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http://www.ncbi.nlm.nih.gov/pubmed/7629360 | 1. J Am Dent Assoc. 1995 Jul;126(7):842-53. doi: 10.14219/jada.archive.1995.0305.
Burning mouth syndrome: an update.
Ship JA(1), Grushka M, Lipton JA, Mott AE, Sessle BJ, Dionne RA.
Author information:
(1)Hospital Dentistry, University of Michigan School of Dentistry, Ann Arbor
48109-1078, USA.
Though it has been the subject of much research, burning mouth syndrome--a
chronic oral-facial pain condition that affects many U.S. adults--remains poorly
understood. It has been associated with numerous oral and systemic conditions.
Treatment options frequently include various medications. While patients with
symptoms of BMS are more likely to seek care from physicians, dentists should be
involved in the evaluation and management of these patients.
DOI: 10.14219/jada.archive.1995.0305
PMID: 7629360 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22414580 | 1. Cancer Res. 2012 May 1;72(9):2428-39. doi: 10.1158/0008-5472.CAN-11-3711. Epub
2012 Mar 13.
Proteomic portrait of human breast cancer progression identifies novel
prognostic markers.
Geiger T(1), Madden SF, Gallagher WM, Cox J, Mann M.
Author information:
(1)Department of Proteomics and Signal Transduction, Max Planck Institute of
Biochemistry, Martinsried, Germany.
Breast cancer is the second leading cause of cancer death for women in the
United States. Of the different subtypes, estrogen receptor-negative (ER(-))
tumors, which are ErbB2+ or triple-negative, carry a relatively poor prognosis.
In this study, we used system-wide analysis of breast cancer proteomes to
identify proteins that are associated with the progression of ER(-) tumors. Our
two-step approach included an initial deep analysis of cultured cells that were
obtained from tumors of defined breast cancer stages, followed by a validation
set using human breast tumors. Using high-resolution mass spectrometry and
quantification by Stable Isotope Labeling with Amino Acids in Cell Culture
(SILAC), we identified 8,750 proteins and quantified 7,800 of them. A
stage-specific signature was extracted and validated by mass spectrometry and
immunohistochemistry on tissue microarrays. Overall, the proteomics signature
reflected both a global loss of tissue architecture and a number of metabolic
changes in the transformed cells. Proteomic analysis also identified high levels
of IDH2 and CRABP2 and low levels of SEC14L2 to be prognostic markers for
overall breast cancer survival. Together, our findings suggest that global
proteomic analysis provides information about the protein changes specific to
ER(-) breast tumor progression as well as important prognostic information.
©2012 AACR
DOI: 10.1158/0008-5472.CAN-11-3711
PMID: 22414580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20594164 | 1. Curr Diabetes Rev. 2010 Sep;6(5):304-12. doi: 10.2174/157339910793360815.
Angiogenic growth factors and their inhibitors in diabetic retinopathy.
Praidou A(1), Androudi S, Brazitikos P, Karakiulakis G, Papakonstantinou E,
Dimitrakos S.
Author information:
(1)2nd Department of Ophthalmology, Aristotle University of Thessaloniki,
Thessaloniki, Greece. [email protected]
Diabetic retinopathy is considered one of the vision-threatening diseases among
working-age population. The pathogenesis of the disease is regarded
multifactorial and complex: capillary basement membrane thickening, loss of
pericytes, microaneuryms, loss of endothelial cells, blood retinal barrier
breakdown and other anatomic lesions might contribute to macular edema and/or
neovascularization the two major and sight threatening complications of diabetic
retinopathy. A number of proangiogenic, angiogenic and antiangiogenic factors
are involved in the pathogenesis and progression of diabetic retinal disease,
Vascular Endothelial Growth Factor (VEGF) being one of the most important. Other
growth factors, which are known to participate in the pathogenesis of the
disease, are: Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor
(FGF), Hepatocyte Growth Factor (HGF), Transforming Growth Factor (TGF),
Placental Endothelial Cell Growth Factor (PlGF), Connective Tissue Growth Factor
(CTGF). Other molecules that are involved in the disease mechanisms are:
intergrins, angiopoietins, protein kinase C (PKC), ephrins, interleukins,
leptin, angiotensin, monocyte chemotactic protein (MCP), vascular cell adhesion
molecule (VCAM), tissue plasminogen activator (TPA), and extracellular matrix
metalloproteinases (ECM-MMPs). However, the intraocular concentration of
angiogenic factors is counterbalanced by the ocular synthesis of several
antioangiogenic factors such as pigment epithelial derived factor (PEDF),
angiostatin, endostatin, thrombospondin, steroids, atrial natriuretic peptide
(ANP), inteferon, aptamer, monoclonal antibodies, VEGF receptor blocker, VEGF
gene suppressors, intracellular signal transduction inhibitors, and
extracellular matrix antagonists. Growth stimulation or inhibition by these
factors depends on the state of development and differentiation of the target
tissue. The mechanisms of angiogenesis factor action are very different and most
factors are multipotential; they stimulate proliferation or differentiation of
endothelial cells. This review attempts to briefly outline the knowledge about
peptide growth factor involvement in diabetic retinopathy. Further ongoing
research may provide better understanding of molecular mechanisms, disease
pathogenesis and therapeutic interactions.
DOI: 10.2174/157339910793360815
PMID: 20594164 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9463792 | 1. Drugs. 1998 Jan;55(1):85-120. doi: 10.2165/00003495-199855010-00007.
Paroxetine. An update of its pharmacology and therapeutic use in depression and
a review of its use in other disorders.
Gunasekara NS(1), Noble S, Benfield P.
Author information:
(1)Adis International Limited, Auckland, New Zealand. [email protected]
Paroxetine is a potent and selective inhibitor of the neuronal reuptake of
serotonin (5-hydroxytryptamine; 5-HT), which was previously reviewed as an
antidepressant in Drugs in 1991. Since then, more comparative trials with other
antidepressants have become available, and its use in the elderly and as long
term maintenance therapy has been investigated. Paroxetine has also been studied
in several other disorders with a presumed serotonergic component, primarily
obsessive compulsive disorder (OCD) and panic disorder. In short term clinical
trials in patients with depression, paroxetine produced clinical improvements
that were significantly greater than those with placebo and similar to those
achieved with other agents including tricyclic antidepressants (TCAs),
maprotiline, nefazodone and the selective serotonin reuptake inhibitors (SSRIs)
fluoxetine, fluvoxamine and sertraline. Long term data suggest that paroxetine
is effective in preventing relapse or recurrence of depression in patients
treated for up to 1 year. In the elderly, the overall efficacy of paroxetine was
at least as good as that of comparator agents. In short term clinical trials
involving patients with OCD or panic disorder, paroxetine was significantly more
effective than placebo and of similar efficacy to clomipramine. Limited long
term data show that paroxetine is effective in maintaining a therapeutic
response over periods of 1 year (OCD) and up to 6 months (panic disorder).
Preliminary data suggest that paroxetine has potential in the treatment of
social phobia, premenstrual dysphoric disorder and chronic headache. Like the
other SSRIs, paroxetine is better tolerated than the TCAs, causing few
anticholinergic adverse effects. The most commonly reported adverse event
associated with paroxetine treatment is nausea, although this is generally mild
and subsides with continued use. Fewer withdrawals from treatment due to adverse
effects occurred with paroxetine treatment than with TCAs. The adverse events
profile of paroxetine appears to be broadly similar to that of other SSRIs,
although data from comparative trials are limited. Serious adverse effects
associated with paroxetine are very rare. In conclusion, paroxetine is effective
and well tolerated, and suitable as first-line therapy for depression. It also
appears to be a useful alternative to other available agents for the treatment
of patients with OCD or panic disorder.
DOI: 10.2165/00003495-199855010-00007
PMID: 9463792 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19272424 | 1. Neuroscience. 2009 Jun 2;160(4):796-804. doi:
10.1016/j.neuroscience.2009.03.002. Epub 2009 Mar 9.
Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein
in transgenic mice.
Schell H(1), Hasegawa T, Neumann M, Kahle PJ.
Author information:
(1)Laboratory of Functional Neurogenetics, Department of Neurodegeneration,
Hertie Institute for Clinical Brain Research, University Clinics Tübingen,
Otfried-Müller-Strasse 27, Tübingen, Germany.
Parkinson's disease and dementia with Lewy bodies are very frequent neurological
disorders of the elderly. Mutations in the alpha-synuclein (alphaSYN) gene cause
Parkinson's disease, often associated with dementia. Neuropathologically these
diseases are characterized by the presence of Lewy bodies and Lewy neurites,
intraneuronal inclusions mostly composed of alphaSYN protein fibrils. Moreover,
alphaSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in
neuropathological lesions. Using our (Thy1)-[A30P]alphaSYN transgenic mouse
model that develops age-dependent impairment in fear conditioning behavior, we
investigated PSer129 immunostaining in the brain. We found distinct staining
patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129
immunoreactivity increased with age in hippocampal and cortical areas as well as
the lateral/basolateral amygdalar nuclei and was present also in young,
pre-symptomatic mice, but not wild-type controls. The tendency of PSer129
immunostaining to accumulate in the nucleus was confirmed in cell culture.
(Thy1)-[A30P]alphaSYN transgenic mice further developed age-dependent, specific
neuritic/terminal alphaSYN pathology in the medial parts of the central
amygdalar nucleus and one of its projection areas, the lateral hypothalamus.
Interestingly, this type of PSer129 neuropathology was thioflavine S negative,
unlike the Lewy-like neuropathology present in the brain stem of
(Thy1)-[A30P]alphaSYN mice. Thus, alphaSYN becomes phosphorylated in distinct
parts of the brain in this alpha-synucleinopathy mouse model, showing
age-dependent increases of nuclear PSer129 in cortical brain areas and the
formation of neuritic/terminal PSer129 neuropathology with variable amyloid
quality within the fear conditioning circuitry and the brain stem.
DOI: 10.1016/j.neuroscience.2009.03.002
PMID: 19272424 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19715380 | 1. Clin Drug Investig. 2009;29(10):635-46. doi: 10.2165/11317820-000000000-00000.
Cost-utility of treatments for pulmonary arterial hypertension: a Markov
state-transition decision analysis model.
Garin MC(1), Clark L, Chumney EC, Simpson KN, Highland KB.
Author information:
(1)Department of Medicine, Hospital of the University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
BACKGROUND AND OBJECTIVE: Clinicians must choose between an increasing number of
medications for the treatment of pulmonary arterial hypertension (PAH) with
different routes of administration, adverse effects, costs and efficacies. We
constructed a decision analysis to help inform treatment choices in PAH.
METHODS: We created a Markov-type model to evaluate 1-year treatment with
bosentan, treprostinil, epoprostenol, inhaled iloprost, sildenafil, sitaxentan
and ambrisentan. Transition probabilities were based on observed transitions
between WHO functional classes, adjusted by relative risk of improvement in a
6-minute walk test. Utilities were based on reported values for each functional
class, adjusted for burden of treatment administration. Costs were estimated
from Medicare and Medicaid reimbursement data. Sensitivity analyses evaluated
changes in efficacy, utilities and costs.
RESULTS: Treatment with sildenafil was less costly and resulted in a greater
gain in quality-adjusted life-years (QALYs) compared with other treatments.
Treatment with ambrisentan and bosentan resulted in the same gain in QALYs as
sildenafil, but at a higher cost. Sensitivity analyses had minimal impact on
these results.
CONCLUSIONS: Based on this model, sildenafil is a cost-effective treatment for
PAH with a low price and a net increase in QALYs. The results from this analysis
are a tool to help guide clinicians in deciding which PAH medications to use;
however, the final decisions should be individualized because the effectiveness
of therapy, resulting utilities and acceptable costs will differ with each
patient.
DOI: 10.2165/11317820-000000000-00000
PMID: 19715380 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11810275 | 1. Hum Genet. 2001 Dec;109(6):628-37. doi: 10.1007/s00439-001-0613-2. Epub 2001
Oct 27.
A full-length and potentially active LINE element is integrated polymorphically
within the IGL locus in a genomically unstable region of chromosome 22.
Benjes SM(1), Morris CM.
Author information:
(1)Cancer Genetics Research Group, Department of Pathology, Christchurch School
of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand,
[email protected]
Leukemic cells of a patient diagnosed with chronic myeloid leukemia (CML) showed
a complex BCR-ABL1 rearrangement hidden within a normal appearing karyotype.
Previous molecular studies had established that the 3' BCR had recombined at a
novel site within the variable region of the immunoglobulin lambda locus ( IGL).
A segment of DNA mapping very close to the site of the IGL/3' BCR recombination
recognized a previously undescribed insertion polymorphism. A combination of
molecular hybridization studies and long-range polymerase chain reaction was
used to isolate a 6-kb full-length long interspersed nuclear element (LINE or
L1), here designated L1(IGL), which occupies 19% of alleles in the general
population. Although unclonable, DNA sequence analysis by a primer walking
approach established that L1(IGL) has features characteristic of an actively
retrotransposing element. The L1(IGL) element has a 5' untranslated region, two
open reading frames (ORF-1 and ORF-2), a 3' untranslated region and terminates
in a poly-A tail. We compared the DNA sequence and the predicted amino acid
sequence of L1(IGL) with a consensus sequence compiled from seven reported
active L1 elements. This analysis indicated that L1(IGL) has high potential for
involvement in as yet undetermined somatically and constitutionally acquired
disease, not only through recombination mechanisms, but also through
retrotransposition events. This full-length L1 element maps close within the
IGLlocus to L1.2, one of only nine active L1 elements that have been reported so
far. L1(IGL) and L1.2 map within a wider and well-recognized region of genomic
instability on chromosome 22.
DOI: 10.1007/s00439-001-0613-2
PMID: 11810275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16342967 | 1. Biochemistry. 2005 Dec 20;44(50):16766-75. doi: 10.1021/bi0511787.
The Saccharomyces cerevisiae linker histone Hho1p, with two globular domains,
can simultaneously bind to two four-way junction DNA molecules.
Schäfer G(1), Smith EM, Patterton HG.
Author information:
(1)Department of Biotechnology, University of the Free State, P.O. Box 339,
Bloemfontein, 9300 South Africa.
