, have been identified,
the most advanced being LY-450139 (semagacestat), now in Phase III clinical
development. Compounds that stimulate alpha-secretase, the enzyme responsible
for the non-amyloidogenic metabolism of APP, are also being developed, and one
of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of
Abeta aggregation have also been identified, and one of such compounds, PBT-2,
has provided encouraging neuropsychological results in a recently completed
Phase II study. Therapeutic approaches directed against tau protein include
inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for
tau phosphorylation and tau protein aggregation inhibitors. NP-12, a promising
GSK-3 inhibitor, is being tested in a Phase II study, and methylthioninium
chloride, a tau protein aggregation inhibitor, has given initial encouraging
results in a 50-week study. With all these approaches on their way, the hope for
disease-modifying therapy in this devastating disease may become a reality in
the next 5 years.
DOI: 10.1007/BF03327445
PMID: 20154508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7707624 | 1. JAMA. 1995 Apr 19;273(15):1179-84.
Exercise intensity and longevity in men. The Harvard Alumni Health Study.
Lee IM(1), Hsieh CC, Paffenbarger RS Jr.
Author information:
(1)Department of Epidemiology, Harvard School of Public Health, Boston, MA
02115, USA.
Comment in
ACP J Club. 1995 Sep-Oct;123(2):52-3.
JAMA. 1995 Oct 11;274(14):1132-3.
OBJECTIVE: To examine the independent associations of vigorous (> or = 6 resting
metabolic rate [MET] score) and nonvigorous (< 6 MET score) physical activity
with longevity.
DESIGN: Prospective cohort study, following up men from 1962 or 1966 through
1988.
SETTING/PARTICIPANTS: Subjects were Harvard University alumni, without
self-reported, physician-diagnosed cardiovascular disease, cancer, or chronic
obstructive pulmonary disease (n = 17,321). Men with a mean age of 46 years
reported their physical activities on questionnaires at baseline.
MAIN OUTCOME MEASURE: All-cause mortality (3728 deaths).
RESULTS: Total energy expenditure and energy expenditure from vigorous
activities, but not energy expenditure from nonvigorous activities, related
inversely to mortality. After adjustment for potential confounders, the relative
risks of dying associated with increasing quintiles of total energy expenditure
were 1.00 (referent), 0.94, 0.95, 0.91 and 0.91, respectively (P [trend] < .05).
The relative risks of dying associated with less than 630, 630 to less than
1680, 1680 to less than 3150, 3150 to less than 6300, and 6300 or more kJ/wk
expended on vigorous activities were 1.00 (referent), 0.88, 0.92, 0.87, and
0.87, respectively (P [trend] = .007). Corresponding relative risks for energy
expended on nonvigorous activities were 1.00 (referent), 0.89, 1.00, 0.98, and
0.92, respectively (P [trend] = .36). Analyses of vigorous and nonvigorous
activities were mutually adjusted. Among men who reported only vigorous
activities (259 deaths), we observed decreasing age-standardized mortality rates
with increasing activity (P = .05); among men who reported only nonvigorous
activities (380 deaths), no trend was apparent (P = .99).
CONCLUSIONS: These data demonstrate a graded inverse relationship between total
physical activity and mortality. Furthermore, vigorous activities but not
nonvigorous activities were associated with longevity. These findings pertain
only to all-cause mortality; nonvigorous exercise has been shown to benefit
other aspects of health.
PMID: 7707624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24289293 | 1. Expert Opin Biol Ther. 2014 Jan;14(1):127-35. doi:
10.1517/14712598.2014.866084. Epub 2013 Dec 2.
Current evaluation of alemtuzumab in multiple sclerosis.
Coyle PK(1).
Author information:
(1)MS Comprehensive Care Center, Stony Brook University, Department of Neurology
, Stony Brook, NY 11794-8121 , USA +1 631 444 8188 ; +1 631 444 1474 ;
[email protected].
INTRODUCTION: Alemtuzumab is a humanized IgG1 kappa monoclonal antibody approved
for treatment of B-cell chronic lymphocytic leukemia. This cytolytic antibody is
directed against CD52 and depletes lymphocytes, with monocytes, macrophages,
natural killer cells and a subpopulation of granulocytes being affected to a
much lesser degree. Alemtuzumab is currently under review to treat relapsing
multiple sclerosis (MS) in the United States, based on positive Phase II and
Phase III trials in both treatment-naïve and treated relapsing MS patients.
There was excellent efficacy in suppressing both clinical and neuroimaging
disease activities. In these trials, the comparator arm was not placebo, but
high dose frequently dosed subcutaneous interferon beta 1a. Alemtuzumab has
recently been approved by the European authorities for active relapsing MS, in
essence as a first-line agent. It produces long-standing effects, consistent
with an induction agent. Efficacy will have to be weighed against risk of
adverse effects, which include autoimmune disorders and infection. Alemtuzumab
joins an increasingly crowded market, and will add to the complexity of treating
MS.
AREAS COVERED: This review will discuss alemtuzumab as a therapy for MS,
reviewing PubMed for clinical trials, publications and presentations at
international meetings. It will focus on a United States market perspective.
EXPERT OPINION: Alemtuzumab offers induction strategy for very active relapsing
MS patients who have failed conventional therapy, and possibly selected
treatment-naive patients. Alemtuzumab use is likely to be restricted to
specialized MS centers, with long-term monitoring to determine the true risk for
adverse effects.
DOI: 10.1517/14712598.2014.866084
PMID: 24289293 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20525577 | 1. Syst Biol. 2009 Apr;58(2):184-98. doi: 10.1093/sysbio/syp019. Epub 2009 Jun
29.
Homoplasy and clade support.
Brandley MC(1), Warren DL, Leaché AD, McGuire JA.
Author information:
(1)Museum of Vertebrate Zoology and Department of Integrative Biology,
University of California, Berkeley, CA 94720-3160, USA.
Distinguishing phylogenetic signal from homoplasy (shared similarities among
taxa that do not arise by common ancestry) is an implicit goal of any
phylogenetic study. Large amounts of homoplasy can interfere with accurate tree
inference, and it is expected that common measures of clade support, including
bootstrap proportions and Bayesian posterior probabilities, should also be
impacted to some degree by homoplasy. Through data simulation and analysis of 38
empirical data sets, we show that high amounts of homoplasy will affect all
measures of clade support in a manner that is dependent on clade size. More
specifically, the smallest taxon bipartitions in an unrooted tree topology will
receive higher support relative to clades of intermediate sizes, even when all
clades are supported by the same amount of data. We determine that the ultimate
causes of this effect are the inclusion of random trees (due to homoplasy)
during bootstrap resampling and Markov chain Monte Carlo (MCMC) topology
searching and the higher relative proportion of small taxon bipartitions (i.e.,
2 or 3 taxa) to larger sized bipartitions. However, the use of explicit
model-based methods, especially Bayesian MCMC methods, effectively overcomes
this clade size effect even when very small amounts of phylogenetic signal are
present. We develop a post hoc statistic, the clade disparity index (CDI), to
measure both the relative magnitude of the clade size effect and its statistical
significance. In analyses of both simulated and empirical data, CDI values
indicate that Bayesian MCMC analyses are substantially more likely to estimate
clade support values that are uncorrelated with clade size than are maximum
parsimony and maximum likelihood bootstrap analyses and thus less affected by
homoplasy. These results may be especially relevant to "deep" phylogenetic
problems, such as reconstructing the tree of life, as they represent the largest
possible extremes of time and evolutionary rates, 2 factors that cause
homoplasy.
DOI: 10.1093/sysbio/syp019
PMID: 20525577 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19114542 | 1. Eur J Endocrinol. 2009 Mar;160(3):409-15. doi: 10.1530/EJE-08-0742. Epub 2008
Dec 29.
Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid
patients during normalization of thyroid function: a double-blind,
placebo-controlled study.
Nagasaki T(1), Inaba M, Yamada S, Shirakawa K, Nagata Y, Kumeda Y, Hiura Y,
Tahara H, Ishimura E, Nishizawa Y.
Author information:
(1)Department of Metabolism, Endocrinology and Molecular Medicine, Internal
Medicine, Osaka City University Graduate School of Medicine, Osaka-City, Japan.
OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population,
is especially prevalent in females, and may be associated with increased
morbidity from cardiovascular disease, although it remains controversial. We
recently reported a significant increase in the brachial-ankle pulse wave
velocity (baPWV), a parameter of arterial stiffening and an independent
predictor of cardiovascular events, in subclinical hypothyroidism without
thyroiditis. The current study was performed to assess changes in baPWV in
female subclinical hypothyroidism with autoimmune chronic thyroiditis
(Hashimoto's disease) after restoration of normal thyroid function.
METHODS: In a randomized placebo-controlled study, 95 female subclinical
hypothyroid patients were monitored for changes in baPWV before and after
levothyroxine (l-T(4)) replacement therapy. Changes in baPWV were also measured
in 42 age-matched normal female subjects.
RESULTS: The baseline baPWV values in patients with subclinical hypothyroidism
were significantly higher than in normal subjects. With attainment of
euthyroidism, baPWV showed a significant decrease from 1776.7+/-86.0 to
1674.3+/-79.2 cm/s (P=0.006) in patients treated with l-T(4), but the changes in
baPWV and TSH were not correlated. The change in baPWV was significantly and
negatively correlated with age and baseline pulse pressure, but multiple
regression analysis revealed that these parameters failed to be associated with
the change in baPWV.
CONCLUSIONS: Sustained normalization of thyroid function during l-T(4)
replacement therapy significantly decreases baPWV in female subclinical
hypothyroid patients with autoimmune chronic thyroiditis, suggesting the
improvement of arterial stiffening and, consequently, possible prevention of
cardiovascular disease.
DOI: 10.1530/EJE-08-0742
PMID: 19114542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1283315 | 1. Genes Chromosomes Cancer. 1992 Nov;5(4):271-7. doi: 10.1002/gcc.2870050402.
Cloning and characterization of the Ewing's sarcoma and peripheral
neuroepithelioma t(11;22) translocation breakpoints.
Zucman J(1), Delattre O, Desmaze C, Plougastel B, Joubert I, Melot T, Peter M,
De Jong P, Rouleau G, Aurias A, et al.
Author information:
(1)Laboratoire de Génétique des Tumeurs, Institut Curie, Paris, France.
Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are related tumors,
possibly of neural crest origin, which are cytogenetically characterized by the
specific translocation t(11;22)(q24;q12). The cos5 locus, previously identified
in the vicinity of the chromosome 22 breakpoint of this translocation, was shown
by in situ hybridization on interphase nuclei to lie between VIIIF2 and LIF, two
loci located on either side of the breakpoint and at a distance of less than
2,000 kb. The progressive expansion of this locus by chromosome walking led to
the construction of a 300 kb contig, which finally crossed the breakpoint. The
subsequent cloning of the two translocation junction fragments of a PN, followed
by the molecular characterization of the translocation breakpoints of 20 ES and
PN, showed that most chromosome 22 breakpoints are clustered within a small, 2
kb region. In contrast, the chromosome 11 breakpoints are scattered over a
region of at least 40 kb. The translocation leads to the synthesis of chimeric
transcript that links sequences from chromosomes 22 and 11. Finally, no evidence
was found of any specific difference in the position of ES and PN translocation
breakpoints.
DOI: 10.1002/gcc.2870050402
PMID: 1283315 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23940258 | 1. J Exp Med. 2013 Aug 26;210(9):1779-91. doi: 10.1084/jem.20130315. Epub 2013
Aug 12.
Human L-ferritin deficiency is characterized by idiopathic generalized seizures
and atypical restless leg syndrome.
Cozzi A(1), Santambrogio P, Privitera D, Broccoli V, Rotundo LI, Garavaglia B,
Benz R, Altamura S, Goede JS, Muckenthaler MU, Levi S.
Author information:
(1)San Raffaele Scientific Institute, Division of Neuroscience and 2 University
Vita-Salute San Raffaele, Milan, Italy.
The ubiquitously expressed iron storage protein ferritin plays a central role in
maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy
(H) and light (L) subunits that co-assemble into a hollow spherical shell with
an internal cavity where iron is stored. The ferroxidase activity of the
ferritin H chain is critical to store iron in its Fe3+ oxidation state, while
the L chain shows iron nucleation properties. We describe a unique case of a
23-yr-old female patient affected by a homozygous loss of function mutation in
the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg
syndrome (RLS). We show that L chain ferritin is undetectable in primary
fibroblasts from the patient, and thus ferritin consists only of H chains.
Increased iron incorporation into the FtH homopolymer leads to reduced cellular
iron availability, diminished levels of cytosolic catalase, SOD1 protein levels,
enhanced ROS production and higher levels of oxidized proteins. Importantly, key
phenotypic features observed in fibroblasts are also mirrored in reprogrammed
neurons from the patient's fibroblasts. Our results demonstrate for the first
time the pathophysiological consequences of L-ferritin deficiency in a human and
help to define the concept for a new disease entity hallmarked by idiopathic
generalized seizure and atypical RLS.
DOI: 10.1084/jem.20130315
PMCID: PMC3754865
PMID: 23940258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20822494 | 1. Essays Biochem. 2010 Sep 20;48(1):187-200. doi: 10.1042/bse0480187.
Genomic imprinting and human disease.
Hirasawa R(1), Feil R.
Author information:
(1)Institute of Molecular Genetics, CNRS UMR-5535 and the University of
Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
In many epigenetic phenomena, covalent modifications on DNA and chromatin
mediate somatically heritable patterns of gene expression. Genomic imprinting is
a classical example of epigenetic regulation in mammals. To date, more than 100
imprinted genes have been identified in humans and mice. Many of these are
involved in foetal growth and deve lopment, others control behaviour.
Mono-allelic expression of imprinted genes depends on whether the gene is
inherited from the mother or the father. This remarkable pattern of expression
is controlled by specialized sequence elements called ICRs (imprinting control
regions). ICRs are marked by DNA methylation on one of the two parental alleles.