Saccharomyces cerevisiae encodes a single linker histone, Hho1p, with two
globular domains. This raised the possibility that Hho1p could bind to two
nucleosome cores simultaneously. To evaluate this idea, we studied the ability
of a four-way junction, immobilized on the surface of a magnetic bead, to pull
down a radiolabeled four-way junction in the presence of different Hho1
proteins. Four-way junctions are known to bind to H1, presumably due to
structure similarities to the DNA at the nucleosomal entry/exit point. We found
a significant increase in the ability of full-length Hho1p to pull down
radiolabeled four-way junction DNA under ionic conditions where both globular
domains could bind. The binding was structure specific, since the use of
double-stranded DNA, or a mutant Hho1p in which the second DNA binding site of
globular domain 1 was abolished, resulted in a significant decrease in bridged
binding. Additionally, bridged binding required a covalent attachment between
the two globular domains, since factor Xa protease treatment of the complex
formed by a modified Hho1p that contained a factor Xa cleavage site between the
two globular domains resulted in a significant release of radiolabeled four-way
junction. These findings demonstrated that the two globular domains
independently associated with two different four-way junction molecules in a
manner that required amino acid residues implicated in structure-specific
binding in the nucleosome. We discuss the implication of these findings on the
chromatin structure of yeast and propose a model where a single Hho1 protein
binds to two serially adjacent nucleosomes.
DOI: 10.1021/bi0511787
PMID: 16342967 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9759660 | 1. Lab Invest. 1998 Sep;78(9):1169-77.
Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid
precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and
formic acid pretreatment.
Takeda A(1), Hashimoto M, Mallory M, Sundsumo M, Hansen L, Sisk A, Masliah E.
Author information:
(1)Department of Neurosciences, University of California, San Diego, School of
Medicine, La Jolla 92093-0624, USA.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP)
(also known as alpha-synuclein) is a presynaptic terminal molecule that
abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the
Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and
Parkinson's disease. To better understand the distribution of
NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites,
as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization,
we studied NACP/alpha-synuclein immunoreactivity using antibodies against the
C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid
treatment in the cortex of patients with LBs. Furthermore, studies of the
subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were
performed by immunogold electron microscopy. These studies showed that the
N-terminal antibody immunolabeled the LBs and dystrophic neurites with great
intensity and, to a lesser extent, the synapses. In contrast, the C-terminal
antibody strongly labeled the synapses and, to a lesser extent, the LBs and
dystrophic neurites. Whereas Proteinase K treatment enhanced
NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it
diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore,
formic acid enhanced LB and dystrophic neurite labeling with both the C- and
N-terminal antibodies. In addition, whereas without pretreatment only slight
anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment
revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells.
Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was
diffusely distributed within the amorphous electrodense material in the LBs and
as small clusters in the filaments of LBs and neurites. These results support
the view that aggregated NACP/alpha-synuclein might play an important role in
the pathogenesis of disorders associated with LBs.
PMID: 9759660 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23724359 | 1. Tremor Other Hyperkinet Mov (N Y). 2013 May 3;3:tre-03-131-3076-1. doi:
10.7916/D8QN65GQ. Print 2013.
The environmental epidemiology of primary dystonia.
Defazio G(1), Gigante AF.
Author information:
(1)Department of Basic Medical Sciences, Neurosciences and Sense Organs, "Aldo
Moro" University of Bari, Bari, Italy.
BACKGROUND: Dystonia is a movement disorder characterized by involuntary muscle
contractions that cause twisting movements and abnormal postures. Primary
dystonia is the most common form and is thought to be a multifactorial condition
in which one or more genes combine with environmental factors to reach disease.
METHODS: We reviewed controlled studies on possible environmental risk factors
for primary early- and late-onset dystonia.
RESULTS: Environmental factors associated with primary early-onset dystonia are
poorly understood. Early childhood illnesses have been reported to be more
frequent in patients with DYT1 dystonia than in subjects carrying the DYT1
mutation that did not manifest dystonia, thus raising the possibility that such
exposures precipitate dystonia among DYT1 carriers. Conversely, several
environmental factors have been associated with primary adult-onset focal
dystonias compared to control subjects. Namely, eye diseases, sore throat,
idiopathic scoliosis, and repetitive upper limb motor action seem to be
associated with blepharospasm (BSP), laryngeal dystonia (LD), cervical dystonia
(CD), and upper limb dystonia, respectively. In addition, an inverse association
between coffee drinking and BSP has been observed in both case-unrelated control
and family-based case-control studies. Additional evidence supporting a causal
link with different forms of primary late-onset dystonia is only available for
diseases of the anterior segment of the eye, writing activity, and coffee
intake.
CONCLUSION: There is reasonable epidemiological evidence that some environmental
factors are risk-modifying factors for specific forms of primary adult-onset
focal dystonia.
DOI: 10.7916/D8QN65GQ
PMCID: PMC3628345
PMID: 23724359
Conflict of interest statement: Financial disclosures: Dr G. Defazio received
funds from the Italian Ministry of University for a research project on
dystonia. Dr A.F. Gigante reports no disclosure. Conflict of Interests: The
authors report no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/15950200 | 1. Cardiovasc Res. 2005 Aug 15;67(3):487-97. doi:
10.1016/j.cardiores.2005.05.003.
Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked
to Romano-Ward syndrome.
Thomas D(1), Wimmer AB, Karle CA, Licka M, Alter M, Khalil M, Ulmer HE, Kathöfer
S, Kiehn J, Katus HA, Schoels W, Koenen M, Zehelein J.
Author information:
(1)Universitätsklinik Heidelberg, Innere Medizin III, Im Neuenheimer Feld 410,
69120 Heidelberg, Germany.
OBJECTIVE: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous
disease characterized by prolonged QT intervals and an increased risk for
ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated
potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is
associated with two different entities of LQTS, the autosomal-dominant
Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and
Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to
cardiac arrhythmias. In this study, we investigate and discuss dominant-negative
I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family.
METHODS: Single-strand conformation polymorphism analysis and direct sequencing
were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were
heterologously expressed in Xenopus oocytes, and potassium currents were
recorded using the two-microelectrode voltage clamp technique.
RESULTS: A heterozygous deletion of three nucleotides (CTT) identified in the
KCNQ1 gene caused the loss of a single phenylalanine residue at position 339
(KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence
of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of
an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger
dominant-negative current reduction than the mutant form of the full-length
KCNQ1 subunit (isoform 1).
CONCLUSION: This study highlights the functional relevance of the truncated
KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in
long QT syndrome. In the RWS family presented here, the autosomal-dominant trait
is caused by multiple dominant-negative effects provoked by heteromultimeric
channels formed by wild type and mutant KCNQ1-isoforms in combination with
KCNE1.
DOI: 10.1016/j.cardiores.2005.05.003
PMID: 15950200 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21308753 | 1. J Orthop Res. 2011 Jul;29(7):1055-8. doi: 10.1002/jor.21347. Epub 2011 Feb 9.
Lack of association between adolescent idiopathic scoliosis and previously
reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a
Japanese population.
Takahashi Y(1), Matsumoto M, Karasugi T, Watanabe K, Chiba K, Kawakami N, Tsuji
T, Uno K, Suzuki T, Ito M, Sudo H, Minami S, Kotani T, Kono K, Yanagida H,
Taneichi H, Takahashi A, Toyama Y, Ikegawa S.
Author information:
(1)Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN,
4-6-1 Sirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Orthopaedic
Surgery, School of Medicine, Keio University, Tokyo, Japan.
Adolescent idiopathic scoliosis (AIS) is a spinal deformity most commonly
arising in apparently healthy girls around puberty. AIS has a strong genetic
predisposition. Several genetic associations between AIS and single nucleotide
polymorphisms (SNPs) have been reported; common SNPs in the genes for matrilin 1
(MATN1), melatonin receptor 1B (MTNR1B), tryptophan hydroxylase 1 (TPH1), and
insulin-like growth factor 1 (IGF1) are reported to be associated with AIS in
Chinese. However, these associations have not been replicated so far. To confirm
the associations, we compared these SNPs with AIS predisposition and curve
severity in a population of Japanese females consisting of 798 AIS patients and
1,239 controls. All the subjects were genotyped using the PCR-based Invader
assay. We found no association of any of the SNPs with AIS predisposition or
curve severity. Considering the statistical power and sample size of the present
study, we concluded that these SNPs are not associated with either AIS
predisposition or curve severity in Japanese.
Copyright © 2011 Orthopaedic Research Society.
DOI: 10.1002/jor.21347
PMID: 21308753 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16831322 | 1. Zhonghua Nei Ke Za Zhi. 2006 Jun;45(6):463-6.
[Novel mutations of potassium channel KCNQ1 S145L and KCNH2 Y475C genes in
Chinese pedigrees of long QT syndrome].
[Article in Chinese]
Liu WL(1), Hu DY, Li P, Li CL, Qin XG, Li YT, Li L, Li ZM, Dong W, Qi Y, Wang Q.
Author information:
(1)Cardiology Division, People's Hospital, Peking University, Beijing 100044,
China.
OBJECTIVE: Hereditary long QT syndrome (LQTS) is a cardiac disorder
characterized by prolongation of QT interval on electrocardiograms (ECGs) and
syncope and sudden death caused by a specific multi-polymorphic ventricular
tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in
cardiac sodium channel gene SCN5A; potassium channel subunit genes KCNQ1, KCNH2,
KCNE1, KCNE2, KCNJ2; calcium channel gene Cav2.1. and ankyrin-B gene ANK2.
METHODS: We characterized 77 Chinese LQTS patients with clinical manifestations
and mutations in the main LQTS genes, KCNQ1 and KCNH2 using PCR and sequence
analysis.
RESULTS: The spectrum of ST-T-wave patterns of 24 (31.2%) probands were
considered as LQT1, 42 (54.5%) as LQT2 and 3 (3.9%) as LQT3. The remaining 8
(10.3%) could not be characterized. The average age for this population of LQTS
patients was (27.6 +/- 16.4) years and the average QTc (561 +/- 70) ms, and the
age of the first syncopal attack was (17.6 +/- 14.7) years. The triggering
factors for cardiac events happening in these mutation carriers included
physical exercise, emotional excitement and auditory irritation. We identified 4
KCNQ1 mutations and 7 KCNH2 mutations. Six of them were first identified with
some data already shown. In this paper we showed the data of 6 other mutations.
CONCLUSIONS: LQT2 is the most common type of LQTS in Chinese; 2 mutations of
KCNQ1 and KCNH2 were first identified in this report; there are some differences
between Chinese and North American or European LQTS patients in clinical
characters and ECG.
PMID: 16831322 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16540873 | 1. Spine (Phila Pa 1976). 2006 Mar 15;31(6):679-81. doi:
10.1097/01.brs.0000202527.25356.90.
The search for idiopathic scoliosis genes.
Ogilvie JW(1), Braun J, Argyle V, Nelson L, Meade M, Ward K.
Author information:
(1)Axial Biotech, Inc., Salt Lake City, UT, USA. [email protected]
STUDY DESIGN: A cohort of 145 patients with adolescent idiopathic scoliosis
(AIS) were identified and contacted to determine whether they had a family
history of scoliosis. These results were submitted to an internal genealogical
database to screen for potential connections to other AIS families. The severity
and incidence of AIS in extended family groups were also analyzed.
OBJECTIVES: Our objectives were to quantify the genetic effect in AIS, determine
the expressivity and penetrance of AIS in large family groupings, and examine
larger scoliosis pedigrees for evidence of multiple genes.
SUMMARY OF BACKGROUND DATA: Previous reports have suggested an 80% connectedness
among scoliosis families, but no clear evidence of multiple genes. It is not
known if there are major gene(s).
METHODS: A cohort of 145 AIS probands were identified and contacted to ascertain
whether they had a family history of AIS. Their medical records and spine
radiographs were reviewed to confirm the diagnosis and determine the disease
severity. Using an internal genealogical database, the cases were screened for
potential connections that would produce larger extended pedigrees.
RESULTS: Overall, 131 of the probands were in the database and 127 showed
connections to other scoliosis families, a 97% connectedness. These results
suggest a major scoliosis gene, as more than 50% of the probands were connected
by founders that all resided in England in the mid 1500s. The differences in
penetrance (41% vs. 34%) and expressivity (38% vs. 61%) between seemingly
unrelated large family groupings might suggest that two different genes are a
major influence for AIS in these families.
CONCLUSIONS: Nearly all (97%) AIS patients have familial origins. There appears
to be at least one major gene, and the differences in penetrance and
expressivity in two large unconnected pedigrees might suggest the presence of
more than one gene.
DOI: 10.1097/01.brs.0000202527.25356.90
PMID: 16540873 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18417974 | 1. Fetal Diagn Ther. 2008;23(3):169-72. doi: 10.1159/000116737. Epub 2008 Feb 20.
Fetal cytomegalovirus infection associated with cerebral hemorrhage, hydrops
fetalis, and echogenic bowel: case report.
Tongsong T(1), Sukpan K, Wanapirak C, Phadungkiatwattna P.
Author information:
(1)Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai
University, Chiang Mai, Thailand. [email protected]
We describe some fetal ultrasound findings associated with intrauterine
cytomegalovirus (CMV) infection. We report a 38-year-old gravida 3, para 2 at 16
weeks of gestation who underwent ultrasound examination for anomaly screening.
The scan revealed an extensive irregular echogenic area in the fetal brain,
especially at the level of lateral ventricles, suggestive of intraventricular
and cerebral hemorrhage. Cardiomegaly, hepatomegaly, and mild ascites as well as
an echogenic bowel were demonstrated. Abnormal chromosomes and hemoglobin Bart
disease were excluded by analysis of fetal blood. Follow-up ultrasound at 20
weeks of gestation showed frank hydrops fetalis, and termination of the
pregnancy was performed based on the couple's decision, giving stillbirth to a
male fetus weighing 450 g. Autopsy findings showed intracerebral hemorrhage
(right cerebral hemisphere) and hydrops fetalis with hepatosplenomegaly.
Microscopic investigation showed typical changes of CMV infection in several
organs, including brain, thyroid gland, lung, liver, kidney, heart, pancreas,
and placenta. Sonographically, the combination of hydrops fetalis, cerebral
hemorrhage, and hyperechoic bowel should raise the possibility of a CMV
infection, particularly in cases with no obvious cause of hydrops fetalis.
Copyright 2008 S. Karger AG, Basel.
DOI: 10.1159/000116737
PMID: 18417974 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24023978 | 1. Oxid Med Cell Longev. 2013;2013:437146. doi: 10.1155/2013/437146. Epub 2013
Aug 19.
Saccharomyces cerevisiae linker histone-Hho1p maintains chromatin loop
organization during ageing.
Uzunova K(1), Georgieva M, Miloshev G.
Author information:
(1)Acad. Roumen Tsanev Institute of Molecular Biology, Bulgarian Academy of
Sciences, Sofia, Bulgaria.
Intricate, dynamic, and absolutely unavoidable ageing affects cells and
organisms through their entire lifetime. Driven by diverse mechanisms all
leading to compromised cellular functions and finally to death, this process is
a challenge for researchers. The molecular mechanisms, the general rules that it
follows, and the complex interplay at a molecular and cellular level are yet
little understood. Here, we present our results showing a connection between the
linker histones, the higher-order chromatin structures, and the process of
chronological lifespan of yeast cells. By deleting the gene for the linker
histone in Saccharomyces cerevisiae we have created a model for studying the
role of chromatin structures mainly at its most elusive and so far barely
understood higher-order levels of compaction in the processes of yeast
chronological lifespan. The mutant cells demonstrated controversial features
showing slower growth than the wild type combined with better survival during
the whole process. The analysis of the global chromatin organization during
different time points demonstrated certain loss of the upper levels of chromatin
compaction in the cells without linker histone. The results underlay the
importance of this histone for the maintenance of the chromatin loop structures
during ageing.
DOI: 10.1155/2013/437146
PMCID: PMC3760111
PMID: 24023978 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17204284 | 1. J Mol Biol. 2007 Mar 2;366(4):1055-63. doi: 10.1016/j.jmb.2006.11.089. Epub
2006 Dec 6.
Exonization of Alu-generated splice variants in the survivin gene of human and
non-human primates.
Mola G(1), Vela E, Fernández-Figueras MT, Isamat M, Muñoz-Mármol AM.
Author information:
(1)Department of Pathology, Hospital Universitari Germans Trias i Pujol,
Autonomous University of Barcelona, Spain.
Survivin is a member of the inhibitor apoptosis family that is overexpressed in
many malignancies. It has five known alternative splice forms, some of which
differ in their antiapoptotic properties and expression levels in human cancers.
Here we describe a novel donor splice site (DSS), 2B+32 DSS, which is used in
conjunction with survivin alternative exon 2B, resulting in the inclusion of 32
additional nucleotides from intron 2 at the 3' end of this exon. Sequence
analysis showed that both the classical exon 2B DSS and 2B+32 are provided by an
Alu sequence, which is inserted in intron 2 downstream of a functional acceptor
splice site, leading to the exonization of part of the repetitive element. Minor
transcripts including the 2B+32 alternative exon, or retaining the whole
intronic region comprised between exons 2B and 3, were detected in several human
cell lines and in some human tissues. Survivin 2B+32 containing variants acquire
a premature stop codon (PTC) and may therefore be degraded by the nonsense
mediated decay pathway. The implication of these novel isoforms, as well as
other PTC+ survivin variants, in the overall regulation of survivin expression
is discussed. Sequence analysis of intron 2 which contains the Alu Y element was
performed on different primate species in order to trace its insertion and
exonization during primate evolution.
DOI: 10.1016/j.jmb.2006.11.089
PMID: 17204284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15195112 | 1. Mod Pathol. 2004 Nov;17(11):1378-85. doi: 10.1038/modpathol.3800203.
Survivin expression in hepatocellular carcinoma: correlation with proliferation,
prognostic parameters, and outcome.
Fields AC(1), Cotsonis G, Sexton D, Santoianni R, Cohen C.
Author information:
(1)Department of Pathology and Laboratory Medicine, Emory University School of
Medicine, Atlanta, GA 30322, USA.
Survivin is a novel inhibitor of apoptosis. It is detected in fetal and
neoplastic adult tissue, but not in normal tissues. Several recent studies have
shown that survivin not only inhibits apoptosis, but also accelerates cancer
cell proliferative activity. Expression of the protein may be of prognostic
significance and therapeutic relevance in many cancers. We investigated survivin
expression in hepatocellular carcinoma, correlating results with proliferation
(MIB-1), prognostic factors, and outcome. Paraffin-embedded sections of 72
hepatocellular carcinoma were immunostained for survivin and MIB-1 using tissue
microarray technology. Expression was evaluated in nuclei and cytoplasm as
intensity (0-3+), and percentage of positive cells scored on a four-tiered
system with less than 10%=negative; 10-25%=1; 26-50%=2; 51-75%=3; and 76-100%=4.
Frequency of nuclear survivin expression was 43%. There was a significant
correlation between nuclear survivin expression and nuclear grade (P=0.0271),
microvascular invasion (P=0.0064), mitotic rate (P=0.0017), and MIB-1
(P=0.0001), as well as local recurrence (P=0.0487), and disease-free survival
(P=0.0098). Histologic grade (P=0.0544) and stage (P=0.0548) tended to correlate
with survivin expression, which did not correlate with cirrhosis, tumor
necrosis, multiple tumors, metastatic disease, or overall survival. Survivin
expression correlates with poor prognostic parameters (high nuclear and
histologic grade, microvascular invasion, increased proliferation (mitotic
count, MIB-1)), local recurrence, and shorter disease-free survival, but does
not correlate with overall survival. An important role is suggested for survivin
in progression, recurrence, and treatment of hepatocellular carcinoma.
DOI: 10.1038/modpathol.3800203
PMID: 15195112 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16478717 | 1. Mol Cell Proteomics. 2006 May;5(5):949-58. doi: 10.1074/mcp.T500042-MCP200.
Epub 2006 Feb 13.
Top-down protein sequencing and MS3 on a hybrid linear quadrupole ion
trap-orbitrap mass spectrometer.
Macek B(1), Waanders LF, Olsen JV, Mann M.
Author information:
(1)Department of Proteomics and Signal Transduction, Max Planck Institute of
Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Top-down proteomics, the analysis of intact proteins (instead of first digesting
them to peptides), has the potential to become a powerful tool for mass
spectrometric protein characterization. Requirements for extremely high mass
resolution, accuracy, and ability to efficiently fragment large ions have often
limited top-down analyses to custom built FT-ICR mass analyzers. Here we explore
the hybrid linear ion trap (LTQ)-Orbitrap, a novel, high performance, and
compact mass spectrometric analyzer, for top-down proteomics. Protein standards
from 10 to 25 kDa were electrosprayed into the instrument using a
nanoelectrospray chip. Resolving power of 60,000 was ample for isotope
resolution of all protein charge states. We achieved absolute mass accuracies
for intact proteins between 0.92 and 2.8 ppm using the "lock mass" mode of
operation. Fifty femtomole of cytochrome c applied to the chip resulted in
spectra with excellent signal-to-noise ratio and only low attomole sample
consumption. Different protein charge states were dissociated in the LTQ, and
the sensitivity of the orbitrap allowed routine, high resolution, and high mass
accuracy fragment detection. This resulted in unambiguous charge state
determination of fragment ions and identification of unmodified and modified
proteins by database searching. Protein fragments were further isolated and
fragmented in the LTQ followed by analysis of MS(3) fragments in the orbitrap,
localizing modifications to part of the sequence and helping to identify the
protein with these small peptide-like fragments. Given the ready availability
and ease of operation of the LTQ-Orbitrap, it may have significant impact on
top-down proteomics.
DOI: 10.1074/mcp.T500042-MCP200
PMID: 16478717 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22278929 | 1. J Orthop Res. 2012 Sep;30(9):1459-63. doi: 10.1002/jor.22075. Epub 2012 Jan
25.
Single-nucleotide polymorphism in Turkish patients with adolescent idiopathic
scoliosis: curve progression is not related with MATN-1, LCT C/T-13910, and VDR
BsmI.
Yilmaz H(1), Zateri C, Uludag A, Bakar C, Kosar S, Ozdemir O.
Author information:
(1)Departments of Physical Medicine, Faculty of Medicine, Canakkale Onsekiz Mart
University, Canakkale, Turkey. [email protected]
The role of genetics in the etiopathogenesis of adolescent idiopathic scoliosis
(AIS) is unclear. In this study, we investigated the relationship between AIS
and polymorphisms in MATN-1, LCT C/T-13910, and VDR BsmI genes. 53 Turkish
adolescents with diagnosed AIS and 54 healthy adult individuals were included in
the study. MATN-1, LCT C/T-13910, and VDR BsmI gene mutations were analyzed with
real-time PCR. We did not detect a statistically significant difference between
AIS and control groups in respect to those three different gene polymorphisms
(p < 0.05). We next evaluated the associations of all three SNPs with scoliosis
curve severity. There was no significant difference between curve severity and
gene polymorphisms (p < 0.05). In terms of gene polymorphisms, AIS patients with
a family history of AIS did not significantly differ from AIS patients who did
not have history (p < 0.05). AIS might be caused by many different gene
mutations, biomechanical mechanisms that have been modified by environmental
factors, different biological interactions, modulation of growth, or a synergy
of different factors causing abnormal control of growth. However, the existing
knowledge is still not enough to explain the etiopathogenesis of AIS.
Copyright © 2012 Orthopaedic Research Society.
DOI: 10.1002/jor.22075
PMID: 22278929 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11754060 | 1. Am J Med Genet. 2001 Dec 15;104(4):282-6. doi: 10.1002/ajmg.10068.
A patient defines the interstitial 1q deletion syndrome characterized by
antithrombin III deficiency.
Pallotta R(1), Dalprà L, Miozzo M, Ehresmann T, Fusilli P.
Author information:
(1)Regional Service for Diagnosis, Prevention and Care of Birth Defects,
Department of Medicine, G. D'Annunzio University, Chieti, Italy.
[email protected]
A patient with microbrachycephaly, high forehead, long philtrum, thin upper lip,
downturned corners of the mouth, low set ears with overlapping helix,
fifth-finger clinodactyly, small hands and feet, bilateral transverse palmar
crease, low total finger ridge count, hypotonia, severe growth and psychomotor
delay, mild hypoplasia of corpus callosum, and Arnold-Chiari type 1 malformation
is reported. The karyotype showed 46, XY, del(1)(q23q31.2). Coagulation factor V
(F5, 1q23) and coagulation factor XIII (F13B, 1q31-q32.1) levels were normal. As
expected, antithrombin III (AT3, 1q23-q25.1) serum level and activity were half
of normal. We performed a review of the literature on proximal and intermediate
deletion 1q syndrome, and we hypothesize the existence of only one 1q
interstitial deletion syndrome, clinically characterized by ATIII deficiency.
Copyright 2001 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.10068
PMID: 11754060 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6626051 | 1. Aust J Exp Biol Med Sci. 1983 Jun;61 (Pt 3):313-20. doi: 10.1038/icb.1983.30.
Inhibition by lanthanum of the calcium paradox phenomenon in rat heart.
Hunt WG, Willis RJ.
Injury is sustained by isolated hearts on repletion with calcium after a short
period of perfusion with calcium-free medium at 37 degrees. A possible mechanism
for the 'calcium paradox' is that exposure to a calcium-fre medium removes
extracellular calcium rendering the sarcolemma more permeable to calcium. On
calcium repletion, cell injury is triggered by calcium influx. Since lanthanum
is known to displace calcium from extracellular pools in heart, it was used in
an attempt to modulate the injury of the calcium paradox. The presence of 10
microM lanthanum in the calcium-free perfusion fluid was found to inhibit
totally protein release normally produced by subsequent calcium exposure. When
lanthanum was added after the calcium-free period and before calcium repletion,
protein release was only partly prevented. This shows that a change in membrane
properties occurred during the calcium-free perfusion period which could be
prevented, but not reversed, by the addition of lanthanum.
DOI: 10.1038/icb.1983.30
PMID: 6626051 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/4058248 | 1. Life Sci. 1985 Nov 4;37(18):1705-10. doi: 10.1016/0024-3205(85)90298-x.
Taurine's possible protective role in age-dependent response to calcium paradox.
Takihara K, Azuma J, Awata N, Ohta H, Sawamura A, Kishimoto S, Sperelakis N.
When hearts were reperfused with Ca++ after a short period of Ca++-free
perfusion, irreversible loss of electrical and mechanical activity was observed.
This phenomenon, first described by Zimmerman and Hulsmann, was termed the
"calcium paradox". Chizzonite and Zak recently reported that rat hearts
exhibited an age-dependent response in a calcium paradox model. The taurine
(2-aminoethanesulfonic acid) content of hearts in the newborn animal is high,
and decreases rapidly during the first few days of life. The present experiments
were performed to test whether the myocardial taurine content was closely linked
to an age-dependent response in the calcium paradox model, using post-hatched
chicks. The mechanical dysfunction of the heart was much more severe in
9-day-old post-hatched chicks than in 2-day-old chicks when the hearts were
subjected to the calcium paradox. Myocardial taurine content was lower in the
9-day-old chicks than in the 2-day-old chicks. The age-related response to the
calcium paradox was partially protected by oral pretreatment with taurine, and
there was a small increase in myocardial taurine level. It is proposed that
myocardial taurine is one factor in the protection against the calcium paradox
phenomenon.
DOI: 10.1016/0024-3205(85)90298-x
PMID: 4058248 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2720439 | 1. Bratisl Lek Listy. 1989 Feb;90(2):67-73.
[Transmural differences between damaged cardiomyocytes due to post-ischemic
reperfusion and calcium paradox].
[Article in Slovak]
Slezák J, Tribulová N, Ravingerová T, Ziegelhöffer A, Okolicány J.
Normothermic 3 min lasting perfusion of the isolated rat heart by
Krebs--Henseleit solution in which Ca2+ was replaced by EDTA and subsequent
perfusion with a Ca2+ containing medium induced structural and metabolic changes
demonstrated electron microscopically and histochemically. In contrast to the
ischemic reperfusion damage, in calcium paradox, the histochemically studied
enzymes alpha-glucan-phosphorylase, lactate dehydrogenase, succinic
dehydrogenase, beta-hydroxybutyric dehydrogenase, and ATPases were better
preserved in the subendocardial region of the left ventricle. Ultrastructural
analysis of this phenomenon showed good correlation with histochemical findings.