These allelic marks originate from either the maternal or the paternal germ
line. Perturbation of the allelic DNA methylation at ICRs is causally involved
in several human diseases, including the Beckwith-Wiedemann and Silver-Russell
syndromes, associated with aberrant foetal growth. Perturbed imprinted gene
expression is also implicated in the neuro-developmental disorders Prader-Willi
syndrome and Angelman syndrome. Embryo culture and human-assisted reproduction
procedures can increase the occurrence of imprinting-related disorders. Recent
research shows that, besides DNA methylation, covalent histone modifications and
non-histone proteins also contribute to imprinting regulation. The involvement
of imprinting in specific human pathologies (and in cancer) emphasizes the need
to further explore the underlying molecular mechanisms.
DOI: 10.1042/bse0480187
PMID: 20822494 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21562592 | 1. Gene Ther. 2012 Jan;19(1):15-24. doi: 10.1038/gt.2011.70. Epub 2011 May 12.
CTF/NF1 transcription factors act as potent genetic insulators for integrating
gene transfer vectors.
Gaussin A(1), Modlich U, Bauche C, Niederländer NJ, Schambach A, Duros C, Artus
A, Baum C, Cohen-Haguenauer O, Mermod N.
Author information:
(1)Institute of Biotechnology, University of Lausanne, Lausanne, Switzerland.
Gene transfer-based therapeutic approaches have greatly benefited from the
ability of some viral vectors to efficiently integrate within the cell genome
and ensure persistent transmission of newly acquired transgenes to the target
cell progeny. However, integration of provirus has been associated with
epigenetic repercussions that may influence the expression of both the transgene
and cellular genes close to vector integration loci. The exploitation of genetic
insulator elements may overcome both issues through their ability to act as
barriers that limit transgene silencing and/or as enhancer-blockers preventing
the activation of endogenous genes by the vector enhancer. We established
quantitative plasmid-based assay systems to screen enhancer-blocker and barrier
genetic elements. Short synthetic insulators that bind to nuclear factor-I
protein family transcription factors were identified to exert both
enhancer-blocker and barrier functions, and were compared to binding sites for
the insulator protein CTCF (CCCTC-binding factor). Gamma-retroviral vectors
enclosing these insulator elements were produced at titers similar to their
non-insulated counterparts and proved to be less genotoxic in an in vitro
immortalization assay, yielding lower activation of Evi1 oncogene expression and
reduced clonal expansion of bone marrow cells.
DOI: 10.1038/gt.2011.70
PMID: 21562592 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8918594 | 1. J Mol Biol. 1996 Nov 1;263(3):385-9. doi: 10.1006/jmbi.1996.0582.
Comparison of CH1 domains in different classes of murine antibodies.
Sheriff S(1), Jeffrey PD, Bajorath J.
Author information:
(1)Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ
08543-4000, USA.
The CH1 domains of antibodies belonging to the following five murine
immunoglobulin (Ig) classes IgG1, IgG2a, IgG2b, IgG3 and IgA have been compared.
The IgG CH1 domain structures are, as would be expected, similar overall, but
show local conformational variations. When compared with IgG CH1 domain
structures, the IgA CH1 domain displays several significant structural
differences, which are a consequence of insertions/ deletions and specific
structural constraints. In regions of structural differences in the IgG CH1
domains, the spatial correspondence of residues is not reflected by conventional
(Kabat) sequence number. Thus the sequence alignment and numbering for CH1
domains has been revised to be consistent with the three-dimensional alignments.
DOI: 10.1006/jmbi.1996.0582
PMID: 8918594 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20497044 | 1. Expert Opin Biol Ther. 2010 Jul;10(7):1121-30. doi:
10.1517/14712598.2010.493872.
Bapineuzumab.
Kerchner GA(1), Boxer AL.
Author information:
(1)Stanford University School of Medicine, Stanford Center for Memory Disorders,
300 Pasteur Drive, Room A343, Stanford, CA 94305-5235, USA.
IMPORTANCE OF THE FIELD: Alzheimer's disease is the leading cause of dementia in
the elderly, and there is no disease-modifying therapy yet available.
Immunotherapy directed against the beta-amyloid peptide may be capable of
slowing the rate of disease progression. Bapineuzumab, an anti-beta-amyloid
monoclonal antibody, will be the first such agent to emerge from Phase III
clinical trials.
AREAS COVERED IN THIS REVIEW: The primary literature on bapineuzumab from 2009
and 2010 is reviewed in its entirety, along with the literature on AN1792, a
first-generation anti-beta-amyloid vaccine, from 2003 to 2009. Other Alzheimer's
disease immunotherapeutics currently in development, according to
www.clinicaltrials.gov , are also discussed.
WHAT THE READER WILL GAIN: In addition to a critical appraisal of the Phase II
trial results for bapineuzumab, this review considers the broader field of
immunotherapy for Alzheimer's disease as a whole, including the challenges
ahead.
TAKE HOME MESSAGE: Bapineuzumab appears capable of reducing the cerebral
beta-amyloid peptide burden in patients with Alzheimer's disease. However,
particularly in APOE 4 carriers, its ability to slow disease progression remains
uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse
reaction - may limit its clinical applicability.
DOI: 10.1517/14712598.2010.493872
PMCID: PMC3000430
PMID: 20497044 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22362900 | 1. Postgrad Med J. 2012 Jul;88(1041):382-90. doi:
10.1136/postgradmedj-2011-130215. Epub 2012 Feb 23.
Sudden cardiac death among competitive adult athletes: a review.
Pugh A(1), Bourke JP, Kunadian V.
Author information:
(1)Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle
University, 3rd Floor William Leech Building, Newcastle upon Tyne, UK.
Sudden cardiac death is the leading cause of mortality among young athletes with
an incidence of 1-2 per 100,000 athletes per annum. It is described as 'an event
that is non-traumatic, non-violent, unexpected, and resulting from sudden
cardiac arrest within six hours of previously witnessed normal health'. Most
predisposed athletes have no symptoms and there is no warning for the impending
tragic event. The majority of cases are caused by an underlying structural
cardiac abnormality, most commonly hypertrophic cardiomyopathy. More recently,
the understanding of non-structural causes such as long QT syndrome and Brugada
syndrome has grown and diagnostic criteria have been developed. This review
presents the known aetiologies of sudden cardiac death among athletes and
outlines their identification and management including implications for future
sporting participation as laid out in the consensus documents produced by the
European Society of Cardiology and the 36th Bethesda Conference.
DOI: 10.1136/postgradmedj-2011-130215
PMID: 22362900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19467991 | 1. Brain. 2009 Sep;132(Pt 9):2403-12. doi: 10.1093/brain/awp125. Epub 2009 May
25.
Altered dopaminergic profile in the putamen and substantia nigra in restless leg
syndrome.
Connor JR(1), Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, Earley CJ.
Author information:
(1)Department of Neurosurgery, Penn State College of Medicine, Hershey, PA
17033-0850, USA. [email protected]
Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have
implicated the dopaminergic system in RLS, while others have suggested that it
is associated with insufficient levels of brain iron. To date, alterations in
brain iron status have been demonstrated but, despite suggestions from the
clinical literature, there have been no consistent findings documenting a
dopaminergic abnormality in RLS brain tissue. In this study, the substantia
nigra and putamen were obtained at autopsy from individuals with primary RLS and
a neurologically normal control group. A quantitative profile of the
dopaminergic system was obtained. Additional assays were performed on a
catecholaminergic cell line and animal models of iron deficiency. RLS tissue,
compared with controls, showed a significant decrease in D2R in the putamen that
correlated with severity of the RLS. RLS also showed significant increases in
tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls,
but not in the putamen. Both TH and phosphorylated (active) TH were
significantly increased in both the substantia nigra and putamen. There were no
significant differences in either the putamen or nigra for dopamine receptor 1,
dopamine transporters or for VMAT. Significant increases in TH and
phosphorylated TH were also seen in both the animal and cell models of iron
insufficiency similar to that from the RLS autopsy data. For the first time, a
clear indication of dopamine pathology in RLS is revealed in this autopsy study.
The results suggest cellular regulation of dopamine production that closely
matches the data from cellular and animal iron insufficiency models. The results
are consistent with the hypothesis that a primary iron insufficiency produces a
dopaminergic abnormality characterized as an overly activated dopaminergic
system as part of the RLS pathology.
DOI: 10.1093/brain/awp125
PMCID: PMC2732265
PMID: 19467991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19581928 | 1. Oncogene. 2009 Aug 20;28(33):2940-7. doi: 10.1038/onc.2009.180. Epub 2009 Jul
6.
Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human
breast cancer cells.
Sullivan NJ(1), Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM,
Hall BM.
Author information:
(1)Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio
State University, Columbus, OH 43210, USA.
Comment in
Oncogene. 2010 Apr 29;29(17):2599-600; author reply 2601-3. doi:
10.1038/onc.2010.4.
Breast tumor interleukin-6 (IL-6) levels increase with tumor grade, and elevated
serum IL-6 correlates with poor breast cancer patient survival.
Epithelial-mesenchymal transition (EMT) phenotypes such as impaired E-cadherin
expression or aberrant Vimentin induction are associated with enhanced
metastasis and unfavorable clinical outcome in breast cancer. Despite this fact,
few tumor microenvironment-derived extracellular signaling factors capable of
provoking such a phenotypic transition have been identified. In this study, we
showed that IL-6 promoted E-cadherin repression among a panel of estrogen
receptor-alpha-positive human breast cancer cells. Furthermore, ectopic stable
IL-6 expressing MCF-7 breast adenocarcinoma cells (MCF-7(IL-6)) exhibited an EMT
phenotype characterized by impaired E-cadherin expression and induction of
Vimentin, N-cadherin, Snail and Twist. MCF-7(IL-6) cells formed xenograft tumors
that displayed loss of E-cadherin, robust Vimentin induction, increased
proliferative indices, advanced tumor grade and undifferentiated histology.
Finally, we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells
that constitutively express Twist, a metastatic regulator and direct
transcriptional repressor of E-cadherin. To our knowledge, this is the first
study that shows IL-6 as an inducer of an EMT phenotype in breast cancer cells
and implicates its potential to promote breast cancer metastasis.
DOI: 10.1038/onc.2009.180
PMCID: PMC5576031
PMID: 19581928 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest The authors declare no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/19674435 | 1. Alzheimers Res Ther. 2009 Jul 9;1(1):2. doi: 10.1186/alzrt2.
Alzheimer's disease therapeutic research: the path forward.
Aisen PS(1).
Author information:
(1)Department of Neurosciences, University of California San Diego, Gilman
Drive, La Jolla, CA 92093, USA. [email protected].
The field of Alzheimer's disease therapeutic research seems poised to bring to
clinic the next generation of treatments, moving beyond symptomatic benefits to
modification of the underlying neurobiology of the disease. But a series of
recent trials has had disappointingly negative results that raise questions
about our drug development strategies. Consideration of ongoing programs
demonstrates difficult pitfalls. But a clear path forward is emerging.
Successful strategies will utilize newly available tools to reconsider issues of
diagnosis, assessment and analysis, facilitating the study of new treatments at
early stages in the disease process at which they are most likely to yield major
clinical benefits.
DOI: 10.1186/alzrt2
PMCID: PMC2719107
PMID: 19674435 |
http://www.ncbi.nlm.nih.gov/pubmed/23221354 | 1. Cerebrovasc Dis. 2012;34(5-6):419-23. doi: 10.1159/000345067. Epub 2012 Dec 5.
NIHSS scores in ischemic small vessel disease: a study in CADASIL.
Yao M(1), Hervé D, Allili N, Jouvent E, Duering M, Dichgans M, Chabriat H.
Author information:
(1)Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) is widely
used to measure neurological deficits, evaluate the effectiveness of treatment
and predict outcome in acute ischemic stroke. It has also been used to measure
the residual neurological deficit at the chronic stage after ischemic events.
However, the value of NIHSS in ischemic cerebral small vessel disease has not
been specifically evaluated. The purpose of this study was to investigate the
link between the NIHSS score and clinical severity in a large population of
subjects with CADASIL (cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy), a unique model to investigate the
pathophysiology and natural history of ischemic small vessel disease.
METHODS: Demographic and clinical data of 220 patients with one or more lacunar
infarcts confirmed by MRI examination and enrolled from a prospective cohort
study were analyzed. Detailed neurological examinations, including evaluation of
the NIHSS and modified Rankin Scale score (mRS) for evaluating the clinical
severity, were performed in all subjects. The sensitivity, specificity, positive
and negative predictive values of various NIHSS thresholds to capture the
absence of significant disability (mRS <3) were calculated. General linear
models, controlling for age, educational level and different clinical
manifestations frequently observed in CADASIL, were used to evaluate the
relationships between NIHSS and clinical severity.
RESULTS: In the whole cohort, 45 (20.5%) subjects presented with mRS ≥3, but
only 16 (7.3%) had NIHSS >5. All but 1 subject with NIHSS >5 showed mRS ≥3.
NIHSS ≤5 had an 85.3% positive predictive value for no or slight disability with
only 33.3% specificity. The NIHSS, MMSE score and presence or absence of gait
disturbances were found to be strongly and independently correlated with
disability (all p < 0.001). Altogether, they accounted for 73% of the variance
of mRS in contrast with the NIHSS alone accounting for only 50% of this
variance. Among patients with NIHSS ≤5, subjects with mRS ≥3 showed a lower MMSE
score than those with mRS <3 (p < 0.001). All patients with NIHSS ≤5 but with
mRS ≥3 presented either with gait disturbances or MMSE score <25.
CONCLUSIONS: The present results suggest that the NIHSS cannot reflect the
extent of neurological deficit and clinical severity in subjects with lacunar
infarctions in the context of a chronic and diffuse small vessel disease. A
specific and global neurological scale, including the assessment of cognitive
and gait performances, should be developed for ischemic cerebral
microangiopathy.
Copyright © 2012 S. Karger AG, Basel.
DOI: 10.1159/000345067
PMID: 23221354 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21197470 | 1. Stroke Res Treat. 2010 Dec 9;2011:304921. doi: 10.4061/2011/304921.
The migraine-ischemic stroke relation in young adults.
Pezzini A(1), Del Zotto E, Giossi A, Volonghi I, Costa P, Dalla Volta G,
Padovani A.