A large portion of cardiomyocytes in the subendocardial layer exhibited but
small changes. On the other hand, myocytes in the subepicardial region and in
the midmyocardium were markedly damaged and all characteristic signs of calcium
paradox were present, including hypercontraction bands with myofilament fusion,
extrusion and accumulation of edematous mitochondria with occurrence of electron
dense material in mitochondrial cristae, ruptures of the sarcolemma in all its
layers, separation of intercalated discs, etc. The better preservation of the
subendocardial region in experiments with calcium paradox is attributable to
inadequate perfusion of this region by calcium free medium due to transmural
anatomic inhomogeneity of capillary supply whose insufficiency in the
subendocardial region results in a better protection of these myocytes from Ca2+
paradox.
PMID: 2720439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16905808 | 1. Georgian Med News. 2006 Jun;(135):48-52.
[Role of various etiologic factors in the development of burning mouth
syndrome].
[Article in Russian]
Kenchadze RL, Iverieli MV, Geladze NM.
Burning mouth syndrome (BMS) has been comparatively recently isolated as the
separate nosologic diagnosis. This disease is characterized by the feeling of
burning, dryness, numbness, pricking and seldom by pain in the tongue or mouth
cavity area (palate, lips, alveoli) without any changes in mucous membrane.
Absence of visible causes of the disease complicates its treatment and makes the
patients to address the physicians of various profiles, often without any
result. All the above stated made the authors to define the etiologic factors of
various clinical versions of BMS and to carry out their differential diagnostics
along with the development of pathogenetic therapy of BMS. 30 women of 40 to 70
year of age were examined. According to the anamnesis, BMS was developing
gradually and in most cases it was associated with the aggravation of the
existing disease (hypertension, diabetes mellitus, aggravation of climacteric
state) or with deterioration of psycho-emotional sphere due to conflicting
situation. The carried out studies enabled the authors to select and divide
patients with BMS into groups according to clinical values and the etiologic
factors. In most cases diverse clinical versions of the burning mouth syndrome
are cause-and-effect expressions of various somatic diseases, the timely
determination and adequate therapy of which give the best results in the
struggle against BMS.
PMID: 16905808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14756674 | 1. Clin Genet. 2004 Mar;65(3):233-41. doi: 10.1111/j.0009-9163.2004.00221.x.
Effective long-term control of cardiac events with beta-blockers in a family
with a common LQT1 mutation.
Wedekind H(1), Schwarz M, Hauenschild S, Djonlagic H, Haverkamp W, Breithardt G,
Wülfing T, Pongs O, Isbrandt D, Schulze-Bahr E.
Author information:
(1)Departments of Cardiology and Angiology,University of Münster,
Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. [email protected]
The congenital long QT syndrome (LQTS) is characterized by a prolonged QT
interval on the surface electrocardiogram and an increased risk of recurrent
syncope and sudden cardiac death. Mutations in seven genes have been identified
as the molecular basis of LQTS. beta-blockers are the treatment of choice to
reduce cardiac symptoms. However, long-term follow-up of genotyped families with
LQTS has been rarely reported. We have clinically followed a four-generation
family with LQTS being treated with beta-blocker therapy over a period of 23
years. Seven family members were carriers of two amino acid alterations in cis
(V254M-V417M) in the cardiac potassium channel gene KCNQ1. Voltage-clamp
recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M
mutation reduced the IKs current and that the effect of the V417M variant was
negligible. The family exhibited the complete clinical spectrum of the disease,
from asymptomatic patients to victims of sudden death before beta-blocker
therapy. There was no significant reduction in QTc (556 +/- 40 ms(1/2) before
therapy, 494 +/- 20 ms(1/2) during 17 years of treatment; n = 5 individuals). Of
nine family members, one female died suddenly before treatment, three females of
the second generation were asymptomatic, and four individuals of the third and
fourth generation were symptomatic. All mutation carriers were treated with
beta-blockers and remained asymptomatic for a follow-up up to 23 years.
Long-term follow-up of a LQT1 family with a common mutation (V254M) being on
beta-blocker therapy was effective and safe. This study underscores the
importance of long-term follow-up in families with specific LQT mutations to
provide valuable information for clinicians for an appropriate antiarrhythmic
treatment.
DOI: 10.1111/j.0009-9163.2004.00221.x
PMID: 14756674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16981927 | 1. Pacing Clin Electrophysiol. 2006 Sep;29(9):1013-5. doi:
10.1111/j.1540-8159.2006.00478.x.
The homozygous KCNQ1 gene mutation associated with recessive Romano-Ward
syndrome.
Novotny T(1), Kadlecova J, Janousek J, Gaillyova R, Bittnerova A, Florianova A,
Sisakova M, Toman O, Chroust K, Papousek I, Spinar J.
Author information:
(1)Department of Internal Medicine and Cardiology, University Hospital Brno,
Brno, Czech Republic. [email protected]
In a 7-year-old boy with normal hearing suffering from repeated syncope an
extremely prolonged QTc interval (up to 700 ms) was found. The mother was
completely asymptomatic and the father had an intermittently borderline QTc
interval (maximum 470 ms) but no symptoms. In the proband a mutation analysis of
KCNQ1 gene revealed a homozygous 1893insC mutation. The parents were
heterozygous for this mutation. There was no consanguineous marriage in the
family. The clinical relevance of these findings is that apparently normal
individuals may have a latent reduction of repolarizing currents, a "reduced
repolarization reserve," because they are carriers of latent ion channel genes
mutations.
DOI: 10.1111/j.1540-8159.2006.00478.x
PMID: 16981927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10461463 | 1. Photochem Photobiol. 1999 Aug;70(2):243-7.
Epidemiological support for an hypothesis for melanoma induction indicating a
role for UVA radiation.
Moan J(1), Dahlback A, Setlow RB.
Author information:
(1)Department of Biophysics, Institute for Cancer Research, Montebello, Oslo,
Norway.
An hypothesis for melanoma induction is presented: UV radiation absorbed by
melanin in melanocytes generates products that may activate the carcinogenic
process. Products formed by UV absorption in the upper layers of the epidermis
cannot diffuse down as far as to the melanocytes. Thus, melanin in the upper
layer of the skin may be protective, while that in melanocytes may be
photocarcinogenic. Observations that support this hypothesis include: (1)
Africans with dark skin have a reduced risk of getting all types of skin cancer
as compared with Caucasians, but the ratio of their incidence rates of cutaneous
malignant melanoma to that of squamous cell carcinoma is larger than the
corresponding ratio for Caucasians. (2) Albino Africans, as compared with
normally pigmented Africans, seem to have a relatively small risk of getting
cutaneous malignant melanomas compared to nonmelanomas. This is probably also
true for albino and normally pigmented Caucasians. (3) Among sun-sensitive,
poorly tanning persons, frequent UV exposures are associated with increased risk
of melanoma, whereas among sun-resistant, well-tanning persons, increased
frequency of exposure is associated with decreased melanoma risk. (4) It is
likely that UVA, being absorbed by melanin, might have a melanoma-inducing
effect. This is in agreement with some epidemiological investigations which
indicate that sun-screen lotions may not protect sufficiently against melanoma
induction. The relative latitude gradient for UVA is much smaller than that for
UVB. The same is true for the relative latitude gradient of cutaneous malignant
melanoma as compared with squamous cell carcinoma and basal cell carcinoma.
Under the assumption that the average slopes of the curves relating incidence
rates with fluences of carcinogenic UV radiation are similar for melanomas and
nonmelanomas, these facts are in agreement with the assumption that UVA plays a
significant role in the induction of melanomas in humans. This is in agreement
with the experimental results with Xiphophorus.
PMID: 10461463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9641694 | 1. Circulation. 1998 Jun 23;97(24):2420-5. doi: 10.1161/01.cir.97.24.2420.
A recessive variant of the Romano-Ward long-QT syndrome?
Priori SG(1), Schwartz PJ, Napolitano C, Bianchi L, Dennis A, De Fusco M, Brown
AM, Casari G.
Author information:
(1)Telethon Institute of Genetics and Medicine, San Raffaele Biomedical Science
Park, Milan, Italy.
BACKGROUND: The congenital long-QT syndrome (LQTS) is a genetically
heterogeneous disease characterized by prolonged ventricular repolarization and
life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium
channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a
dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an
autosomal recessive trait.
METHODS AND RESULTS: A consanguineous family with the clinical phenotype of LQTS
was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection
into Xenopus oocytes were prepared, and currents were recorded with the double
microelectrode technique. A homozygous missense mutation, leading to an
alanine-to-threonine substitution at the beginning of the pore domain of the
KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing,
a prolonged QT interval, and syncopal episodes during physical exercise. The
parents of the proband were heterozygous for the mutation and had a normal QT
interval. The functional evaluation of the mutant channel activity showed
reduction in total current, a hyperpolarizing shift in activation, and a faster
activation rate consistent with a mild mutation likely to require homozygosity
to manifest the phenotype.
CONCLUSIONS: These findings provide the first evidence for a recessive form of
the Romano-Ward long-QT syndrome and indicate that homozygous mutations on
KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome. The
implications of this observation prompt a reconsideration of the penetrance of
different mutations responsible for LQTS and suggest that mild mutations in LQTS
genes may be present among the general population and may predispose to
drug-induced ventricular arrhythmias.
DOI: 10.1161/01.cir.97.24.2420
PMID: 9641694 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10779444 | 1. Blood. 2000 May 1;95(9):2947-53.
Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs
(LyGDI and RhoGDI) in neutrophils from patients with severe congenital
neutropenia.
Kasper B(1), Tidow N, Grothues D, Welte K.
Author information:
(1)Department of Pediatric Hematology/Oncology, Medical School Hannover,
Hannover, Germany. [email protected]
Severe congenital neutropenia (SCN) or Kostmann syndrome is a disorder of
myelopoiesis characterized by a maturation arrest at the stage of promyelocytes
or myelocytes in bone marrow and absolute neutrophil counts less than 200/microL
in peripheral blood. Treatment of these patients with granulocyte
colony-stimulating factor (G-CSF) leads to a significant increase in circulating
neutrophils and a reduction in infection-related events in more than 95% of the
patients. To date, little is known regarding the underlying pathomechanism of
SCN. G-CSF-induced neutrophils of patients with SCN are functionally defective
(eg, chemotaxis, superoxide anion generation, Ca(++ )mobilization). Two
guanosine triphosphatases (GTPases), Rac2 and RhoA, were described to be
involved in many neutrophil functions. The expression of these GTPases and their
regulation in patients' neutrophils were of interest. This study determined that
the guanosine diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed
at the protein level in patients' neutrophils and that overexpression is a
result of G-CSF treatment. RhoA and LyGDI are expressed at similar levels,
whereas Rac2 shows a decreased expression. In addition, association of Rac2 and
RhoGDI or LyGDI is abrogated or not detectable based on the low Rac2 expression
in patients' neutrophils. (Blood. 2000;95:2947-2953)
PMID: 10779444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16418123 | 1. Women Health. 2005;42(1):75-97. doi: 10.1300/J013v42n01_05.
Gender differences in emotion regulation and relationships with perceived health
in patients with rheumatoid arthritis.
van Middendorp H(1), Geenen R, Sorbi MJ, Hox JJ, Vingerhoets AJ, van Doornen LJ,
Bijlsma JW.
Author information:
(1)Dept. of Health Psychology, Utrecht University, PO Box 80.140, Heidelberglaan
1, 3508 TC Utrecht, The Netherlands. [email protected]
Emotion regulation has been associated with perceived health in rheumatoid
arthritis, which is diagnosed three times more often in women than men. Our aim
was to examine gender differences in styles of emotion regulation (ambiguity,
control, orientation, and expression) and gender-specificity of the associations
between emotion regulation and perceived health (psychological well-being,
social functioning, physical functioning, and disease activity) in 244 female
and 91 male patients with rheumatoid arthritis. Women reported more emotional
orientation than men, but did not differ from men with regard to ambiguity,
control, and expression. Structural equation modelling showed that relationships
between emotion regulation and perceived health were more frequent and stronger
for women than men. This held especially for the affective dimension of health,
while associations were similar for both women and men with regard to social and
physical functioning. Only for women, the association between ambiguity and
disease activity was significant, which appeared to be mediated by affective
functioning. The observations that women are more emotionally oriented than men
and that emotion regulation is more interwoven with psychological health in
women than men, support the usefulness of a gender-sensitive approach in
research and health care of patients with rheumatoid arthritis.
DOI: 10.1300/J013v42n01_05
PMID: 16418123 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9791861 | 1. Mol Med Today. 1998 Sep;4(9):382-8. doi: 10.1016/s1357-4310(98)01320-3.
The molecular basis of long QT syndrome and prospects for therapy.
Wang Q(1), Bowles NE, Towbin JA.
Author information:
(1)Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of
Medicine, Texas Children's Hospital, Houston 77030, USA.
Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from
ventricular tachyarrhythmias, specifically torsade de pointes. Two types of LQT
have been reported, autosomal-dominant LQT (Romano-Ward syndrome) and
autosomal-recessive LQT (Jervell and Lange-Nielsen syndrome); Jervell and
Lange-Nielsen syndrome is also associated with deafness. Four LQT genes have
been identified for autosomal-dominant LQT: K+ channel genes KVLQT1 on
chromosome 11p15.5, HERG on 7q35-36 and minK on 21q22, and the cardiac Na+
channel gene SCN5A on chromosome 3p21-24. Two genes, KVLQT1 and minK, have been
identified for Jervell and Lange-Nielsen syndrome. Genetic testing and
gene-specific therapies are available for some LQT patients.
DOI: 10.1016/s1357-4310(98)01320-3
PMID: 9791861 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23875666 | 1. Expert Rev Anticancer Ther. 2013 Jul;13(7):883-93. doi:
10.1586/14737140.2013.811180.
The role of necroptosis, an alternative form of cell death, in cancer therapy.
Yu X(1), Deng Q, Bode AM, Dong Z, Cao Y.
Author information:
(1)Cancer Research Institute, Xiangya School of Medicine, Central South
University, 110 Xiang Ya Road, Changsha 410078, Hunan, China.
Programmed cell death plays an important role in animal development, tissue
homeostasis and eliminating harmful or virally infected cells. Necroptosis, a
novel form of programmed cell death, is caspase independent but RIPK and RIPK3
dependent. Moreover, it is suggested that necroptosis can be specifically
inhibited by small molecular inhibitors such as necrostatin-1. Its signaling
pathways have something in common with apoptosis, although the molecular
mechanisms of necroptosis need to be further elucidated. Previous evidences
suggest that necroptosis has significant effects in regulating various
physiological processes and disease, such as ischemic brain injury, immune
system disorders and cancer. In this review, the molecular mechanism of
necroptosis is described and how it could be manipulated in the treatment of
cancer is summarized.
DOI: 10.1586/14737140.2013.811180
PMID: 23875666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8402099 | 1. Br J Surg. 1993 Aug;80(8):992-4. doi: 10.1002/bjs.1800800818.
Plantar melanoma in black South Africans.
Hudson DA(1), Krige JE.
Author information:
(1)Department of Plastic Surgery, University of Cape Town, South Africa.
The outcome of treatment in 40 black patients (27 women, 13 men; mean age 62.9
years) with plantar melanoma over a 13-year period was analysed to evaluate the
efficacy of wide local excision with split skin grafting. Substantial delay in
seeking medical attention occurred in 35 patients. At presentation, 20 patients
had stage I disease, one stage II, 15 stage III and four stage IV. Acral
lentiginous melanoma (27 patients) was the most common histological type. The
mean Breslow depth was 6.9 mm and 35 patients had lesions of Clark level IV or
V. The mean surface area or plantar lesions was 13.3 cm2. Wide local excision
with split skin grafting was used in 29 patients; four patients with neglected
advanced plantar lesions had below-knee amputation and seven with metastatic
disease did not undergo surgery. Graft sepsis occurred in six patients and local
recurrence in two. Nine patients were alive at follow-up; the 5-year survival
rate was 25 per cent. Delay in presentation and locally advanced disease may
explain the poor prognosis of plantar melanoma in black South Africans.
DOI: 10.1002/bjs.1800800818
PMID: 8402099 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23398686 | 1. Nutr J. 2013 Feb 12;12:24. doi: 10.1186/1475-2891-12-24.
Associations between dietary patterns and gene expression profiles of healthy
men and women: a cross-sectional study.
Bouchard-Mercier A(1), Paradis AM, Rudkowska I, Lemieux S, Couture P, Vohl MC.
Author information:
(1)Institute of Nutraceuticals and Functional Foods-INAF, Laval University, 2440
Hochelaga Blvd, Quebec G1V 0A6, Canada.
BACKGROUND: Diet regulates gene expression profiles by several mechanisms. The
objective of this study was to examine gene expression in relation with dietary
patterns.
METHODS: Two hundred and fifty four participants from the greater Quebec City
metropolitan area were recruited. Two hundred and ten participants completed the
study protocol. Dietary patterns were derived from a food frequency
questionnaire (FFQ) by factor analysis. For 30 participants (in fasting state),
RNA was extracted from peripheral blood mononuclear cells (PBMCs) and expression
levels of 47,231 mRNA transcripts were assessed using the Illumina Human-6 v3
Expression BeadChips®. Microarray data was pre-processed with Flexarray software
and analysed with Ingenuity Pathway Analysis (IPA).
RESULTS: Two dietary patterns were identified. The Prudent dietary pattern was
characterised by high intakes of vegetables, fruits, whole grain products and
low intakes of refined grain products and the Western dietary pattern, by high
intakes of refined grain products, desserts, sweets and processed meats. When
individuals with high scores for the Prudent dietary pattern where compared to
individuals with low scores, 2,083 transcripts were differentially expressed in
men, 1,136 transcripts in women and 59 transcripts were overlapping in men and
women. For the Western dietary pattern, 1,021 transcripts were differentially
expressed in men with high versus low scores, 1,163 transcripts in women and 23
transcripts were overlapping in men and women. IPA reveals that genes
differentially expressed for both patterns were present in networks related to
the immune and/or inflammatory response, cancer and cardiovascular diseases.
CONCLUSION: Gene expression profiles were different according to dietary
patterns, which probably modulate the risk of chronic diseases.
TRIAL REGISTRATION: NCT: NCT01343342.
DOI: 10.1186/1475-2891-12-24
PMCID: PMC3598224
PMID: 23398686 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1156726 | 1. Br J Plast Surg. 1975 Apr;28(2):114-7. doi: 10.1016/s0007-1226(75)90171-x.
Malignant melanoma in the Igbos of Nigeria.
Onuigbo WI.
Twenty-one cases of malignant melanoma occurring in the Igbos of Nigeria have
been analysed. The site of predilection is the sole of the foot. This result
supports the conclusion that Negroes tend to have the disease in the
non-pigmented parts. Since preventive surgery has been advocated in Caucasians
in whom sole melanomas are not common, it merits consideration and, if possible,
implementation in the African Negro. The challenge implicit in this form of
preventive oncology should be accepted by plastic surgeons, including Africans
who specialized in this field abroad.
DOI: 10.1016/s0007-1226(75)90171-x
PMID: 1156726 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19540844 | 1. J Mol Cell Cardiol. 2010 Jan;48(1):230-7. doi: 10.1016/j.yjmcc.2009.06.009.
Epub 2009 Jun 21.
Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome
1.
Thomas D(1), Khalil M, Alter M, Schweizer PA, Karle CA, Wimmer AB, Licka M,
Katus HA, Koenen M, Ulmer HE, Zehelein J.
Author information:
(1)Department of Cardiology, Medical University Hospital Heidelberg, Im
Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
[email protected]
Hereditary long QT syndrome (LQTS) is a cardiovascular disorder characterized by
prolongation of the QT interval on the surface ECG and a high risk for
arrhythmia-related sudden death. Mutations in a cardiac voltage-gated potassium
channel, KCNQ1, account for the most common form of LQTS, LQTS1. The objective
of this study was the characterization of a novel KCNQ1 mutation linked to LQTS.
Electrophysiological properties and clinical features were determined and
compared to characteristics of a different mutation at the same position.
Single-strand conformation polymorphism analysis followed by direct sequencing
was performed to screen LQTS genes for mutations. A novel missense mutation in
the KCNQ1 gene, KCNQ1 P320H, was identified in the index patient presenting with
recurrent syncope and aborted sudden death triggered by physical stress and
swimming. Electrophysiological analyses of KCNQ1 P320H and the previously
reported KCNQ1 P320A mutation indicate that both channels are non-functional and
suppress wild type I(Ks) in a dominant-negative fashion. Based on homology
modeling of the KCNQ1 channel pore region, we speculate that the proline residue
at position 320 limits flexibility of the outer pore and is required to maintain
the functional architecture of the selectivity filter/pore helix arrangement.
Our observations on the KCNQ1 P320H mutation are consistent with previous
studies indicating that pore mutations in potassium channel alpha-subunits are
associated with more severe electrophysiological and clinical phenotypes than
mutations in other regions of these proteins. This study emphasizes the
significance of mutation screening for diagnosis, risk-assessment, and
mutation-site specific management in LQTS patients.
Copyright 2009 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yjmcc.2009.06.009
PMID: 19540844 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/5776549 | 1. J Clin Pathol. 1969 Mar;22(2):183-6. doi: 10.1136/jcp.22.2.183.
Melanoma and pigmentation of the leptomeninges in Ugandan Africans.
Lewis MG.
A case of leptomeningeal melanoma in an African child of 7 years is presented
together with a survey of pigmentation in the normal African brain. There is a
direct relationship between the depth of pigment of the leptomeninges and the
skin in Ugandan Africans, suggesting that similar factors operate in the control
of melanocytes in these two sites.
DOI: 10.1136/jcp.22.2.183
PMCID: PMC474030
PMID: 5776549 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9252010 | 1. Pain. 1996 Nov;68(1):151-155. doi: 10.1016/S0304-3959(96)03223-X.
Venlafaxine hydrochloride (Effexor) relieves thermal hyperalgesia in rats with
an experimental mononeuropathy.
Lang E(1), Hord HA, Denson D.
Author information:
(1)Division of Pain Medicine, Department of Anethesiology, Emory University
School of Medicine,Atlanta, GA 30322,USA.
Venlafaxine hydrochloride (Effexor) is a structurally novel antidepressant that
inhibits reuptake of 5-hydroxytryptamine and noradrenaline, but unlike the older
antidepressants, has few side-effects. The objective of this study was to
determine whether venlafaxine relieves thermal hyperalgesia in rats with
neuropathic pain due to chronic constriction injury (CCI) of the sciatic nerve.
Paw withdrawal latency (PWL) to heat was tested for each hind paw. A painful
neuropathy was induced in 24 male Sprague-Dawley rats (Group 1) as described by
Bennett and Xie. Rats randomly received either oral venlafaxine (22 mg/kg) or
placebo via gavage feeding beginning the day after surgery. Postoperative PWL
testing began 3 days after CCI (Time 0). A second group of 12 rats (Group 2) was
used to confirm that venlafaxine reverses hyperalgesia in rats with a fully
developed neuropathic lesion. These animals began to receive oral venlafaxine
(22 mg/kg) starting on the third postoperative day, after the presence of
thermal hyperalgesia was verified through PWL testing. Testing was continued for
5 days, during venlafaxine administration. A third group of 12 rats (Group 3)
had activity measured before and after treatment with venlafaxine (22 mg/kg).
Rats in the placebo group developed thermal hyperalgesia while those that
received venlafaxine did not. Venlafaxine also appeared to have a mild
non-specific analgesic effect that increased PWL in the sham limb. In Group 2,
thermal hyperalgesia was present on day 3, but following treatment with
venlafaxine, thermal hyperalgesia resolved. Activity measurements confirmed that
venlafaxine was not sedating in this rat model.
DOI: 10.1016/S0304-3959(96)03223-X
PMID: 9252010 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18759162 | 1. Scand J Rheumatol. 2008 Nov-Dec;37(6):410-3. doi: 10.1080/03009740802241717.
SDAI/CDAI levels in rheumatoid arthritis patients are highly dependent on
patient's pain perception and gender.
Rintelen B(1), Haindl PM, Maktari A, Nothnagl T, Hartl E, Leeb BF.
Author information:
(1)1st and 2nd Department of Medicine, Centre for Rheumatology, Lower Austrian,
State Hospital Weinviertel Stockerau, Karl Landsteiner Institute for Clinical
Rheumatology, Stockerau, Austria.
OBJECTIVE: To determine whether the Simplified Disease Activity Index (SDAI) and
the Clinical Disease Activity Index (CDAI) are equally applicable for the total
population with rheumatoid arthritis (RA).
METHODS: Five hundred and fifty-seven outpatients with RA [432 females, 125
males; median age 64 years (range 18-85); median disease duration 48 months
(range 2-548)] were enrolled consecutively in this cross-sectional study. SDAI,
CDAI, patient's assessment of pain on the visual analogue scale (VAS) 0-100,
rheumatoid factor (RF), and disease duration were recorded. Linear regression
analysis was performed for each confounding factor.
RESULTS: The median SDAI for all 557 patients was 11.6 (range 0.07-46.60) and
the median CDAI was 10.7 (0.00-42.10). The median SDAI was 12.2 (0.07-46.60) in
females and 8.0 (0.10-35.20) in males. The respective medians for the CDAI were
11.3 (0.00-42.10) and 7.1 (0.00-32.00). These differences were highly
statistically significant (p<0.001). Patient's assessment of pain on the VAS
0-100 scale had a median value of 32 mm. Regression analysis revealed a highly
significant relationship between SDAI/CDAI levels and patient's pain rating
(SDAI: r = 0.660, p<0.001; CDAI: r = 0.671, p<0.001). On multiple regression
analysis, pain exerted a highly significant influence on SDAI and CDAI levels
(p<0.001), whereas age, disease duration, and RF were not correlated with either
level.
CONCLUSION: SDAI and CDAI values are highly dependent on the patient's pain
perception and gender. The effects of patient's age, disease duration, and RF
were inconclusive with respect to the values of the respective disease activity
indexes.
DOI: 10.1080/03009740802241717
PMID: 18759162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23885043 | 1. Am J Clin Nutr. 2013 Sep;98(3):813-20. doi: 10.3945/ajcn.112.052761. Epub 2013
Jul 24.
Prospective study on long-term dietary patterns and incident depression in
middle-aged and older women.
Chocano-Bedoya PO(1), O'Reilly EJ, Lucas M, Mirzaei F, Okereke OI, Fung TT, Hu
FB, Ascherio A.
Author information:
(1)Department of Nutrition, Harvard School of Public Health, Boston, MA 02115,
USA. [email protected]
BACKGROUND: Although individual nutrients have been investigated in relation to
depression risk, little is known about the overall role of diet in depression.
OBJECTIVE: We examined whether long-term dietary patterns derived from a
food-frequency questionnaire (FFQ) predict the development of depression in
middle-aged and older women.
DESIGN: We conducted a prospective study in 50,605 participants (age range:
50-77 y) without depression in the Nurses' Health Study at baseline (1996) who
were followed until 2008. Long-term diet was assessed by using FFQs every 4 y
since 1986. Prudent (high in vegetables) and Western (high in meats) patterns
were identified by using a principal component analysis. We used 2 definitions
for clinical depression as follows: a strict definition that required both a
reported clinical diagnosis and use of antidepressants (3002 incident cases) and
a broad definition that further included women who reported either a clinical
diagnosis or antidepressant use (7413 incident cases).
RESULTS: After adjustment for age, body mass index, and other potential
confounders, no significant association was shown between the diet patterns and
depression risk under the strict definition. Under the broad definition, women
with the highest scores for the Western pattern had 15% higher risk of
depression (95% CI: 1.04, 1.27; P-trend = 0.01) than did women with the lowest
scores, but after additional adjustment for psychological scores at baseline,
results were no longer significant (RR: 1.09; 95% CI: 0.99, 1.21; P-trend =
0.08).
CONCLUSION: Overall, results of this large prospective study do not support a
clear association between dietary patterns from factor analysis and depression
risk.
DOI: 10.3945/ajcn.112.052761
PMCID: PMC3743738
PMID: 23885043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24705156 | 1. Pharmacol Res. 2014 Apr;82:34-9. doi: 10.1016/j.phrs.2014.03.008. Epub 2014
Apr 3.