Author information:
(1)Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica,
Università degli Studi di Brescia, Piazzale Spedali Civili, 1, 25100 Brescia,
Italy.
In spite of the strong epidemiologic evidence linking migraine and ischemic
stroke in young adults, the mechanisms explaining this association remain poorly
understood. The observation that stroke occurs more frequently during the
interictal phase of migraine prompts to speculation that an indirect relation
between the two diseases might exist. In this regard, four major issues might be
considered which may be summarized as follows: (1) the migraine-ischemic stroke
relation is influenced by specific risk factors such as patent foramen ovale or
endothelial dysfunction and more frequent in particular conditions like
spontaneous cervical artery dissection; (2) migraine is associated with an
increased prevalence of cardiovascular risk factors; (3) the link is caused by
migraine-specific drugs; (4) migraine and ischemic vascular events are linked
via a genetic component. In the present paper, we will review epidemiological
studies, discuss potential mechanisms of migraine-induced stroke and comorbid
ischemic stroke, and pose new research questions.
DOI: 10.4061/2011/304921
PMCID: PMC3005862
PMID: 21197470 |
http://www.ncbi.nlm.nih.gov/pubmed/21475904 | 1. Mol Med Rep. 2009 Sep-Oct;2(5):799-803. doi: 10.3892/mmr_00000175.
Construction of novel conditional transgenic vectors for molecular therapy based
on the Tet-On system and flanked with insulators in a single plasmid.
Wang YA(1), Fei ZL, Zhang ZY, Jiang XQ, Chen WT, Wang ZG, Fei J, Zheng JW.
Author information:
(1)Department of Oral and Maxillofacial Surgery, Ninth People's Hospital,
Shanghai JiaoTong University School of Medicine, Shanghai 200011, P.R. China.
Regulated expression of a gene of interest is crucial for transgenic research,
as well as for safe and efficacious gene therapy. The most commonly used
conditional expression system requires the generation of two transgenic strains,
one carrying an inducible promoter and the other a transactivator. The
generation of conditional transgenic models using this method is costly and time
consuming. In this study, we report the design and construction of novel
simplified gene delivery vectors that integrate both the regulatory and
responsive elements in a single vector. The Tet-On system was used and
integrated the inducible promoter and transactivator in a single plasmid,
between which a copy of an insulator was inserted to minimize interference
between the two units. Another copy of an insulator was inserted upstream of the
transgene cassette to eliminate transgene silencing and to lower basal
expression. The two insulators were in the same orientation. To further decrease
basal expression, the most powerful repressor domain containing a
'kruppel-associated box' of the zinc finger protein NK10 was used and fused to
TetR in one of the two vectors. The function of this system was confirmed after
in?vitro transient transfection. The two conditional plasmids were successfully
constructed, and the expression of the gene of interest was regulated tightly in
vitro. In conclusion, the vectors described here may be useful for gene therapy
applications, as well as for the establishment of conditional animal models.
DOI: 10.3892/mmr_00000175
PMID: 21475904 |
http://www.ncbi.nlm.nih.gov/pubmed/21914854 | 1. Mol Cancer Ther. 2011 Dec;10(12):2415-25. doi: 10.1158/1535-7163.MCT-11-0401.
Epub 2011 Sep 13.
The NEDD8-activating enzyme inhibitor, MLN4924, cooperates with TRAIL to augment
apoptosis through facilitating c-FLIP degradation in head and neck cancer cells.
Zhao L(1), Yue P, Lonial S, Khuri FR, Sun SY.
Author information:
(1)Department of Hematology and Medical Oncology, Emory University School of
Medicine and Winship Cancer Institute, 1365-C Clifton Road NE, C3088, Atlanta,
GA 30322, USA.
TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective cytokine with
potential anticancer activity and is currently under clinical testing. Head and
neck squamous cell carcinoma (HNSCC), like other cancer types, exhibits varied
sensitivity to TRAIL. MLN4924 is a newly developed investigational small
molecule inhibitor of NEDD8-activating enzyme with potent anticancer activity.
This study reveals a novel function of MLN4924 in synergizing with TRAIL to
induce apoptosis in HNSCC cells. MLN4924 alone effectively inhibited the growth
of HNSCC cells and induced apoptosis. When combined with TRAIL, synergistic
effects on decreasing the survival and inducing apoptosis of HNSCC cells
occurred. MLN4924 decreased c-FLIP levels without modulating death receptor 4
and death receptor 5 expression. Enforced expression of c-FLIP substantially
attenuated MLN4924/TRAIL-induced apoptosis. Thus c-FLIP reduction plays an
important role in mediating MLN4924/TRAIL-induced apoptosis. Moreover, MLN4924
decreased c-FLIP stability, increased c-FLIP ubiquitination, and facilitated
c-FLIP degradation, suggesting that MLN4924 decreases c-FLIP levels through
promoting its degradation. MLN4924 activated c-jun-NH(2)-kinase (JNK) signaling,
evidenced by increased levels of phospho-c-Jun in MLN4924-treated cells.
Chemical inhibition of JNK activation not only prevented MLN4924-induced c-FLIP
reduction, but also inhibited MLN4924/TRAIL-induced apoptosis, suggesting that
JNK activation mediates c-FLIP downregulation and subsequent enhancement of
TRAIL-induced apoptosis by MLN4924. Because knockdown of NEDD8 failed to
activate JNK signaling and downregulate c-FLIP, it is likely that MLN4924
reduces c-FLIP levels and enhances TRAIL-induced apoptosis independent of NEDD8
inhibition.
DOI: 10.1158/1535-7163.MCT-11-0401
PMCID: PMC3237891
PMID: 21914854 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6726718 | 1. J Rheumatol. 1984 Apr;11(2):222-5.
Cardiac tamponade in systemic juvenile rheumatoid arthritis requiring emergency
pericardiectomy.
Alukal MK, Costello PB, Green FA.
A 9-year-old boy with systemic onset juvenile rheumatoid arthritis (JRA)
presented with fever and chest pain and rapidly developed pericarditis and
cardiac tamponade. Despite corticosteroid treatment and pericardiocentesis,
rapid deterioration necessitated the emergency placement of a pericardial
window. This is the first reported instance of this type of emergency surgical
intervention for JRA. Of 220 children with JRA followed for 12 years (7%
systemic onset), 8 had evidence of acute pericarditis but no other had definite
evidence of tamponade.
PMID: 6726718 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22375212 | 1. Asian J Sports Med. 2011 Mar;2(1):1-15. doi: 10.5812/asjsm.34818.
Sudden cardiac death in young athletes; a literature review and special
considerations in Asia.
Halabchi F(1), Seif-Barghi T, Mazaheri R.
Author information:
(1)Sports Medicine Research Center, Tehran University of Medical Sciences,
Tehran, IR Iran.
Comment in
Asian J Sports Med. 2011 Jun;2(2):117-9; author reply 123. doi:
10.5812/asjsm.34779.
Asian J Sports Med. 2011 Jun;2(2):120-2; author reply 123. doi:
10.5812/asjsm.34778.
Sudden cardiac death (SCD) in a young athlete is rare, but catastrophic.
Exercise acts as a risk factor for SCD in people with cardiovascular disease. A
diversity of cardiovascular disorders including hypertrophic cardiomyopathy,
congenital coronary anomalies, arrhythmogenic right ventricular dysplasia,
dilated cardiomyopathy, aortic rupture due to Marfan syndrome, myocarditis,
valvular disease and electrical disorders (Wolff-Parkinson-White syndrome, long
QT syndrome, Brugada syndrome), as well as commotio cordis represent the common
causes of SCD in young athletes.As the outcome of lethal cardiovascular
disorders is not reversible except in few cases, effective measures should be
addressed to reduce the burden of sudden cardiac death in young athletes.
Currently, two types of recommendations are proposed by American and European
countries.It seems that there are some special considerations in Asia, entirely
different from North America or Europe, which warrant more comprehensive
research on epidemiology and etiology of SCD in young Asian athletes by country
and evaluation of current national preventive strategies and their achievements
in decreasing the risk. Using these data and considering regional restrictions,
an expert group will be able to plan a practical and feasible preventive
strategy.
DOI: 10.5812/asjsm.34818
PMCID: PMC3289188
PMID: 22375212 |
http://www.ncbi.nlm.nih.gov/pubmed/22090498 | 1. J Neurosci. 2011 Nov 16;31(46):16709-15. doi: 10.1523/JNEUROSCI.3736-11.2011.
Perinatal citalopram exposure selectively increases locus ceruleus circuit
function in male rats.
Darling RD(1), Alzghoul L, Zhang J, Khatri N, Paul IA, Simpson KL, Lin RC.
Author information:
(1)Department of Neurobiology and Anatomical Sciences, University of Mississippi
Medical Center, Jackson, Mississippi 39216, USA.
Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), have
been widely prescribed for major depressive disorder, not only for adult
populations, but also for children and pregnant mothers. Recent evidence
suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels
in the raphe system and decreases norepinephrine (NE) locus ceruleus (LC) neural
activity, suggesting a robust opposing interaction between these two monoamines.
In contrast, perinatal SSRI exposure induces a long-lasting downregulation of
the 5-HT-raphe system, which is opposite to that seen with chronic adult
treatment. Therefore, the goal of the present investigation was to test the
hypothesis that perinatal CTM exposure (20 mg/kg/d) from postnatal day 1 (PN1)
to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). Our
single-neuron LC electrophysiological data demonstrated an increase in
spontaneous and stimulus-driven neural activity, including an increase in phasic
bursts in CTM-exposed animals. In addition, we demonstrated a corresponding
immunoreactive increase in the rate-limiting catalyzing catecholamine enzyme
(tyrosine hydroxylase) within the LC and their neocortical target sites compared
to saline controls. Moreover, these effects were only evident in male exposed
rats, suggesting a sexual dimorphism in neural development after SSRI exposure.
Together, these results indicate that administration of SSRIs during a sensitive
period of brain development results in long-lasting alterations in NE-LC circuit
function in adults and may be useful in understanding the etiology of pervasive
developmental disorders such as autism spectrum disorder.
DOI: 10.1523/JNEUROSCI.3736-11.2011
PMCID: PMC3312583
PMID: 22090498 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16702122 | 1. J Agromedicine. 2005;10(4):43-54. doi: 10.1300/J096v10n04_07.
Persistent neuropathy and hyperkeratosis from distant arsenic exposure.
Baker BA(1), Topliff AR, Messing RB, Durkin D, Johnson JS.
Author information:
(1)Occupational and Environmental Medicine, Regions Medical Center, 640 Jackson
St, St. Paul, MN 55101, USA. [email protected]
The purpose of this case series is to assess long-term sequelae of arsenic
exposure in a cohort acutely exposed to arsenic in drinking water from a well
dug into a landfill containing arsenical pesticides. Ten of the 13 individuals
(or next of kin) in the initial study agreed to participate in the follow-up
study. Next of kin provided questionnaire data and released medical information
on the three individuals who had died. The remaining seven cohort members were
assessed by an interview, questionnaire, detailed physical examination and
sensory nerve testing. Available medical records were obtained and reviewed.
Sensory testing was performed using an automated electrodiagnostic sensory Nerve
Conduction Threshold (sNCT) evaluation. Sensory complaints and electrodiagnostic
findings consistent with polyneuropathy were found in a minority (3/7) of
subjects 28 years after an acute toxic arsenic exposure. Two of the seven
patients examined (1 of 3 with neuropathic findings) also had hyperkeratotic
lesions consistent with arsenic toxicity and one of the patients had
hyperpigmentation on their lower extremities possibly consistent with arsenic
toxicity.
DOI: 10.1300/J096v10n04_07
PMID: 16702122 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22727060 | 1. FEBS J. 2012 Aug;279(16):2929-39. doi: 10.1111/j.1742-4658.2012.08674.x. Epub
2012 Jul 12.
Functional regulation of Slug/Snail2 is dependent on GSK-3β-mediated
phosphorylation.
Kim JY(1), Kim YM, Yang CH, Cho SK, Lee JW, Cho M.
Author information:
(1)Department of Biochemistry, School of Medicine, Jeju National University,
South Korea.
Snail family proteins regulate transcription of molecules for cell-cell adhesion
during epithelial-mesenchymal transition (EMT). Based on putative glycogen
synthase kinase 3β (GSK-3β) phosphorylation sites within the Slug/Snail2, we
explored the significance of GSK-3β-mediated phosphorylation in Slug/Snail2
expression during EMT. Mutation of the putative GSK-3β phosphorylation sites
(S92/96A or S100/104A) enhanced the Slug/Snail2-mediated EMT properties of
E-cadherin repression and vimentin induction, compared with wild-type
Slug/Snail2. S92/96A mutation inhibited degradation of Slug/Snail2 and S100/104A
mutation extended nuclear stabilization. Inhibition of GSK-3β activity caused
similar effects, as did the phosphorylation mutations. Thus, our study suggests
that GSK-3β-mediated phosphorylation of Slug/Snail2 controls its turnover and
localization during EMT.
© 2012 The Authors Journal compilation © 2012 FEBS.
DOI: 10.1111/j.1742-4658.2012.08674.x
PMID: 22727060 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24312663 | 1. PLoS One. 2013 Dec 3;8(12):e82559. doi: 10.1371/journal.pone.0082559.
eCollection 2013.
Optimization of the piggyBac transposon using mRNA and insulators: toward a more
reliable gene delivery system.
Bire S(1), Ley D, Casteret S, Mermod N, Bigot Y, Rouleux-Bonnin F.
Author information:
(1)GICC, UMR CNRS 7292, Université François Rabelais, Tours, France ; Institute
of Biotechnology, University of Lausanne, and Center for Biotechnology
UNIL-EPFL, Lausanne, Switzerland ; PRC, UMR INRA-CNRS 7247, Centre INRA Val de
Loire, Nouzilly, France.