Dapagliflozin: glucuretic action and beyond.
Balakumar P(1), Sundram K(2), Dhanaraj SA(3).
Author information:
(1)Pharmacology Unit, Faculty of Pharmacy, Asian Institute of Medicine, Science
and Technology (AIMST) University, Semeling, 08100 Bedong, Kedah Darul Aman,
Malaysia. Electronic address: [email protected].
(2)Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University,
Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia.
(3)Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University,
Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia.
Diabetes mellitus is a greatly challenging disease of the 21 century, and the
mortality rate due to this insidious disease is increasing worldwide in spite of
availability of effective oral hypoglycemic agents. Satisfactory management of
glycemic control in patients afflicted with type 2 diabetes mellitus (T2DM)
remains a major clinical challenge. Identification of potential pharmacological
target sites is therefore continuing as an integral part of the diabetic
research. The sodium-glucose co-transporter type 2 (SGLT2) expressed in the
renal proximal tubule plays an essential role in glucose reabsorption.
Pharmacological blockade of SGLT2 prevents glucose reabsorption and subsequently
induces the elimination of filtered glucose via urine, the process is known as
'glucuresis'. Dapagliflozin is a selective inhibitor of SGLT2. The US FDA
approved dapagliflozin in January 2014 to improve glycemic control along with
diet and exercise in adult patients afflicted with T2DM. It has a potential to
decrease glycated hemoglobin and to promote weight loss. Although the mechanism
of action of dapagliflozin is not directly linked with insulin or insulin
sensitivity, reduction of plasma glucose by dapagliflozin via induction of
glucosuria could improve muscle insulin sensitivity. Moreover, dapagliflozin
could cause diuresis and subsequently fall in blood pressure. In addition to
general discussion on the pharmacology of dapagliflozin, we propose in this
review the possibilities of dual antidiabetic effect of dapagliflozin and its
possible additional beneficial actions in hypertensive-obese-T2DM patients
through its indirect blood pressure-lowering action and reduction of body
calories and weight. Long-term clinical studies are however needed to clarify
this contention.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.phrs.2014.03.008
PMID: 24705156 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11035915 | 1. Exp Cell Res. 2000 Nov 1;260(2):208-15. doi: 10.1006/excr.2000.4994.
Arrest of S-phase progression is impaired in Fanconi anemia cells.
Sala-Trepat M(1), Rouillard D, Escarceller M, Laquerbe A, Moustacchi E,
Papadopoulo D.
Author information:
(1)UMR218 du CNRS, Paris, 75248, France.
Fanconi anemia (FA) is an inherited cancer-susceptibility disorder,
characterized by genomic instability, hypersensitivity to DNA cross-linking
agents, and a prolonged G2 phase of the cell cycle. We observed a marked
dose-dependent accumulation of FA cells in the G2 compartment after treatment
with 4,5',8-trimethylpsoralen (Me(3)Pso) in combination with 365 nm irradiation.
Using bivariate DNA distribution methodology, we determined the proportion of
replicating and arresting S-phase cells and observed that, whereas normal cells
arrested DNA replication in the presence of Me(3)Pso cross-links and
monoadducts, FA lymphoblasts failed to arrest DNA synthesis. Taken together, the
above data suggest that, in response to damage induced by DNA cross-linking
agents, the S-phase checkpoint is inefficient in FA cells. This would lead to
accumulation of secondary lesions, such as single- and double-strand breaks and
gaps. The prolonged time in G2 phase seen in FA cells therefore exists in order
to allow the cells to remove lesions which accumulated during the preceding
abnormal S phase.
Copyright 2000 Academic Press.
DOI: 10.1006/excr.2000.4994
PMID: 11035915 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3819049 | 1. J Am Acad Dermatol. 1987 Jan;16(1 Pt 2):178-83. doi:
10.1016/s0190-9622(87)80057-9.
Acrokeratosis paraneoplastica (Bazex' syndrome).
Richard M, Giroux JM.
A 55-year-old white man born in Canada presented with all the clinical features
of acrokeratosis paraneoplastica of Bazex. He showed the characteristic
violaceous erythema and scaling of the nose and face, the aural helices, and the
palmoplantar regions with severe nail dystrophy. Extensive examinations failed
to reveal any associated malignancy up to 5 months after the onset of the skin
eruption. While the skin was improving, and although the patient was still
asymptomatic except for a weight loss of 5 kg, evidence of metastatic squamous
cell carcinoma of the cervical region was obtained. Only palliative treatment
could be undertaken. The bizarre clinical aspects of the syndrome are reviewed.
DOI: 10.1016/s0190-9622(87)80057-9
PMID: 3819049 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24633706 | 1. Med Res Rev. 2014 Nov;34(6):1146-67. doi: 10.1002/med.21314. Epub 2014 Mar 14.
Ramping glucosuria for management of type 2 diabetes mellitus: an emerging
cynosure.
Malla P(1), Kumar R, Mahapatra MK, Kumar M.
Author information:
(1)University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh, India.
Chronic hyperglycemia is a characteristic feature of type 2 diabetes mellitus
(T2DM). The kidney plays a vital role in maintaining blood glucose homeostasis
by recovering glucose from glomerular filtrate which is controlled by SGLT2
cotransporters expressed mainly in proximal tubule. In T2DM patients, inhibition
of SGLT2 normalizes glycemic levels by preventing glucose from being reabsorbed
through SGLT2 and re-entering the circulation. Thus, SGLT2 inhibition seems to
be a logical approach and pose a novel insulin-independent mechanism of action
for management of T2DM by promoting urinary glucose excretion in the body.
Canagliflozin is the first SGLT2 inhibitor approved by US Food and Drug
Administration (US FDA) followed by dapagliflozin while empagliflozin is under
FDA review. Various other drug candidates in late-stage clinical developments
are also expected to hit the global markets in the coming years. In this review,
studies on various early- and late-stage SGLT2 inhibitors have been investigated
and recent clinical developments summarized.
© 2014 Wiley Periodicals, Inc.
DOI: 10.1002/med.21314
PMID: 24633706 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23625539 | 1. Mol Carcinog. 2014 Sep;53(9):675-85. doi: 10.1002/mc.22027. Epub 2013 Apr 26.
FLIP: molecular switch between apoptosis and necroptosis.
Gong J(1), Kumar SA, Graham G, Kumar AP.
Author information:
(1)Department of Urology, School of Medicine, South Texas Veterans Health
Affairs System, The University of Texas Health Science Center, San Antonio,
Texas.
Cancerous growth is one of the most difficult diseases to target as there is no
one clear cause, and targeting only one pathway does not generally produce
quantifiable improvement. For a truly effective cancer therapy, multiple
pathways must be targeted at the same time. One way to do this is to find a gene
that is associated with several pathways; this approach expands the
possibilities for disease targeting and enables multiple points of attack rather
than one fixed point, which does not allow treatment to evolve over time as
cancer does. Inducing programmed cell death (PCD) is a promising method to
prevent or inhibit the progression of tumor cells. Intricate cross talk among
various programmed cell death pathways including cell death by apoptosis,
necroptosis or autophagy plays a critical role in the regulation of PCD. In
addition, the complex and overlapping patterns of signaling and lack of
understanding of such networks between these pathways generate hurdles for
developing effective therapeutic approaches. This review article focuses on
targeting FLIP (Fas-associated death domain-like interleukin-1-converting
enzyme-like inhibitory protein) signaling as a bridge between various PCD
processes as an effective approach for cancer management.
© 2013 Wiley Periodicals, Inc.
DOI: 10.1002/mc.22027
PMID: 23625539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23530637 | 1. Nutr Cancer. 2013;65(3):384-9. doi: 10.1080/01635581.2013.761254.
Dietary patterns and risk of cancers of the upper aerodigestive tract: a factor
analysis in Uruguay.
De Stefani E(1), Boffetta P, Correa P, Deneo-Pellegrini H, Ronco AL, Acosta G,
Mendilaharsu M.
Author information:
(1)Department of Pathology, School of Medicine, University of the Republic,
Montevideo, Uruguay. [email protected]
In the time period 1996-2004, we conducted a case-control study in Montevideo,
Uruguay with the objective of exploring the role of foods and alcoholic
beverages in the etiology of cancers of the upper aerodigestive tract (UADT). In
brief, 563 male cases and 1099 male controls were frequency matched on age and
residence using random sampling. All the participants were drawn from the 4
major public hospitals in Montevideo. We used exploratory factor analysis among
controls. Through Scree plot test, the model retained 4 factors, which were
labeled as prudent, starchy plants, Western, and drinker. These dietary patterns
explained 34.8% of the total variance. Whereas the prudent pattern was inversely
associated with UADT cancer [odds ratios (OR) for the upper tertile vs. the
lowest one 0.52, 95% confidence intervals 0.32-0.76, P value for trend =
0.0005), the remaining patterns were significantly and positively associated
with UADT cancers. We conclude that these patterns were similar among the oral
and laryngeal cancers, both in the direction of the ORs and in the magnitude of
the associations, suggesting that these cancer sites share the effect of dietary
patterns in the etiology of cancer of the upper aerodigestive tract.
DOI: 10.1080/01635581.2013.761254
PMID: 23530637 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17135191 | 1. Nucleic Acids Res. 2007 Jan;35(Database issue):D690-5. doi:
10.1093/nar/gkl934. Epub 2006 Nov 28.
FINDbase: a relational database recording frequencies of genetic defects leading
to inherited disorders worldwide.
van Baal S(1), Kaimakis P, Phommarinh M, Koumbi D, Cuppens H, Riccardino F,
Macek M Jr, Scriver CR, Patrinos GP.
Author information:
(1)Erasmus MC, MGC-Department of Cell Biology and Genetics, Rotterdam, The
Netherlands.
Frequency of INherited Disorders database (FINDbase) (http://www.findbase.org)
is a relational database, derived from the ETHNOS software, recording
frequencies of causative mutations leading to inherited disorders worldwide.
Database records include the population and ethnic group, the disorder name and
the related gene, accompanied by links to any corresponding locus-specific
mutation database, to the respective Online Mendelian Inheritance in Man entries
and the mutation together with its frequency in that population. The initial
information is derived from the published literature, locus-specific databases
and genetic disease consortia. FINDbase offers a user-friendly query interface,
providing instant access to the list and frequencies of the different mutations.
Query outputs can be either in a table or graphical format, accompanied by
reference(s) on the data source. Registered users from three different groups,
namely administrator, national coordinator and curator, are responsible for
database curation and/or data entry/correction online via a password-protected
interface. Databaseaccess is free of charge and there are no registration
requirements for data querying. FINDbase provides a simple, web-based system for
population-based mutation data collection and retrieval and can serve not only
as a valuable online tool for molecular genetic testing of inherited disorders
but also as a non-profit model for sustainable database funding, in the form of
a 'database-journal'.
DOI: 10.1093/nar/gkl934
PMCID: PMC1747180
PMID: 17135191 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23453657 | 1. Spine J. 2013 Mar;13(3):289-98. doi: 10.1016/j.spinee.2013.01.040. Epub 2013
Feb 27.
Increased periostin gene expression in degenerative intervertebral disc cells.
Tsai TT(1), Lai PL, Liao JC, Fu TS, Niu CC, Chen LH, Lee MS, Chen WJ, Fang HC,
Ho NY, Pang JH.
Author information:
(1)Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang
Gung University, 259 Wen-Hwa 1st Rd, Kwei-Shan, Tao-Yuan, Taiwan, Republic of
China.
BACKGROUND CONTEXT: Disc degeneration is a multifactorial disease that may cause
clinical symptoms such as chronic back pain or radiculopathy in the extremities.
Periostin, an extracellular matrix protein involved in the process of fibrosis,
expressed in tissues subjected to mechanical stress such as intervertebral disc.
However, the expression of periostin during disc degeneration has not yet been
studied.
PURPOSE: The aim of this study is to elucidate the difference in gene expression
profiles between degenerative and nondegenerative intervertebral discs for a
better understanding of disc degeneration.
STUDY DESIGN: Degenerative and nondegenerative nucleus pulposus cells were
isolated from elderly patients with degenerative disc disease and younger
patients with adolescent idiopathic scoliosis, respectively.
METHODS: Affymetrix GeneChip Human arrays were used to derive gene expression
profiles for disc degeneration, and gene expressions of periostin and other
degeneration-related markers were confirmed by reverse transcription-polymerase
chain reaction (RT-PCR), real-time RT-PCR, and western blot analysis.
Immunohistochemical analysis of periostin and Gomori trichrome stain was
performed to show the relationship of periostin, fibrosis, and disc
degeneration. The mechanical stress experiment was designed to demonstrate the
relationship of periostin, stress, and disc degeneration.
RESULTS: Fourteen genes were identified to express at significantly different
levels between degenerative and nondegenerative groups. An increase of periostin
gene expression was observed in human degenerative nucleus pulposus cells for
the messenger RNA and protein levels. Histological examination demonstrated an
increased positive staining of periostin in degenerative discs from human
tissues and rat needle-punctured tails and more fibrosis with architectural
disorder and fragmentation in human degenerative disc as compared with
nondegenerative discs. The expression of periostin was significantly induced by
stress in human degenerative nucleus pulposus cells but not in nondegenerative
cells.
CONCLUSIONS: This study demonstrates for the first time an upregulation of
periostin in addition to the expression levels of Type I collagen and matrix
metalloproteinase-2 in human disc degeneration. It suggests that periostin may
be a candidate gene that shows promise as a new prognostic marker and a
therapeutic target that is worth further study to expand our knowledge of its
role in disc degeneration.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.spinee.2013.01.040
PMID: 23453657 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23301705 | 1. J Cell Mol Med. 2013 Jan;17(1):12-29. doi: 10.1111/jcmm.12001. Epub 2013 Jan
10.
Interconnections between apoptotic, autophagic and necrotic pathways:
implications for cancer therapy development.
Jain MV(1), Paczulla AM, Klonisch T, Dimgba FN, Rao SB, Roberg K, Schweizer F,
Lengerke C, Davoodpour P, Palicharla VR, Maddika S, Łos M.
Author information:
(1)Department of Clinical & Experimental Medicine, Division of Cell Biology,
Integrative Regenerative Medicine Center (IGEN), Linköping University,
Linköping, Sweden.