Integrating and expressing stably a transgene into the cellular genome remain
major challenges for gene-based therapies and for bioproduction purposes. While
transposon vectors mediate efficient transgene integration, expression may be
limited by epigenetic silencing, and persistent transposase expression may
mediate multiple transposition cycles. Here, we evaluated the delivery of the
piggyBac transposase messenger RNA combined with genetically insulated
transposons to isolate the transgene from neighboring regulatory elements and
stabilize expression. A comparison of piggyBac transposase expression from
messenger RNA and DNA vectors was carried out in terms of expression levels,
transposition efficiency, transgene expression and genotoxic effects, in order
to calibrate and secure the transposition-based delivery system. Messenger RNA
reduced the persistence of the transposase to a narrow window, thus decreasing
side effects such as superfluous genomic DNA cleavage. Both the CTF/NF1 and the
D4Z4 insulators were found to mediate more efficient expression from a few
transposition events. We conclude that the use of engineered piggyBac
transposase mRNA and insulated transposons offer promising ways of improving the
quality of the integration process and sustaining the expression of transposon
vectors.
DOI: 10.1371/journal.pone.0082559
PMCID: PMC3849487
PMID: 24312663 [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/12718377 | 1. Turk J Pediatr. 2003 Jan-Mar;45(1):67-70.
Late-onset distal polyneuropathy due to acute organophosphate intoxication case
report.
Genel F(1), Arslanoğlu S, Uran N, Doğan M, Atlihan F.
Author information:
(1)Dr. Behçet Uz Children's Hospital, Izmir, Turkey.
Intoxications due to organophosphate insecticides are common in our country,
since agriculture has an important place. Besides the well known acute
cholinergic toxicity, these compounds may cause late-onset distal polyneuropathy
occurring two to three weeks after the acute exposure. An eight-year-old boy and
a 13-year-old girl admitted to the hospital with gait disturbances. Beginning 15
and 20 days, respectively, after organophosphate ingestion. Neurologic
examination revealed bilateral dropped foot, absent Achilles tendon reflexes and
peripheral sensory loss. Electromyography demonstrated motor weighed
sensory-motor polyneuropathy with axonal degeneration significant in the distal
parts of bilateral lower extremities. Biochemical, radiological findings and
magnetic resonance imagings were normal. The two cases were taken under a
physiotherapy program. The two cases are presented here since organophosphate
poisonings are common in our country, and since late-onset polyneuropathy is not
a well known clinical presentation as acute toxicity.
PMID: 12718377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23251841 | 1. Saf Health Work. 2012 Dec;3(4):257-67. doi: 10.5491/SHAW.2012.3.4.257. Epub
2012 Nov 30.
Occupational neurotoxic diseases in taiwan.
Liu CH(1), Huang CY, Huang CC.
Author information:
(1)Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Occupational neurotoxic diseases have become increasingly common in Taiwan due
to industrialization. Over the past 40 years, Taiwan has transformed from an
agricultural society to an industrial society. The most common neurotoxic
diseases also changed from organophosphate poisoning to heavy metal
intoxication, and then to organic solvent and semiconductor agent poisoning. The
nervous system is particularly vulnerable to toxic agents because of its high
metabolic rate. Neurological manifestations may be transient or permanent, and
may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism,
sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction
disorders. This study attempts to provide a review of the major outbreaks of
occupational neurotoxins from 1968 to 2012. A total of 16 occupational
neurotoxins, including organophosphates, toxic gases, heavy metals, organic
solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles
related to the electrophysiology, neuroimaging, treatment and long-term follow
up of these neurotoxic diseases were also obtained. The heavy metals involved
consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The
organic solvents included n-hexane, toluene, mixed solvents and carbon
disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also
included, along with toxic chemicals including polychlorinated biphenyls,
tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In
addition we attempted to correlate these events to the timeline of industrial
development in Taiwan. By researching this topic, the hope is that it may help
other developing countries to improve industrial hygiene and promote
occupational safety and health care during the process of industrialization.
DOI: 10.5491/SHAW.2012.3.4.257
PMCID: PMC3521924
PMID: 23251841
Conflict of interest statement: No potential conflict of interest relevant to
this article was reported. |
http://www.ncbi.nlm.nih.gov/pubmed/26380465 | 1. Harefuah. 2015 Jul;154(7):446-50, 469, 468.
[Novel therapies for idiopathic pulmonary fibrosis].
[Article in Hebrew]
Wand O, Kremer MR.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown
cause. The clinical course is unpredictable, but the disease is usually
progressive with a median survival of 2-5 years as a result of advanced
respiratory failure. The current hypothesis of the disease mechanism is
recurrent injury to the respiratory epithelium which leads to an uncontrolled
wound healing process resulting in fibrosis rather than repair. Despite better
understanding of the pathogenesis, there is no effective therapy for the
disease. In this review, we present the positive results of recently published
clinical trials regarding therapy for IPF, with emphasis on pirfenidone and
nintedanib.
PMID: 26380465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24348481 | 1. Front Immunol. 2013 Dec 3;4:417. doi: 10.3389/fimmu.2013.00417.
Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor
Microenvironment for DC Vaccination: A Game of Stop and Go.
Vasaturo A(1), Di Blasio S(1), Peeters DG(1), de Koning CC(1), de Vries JM(2),
Figdor CG(1), Hato SV(1).
Author information:
(1)Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences,
Radboud University Nijmegen Medical Centre , Nijmegen , Netherlands.
(2)Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences,
Radboud University Nijmegen Medical Centre , Nijmegen , Netherlands ; Department
of Medical Oncology, Nijmegen Centre for Molecular Life Sciences, Radboud
University Nijmegen Medical Centre , Nijmegen , Netherlands.
The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is
to activate cytotoxic T cells to recognize and attack the tumor. T cell
activation requires the interaction of the T cell receptor with a cognate
major-histocompatibility complex-peptide complex. Although initiated by antigen
engagement, it is the complex balance between co-stimulatory and co-inhibitory
signals on DCs that results in T cell activation or tolerance. Even when already
activated, tumor-specific T cells can be neutralized by the expression of
co-inhibitory molecules on tumor cells. These and other immunosuppressive cues
in the tumor microenvironment are major factors currently hampering the
application of DC vaccination. In this review, we discuss recent data regarding
the essential and complex role of co-inhibitory molecules in regulating the
immune response within the tumor microenvironment. In particular, possible
therapeutic intervention strategies aimed at reversing or neutralizing
suppressive networks within the tumor microenvironment will be emphasized.
Importantly, blocking co-inhibitory molecule signaling, often referred to as
immune checkpoint blockade, does not necessarily lead to an effective activation
of tumor-specific T cells. Therefore, combination of checkpoint blockade with
other immune potentiating therapeutic strategies, such as DC vaccination, might
serve as a synergistic combination, capable of reversing effector T cells
immunosuppression while at the same time increasing the efficacy of T
cell-mediated immunotherapies. This will ultimately result in long-term
anti-tumor immunity.
DOI: 10.3389/fimmu.2013.00417
PMCID: PMC3847559
PMID: 24348481 |
http://www.ncbi.nlm.nih.gov/pubmed/15802919 | 1. Hum Hered. 2005;59(1):26-33. doi: 10.1159/000084734. Epub 2005 Mar 30.
Parametric approach to genomic imprinting analysis with applications to
Angelman's syndrome.
Shete S(1), Zhou X.
Author information:
(1)Department of Epidemiology, The University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030, USA. [email protected]
Genomic imprinting is a mechanism by which only one copy of a gene pair is
expressed, and this expression is determined by the parental origin of the copy.
The deregulation of imprinted genes has been implicated in a number of human
diseases. The Imprinted Gene Catalogue now has more than 200 genes listed, and
estimates based on mouse models suggest many more may exist in humans.
Therefore, the development of methods to identify such genes is important. In
this communication, we present a parametric model-based approach to analyzing
arbitrary-sized pedigree data for genomic imprinting. We have modified widely
used LINKAGE program to incorporate our proposed approach. In addition, our
approach allows for the use of sex-specific recombinations in the analysis,
which is of particular importance in a genome-wide analysis for imprinted genes.
We compared our imprinting analysis approach to that implemented in the
GENEHUNTER-IMPRINT program using simulation studies as well as by analyzing
causal genes in Angelman's syndrome families, which are known to be imprinted.
These analyses showed that the proposed approach is very powerful for detecting
imprinted genes in large pedigrees.
Copyright 2005 S. Karger AG, Basel.
DOI: 10.1159/000084734
PMID: 15802919 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24098520 | 1. PLoS One. 2013 Oct 3;8(10):e76528. doi: 10.1371/journal.pone.0076528.
eCollection 2013.
Identification and characterization of enhancer-blocking insulators to reduce
retroviral vector genotoxicity.
Groth AC(1), Liu M, Wang H, Lovelett E, Emery DW.
Author information:
(1)Department of Medicine, Division of Medical Genetics, University of
Washington, Seattle, Washington, United States of America.
The chromatin insulator cHS4 can reduce silencing chromosomal position effects
and genotoxicity associated with integrating viral vectors. However, the fully
active version of this element can also reduce vector titers and is only
partially effective. In order to identify alternatives to cHS4, we developed a
functional lentiviral vector-based reporter screen for enhancer-blocking
insulators. Using this system, we screened candidate sequences that were
initially identified by chromatin profiling for binding by CTCF and for DNase
hypersensitivity. All 12 analyzed candidates blocked enhancer-promoter activity.
The enhancer-blocking activity of the top two candidates was confirmed in two
complementary plasmid-based assays. Studies in a gammaretroviral reporter vector
indicated these two candidates have little to no effect on vector titers, and do
not diminish vector expression in primary mouse bone marrow cultures. Subsequent
assessment in a mouse in vivo tumor formation model demonstrated that both
candidates reduced the rate of gammaretroviral vector-mediated genotoxicity as
effectively as the cHS4 insulator. In summary, we have developed a novel
lentiviral vector-based method of screening candidate elements for insulator
activity, and have used this method to identify two new insulator elements
capable of improving the safety of retroviral vectors without diminishing vector
titers or expression. These findings expand the limited arsenal of insulators
functionally validated to reduce the rate of retroviral vector-mediated
genotoxicity.
DOI: 10.1371/journal.pone.0076528
PMCID: PMC3789682
PMID: 24098520 [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/23639391 | 1. J Neurol Sci. 2013 Jul 15;330(1-2):45-51. doi: 10.1016/j.jns.2013.04.002. Epub
2013 Apr 30.
Cerebral hemorrhages in CADASIL: report of four cases and a brief review.
Rinnoci V(1), Nannucci S, Valenti R, Donnini I, Bianchi S, Pescini F, Dotti MT,
Federico A, Inzitari D, Pantoni L.
Author information:
(1)Department of Neurological and Psychiatric Sciences, University of Florence,
Italy.
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease,
clinically characterized by migraine, recurrent transient ischemic attacks or
strokes, psychiatric disorders and cognitive decline. Strokes are typically
ischemic, while hemorrhagic events have been only sporadically described.
However, cerebral microbleeds have been found in 31-69% of CADASIL patients.
METHODS: We describe four unrelated CADASIL patients who had hemorrhagic
strokes. We also briefly review the literature on intracerebral hemorrhage (ICH)
in CADASIL.
RESULTS: Three patients had a thalamo-capsular hemorrhage (age at onset: 54, 67,
77) and one of these had a second hemispheric cerebellar hemorrhage. Another
patient experienced an interpeduncular cistern subarachnoid hemorrhage when he
was 39. None of these patients was receiving antiplatelets, anticoagulants or
statins at the time of hemorrhage; all were hypertensive. NOTCH3 gene analysis
revealed mutations on exons 14, 22 (two patients presenting the same mutation),
and 24. MRI signs of previous hemorrhages were present in all these patients.
CONCLUSIONS: Hemorrhagic stroke can occur in CADASIL similarly to sporadic
cerebral small vessel diseases; this finding expands the phenotype of the
disease. A diagnosis of CADASIL should probably be considered also in patients
with ICH. These data bear potential implications in terms of need of better
control of risk factors, particularly hypertension, and raise relevant questions
about the use of antiplatelets as prevention measures in CADASIL patients.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jns.2013.04.002
PMID: 23639391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22655091 | 1. PLoS One. 2012;7(5):e37987. doi: 10.1371/journal.pone.0037987. Epub 2012 May
24.
Autonomic function following acute organophosphorus poisoning: a cohort study.
Jayasinghe SS(1), Pathirana KD.
Author information:
(1)Department of Pharmacology, Faculty of Medicine, University of Ruhuna,
Karapitiya, Galle, Sri Lanka. [email protected]
Autonomic dysfunction after chronic low level exposure to organophosphorus (OP)
pesticides has been consistently reported in the literature, but not following a
single acute overdose. In order to study autonomic function after an acute OP
overdose, sixty-six overdose patients were compared to 70 matched controls.
Assessment of autonomic function was done by heart rate response to standing,
deep breathing (HR-DB) and Valsalva manoeuvre; blood pressure (BP) response to
standing and sustained hand grip; amplitude and latency of sympathetic skin
response (SSR); pupil size and post-void urine volume. The patients were
assessed one and six weeks after the exposure. The number of patients who showed
abnormal autonomic function compared to standard cut-off values did not show
statistically significantly difference from that of controls by Chi-Square test.
When compared to the controls at one week the only significant differences
consistent with autonomic dysfunction were change of diastolic BP 3 min after
standing, HR-DB, SSR-Amplitude, SSR-Latency, post-void urine volume and size of
the pupil. At 6 weeks significant recovery of autonomic function was observed
and only HR-DB was decreased to a minor degree, -5 beats/min [95%CI 2-8]. This
study provides good evidence for the lack of long term autonomic dysfunction
following acute exposure to OP pesticides.
DOI: 10.1371/journal.pone.0037987
PMCID: PMC3360024
PMID: 22655091 [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/21258583 | 1. J Korean Med Sci. 2010 Dec;25(Suppl):S112-8. doi: 10.3346/jkms.2010.25.S.S112.
Epub 2010 Dec 15.
Disease prevalence and mortality among agricultural workers in Korea.
Lee WJ(1), Cha ES, Moon EK.
Author information:
(1)Department of Preventive Medicine, Korea University, College of Medicine,
Seoul, Korea.
The aim of this paper was to provide an overview of mortality and disease
prevalence related to occupational diseases among agricultural workers in Korea.
We evaluated the age-standardized mortality rates and the prevalence of chronic
diseases and compared them with those of other populations using death
registration data from 2004 through 2008 and the 2005 Korean National Health and
Nutrition Examination Survey. In addition, we conducted a literature review on
published articles examining the health status of farmers in Korea. Agricultural
workers have a significantly higher mortality of cancer, tuberculosis, chronic
respiratory diseases, liver diseases, suicide, motor and non-motor vehicle
accidents. Compared to other populations, farmers have higher prevalence rates
of arthritis and intervertebral disc disorders. The literature review revealed a
number of work-related diseases among farmers, such as musculoskeletal diseases,
pesticide poisoning, infections, and respiratory and neurologic diseases. Korean
farmers demonstrate a distinct pattern of mortality and disease prevalence
compared to other populations. Although lifestyle factors remain important
contributors to those deaths and diseases, our study suggests that occupation is
a major determinant as well. Intensive programs such as surveillance systems,
therefore, should be developed in order to identify and prevent work-related
diseases among agricultural workers in Korea.
DOI: 10.3346/jkms.2010.25.S.S112
PMCID: PMC3023354
PMID: 21258583 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14685672 | 1. Med Klin (Munich). 2003 Dec 15;98(12):712-6. doi: 10.1007/s00063-003-1317-2.
[Clinical genetics of neuroendocrine tumors].
[Article in German]
Karges W(1), Adler G.
Author information:
(1)Abteilung Innere Medizin 1, Universitätsklinikum, Ulm.
[email protected]
Neuroendocrine tumors (NETs) are a heterogeneous group of benign and malignant
neoplasias, detectable in the context of hereditary tumor syndromes in up to 30%
of cases. The pathogenic understanding of NETs has increased considerably during
the last decade, mainly due to the identification of underlying genetic defects
and the availability of genetically modified animal models. These developments
are reflected in a revised WHO classification of gastrointestinal NETs. In
contrast to a variety of rare neuroendocrine tumor syndromes, multiple endocrine
neoplasia syndrome type 1 (MEN1) and type 2 (MEN2) play clinically significant
roles due to their common incidence. MEN1 and MEN2 are classic
autosomal-dominant familial tumor diseases with a high penetrance and variable
clinical expression, caused by germ line mutations of the MEN1 tumor suppressor
gene and the RET protooncogene, respectively. The clinical management of
patients with NETs has changed significantly after the introduction of clinical
genetic screening. The detection of MEN1 mutations allows for risk-adapted
treatment and follow-up. RET gene analysis can identify individuals with a very
high risk to develop familial medullary cancer (MEN2), who may be successfully
treated by prophylactic thyroidectomy. NETs thus represent a paradigmatic
example of the successful link between basic genetic science and clinical care
in molecular medicine.
DOI: 10.1007/s00063-003-1317-2
PMID: 14685672 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9005271 | 1. JAMA. 1997 Jan 15;277(3):215-22.
Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of
symptoms.
Haley RW(1), Kurt TL, Hom J.
Author information:
(1)Epidemiology Division, Department of Internal Medicine, University of Texas
Southwestern Medical Center at Dallas, 75235-8874, USA.
Erratum in
JAMA 1997 Aug 6;278(5):388.
Comment in
JAMA. 1997 Jan 15;277(3):259-61. doi: 10.1001/jama.277.3.259.
JAMA. 1997 Aug 6;278(5):383; author reply 385-7. doi:
10.1001/jama.278.5.383c.
JAMA. 1997 Aug 6;278(5):383; author reply 385-7. doi:
10.1001/jama.278.5.383b.
JAMA. 1997 Aug 6;278(5):383-4; author reply 385-7. doi:
10.1001/jama.1997.03550050045020.
JAMA. 1997 Aug 6;278(5):384; author reply 385-7. doi:
10.1001/jama.278.5.384b.
JAMA. 1997 Aug 6;278(5):384-5; author reply 385-7. doi:
10.1001/jama.1997.03550050046022.
JAMA. 1997 Aug 6;278(5):385; author reply 385-7. doi:
10.1001/jama.278.5.385b.
JAMA. 1997 Aug 6;278(5):385-7. doi: 10.1001/jama.1997.03550050047024.
OBJECTIVE: To search for syndromes in Persian Gulf War veterans.
PARTICIPANTS: Two hundred forty-nine (41%) of the 606 Gulf War veterans of the
Twenty-fourth Reserve Naval Mobile Construction Battalion living in 5
southeastern states participated; 145 (58%) had retired from service, and the
rest were still serving in the battalion.
DESIGN: Participants completed a standardized survey booklet measuring the
anatomical distributions or characteristics of each symptom, a booklet measuring
wartime exposures, and a standard psychological personality assessment
inventory. Two-stage factor analysis was used to disentangle ambiguous symptoms
and identify syndromes.
MAIN OUTCOME MEASURES: Factor analysis-derived syndromes.
RESULTS: Of 249 participants, 175 (70%) reported having had serious health
problems that most attributed to the war, and 74 (30%) reported no serious
health problems. Principal factor analysis yielded 6 syndrome factors,
explaining 71% of the variance. Dichotomized syndrome indicators identified the
syndromes in 63 veterans (25%). Syndromes 1 ("impaired cognition," characterized
by problems with attention, memory, and reasoning, as well as insomnia,
depression, daytime sleepiness, and headaches), 2 ("confusion-ataxia,"
characterized by problems with thinking, disorientation, balance disturbances,
vertigo, and impotence), and 3 ("arthro-myo-neuropathy," characterized by joint
and muscle pains, muscle fatigue, difficulty lifting, and extremity
paresthesias) represented strongly clustered symptoms; whereas, syndromes 4
("phobia-apraxia"), 5 ("fever-adenopathy"), and 6 ("weakness-incontinence")
involved weaker clustering and mostly overlapped syndromes 2 and 3. Veterans
with syndrome 2 were 12.5 times (95% confidence interval, 3.5-44.8) more likely
to be unemployed than those with no health problems. A psychological profile,
found in 48.4% of those with the syndromes, differed from posttraumatic stress
disorder, depression, somatoform disorder, and malingering.
CONCLUSION: These findings support the hypothesis that clusters of symptoms of
many Gulf War veterans represent discrete factor analysis-derived syndromes that
appear to reflect a spectrum of neurologic injury involving the central,
peripheral, and autonomic nervous systems.
PMID: 9005271 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14655925 | 1. Sleep. 2003 Nov 1;26(7):888-92. doi: 10.1093/sleep/26.7.888.
Association between nocturnal bruxism and gastroesophageal reflux.
Miyawaki S(1), Tanimoto Y, Araki Y, Katayama A, Fujii A, Takano-Yamamoto T.
Author information:
(1)Department of Orthodontics and Dentofacial Orthopedics, Okayama University
Graduate School of Medicine and Dentistry, Okayama, Japan.
Comment in
Sleep. 2003 Dec 15;26(8):939-40.
STUDY OBJECTIVE: To examine the relationship between nocturnal bruxism and
gastroesophageal reflux.
DESIGN: Controlled descriptive study and double-blind, placebo-controlled,
clinical study.
SETTING: Portable pH monitoring, electromyography, and audio-video recordings
were conducted during the night in the subjects' home.
PARTICIPANTS: Ten patients with bruxism and 10 normal subjects were matched for
height, weight, age, and sex. They did not have symptoms of gastroesophageal
reflux disease.
INTERVENTION: Medication with a proton pump inhibitor (ie, a
gastric-acid-inhibiting drug).
MEASUREMENTS AND RESULTS: The bruxism group showed a significantly higher
frequency of nocturnal rhythmic masticatory muscle activity (RMMA) episodes
(mean +/- SD: 6.7 +/- 2.2 times per hour) and a higher frequency and percentage
of time of gastroesophageal reflux episodes with a pH less than 4.0 and 5.0 (0.5
+/- 0.9 and 3.6 +/- 1.6 times per hour and 1.3% +/- 2.5% and 7.4% +/- 12.6%,
respectively) than the control group (RMMA episodes: 2.4 +/- 0.9 times per hour;
gastroesophageal reflux episodes: 0.0 +/- 0.0 and 0.1 +/- 0.3 times per hour and
0.0% +/- 0.0% and 0.0% +/- 0.0%, respectively). In the bruxism group, 100% of
the gastroesophageal reflux episodes with a pH less than 3.0 and 4.0 included
both an RMMA episode and an electromyographic burst, the duration of which was
approximately 0.5 to 1.0 seconds, probably representing swallowing of saliva.
The majority of gastroesophageal reflux episodes with a pH of 4.0 to 5.0 also
included both an RMMA episode and an electromyographic burst in the control and
bruxism groups (100% +/- 0.0% vs 70.7% +/- 16.5%), again probably due to
swallowing of saliva. The remaining minority of gastroesophageal reflux episodes
with a pH of 4.0 to 5.0 contained only an electromyographic burst (swallowing of
saliva). The frequency of RMMA episodes after the release of the medication from
the proton pump inhibitor, which increased the gastric and esophageal pH, was
significantly lower than that after administration of the placebo in the control
and bruxism groups (1.0 +/- 0.6 vs 1.9 +/- 3.2 times per hour, and 3.7 +/- 1.9
vs. 6.0 +/- 2.2 times per hour, respectively).
CONCLUSIONS: Nocturnal bruxism may be secondary to nocturnal gastroesophageal
reflux, occurring via sleep arousal and often together with swallowing. The
physiologic link between bruxism and the increase in salivation needs to be
investigated.
DOI: 10.1093/sleep/26.7.888
PMID: 14655925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16856766 | 1. Toxicol Rev. 2006;25(1):1-14. doi: 10.2165/00139709-200625010-00001.
Organophosphate-induced intermediate syndrome: aetiology and relationships with
myopathy.
Karalliedde L(1), Baker D, Marrs TC.
Author information:
(1)Chemical Hazards and Poisons Division (London), Health Protection Agency,
London, UK.
The intermediate syndrome (IMS) following organophosphorus (OP) insecticide
poisoning was first described in the mid-1980s. The syndrome described comprised
characteristic symptoms and signs occurring after apparent recovery from the
acute cholinergic syndrome. As the syndrome occurred after the acute cholinergic
syndrome but before organophosphate-induced delayed polyneuropathy, the syndrome
was called 'intermediate syndrome'. The IMS occurs in approximately 20% of
patients following oral exposure to OP pesticides, with no clear association
between the particular OP pesticide involved and the development of the
syndrome. It usually becomes established 2-4 days after exposure when the
symptoms and signs of the acute cholinergic syndrome (e.g. muscle
fasciculations, muscarinic signs) are no longer obvious. The characteristic
features of the IMS are weakness of the muscles of respiration (diaphragm,
intercostal muscles and accessory muscles including neck muscles) and of
proximal limb muscles. Accompanying features often include weakness of muscles
innervated by some cranial nerves. It is now emerging that the degree and extent
of muscle weakness may vary following the onset of the IMS. Thus, some patients
may only have weakness of neck muscles whilst others may have weakness of neck
muscles and proximal limb muscles. These patients may not require ventilatory
care but close observation and monitoring of respiratory function is mandatory.
Management is essentially that of rapidly developing respiratory distress and
respiratory failure. Delays in instituting ventilatory care will result in
death. Initiation of ventilatory care and maintenance of ventilatory care often
requires minimal doses of non-depolarising muscle relaxants. The use of
depolarising muscle relaxants such as suxamethonium is contraindicated in OP
poisoning. The duration of ventilatory care required by patients may differ
considerably and it is usual for patients to need ventilatory support for 7-15
days and even up to 21 days. Weaning from ventilatory care is best carried out
in stages, with provision of continuous positive airway pressure prior to
complete weaning. Continuous and close monitoring of respiratory function
(arterial oxygen saturation, partial pressure of oxygen in arterial blood,
partial pressure of carbon dioxide in arterial blood) and acid-base status are
an absolute necessity. Prophylactic antibiotics are usually not required unless
there has been evidence of aspiration of material into the lungs. Close
monitoring of fluid and electrolyte balance is mandatory in view of the profuse
offensive diarrhoea that most patients develop. Maintenance of nutrition,
physiotherapy, prevention of bed sores and other routine measures to minimise
discomfort during ventilatory care are necessary. Recovery from the intermediate
syndrome is normally complete and without any sequelae. The usefulness of oximes
during the IMS remains uncertain. In animal experiments, very early
administration of oximes has prevented the occurrence of myopathy. There are
reports from developed countries where administration of oximes at recommended
doses and within 2 hours of ingestion of OP insecticide did not prevent the
onset of the IMS. Controlled randomised clinical studies are necessary to
evaluate the efficacy of oximes in combating the IMS. Electrophysiological
studies following OP poisoning have revealed three characteristic phenomena: (i)
repetitive firing following a single stimulus; (ii) gradual reduction in twitch
height or compound muscle action potential followed by an increase with
repetitive stimulation (the 'decrement-increment response'); and (iii) continued
reduction in twitch height or compound muscle action potential with repetitive
simulation ('decrementing response'). Of these, the decrementing response is the
most frequent finding during the IMS, whilst repetitive firing is observed
during the acute cholinergic syndrome. The distribution of the weakness in human
cases of the IMS, in general, parallels the distribution of the myopathy
observed in a number of studies in experimental animals. This has led to
speculation that myopathy is involved in the causation of the IMS. However,
while myopathy and the IMS have a common origin in acetylcholine accumulation,
they are not causally related to one another.
DOI: 10.2165/00139709-200625010-00001
PMID: 16856766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12672169 | 1. Hum Psychopharmacol. 2003 Apr;18(3):185-90. doi: 10.1002/hup.467.
Use of paroxetine for the treatment of depression and anxiety disorders in the
elderly: a review.
Bourin M(1).
Author information:
(1)Neurobiology of Anxiety and Depression, Faculty of Medicine, Nantes, France.
[email protected]
Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) with
indications for the treatment of depression, obsessive- compulsive disorder,
panic disorder and social phobia. It is also used in the treatment of
generalized anxiety disorder, post-traumatic stress disorder, premenstrual
dysphoric disorder and chronic headache. There is wide interindividual variation
in the pharmacokinetics of paroxetine in adults as well as in the elderly with
higher plasma concentrations and slower elimination noted in the latter.