The rapid accumulation of knowledge on apoptosis regulation in the 1990s was
followed by the development of several experimental anticancer- and
anti-ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic
pathways or the removal of cellular apoptotic inhibitors has been suggested to
aid cancer therapy and the inhibition of apoptosis was thought to limit
ischaemia-induced damage. However, initial clinical studies on
apoptosis-modulating drugs led to unexpected results in different clinical
conditions and this may have been due to co-effects on non-apoptotic
interconnected cell death mechanisms and the 'yin-yang' role of autophagy in
survival versus cell death. In this review, we extend the analysis of cell death
beyond apoptosis. Upon introduction of molecular pathways governing autophagy
and necrosis (also called necroptosis or programmed necrosis), we focus on the
interconnected character of cell death signals and on the shared cell death
processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular
signals playing prominent roles in multiple pathways (e.g. Bcl2-family members
and p53). We also briefly highlight stress-induced cell senescence that plays a
role not only in organismal ageing but also offers the development of novel
anticancer strategies. Finally, we briefly illustrate the interconnected
character of cell death forms in clinical settings while discussing
irradiation-induced mitotic catastrophe. The signalling pathways are discussed
in their relation to cancer biology and treatment approaches.
© 2012 The Authors. Published by Foundation for Cellular and Molecular
Medicine/Blackwell Publishing Ltd. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited.
DOI: 10.1111/jcmm.12001
PMCID: PMC3823134
PMID: 23301705 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20810033 | 1. Clin Exp Rheumatol. 2010 Jul-Aug;28(4):454-61. Epub 2010 Aug 30.
Gender, body mass index and rheumatoid arthritis disease activity: results from
the QUEST-RA Study.
Jawaheer D(1), Olsen J, Lahiff M, Forsberg S, Lähteenmäki J, da Silveira IG,
Rocha FA, Magalhães Laurindo IM, Henrique da Mota LM, Drosos AA, Murphy E,
Sheehy C, Quirke E, Cutolo M, Rexhepi S, Dadoniene J, Verstappen SM, Sokka T;
QUEST-RA.
Collaborators: Toloza S, Aguero S, Barrera SO, Retamozo S, Alba P, Lascano C,
Babini A, Albiero E, Pinheiro Gda R, da Mota LM, da Silveira IG, Rocha FA,
Laurindo IM, Lazovskis J, Hetland ML, Hørslev-Petersen K, Hansen TM, Knudsen LS,
Hamoud H, Sobhy M, Fahmy A, Magdy M, Aly H, Saeid H, Nagm A, Fathi NA, Abda E,
Ebraheam Z, Müller R, Kuuse R, Tammaru M, Kallikorm R, Peets T, Otsa K, Laas K,
Valter I, Mäkinen H, Immonen K, Forsberg S, Lähteenmäki J, Luukkainen R, Gossec
L, Dougados M, Maillefert JF, Combe B, Sibilia J, Drosos AA, Exarchou S,
Moutsopoulos HM, Tsirogianni A, Skopouli FN, Mavrommati M, Herborn G, Rau R,
Alten R, Pohl C, Burmester GR, Marsmann B, Géher P, Rojkovich B, Ujfalussy I,
Bresnihan B, Minnock P, Murphy E, Sheehy C, Quirke E, Devlin J, Alraqi S,
Aggarwal A, Pandya S, Sharma B, Cazzato M, Bombardieri S, Ferraccioli G, Morelli
A, Cutolo M, Salaffi F, Stancati A, Yamanaka H, Nakajima A, Fukuda W, Shono E,
Oyoo O, Rexhepi S, Rexhepi M, Anderson D, Stradina P, Stropuviene S, Dadoniene
J, Baranauskaite A, Hajjaj-Hassouni N, Benbouazza K, Allali F, Bahiri R, Amine
B, Verstappen SM, Jacobs JW, Huisman M, Hoekstra M, Haugeberg G, Gjelberg H,
Sierakowski S, Majdan M, Romanowski W, Tlustochowicz W, Kapolka D, Sadkiewicz S,
Zarowny-Wierzbinska D, Ionescu R, Predeteanu D, Karateev D, Luchikhina E,
Chichasova N, Badokin V, Skakic V, Dimic A, Nedovic J, Stankovic A, Naranjo A,
Rodríguez-Lozano C, Calvo-Alen J, Belmonte M, Baecklund E, Henrohn D, Oding R,
Liveborn M, Holmqvist AC, Gogus F, Tunc R, Celic S, Badsha H, Mofti A, Taylor P,
McClinton C, Cross C, Woolf A, Chorghade G, Choy E, Kelly S, Pincus T, Yazici Y,
Bergman M, Craig-Muller J, Sokka T, Kautiainen H, Swearingen C, Pincus T.
Author information:
(1)University of California Los Angeles, Los Angeles, USA. [email protected]
OBJECTIVES: To investigate whether body mass index (BMI), as a proxy for body
fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific
manner.
METHODS: Consecutive patients with RA were enrolled from 25 countries into the
QUEST-RA program between 2005 and 2008. Clinical and demographic data were
collected by treating rheumatologists and by patient self-report. Distributions
of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed
for each country and for the entire dataset; mean values between genders were
compared using Student's t-tests. An association between BMI and DAS28 was
investigated using linear regression, adjusting for age, disease duration and
country.
RESULTS: A total of 5,161 RA patients (4,082 women and 1,079 men) were included
in the analyses. Overall, women were younger, had longer disease duration, and
higher DAS28 scores than men, but BMI was similar between genders. The mean
DAS28 scores increased with increasing BMI from normal to overweight and obese,
among women, whereas the opposite trend was observed among men. Regression
results showed BMI (continuous or categorical) to be associated with DAS28.
Compared to the normal BMI range, being obese was associated with a larger
difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12,
95% CI: 0.03, 0.21); being underweight was not associated with disease activity.
These associations were more pronounced among women, and were not explained by
any single component of the DAS28.
CONCLUSIONS: BMI appears to be associated with RA disease activity in women, but
not in men.
PMCID: PMC3012645
PMID: 20810033 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: none declared. |
http://www.ncbi.nlm.nih.gov/pubmed/20616498 | 1. Front Horm Res. 2010;38:77-86. doi: 10.1159/000318497. Epub 2010 Jul 5.
Familial isolated pituitary adenoma: evidence for genetic heterogeneity.
Toledo RA, Lourenço DM Jr, Toledo SPA.
The identification of mutations in the Aryl hydrocarbon receptor interacting
protein (AIP) gene in a subset of familial isolated pituitary adenoma (FIPA)
cases has recently expanded our understanding of the pathophysiology of
inherited pituitary adenoma disorders. However, a genetic cause of has not yet
been determined in the majority (85%) of FIPA families and half of the families
with isolated familial somatotropinoma. Several studies and reviews have
assessed the genetic and clinical features of AIP-mutated FIPA patients, which
range from a complete lack of symptoms in adult/elderly individuals to large,
aggressive early-onset pituitary tumors. In this study, we aimed to briefly
revise the data available for the 11q13 locus and other additional loci that
have been implicated in genetic susceptibility to FIPA: 2p16-12; 3q28;
4q32.3-4q33; chr 5, 8q12.1, chr 14, 19q13.4 and 21q22.1. These candidate regions
may contain unidentified gene(s) that can be potentially disrupted in
AIP-negative FIPA families. A better knowledge of these susceptibility loci may
disclose modifier genes that are likely to play exacerbating or protective roles
in the phenotypic diversity of AIP-mutated families.
Copyright (c) 2010 S. Karger AG, Basel.
DOI: 10.1159/000318497
PMID: 20616498 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22328731 | 1. Nucleic Acids Res. 2012 May;40(10):e77. doi: 10.1093/nar/gks149. Epub 2012 Feb
10.
Genome-wide enhancer prediction from epigenetic signatures using genetic
algorithm-optimized support vector machines.
Fernández M(1), Miranda-Saavedra D.
Author information:
(1)Bioinformatics and Genomics Laboratory, WPI-Immunology Frontier Research
Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita 565-0871, Osaka, Japan.
The chemical modification of histones at specific DNA regulatory elements is
linked to the activation, inactivation and poising of genes. A number of tools
exist to predict enhancers from chromatin modification maps, but their practical
application is limited because they either (i) consider a smaller number of
marks than those necessary to define the various enhancer classes or (ii) work
with an excessive number of marks, which is experimentally unviable. We have
developed a method for chromatin state detection using support vector machines
in combination with genetic algorithm optimization, called ChromaGenSVM.
ChromaGenSVM selects optimum combinations of specific histone epigenetic marks
to predict enhancers. In an independent test, ChromaGenSVM recovered 88% of the
experimentally supported enhancers in the pilot ENCODE region of interferon
gamma-treated HeLa cells. Furthermore, ChromaGenSVM successfully combined the
profiles of only five distinct methylation and acetylation marks from ChIP-seq
libraries done in human CD4(+) T cells to predict ∼21,000 experimentally
supported enhancers within 1.0 kb regions and with a precision of ∼90%, thereby
improving previous predictions on the same dataset by 21%. The combined results
indicate that ChromaGenSVM comfortably outperforms previously published methods
and that enhancers are best predicted by specific combinations of histone
methylation and acetylation marks.
DOI: 10.1093/nar/gks149
PMCID: PMC3378905
PMID: 22328731 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10440458 | 1. J Clin Psychopharmacol. 1999 Aug;19(4):316-21. doi:
10.1097/00004714-199908000-00006.
Weight gain: side effect of atypical neuroleptics?
Wetterling T(1), Müssigbrodt HE.
Author information:
(1)Department of Psychiatry, Lübeck University School of Medicine, Germany.
[email protected]
During clinical experience with the "atypical" neuroleptic drugs clozapine,
risperidone, and zotepine, some patients have shown a marked weight gain. To
prove whether weight gain is a relevant side effect of atypical neuroleptics,
the charts of all patients admitted with DSM-III-R diagnoses of schizophrenia,
schizoaffective disorder, or delusional disorder in the years 1991 to 1995 were
evaluated. A retrospective chart review was performed, which included all
patients who were treated longer than 2 weeks with a single neuroleptic. The
data analysis showed that weight gain must be considered as a common side effect
of atypical neuroleptics (clozapine, risperidone, sulpiride, or zotepine). The
mean weight gain (3.1, 1.5, 1.9, or 4.3 kg, respectively) was significantly
higher than that of patients treated with "classic" neuroleptics (mean, 0.0-0.5
kg) (Kruskal-Wallis, p = 0.01). Young and not obese patients show the highest
weight increase. Because weight gain occurs in the first weeks of treatment,
particularly in previously untreated subjects, this side effect has to be
considered in view of compliance with long-term neuroleptic medication.
DOI: 10.1097/00004714-199908000-00006
PMID: 10440458 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8080508 | 1. Ann Neurol. 1994 Mar;35(3):326-30. doi: 10.1002/ana.410350313.
Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy,
and dysmorphic features.
Tawil R(1), Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC.
Author information:
(1)University of Rochester School of Medicine and Dentistry, Neuromuscular
Disease Center, New York.
Comment in
Ann Neurol. 1994 Aug;36(2):252-3. doi: 10.1002/ana.410360223.
Andersen's syndrome is a clinically distinct form of potassium-sensitive
periodic paralysis associated with cardiac dysrhythmias. The subtle nature of
the cardiac and dysmorphic features may delay the recognition of this syndrome
and its potentially lethal cardiac dysrhythmias. The genetic defect in
Andersen's syndrome is not genetically linked to other forms of
potassium-sensitive periodic paralysis and is probably distinct from the long QT
syndrome locus.
DOI: 10.1002/ana.410350313
PMID: 8080508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18581057 | 1. J Neurooncol. 2008 Oct;90(1):89-97. doi: 10.1007/s11060-008-9637-y. Epub 2008
Jun 26.
Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with
recurrent glioblastoma.
de Groot JF(1), Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, Groves MD,
Conrad C, Colman H, Puduvalli VK, Levin V, Yung WK.
Author information:
(1)Department of Neuro-Oncology, University of Texas - M.D. Anderson Cancer
Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. [email protected]
Targeting the epidermal growth factor receptor (EGFR) may be effective in a
subset of glioblastoma patients. This phase II study assessed the clinical
activity of erlotinib plus carboplatin and to determine molecular predictors of
response. The primary endpoint was progression free survival (PFS). Patients
with recurrent glioblastoma with no more than two prior relapses received
carboplatin intravenously on day 1 of every 28-day cycle (target AUC of 6 mg x
ml/min). Daily erlotinib at 150 mg/day was dose escalated to 200 mg/day, as
tolerated. Clinical and MRI assessments were made every 4 and 8 weeks,
respectively. Tumor tissue was evaluated for EGFR, AKT and phosphatase and
tensin homolog (PTEN) status. One partial response (PR) was observed out of 43
assessable patients. Twenty patients (47%) had stable disease (SD) for an
average of 12 weeks. Median PFS was 9 weeks. The 6-month PFS rate was 14%.
Median overall survival (OS) was 30 weeks. This regimen was well tolerated with
grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring
dose reductions. A recursive partitioning analysis (RPA) predicted that patients
with KPS >or=90 treated with more than 1 prior regimen had the highest OS. No
correlation was observed between EGFR, Akt or PTEN expression and either PFS or
OS. Carboplatin plus erlotinib is well tolerated but has modest activity in
unselected patients. Future trials should be stratified based on optimal
molecular or clinical characteristics.
DOI: 10.1007/s11060-008-9637-y
PMCID: PMC6059769
PMID: 18581057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15062207 | 1. Sleep Med Rev. 2004 Feb;8(1):7-17. doi: 10.1016/S1087-0792(03)00042-X.
The treatment of chronic insomnia: drug indications, chronic use and abuse
liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting
symposium.
Mendelson WB(1), Roth T, Cassella J, Roehrs T, Walsh JK, Woods JH, Buysse DJ,
Meyer RE.