Elimination is also reduced in severe renal and hepatic impairment, however,
serious adverse events are extremely rare even in overdose. A Pub Med search was
used to collect information on the efficacy and tolerability in elderly
patients. There are few studies of depression in the elderly and only one study
in the old-old. In anxiety disorders including general anxiety disorder, panic
disorder, obsessive-compulsive disorder and social anxiety, there are no studies
at all in the elderly. However, the safety of the drug allows its prescription
in the elderly. In summary, paroxetine is well tolerated in the treatment of
depression in those between the ages of 65 and 75, although few studies have
examined its use in those of 75 and older.
Copyright 2002 John Wiley & Sons, Ltd.
DOI: 10.1002/hup.467
PMID: 12672169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22564980 | 1. J Vis Exp. 2012 Apr 30;(62):3770. doi: 10.3791/3770.
Chromatin Interaction Analysis with Paired-End Tag Sequencing (ChIA-PET) for
mapping chromatin interactions and understanding transcription regulation.
Goh Y(1), Fullwood MJ, Poh HM, Peh SQ, Ong CT, Zhang J, Ruan X, Ruan Y.
Author information:
(1)Genome Institute of Singapore, Agency for Science, Technology and Research,
Singapore.
Genomes are organized into three-dimensional structures, adopting higher-order
conformations inside the micron-sized nuclear spaces (7, 2, 12). Such
architectures are not random and involve interactions between gene promoters and
regulatory elements (13). The binding of transcription factors to specific
regulatory sequences brings about a network of transcription regulation and
coordination (1, 14). Chromatin Interaction Analysis by Paired-End Tag
Sequencing (ChIA-PET) was developed to identify these higher-order chromatin
structures (5,6). Cells are fixed and interacting loci are captured by covalent
DNA-protein cross-links. To minimize non-specific noise and reduce complexity,
as well as to increase the specificity of the chromatin interaction analysis,
chromatin immunoprecipitation (ChIP) is used against specific protein factors to
enrich chromatin fragments of interest before proximity ligation. Ligation
involving half-linkers subsequently forms covalent links between pairs of DNA
fragments tethered together within individual chromatin complexes. The flanking
MmeI restriction enzyme sites in the half-linkers allow extraction of paired end
tag-linker-tag constructs (PETs) upon MmeI digestion. As the half-linkers are
biotinylated, these PET constructs are purified using streptavidin-magnetic
beads. The purified PETs are ligated with next-generation sequencing adaptors
and a catalog of interacting fragments is generated via next-generation
sequencers such as the Illumina Genome Analyzer. Mapping and bioinformatics
analysis is then performed to identify ChIP-enriched binding sites and
ChIP-enriched chromatin interactions (8). We have produced a video to
demonstrate critical aspects of the ChIA-PET protocol, especially the
preparation of ChIP as the quality of ChIP plays a major role in the outcome of
a ChIA-PET library. As the protocols are very long, only the critical steps are
shown in the video.
DOI: 10.3791/3770
PMCID: PMC3466657
PMID: 22564980 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25114054 | 1. Nucleic Acids Res. 2014 Oct;42(18):e143. doi: 10.1093/nar/gku738. Epub 2014
Aug 11.
A statistical model of ChIA-PET data for accurate detection of chromatin 3D
interactions.
Paulsen J(1), Rødland EA(2), Holden L(3), Holden M(3), Hovig E(4).
Author information:
(1)Institute for Cancer Genetics and Informatics, Oslo University Hospital, PO
Box 4950, Nydalen, N-0424 Oslo, Norway [email protected].
(2)Department of Tumor Biology, Institute for Cancer Research, The Norwegian
Radium Hospital, Oslo University Hospital, PO Box 4950, Nydalen, N-0424 Oslo,
Norway.
(3)Statistics for Innovation, Norwegian Computing Center, N-0314 Oslo, Norway.
(4)Institute for Cancer Genetics and Informatics, Oslo University Hospital, PO
Box 4950, Nydalen, N-0424 Oslo, Norway Department of Tumor Biology, Institute
for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, PO
Box 4950, Nydalen, N-0424 Oslo, Norway [email protected].
Identification of three-dimensional (3D) interactions between regulatory
elements across the genome is crucial to unravel the complex regulatory
machinery that orchestrates proliferation and differentiation of cells. ChIA-PET
is a novel method to identify such interactions, where physical contacts between
regions bound by a specific protein are quantified using next-generation
sequencing. However, determining the significance of the observed interaction
frequencies in such datasets is challenging, and few methods have been proposed.
Despite the fact that regions that are close in linear genomic distance have a
much higher tendency to interact by chance, no methods to date are capable of
taking such dependency into account. Here, we propose a statistical model taking
into account the genomic distance relationship, as well as the general
propensity of anchors to be involved in contacts overall. Using both real and
simulated data, we show that the previously proposed statistical test, based on
Fisher's exact test, leads to invalid results when data are dependent on genomic
distance. We also evaluate our method on previously validated cell-line specific
and constitutive 3D interactions, and show that relevant interactions are
significant, while avoiding over-estimating the significance of short nearby
interactions.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gku738
PMCID: PMC4191384
PMID: 25114054 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21120082 | 1. Indian J Occup Environ Med. 2010 Aug;14(2):54-7. doi: 10.4103/0019-5278.72242.
A study of neurologic symptoms on exposure to organophosphate pesticides in the
children of agricultural workers.
Rastogi SK(1), Tripathi S, Ravishanker D.
Author information:
(1)Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.
Pesticides are used extensively throughout the world in agriculture and in pest
control as well as for community health purposes. Organophosphate (OP) pesticide
self-poisoning is an important clinical problem in rural regions of the
developing world that kills an estimated 200,000 people every year.
Unintentional poisoning kills far fewer people but is an apparent problem in
places where highly toxic OP pesticides are available. Neurologic dysfunction is
the best documented health effect of pesticide exposure. High-level exposure has
both acute and long-term neurologic signs and symptoms, and adverse effects have
been reported in most type of pesticides, including organophosphate (OP),
carbamate, organochlorine, and pyrethroid insecticides, herbicides, fungicides,
and fumigants. Acute OP pesticide exposure can involve in wide range of both
central and peripheral neurologic symptoms. Increased neurologic symptom
prevalence may provide early evidence of neurologic dysfunctions, before
clinically measurable signs are evident.In this study, we analyzed the
cross-sectional data on neurologic signs and symptoms from 225 rural children,
both males (n = 132) and females (n = 93) who were occupationally and
paraoccupationally exposed to methyl OPs (dichlorvos, fenthion, malathion,
methyl parathion) and ethyl OPs (chlorpyrifos, diazinon, ethyl parathion) as
they belonged to agricultural families handling, mixing, and spraying the OP
pesticides. The children completed a specially designed questionnaire (Q16) on
neurologic symptoms associated with pesticide exposure with their parental help.
A suitable reference group consisting of rural children (n = 50) never involved
in pesticide handling (neither outdoor nor indoor) belonging to similar
socioeconomic strata included in the study to compare the prevalence of various
neurologic symptoms between the two groups.Among all the neurologic
self-reported symptoms, headache, watering in eyes, and burning sensation in
eye/face were the most important clinical manifestations attributed to OP
pesticide exposure. These symptoms could probably be the consequence of chronic
effects of most pesticides on the central nervous system. The muscarinic
symptoms reported the maximum prevalence of salivation (18.22%), whereas
lacrimation was observed in 17.33% cases, followed by diarrhea in 9.33% cases.
The nicotinic clinical manifestations of acute OP poisoning revealed excessive
sweating in 13.78% cases and tremors in 9.3% cases followed by mydriasis in 8.4%
exposed children. The characteristic cholinergic symptoms, such as insomnia,
headache, muscle cramps, weakness, and anorexia were also reported by both male
and female exposed children. The high frequency of neurologic symptoms observed
in the study may be due to parasympathetic hyperactivity due to the accumulated
ACh resulting from AChE inhibition.
DOI: 10.4103/0019-5278.72242
PMCID: PMC2992866
PMID: 21120082
Conflict of interest statement: Conflict of Interest: None declared |
http://www.ncbi.nlm.nih.gov/pubmed/10528323 | 1. Rev Neurol. 1999 Jul 16-31;29(2):123-7.
[Late onset polyneuropathy due to exposure to organophosphates].
[Article in Spanish]
Carod-Artal FJ(1), Speck-Martins C.
Author information:
(1)Servicio de Neurología, Red Sarah de Hospitales del Aparato Locomotor,
Brasilia DF, Brasil. [email protected]
INTRODUCTION: Organophosphate esters are widely used both in agriculture and in
industry and may give rise to acute intoxication due to their direct
anticholinesterase effect. Less often a polyneuropathic syndrome of late onset
may occur. This is predominantly motor, symmetrical, with muscle atrophy and
pyramidal signs. These neurotoxic features are due to inhibition of the target
esterase of this neuropathy. Histopathological studies show axon degeneration of
'dying back' type.
CLINICAL CASE: We present the case of a 24 year old man with severe sensomotor
neuropathy, predominantly distal, with marked atrophy of the interosseus
muscles, claw hand and foot drop, together with increased deep tendon reflexes.
This patient had worked on the land, cultivating maize, from the age of 14, when
his symptoms began and became progressively worse. On electromyography there was
sensomotor peripheral polyneuropathy, which was primarily axonal and
predominantly motor and distal. Peripheral nerve biopsy confirmed the presence
of 'dying back' type axonopathy. Extensive biochemical investigations ruled out
other causes of polyneuropathy. Cerebral resonance study was normal.
CONCLUSIONS: Agricultural workers chronically exposed to organophosphate
insecticides, without adequate protection, have an increased risk of developing
late onset neuropathy due to organophosphates. The risk of developing late onset
neuropathy is not necessarily related to a history of acute intoxication, since
chronic sublethal exposure may mean that previous acute anticholinergic symptoms
pass undetected.
PMID: 10528323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22728724 | 1. Toxicology. 2013 May 10;307:136-45. doi: 10.1016/j.tox.2012.06.009. Epub 2012
Jun 21.
Toxic effects of pesticide mixtures at a molecular level: their relevance to
human health.
Hernández AF(1), Parrón T, Tsatsakis AM, Requena M, Alarcón R, López-Guarnido O.
Author information:
(1)Department of Legal Medicine and Toxicology, University of Granada School of
Medicine, Granada, Spain. [email protected]
Pesticides almost always occur in mixtures with other ones. The toxicological
effects of low-dose pesticide mixtures on the human health are largely unknown,
although there are growing concerns about their safety. The combined
toxicological effects of two or more components of a pesticide mixture can take
one of three forms: independent, dose addition or interaction. Not all mixtures
of pesticides with similar chemical structures produce additive effects; thus,
if they act on multiple sites their mixtures may produce different toxic
effects. The additive approach also fails when evaluating mixtures that involve
a secondary chemical that changes the toxicokinetics of the pesticide as a
result of its increased activation or decreased detoxification, which is
followed by an enhanced or reduced toxicity, respectively. This review addresses
a number of toxicological interactions of pesticide mixtures at a molecular
level. Examples of such interactions include the postulated mechanisms for the
potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by
organophosphates; how the toxicity of some organophosphates can be potentiated
by other organophosphates or by previous exposure to organochlorines; the
synergism between pyrethroid and carbamate compounds and the antagonism between
triazine herbicides and prochloraz. Particular interactions are also addressed,
such as those of pesticides acting as endocrine disruptors, the cumulative
toxicity of organophosphates and organochlorines resulting in estrogenic effects
and the promotion of organophosphate-induced delayed polyneuropathy.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.tox.2012.06.009
PMID: 22728724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2462700 | 1. Neurotoxicology. 1988 Summer;9(2):249-71.
Toxicological screening for organophosphorus-induced delayed neurotoxicity:
complications in toxicity testing.
Cherniack MG(1).
Author information:
(1)Department of Medicine, Yale University Medical Center, New Haven,
Connecticut 06510.
The acute biocidal effects of organophosphorus pesticides are a central feature
of modern agricultural chemistry, and also define the concerns of regulatory
toxicology. Less well known, but more complex and idiosyncratic, is the
potential for some agents to produce a delayed and progressive
polyneuropathy--Organophosphorus Induced Delayed Neurotox-icity (OPIDN). On
three occasions during the past ten years, the National Institute for
Occupational Safety and Health (NIOSH) had been asked to evaluate human delayed
neurotoxicity from three commercially available pesticides. These were
leptophos, fenthion, and isofenphos. In each case, human disease was either
observed or suggested by specialized toxicity testing. The reasons that
federally recommended screening measures failed to identify a potential for
human neurotoxicity were not accidental, but stem from a systematic approach
that focuses on a traditional definition of acute lethal toxicity. The oral
single dose study on one species appears to be insufficient for recognizing the
delayed neurotoxic hazard of many representatives of this chemical class. The
recent addition of a recommended biochemical assay--neurotoxic esterase
(NTE)--to federal guidelines potentially improves sensitivity, but it is purely
adjunctive and does not amend underlying ambiguities in selecting the dose and
route of administration. It is also quite probable that human neurotoxicity may
be a potential hazard from exposure to more than the handful of organophosphorus
pesticides that have been described in the literature.
PMID: 2462700 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19922373 | 1. Int J Neurosci. 2009;119(10):1538-47. doi: 10.1080/00207450903022406.
Myeloneuritis due to acute organophosphate (DDVP) intoxication.
Koc F(1), Yerdelen D, Kekec Z.
Author information:
(1)Department of Neurology, Cukurova University School of Medicine, Adana,
Turkey. [email protected]
Given the importance of agriculture and widespread use of pesticides,
intoxication due to organophosphate insecticides is common in Turkey.
Organophosphorus compounds may cause late-onset distal polyneuropathy occurring
2 or more weeks after the acute exposure. An 18-year-old woman and a 22-year-old
man were admitted to the hospital with weakness, paresthesia, and gait
disturbances at 35 and 22 days, respectively, after ingesting
dimethyl-2,2-dichloro vinyl phosphate (DDVP). Neurological examination revealed
weakness, vibration sense loss, bilateral dropped foot, brisk deep tendon
reflexes, and bilaterally positive Babinski sign. Electroneurography
demonstrated distal motor polyneuropathy with segmental demyelination associated
with axonal degeneration prominent in the distal parts of both lower
extremities.
DOI: 10.1080/00207450903022406
PMID: 19922373 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19416831 | 1. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73. doi:
10.1073/pnas.0903392106. Epub 2009 May 5.
Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete
responses in triple-negative breast cancer models.
Caldas-Lopes E(1), Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A,
Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS,
Ma Y, Varticovski L, Melnick A, Chiosis G.
Author information:
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
10021, USA.
Triple-negative breast cancers (TNBCs) are defined by a lack of expression of
estrogen, progesterone, and HER2 receptors. Because of the absence of identified
targets and targeted therapies, and due to a heterogeneous molecular
presentation, treatment guidelines for patients with TNBC include only
conventional chemotherapy. Such treatment, while effective for some, leaves
others with high rates of early relapse and is not curative for any patient with
metastatic disease. Here, we demonstrate that these tumors are sensitive to the
heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor
effects in TNBC xenografts, including complete response and tumor regression,
without toxicity to the host are achieved with this agent. Notably, TNBC tumors
respond to retreatment with PU-H71 for several cycles extending for over 5
months without evidence of resistance or toxicity. Through a proteomics
approach, we show that multiple oncoproteins involved in tumor proliferation,
survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC.
PU-H71 induces efficient and sustained downregulation and inactivation, both in
vitro and in vivo, of these proteins. Among them, we identify downregulation of
components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its
anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce
apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to
reduce TNBC invasive potential. The results identify Hsp90 as a critical and
multimodal target in this most difficult to treat breast cancer subtype and
support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving
patients with TNBC.
DOI: 10.1073/pnas.0903392106
PMCID: PMC2688867
PMID: 19416831 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/15089103 | 1. CNS Drugs. 2004;18(6):355-64; discussion 365-6. doi:
10.2165/00023210-200418060-00003.
Paroxetine controlled release.
Bang LM(1), Keating GM.
Author information:
(1)Adis International Limited, Auckland, New Zealand.
A controlled-release (CR) formulation of the SSRI paroxetine has been developed.
This CR formulation delays the release of paroxetine until the tablet has passed
through the stomach; the drug is then released over 4-5 hours. In well designed
placebo-controlled trials in patients with major depressive disorder (including
a study in the elderly), social anxiety disorder or premenstrual dysphoric
disorder (PMDD), paroxetine CR was consistently superior to placebo with regards
to primary endpoints (i.e. mean Hamilton Rating Scale for Depression total score
[major depressive disorder], Liebowitz social anxiety scale total score and
Clinical Global Impressions-Global Improvement score [social anxiety disorder]
and Visual Analogue Scale-Mood score [PMDD]). The duration of treatment was 12
weeks or, in PMDD, over three menstrual cycles (intermittent or continuous
administration). Paroxetine CR also demonstrated efficacy in three well designed
studies in patients with panic disorder with or without agoraphobia. Paroxetine
CR was generally well tolerated in clinical trials, with an adverse-event
profile typical of SSRIs, although recipients of paroxetine CR experienced
significantly less nausea than recipients of immediate-release paroxetine in the
first week of treatment.
DOI: 10.2165/00023210-200418060-00003
PMID: 15089103 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19138385 | 1. BMC Fam Pract. 2009 Jan 12;10:3. doi: 10.1186/1471-2296-10-3.
Factors prompting PSA-testing of asymptomatic men in a country with no
guidelines: a national survey of general practitioners.
Drummond FJ(1), Carsin AE, Sharp L, Comber H.
Author information:
(1)National Cancer Registry, Ireland, Building 6800, Airport Business Park,
Kinsale Rd, Cork, Ireland. [email protected]
BACKGROUND: Increased use of prostate specific antigen (PSA) has been associated
with increased prostate cancer incidence. Ireland is estimated to have one of
the highest prostate cancer incidences in Europe and has no national guidelines
for prostate cancer screening. GPs have a pivotal role in influencing PSA
testing, therefore, our aim was to describe GP testing practices and to identify
factors influencing these.
METHODS: A postal survey, including questions on clinical practice and
experience, knowledge and demographics was distributed to all GPs (n = 3,683).
The main outcomes were (i) PSA testing asymptomatic men and (ii) "inappropriate"
PSA testing, defined as testing asymptomatic men aged < 50 or > 75 years.
Factors associated with these outcomes were identified using logistic
regression.
RESULTS: 1,625 GPs responded (response rate corrected for eligibility = 53%).
Most respondents (79%) would PSA test asymptomatic men. Of these, 34% and 51%
would test asymptomatic men < 50 and > 75 years, respectively. In multivariate
analyses, GPs were more likely to test asymptomatic men if they were >or= 50
years, in practice >or= 10 years, female or less knowledgeable about PSA
efficacy. Male GPs who would have a PSA test themselves were > 8-times more
likely to PSA test asymptomatic men than GPs who would not have a test. GPs who
had an asymptomatic patient diagnosed with prostate cancer following PSA
testing, were > 3-times more likely to test asymptomatic men. Practice-related
factors positively associated with testing included: running 'well man' clinics,
performing occupational health checks and performing other tests routinely with
PSA. Factors positively associated with 'inappropriate' testing included; being
male and willing to have a PSA test, having worked/trained in the UK and
supporting annual PSA testing. 91% of respondents supported the development of
national PSA testing guidelines.
CONCLUSION: Our findings suggest that widespread PSA testing of asymptomatic men
in primary care is primarily due to a combination of clinical experience, poor
knowledge and the support of doctors for PSA testing, as evidenced by the
willingness of male doctors to have a PSA test. There is an urgent need for
education and support for GPs concerning prostate cancer screening, starting
with the implementation of national guidelines.
DOI: 10.1186/1471-2296-10-3
PMCID: PMC2646704
PMID: 19138385 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12783138 | 1. J Formos Med Assoc. 2003 Mar;102(3):193-7.
Primary cutaneous pre-B lymphoblastic lymphoma immunohistologically mimics
Ewing's sarcoma/primitive neuroectodermal tumor.
Hsiao CH(1), Su IJ.
Author information:
(1)Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Precursor B-cell lymphoblastic lymphomas (B-LBLs) are rare and most often
involve the skin in the head and neck region. Histologically, cutaneous B-LBLs
may be confused with other small round-cell neoplasms. Moreover, half of B-LBL
patients are negative for CD45 (leucocyte common antigen, LCA), a widely used
marker for the diagnosis of lymphoma, and a significant portion express CD99, a
marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET).
Therefore, an extranodal B-LBL may be misinterpreted as PNET or ES. Here, we
report on 2 boys, aged 10 and 5 years, with primary cutaneous B-LBL of the
scalp. PNET was initially misdiagnosed because the tumor cells were negative for
CD45 but strongly positive for CD99. Advanced stage of acute lymphoblastic
leukemia (ALL) developed later and both patients died during the course of
treatment for ALL. In retrospective analyses, tumor cells in the initial biopsy
specimens of both patients were found to be reactive to terminal
deoxynucleotidyl transferase (TdT), CD43 and CD10. Thus, the diagnosis of B-LBL
was confirmed. These cases illustrate the possibility that primary cutaneous
B-LBL may mimic ES or PNET immunophenotypically, and that correct diagnosis in
doubtful cases may be facilitated by analysis using a complete panel of
antibodies, particularly including TdT and CD43.
PMID: 12783138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18309944 | 1. J Clin Oncol. 2008 Mar 1;26(7):1098-105. doi: 10.1200/JCO.2007.14.1986.
Phase I trial of nelarabine in indolent leukemias.
Gandhi V(1), Tam C, O'Brien S, Jewell RC, Rodriguez CO Jr, Lerner S, Plunkett W,
Keating MJ.
Author information:
(1)Department of Experimental Therapeutics, Box 71, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
[email protected]
PURPOSE: To test whether nelarabine is an effective agent for indolent leukemias
and to evaluate whether there is a relationship between cellular
pharmacokinetics of the analog triphosphate and clinical responses.
PATIENTS AND METHODS: Thirty-five patients with relapsed/refractory leukemias (n
= 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic
leukemia) were entered onto three different protocols. For schedule A, patient
received nelarabine daily for 5 days, whereas for schedule B, nelarabine was
administered on days 1, 3, and 5. Schedule C was similar to schedule B except
that fludarabine was also infused. Plasma and cellular pharmacokinetics were
studied during the first cycle.
RESULTS: Responses were achieved in 20%, 15%, and 63% of patients receiving
schedule A, B, and C, respectively. Histologic category, number of prior
therapies, and fludarabine refractoriness did not influence the response rate.
The most common nonhematologic toxicity was peripheral neuropathy. Grade 4
neutropenia and thrombocytopenia complicated 23% and 26% of courses
respectively, and were significantly more frequent among patients with
pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and
arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were
similar in the two groups of diagnoses, and the elimination of ara-GTP from
leukemia cells was slow (median, > 24 hours). The median peak intracellular
concentrations of ara-GTP were significantly different (P = .0003) between
responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and
nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15).
CONCLUSION: Nelarabine is an effective regimen against indolent leukemias, and
combining it with fludarabine was most promising. Determination of tumor cell
ara-GTP levels may provide a predictive test for response to nelarabine.
DOI: 10.1200/JCO.2007.14.1986
PMID: 18309944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23567651 | 1. Neurobiol Dis. 2013 Aug;56:47-58. doi: 10.1016/j.nbd.2013.03.014. Epub 2013
Apr 5.
Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A
results in distinctive pathology in a rat model of Parkinson's disease.
Febbraro F(1), Sahin G, Farran A, Soares S, Jensen PH, Kirik D, Romero-Ramos M.
Author information:
(1)Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
Erratum in
Neurobiol Dis. O 2013 Oct;58:191.
Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in
Parkinson's disease patients where it mainly accumulates in the Lewy bodies.
Several groups have studied the role of phosphorylation at the S129 in
α-synuclein in a rat model for Parkinson's disease using recombinant
adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and
accordingly the role of S129 phosphorylation in α-synuclein toxicity remains
unclear. This prompted us to re-examine the neuropathological and behavioral
effects of the S129 modified α-synuclein species in vivo. For this purpose, we
used two mutated forms of human α-synuclein in which the S129 was replaced
either with an alanine (S129A), to block phosphorylation, or with an aspartate
(S129D), to mimic phosphorylation, and compared them with the wild type
α-synuclein. This approach was similar in design to previous studies, however
our investigation of dopaminergic degeneration also included performing a
detailed study of the α-synuclein induced pathology in the striatum and the
analysis of motor deficits. Our results showed that overexpressing S129D or wild
type α-synuclein resulted in an accelerated dopaminergic fiber loss as compared
with S129A α-synuclein. Furthermore, the motor deficit seen in the group treated
with the mutant S129D α-synuclein appeared earlier than the other two forms of
α-synuclein. Conversely, S129A α-synuclein showed significantly larger
pathological α-synuclein-positive inclusions, and slower dopaminergic fiber
loss, when compared to the other two forms of α-synuclein, suggesting a
neuroprotective effect of the mutation. When examined at long-term, all three
α-synuclein forms resulted in pathological accumulations of α-synuclein in
striatal fibers and dopaminergic cell death in the substantia nigra. Our data
show that changes in the S129 residue of α-synuclein influence the rate of
pathology and neurodegeneration, with an overall deleterious effect of
exchanging S129 to a residue mimicking its phosphorylated state.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2013.03.014
PMID: 23567651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20701667 | 1. J Oral Pathol Med. 2010 Sep;39(8):611-6. doi:
10.1111/j.1600-0714.2010.00922.x. Epub 2010 Aug 3.
Different therapeutic strategies for burning mouth syndrome: preliminary data.
Marino R(1), Torretta S, Capaccio P, Pignataro L, Spadari F.
Author information:
(1)Department of Clinical and Biological Sciences, Oral Medicine and Oral
Oncology Section, University of Turin, Turin, Italy. [email protected]
BACKGROUND: To compare different therapeutic supportive approaches in patients
with burning mouth syndrome. A prospective study was carried out for this
purpose.
MATERIALS AND METHODS: The study involved 56 patients with burning mouth
syndrome. They were randomly assigned to treatment with capsaicin, alpha-lipoic
acid or lysozyme-lactoperoxidase (test drugs) or boric acid (control group).
Symptoms were scored after 60 days treatment and 60 days after drug
discontinuation.
RESULTS: At the end of the treatment period, there was a significant reduction
in the symptom scores of all of the patients who received the test drugs
(P<0.01), and at the end of the follow-up period in the test groups as a whole
(P<0.01); the reduction was not significant when considering each test group
separately after the treatment period. All of the treatments were more effective
than boric acid and there was no significant difference in the symptom scores of
the control group at either of the study time-points.
CONCLUSIONS: Our results demonstrate the similar effectiveness of capsaicin and
alpha-lipoic acid in controlling the symptoms of burning mouth syndrome.
Lysozyme-lactoperoxidase may be effective in the supportive care of BMS patients
with xerostomia. The transitory effect observed after discontinuing drug
administration justifies the use of prolonged therapy in chronically affected
patients.
© 2010 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0714.2010.00922.x
PMID: 20701667 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11907227 | 1. J Virol. 2002 Apr;76(8):3873-80. doi: 10.1128/jvi.76.8.3873-3880.2002.
Varied persistent life cycles of Borna disease virus in a human
oligodendroglioma cell line.
Ibrahim MS(1), Watanabe M, Palacios JA, Kamitani W, Komoto S, Kobayashi T,
Tomonaga K, Ikuta K.
Author information:
(1)Department of Virology, Research Institute for Microbial Diseases, Osaka
University, Suita, Osaka 565-0871, Japan.
Borna disease virus (BDV) establishes a persistent infection in the central
nervous system of vertebrate animal species as well as in tissue cultures. In an
attempt to characterize the life cycle of BDV in persistently infected cultured
cells, we developed 30 clones by single-cell cloning from a human
oligodendroglioma (OL) cell line after infection with BDV. According to the
percentage of cells expressing the BDV major proteins, p40 (nucleoprotein) and
p24 (phosphoprotein), the clones were classified into two types: type I (>20%)
and type II (<20%). mRNAs corresponding to both proteins were detected by in
situ hybridization (ISH) in a percentage of cells consistent with that for the
protein expression in the two types. Surprisingly, ISH for the detection of the
genomic RNA, mainly in type II, revealed a significantly larger cell population
harboring the genomic RNA than that with the protein as well as the mRNA
expression. By recloning from type II primary cell clones, the same phenotype
was confirmed in the secondary cell clones obtained: i.e., low percentage of
protein-positive cells and higher percentage of cells harboring the genomic RNA.
After nerve growth factor treatment, the two types of clones showed increases in
the percentage of cells expressing BDV-specific proteins that reached 80% in
type II clones, in addition to increased expression levels per cell. Such
enhancement might have been mediated by the activation of the mitogen-activated
protein kinase in the clones as revealed by the detection of activated ERK1/2.
Thus, our findings show that BDV may have established a persistent infection at
low levels of viral expression in OL cells with the possibility of a latent
infection.
DOI: 10.1128/jvi.76.8.3873-3880.2002
PMCID: PMC136060
PMID: 11907227 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12764983 | 1. N Y State Dent J. 2003 Mar;69(3):18-24.
Burning mouth syndrome. A retrospective analysis of clinical characteristics and
treatment outcomes.
Pinto A, Sollecito TP, DeRossi SS.
Burning mouth syndrome is a condition characterized by burning sensations of the
oral cavity in the absence of physical abnormalities of the mucosa or a
detectable underlying medical disorder. It is a multifactorial disorder with
unclear etiology, affecting predominatly middle-aged women. Multiple approaches
to treatment have been described in the literature, with few controlled clinical
trials regarding their efficacy. The objectives of this retrospective study were
to: 1. determine the epidemiologic characteristics of BMS patients referred to
an oral medicine practice; 2. determine if BMS classification correlates with
response to treatment; 3. determine the efficacy of a variety of known therapies
for BMS. A database was constructed from the charts of 150 consecutive patients
diagnosed with BMS; and these charts were reviewed. Patients were classified
according to previously published criteria for BMS. Presumed etiologies were
grouped into depression/anxiety-associated; hematinic deficiencies, including
iron, folate and vitamin B complex; oral habits: and idiopathic BMS. Treatment
approaches were divided into seven categories: soft desensitizing appliance;
tricyclic antidepressants (TCA); benzodiazepines (BZD); topical analgesics;
hematinic supplements; habit awareness counseling; and multi-modal therapy
(combining two or more of the above). Improvement was recorded using a zero to
100% VAS scale and classified as no relief (0%); mild (0-40%);
meaningful/moderate (41-80%); and profound relief (81-100%). Burning mouth
syndrome without any identifiable cause (idiopathic) was diagnosed in 33
patients (46.6%). Patients were followed up at one month (4 weeks) after the
initial visit. Nine patients (12.7%) reported profound relief; 17 patients
(23.9%) reported meaningful relief; 39 patients (54.9%) reported mild relief.
This retrospective review showed no significant correlation between
classification of BMS and response to therapy. The most effective treatment
modalities were habit awareness, followed by TCAs.
PMID: 12764983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16685074 | 1. Integr Cancer Ther. 2006 Jun;5(2):98-108. doi: 10.1177/1534735406288083.
Mindfulness meditation for oncology patients: a discussion and critical review.
Ott MJ(1), Norris RL, Bauer-Wu SM.
Author information:
(1)Nursing and Patient Care Services, Dana-Farber Cancer Institute, Boston, MA
02115, USA. [email protected]
The purpose of this article is to (1) provide a comprehensive over view and
discussion of mindfulness meditation and its clinical applicability in oncology
and (2) report and critically evaluate the existing and emerging research on
mindfulness meditation as an intervention for cancer patients. Using relevant
keywords, a comprehensive search of MEDLINE, PsycInfo, and Ovid was completed
along with a review of published abstracts from the annual conferences sponsored
by the Center for Mindfulness in Medicine, Health Care, and Society and the
American Psychosocial Oncology Society. Each article and abstract was critiqued
and systematically assessed for purpose statement or research questions,
STUDY DESIGN: The search produced 9 research articles published in the past 5
years and 5 conference abstracts published in 2004. Most studies were conducted
with breast and prostate cancer patients, and the mindfulness intervention was
done in a clinic-based group setting. Consistent benefits--improved
psychological functioning, reduction of stress symptoms, enhanced coping and
well-being in cancer outpatients--were found. More research in this area is
warranted: using randomized, controlled designs, rigorous methods, and different
cancer diagnoses and treatment settings; expanding outcomes to include quality
of life, physiological, health care use, and health-related outcomes; exploring
mediating factors; and discerning dose effects and optimal frequency and length
of home practice. Mindfulness meditation has clinically relevant implications to
alleviate psychological and physical suffering of persons living with cancer.
Use of this behavioral intervention for oncology patients is an area of
burgeoning interest to clinicians and researchers.
DOI: 10.1177/1534735406288083
PMID: 16685074 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19021912 | 1. BMC Urol. 2008 Nov 20;8:17. doi: 10.1186/1471-2490-8-17.
The trends in prostate specific antigen usage amongst United Kingdom
urologists--a questionnaire based study.
Burden HP(1), Davis CR, Tate S, Persad R, Holmes CH, Whittington K.
Author information:
(1)Urology Speciality Registrar, Derriford, Plymouth, UK.
[email protected]
BACKGROUND: Worldwide, the use of prostate specific antigen (PSA) testing as a
screen for prostate cancer is contentious. Whilst there is no National UK
Screening programme, many men undergo opportunistic screening. This study
investigates UK urologist's usage of PSA and the awareness surrounding the
Department of Health (DoH) PSA guidelines.
METHODS: Urologists were sent a questionnaire regarding PSA cut-off values.
RESULTS: Of the 733 urologists eligible to participate in this study 346
returned completed questionnaires giving a response rate of 47%. The most
commonly generally used age-related PSA cut-off values (36% of respondents)
are--3.5 ng/ml for 50 - 59 year olds, 4.5 ng/ml for 60 - 69 year olds and 6.5
ng/ml for over 70 year olds. Two-thirds (58%, 200/346) of respondents were aware
of the DoH PSA guidelines but only 20% (n = 69/346) follow these guidelines. The
majority of respondents (68%, n = 234/346) used higher PSA cut-offs than
recommended by the DoH. The level of compliance showed marked regional variation
with a range from 7% to 44% (median 19%). In addition, it was apparent that
lower PSA cut-off values were used in private practice as opposed to the
National Health Service.
CONCLUSION: A nationwide lack of agreement on PSA cut-off values may generate a
variable standard of care both regionally and in NHS versus private practice.
Generally, higher PSA cut-off values are being used than recommended by the DoH
guidance.
DOI: 10.1186/1471-2490-8-17
PMCID: PMC2606676
PMID: 19021912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11343318 | 1. Am J Med Genet. 2001 May 15;100(4):275-9. doi: 10.1002/ajmg.1290.
Segregation analysis of Scheuermann disease in ninety families from Siberia.
Axenovich TI(1), Zaidman AM, Zorkoltseva IV, Kalashnikova EV, Borodin PM.
Author information:
(1)Department of Recombination and Segregation Analysis, Institute of Cytology
and Genetics, Russian Academy of Science, Novosibirsk, Russia. [email protected]
Scheuermann disease [OMIM number 181440] is the most common cause of structural
kyphosis in adolescence. Segregation analysis using a model with gender effects
was applied to 90 pedigrees from Barnaul (West Siberia, Russia) ascertained
through a proband with Scheuermann disease. The transmission probability model
was used to detect major gene effect. A significant contribution of a major gene
to the control of the pathology was established. Inheritance of the disease can
be described within the framework of a dominant major gene diallele model.
According to this model, Scheuermann disease should never occur in the absence
of the mutant allele. All male carriers of the mutant allele develop the
disease, while only a half of female carriers manifest it. We found a high
frequency of idiopathic scoliosis in the families with Scheuermann disease (0.08
vs. 0.01-0.02 in general population). We also observed a succession of
idiopathic scoliosis and Scheuermann disease in consecutive generations. The
familial aggregation of these two spinal pathologies in the present sample may
indicate a genetic unity of Scheuermann disease and idiopathic scoliosis.
DOI: 10.1002/ajmg.1290
PMID: 11343318 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17471348 | 1. Trans Am Ophthalmol Soc. 2006;104:264-302.
Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal
avascularity, vasculogenesis, and wound healing (an American Ophthalmological
Society thesis).
Azar DT(1).
Author information:
(1)Massachusetts Eye and Ear Infirmary and Schepens Eye Research Institute,
Harvard Medical School, Boston, Massachusetts, USA.
PURPOSE: To determine the molecular basis of corneal avascularity during wound
healing and determine the role of angiogenic and antiangiogenic factors in
corneal vasculogenesis.
METHODS: The expression of proangiogenic factors (vascular endothelial growth
factor [VEGF]; basic fibroblast growth factor [bFGF]; matrix metalloproteinase-2
[MMP-2]; and membrane-type 1-MMP [MT1-MMP]) and antiangiogenic factors (pigment
epithelium-derived factor [PEDF]; angiostatin; restin; and endostatin) was
analyzed in avascular corneas and in models of corneal neovascularization (bFGF
pellet implantation, intrastromal injection of MT1-MMP cDNA, and surgically
induced partial limbal deficiency).
RESULTS: Immunohistochemistry demonstrated the presence of antiangiogenic
factors (PEDF, angiostatin, restin, and endostatin) and proangiogenic molecules
(VEGF, bFGF, MMP-2, and MT1-MMP) in the cornea after wounding. Proangiogenic
MMPs were upregulated in stromal fibroblasts in the vicinity of invading vessels
following bFGF pellet implantation. Corneal neovascularization (NV) was also
induced by intrastromal injection of MT1-MMP naked cDNA in conjunction with
de-epithelialization. Partial limbal deficiency (HLD-) resulted in corneal NV in
MMP-7 and MMP-3 knockout mice but not in wild type controls.
CONCLUSIONS: Corneal angiogenic privilege is an active process involving the
production of antiangiogenic factors to counterbalance the proangiogenic factors
(which are upregulated after wound healing even in the absence of new vessels).
Our finding that the potent antiangiogenic factors, angiostatin and endostatin,
are colocalized with several MMPs during wound healing suggests that MMPs may be
involved in the elaboration of these antiangiogenic molecules by proteolytic
processing of substrates within the cornea.
PMCID: PMC1809914
PMID: 17471348 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15039804 | 1. Tidsskr Nor Laegeforen. 2004 Mar 18;124(6):768-70.
[Treatment of T-cell prolymphocytic leukemia with monoclonal anti- CD52 antibody
(alemtuzumab].
[Article in Norwegian]
Fløisand Y(1), Brinch L, Gedde-Dahl T, Tjønnfjord GE.
Author information:
(1)Seksjon for blodsykdommer, Medisinsk avdeling, Rikshospitalet, 0027 Oslo.
[email protected]
INTRODUCTION: T-cell prolymphocytic leukaemia (T-PLL) is a rare post-thymic
T-cell malignancy with an aggressive clinical course. It has generally been
resistant to alkylating chemotherapy, but some effect has been observed with the
purine analog 2-deoxycoformicin with documented partial or complete response
rates in up to 45% of patients. Treatment with monoclonal antibodies against CD
52 has been shown to be highly effective in T-PLL with response rates of up to
76%. This may allow for further consolidating treatment with high-dose
chemotherapy with autologous stem cell support or allogeneic stem cell
transplantation.
MATERIALS AND METHODS: Five patients treated at Rikshospitalet University
Hospital are evaluated and the literature on T-PLL is reviewed.
RESULTS AND INTERPRETATION: Four of our patients were treated with alemtuzumab.
Three showed complete or partial response. One patient underwent allogeneic stem
cell transplantation with an HLA-identical sibling, but died on day 21 as a
result of transplantation complications. The treatment is generally well
tolerated; the principal management problem is immunosuppression, as shown in
one patient who developed a varicella-zoster meningoencephalomyelitis as a
consequence of not receiving antiviral prophylaxis. The main infusion-related
adverse effects are fever and chills.
PMID: 15039804 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23812140 | 1. J Pediatr Orthop. 2013 Sep;33(6):e65-6. doi: 10.1097/BPO.0b013e31829aac15.
Exploring the link between dystonia genes and idiopathic scoliosis.
Gonzalez-Alegre P(1), Buffard V, Wang K, Henien S, Morcuende JA.
Author information:
(1)Department of Neurology, Roy J and Lucille Carver College of Medicine, The
University of Iowa, Iowa City, IA 52242, USA. [email protected]
BACKGROUND: Adolescent idiopathic scoliosis (AIS) is characterized by a complex
curvature of the spine of unknown etiology. Unknown genetic factors likely play
a role in disease pathogenesis. Recent studies suggest that AIS could result
from central nervous system dysfunction and be related to dystonia. On the basis
of this information, we hypothesized that genes linked to dystonia contribute to
the pathogenesis of AIS.
METHODS: To test this hypothesis, we evaluated the potential association between
sequence variants in candidate dystonia genes and AIS. We sequenced the coding
region of 5 selected dystonia-causing genes in 24 subjects with AIS, followed by
targeted confirmation in additional 89 patients and 73 controls.
RESULTS: No mutations were identified in any of the dystonia genes studied.
CONCLUSIONS: We found no genetic link between dystonia and AIS.
CLINICAL RELEVANCE: This investigation is a genetic evaluation of the
association between dystonia and AIS. Despite the support in the literature for
a pathogenic link between both the disorders, we have not identified any
mutations in dystonia genes in patients with AIS.
DOI: 10.1097/BPO.0b013e31829aac15
PMID: 23812140 [Indexed for MEDLINE] |