Author information:
(1)[email protected]
This paper summarizes a group of presentations and panel discussions on chronic
insomnia at the 2001 NCDEU meeting. The presentations and discussions focused on
the twin issues of efficacy and concerns of abuse liability with long-term
hypnotic therapy. The panel concluded that insomnia may be an epidemiological
marker for a variety of difficulties including accidents, increased health care
utilization and subsequent development of major depression. Whether or not
treatment of insomnia will prevent these long-term problems has not yet been
determined. Since the mid-1980s there has been a rapid rise in the off-label use
of antidepressants, particularly trazodone, for treating insomnia. Some
participants expressed concern at the lack of data for this practice,
particularly the absence of dose-response and tolerance information, and noted
that the small amount of efficacy data available is not encouraging. Similarly,
there are minimal data to support the use of antihistamines as sleep aids;
moreover, their side effect profile and interactions with other drugs may be
under appreciated. The limited data available on nightly long-term usage of the
newer non-benzodiazepine hypnotics, primarily of six-months' duration, suggest
an absence of tolerance, but more data for both nightly and non-nightly
administration are needed. Insomniacs tend to show therapy-seeking, rather than
drug-seeking behavior, and patients without histories of drug abuse are unlikely
to self-escalate dosage of currently available hypnotics. There is fairly good
agreement on the characteristics of an ideal hypnotic. All currently available
agents, while effective and safe, do not achieve this ideal. The next few years
are likely to see the appearance of a variety of agents with new and promising
mechanisms of action.
DOI: 10.1016/S1087-0792(03)00042-X
PMID: 15062207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9213079 | 1. Eur Neuropsychopharmacol. 1997 Aug;7(3):201-6. doi:
10.1016/s0924-977x(97)00404-5.
A naturalistic study of paroxetine in premenstrual syndrome: efficacy and
side-effects during ten cycles of treatment.
Sundblad C(1), Wikander I, Andersch B, Eriksson E.
Author information:
(1)Institute of Physiology and Pharmacology, University of Göteborg, Sweden.
Eighteen women with severe premenstrual syndrome (PMS) (premenstrual dysphoric
disorder, PMDD) were treated openly with paroxetine for 10 consecutive menstrual
cycles. Dosage was flexible (5-30 mg/day); also, the patients were free to chose
between continuous medication and medication in the luteal phase only. The
rating of premenstrual irritability, depressed mood, increase in appetite, and
anxiety/tension was markedly lower during treatment with paroxetine than before,
and this reduction in symptomatology appeared unabated for the entire treatment
period. Sedation, dry mouth, and nausea were common side-effects but declined
during the course of the trial; in contrast, reduced libido and anorgasmia,
which were reported by almost 50% of the participants, were not improved with
time. The results indicate that the beneficial effects as well as the sexual
side-effects of serotonin reuptake inhibitors persist unchanged for at least 10
consecutive cycles of treatment.
DOI: 10.1016/s0924-977x(97)00404-5
PMID: 9213079 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18625105 | 1. Curr Pain Headache Rep. 2008 Aug;12(4):279-84. doi: 10.1007/s11916-008-0047-9.
Burning mouth syndrome.
Speciali JG(1), Stuginski-Barbosa J.
Author information:
(1)Hospital das Clínicas de Ribeirão Preto (Departamento de Neurologia), Avenida
Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14400-000, Brazil.
[email protected]
Burning mouth syndrome (BMS) is a chronic disease characterized by burning of
the oral mucosa associated with a sensation of dry mouth and/or taste
alterations. BMS occurs more frequently among postmenopausal women. The
pathophysiology of the disease is still unknown, and evidence is conflicting;
although some studies suggest a central origin, others point to a peripheral
neuropathic origin. The efficacy of some medications in the treatment of BMS
suggests that the dopaminergic system may be involved.
DOI: 10.1007/s11916-008-0047-9
PMID: 18625105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22455412 | 1. N Engl J Med. 2012 Mar 29;366(13):1181-9. doi: 10.1056/NEJMoa1109017.
Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
Papp KA(1), Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, Aras G,
Li J, Russell CB, Thompson EH, Baumgartner S.
Author information:
(1)Probity Medical Research, Waterloo, ON, Canada. [email protected]
Comment in
N Engl J Med. 2012 Mar 29;366(13):1251-2. doi: 10.1056/NEJMe1201071.
N Engl J Med. 2012 Jul 19;367(3):274; author reply 275. doi:
10.1056/NEJMc1205835.
N Engl J Med. 2012 Jul 19;367(3):274-5; author reply 275. doi:
10.1056/NEJMc1205835.
Br J Dermatol. 2012 Oct;167(4):710-3; discussion 714-5. doi:
10.1111/bjd.12025.
BACKGROUND: In this phase 2, randomized, double-blind, placebo-controlled,
dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827),
a human anti-interleukin-17-receptor monoclonal antibody, for the treatment of
moderate-to-severe plaque psoriasis.
METHODS: We randomly assigned patients with a score of 12 or higher on the
psoriasis area-and-severity index (PASI, on which scores range from 0 to 72,
with higher scores indicating more severe disease) and with 10% or more of their
body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or
210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo.
The primary end point was the percentage improvement from baseline in the PASI
score at week 12. Secondary end points included improvement of at least 75% and
at least 90% in the PASI score and the score on the static physician's global
assessment at week 12.
RESULTS: A total of 198 patients underwent randomization. At week 12, the mean
percentage improvements in the PASI score were 45.0% among patients receiving 70
mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those
receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those
receiving placebo (P<0.001 for all comparisons with placebo). An improvement of
at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and
72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and
75%, respectively, of the patients in the 210-mg group, as compared with 0% in
the placebo group (P<0.001 for all comparisons). The percentage of patients with
a static physician's global assessment of clear or minimal disease was 26%, 85%,
80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of
brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with
placebo). Two cases of grade 3 neutropenia were reported in the 210-mg
brodalumab group. The most commonly reported adverse events in the combined
brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection
(8%), and injection-site erythema (6%).
CONCLUSIONS: Brodalumab significantly improved plaque psoriasis in this 12-week,
phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).
DOI: 10.1056/NEJMoa1109017
PMID: 22455412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20004604 | 1. Mol Genet Metab. 2010 Mar;99(3):275-82. doi: 10.1016/j.ymgme.2009.10.189. Epub
2009 Nov 4.
In silico and functional studies of the regulation of the glucocerebrosidase
gene.
Blech-Hermoni YN(1), Ziegler SG, Hruska KS, Stubblefield BK, Lamarca ME, Portnoy
ME; NISC Comparative Sequencing Program; Green ED, Sidransky E.
Author information:
(1)Section on Molecular Neurogenetics, Medical Genetics Branch, National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD
20892-3708, USA.
In Gaucher disease (GD), the inherited deficiency of glucocerebrosidase results
in the accumulation of glucocerebroside within lysosomes. Although almost 300
mutations in the glucocerebrosidase gene (GBA) have been identified, the ability
to predict phenotype from genotype is quite limited. In this study, we sought to
examine potential GBA transcriptional regulatory elements for variants that
contribute to phenotypic diversity. Specifically, we generated the genomic
sequence for the orthologous genomic region ( approximately 39.4kb) encompassing
GBA in eight non-human mammals. Computational comparisons of the resulting
sequences, using human sequence as the reference, allowed the identification of
multi-species conserved sequences (MCSs). Further analyses predicted the
presence of two putative clusters of transcriptional regulatory elements
upstream and downstream of GBA, containing five and three transcription
factor-binding sites (TFBSs), respectively. A firefly luciferase (Fluc) reporter
construct containing sequence flanking the GBA gene was used to test the
functional consequences of altering these conserved sequences. The predicted
TFBSs were individually altered by targeted mutagenesis, resulting in enhanced
Fluc expression for one site and decreased expression for seven others sites.
Gel-shift assays confirmed the loss of nuclear-protein binding for several of
the mutated constructs. These identified conserved non-coding sequences flanking
GBA could play a role in the transcriptional regulation of the gene contributing
to the complexity underlying the phenotypic diversity seen in GD.
Published by Elsevier Inc.
DOI: 10.1016/j.ymgme.2009.10.189
PMCID: PMC2827879
PMID: 20004604 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2775757 | 1. Biochemistry. 1989 Jul 11;28(14):6110-3. doi: 10.1021/bi00440a057.
Amino acid sequence of bovine angiogenin.
Bond MD(1), Strydom DJ.
Author information:
(1)Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical
School, Boston, Massachusetts 02115.
Erratum in
Biochemistry 1989 Oct 3;28(20):8262.
The amino acid sequence and disulfide bridges of bovine plasma derived
angiogenin were determined by sequencer analysis of the intact protein and
fragments derived by enzymatic and chemical digestion. Bovine angiogenin is a
single-chain protein of 125 amino acids; it contains six cysteines and has a
calculated molecular weight of 14,595. In contrast to the human protein its
amino terminus is unblocked. It has the following sequence:
H2N-Ala1-Gln-Asp-Asp-Tyr-Arg-Tyr-Ile-His-Phe10-Leu-Thr-Gln-His-Tyr -Asp-Ala-Lys-
Pro-Lys20-Gly-Arg-Asn-Asp-Glu-Tyr-Cys-Phe-Asn-Met30-Met-Lys- Asn-Arg-Arg-Leu-Thr
- Arg-Pro-Cys40-Lys-Asp-Arg-Asn-Thr-Phe-Ile-His-Gly-Asn50-Lys-
Asn-Asp-Ile-Lys-Ala -
Ile-Cys-Glu-Asp60-Arg-Asn-Gly-Gln-Pro-Tyr-Arg-Gly-Asp-Leu70- Arg-Ile-Ser-Lys-Ser
- Glu-Phe-Gln-Ile-Thr80-Ile-Cys-Lys-His-Lys-Gly-Ser-Ser-Arg90-
Pro-Pro-Cys-Arg-Tyr -
Gly-Ala-Thr-Glu-Asp100-Ser-Arg-Val-Ile-Val-Val-Gly-Cys-Glu-Asn1 10-Gly-Leu-Pro-
Val-His-Phe-Asp-Glu-Ser-Phe120-Ile-Thr-Pro-Arg-His-OH. Disulfide bonds link
Cys(27)-Cys(82), Cys(40)-Cys(93), and Cys(58)-Cys(108). Bovine angiogenin is 64%
identical with human angiogenin; like the human protein, it is homologous to the
pancreatic ribonucleases, with conservation of active site residues. Two
regions, 6-22 and 65-75, are highly conserved between the angiogenins but are
significantly different from those of the ribonucleases, suggesting a possible
role in the molecules' biological activity.
DOI: 10.1021/bi00440a057
PMID: 2775757 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10968707 | 1. Semin Diagn Pathol. 2000 Aug;17(3):216-24.
Immunohistochemistry of small round-cell tumors.
Devoe K(1), Weidner N.
Author information:
(1)Department of Pathology, University of California, San Diego, USA.
The term "small round-cell tumor" describes a group of highly aggressive
malignant tumors composed of relatively small and monotonous undifferentiated
cells with high nuclear to cytoplasmic ratios. This group includes Ewing's
sarcoma (ES), peripheral neuroepithelioma (aka, primitive neuroectodermal tumor
or extraskeletal ES), peripheral neuroblastoma ("classic-type"),
rhabdomyosarcoma, desmoplastic small round-cell tumor, lymphoma, leukemia,
small-cell osteosarcoma, small-cell carcinoma (either undifferentiated or
neuroendocrine), olfactory neuroblastoma, cutaneous neuroendocrine carcinoma
(aka, Merkel-cell carcinoma), small-cell melanoma, and mesenchymal
chondrosarcoma. Their clinical presentations often overlap, thus making a
definitive diagnosis problematic in some cases. Yet, a clear understanding of
their clinicopathologic features usually allows for a confident diagnosis,
especially if immunohistochemistry is used. The following is a review of the
immunohistochemistry of this small round-cell tumor group.
PMID: 10968707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25712444 | 1. Ann Pharmacother. 2015 May;49(5):582-98. doi: 10.1177/1060028015573564. Epub
2015 Feb 23.
Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus:
a review of the evidence.
White JR Jr(1).
Author information:
(1)Washington State University, Spokane, WA, USA [email protected].
OBJECTIVE: To review available studies of empagliflozin, a sodium glucose
co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission
and the United States Food and Drug Administration for the treatment of type 2
diabetes mellitus (T2DM).
DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI
10773, and BI10773, for entries between January 1, 2000, and December 1, 2014.
Reference lists from retrieved articles were searched manually for additional
peer-reviewed publications.
STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials
of empagliflozin were eligible for inclusion.
DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a
mechanism of action that is independent of β-cell function and the insulin
pathway. Data from a comprehensive phase III clinical trial program have
demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering
agents, and in different patient populations. In these studies, empagliflozin
resulted in improvements in blood glucose levels as well as reductions in body
weight and blood pressure. Empagliflozin was well tolerated and was not
associated with an increased risk of hypoglycemia versus placebo.
CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as
monotherapy or alongside other glucose-lowering treatments, including insulin,
to treat T2DM.
© The Author(s) 2015.
DOI: 10.1177/1060028015573564
PMID: 25712444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18981465 | 1. J Clin Oncol. 2008 Dec 1;26(34):5610-7. doi: 10.1200/JCO.2008.16.7510. Epub
2008 Nov 3.
Randomized phase II study of cilengitide, an integrin-targeting
arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme.
Reardon DA(1), Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, Glantz
M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho
EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB.
Author information:
(1)Duke University Medical Center, Durham, NC 27710, USA. [email protected]
Comment in
J Clin Oncol. 2009 Apr 10;27(11):1921; author reply 1922. doi:
10.1200/JCO.2008.21.5871.
PURPOSE: Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin
receptors, demonstrated minimal toxicity and durable activity across a wide
range of doses administered to adults with recurrent glioblastoma multiforme
(GBM) in a prior phase I study. The current multicenter phase II study was
conducted to evaluate the activity and safety of cilengitide in GBM patients at
first recurrence.
PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either
500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were
assessed every 4 weeks. The primary end point was 6-month progression-free
survival (PFS) rate. Secondary end points included PFS, overall survival (OS),
and radiographic response, as well as quality-of-life and pharmacokinetic
assessments.
RESULTS: Eighty-one patients were enrolled, including 41 on the 500-mg arm and
40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no
significant reproducible toxicities observed on either arm. Antitumor activity
was observed in both treatment cohorts but trended more favorably among patients
treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9
months.
CONCLUSION: Cilengitide monotherapy is well tolerated and exhibits modest
antitumor activity among recurrent GBM patients. Additional studies integrating
cilengitide into combinatorial regimens for GBM are warranted.
DOI: 10.1200/JCO.2008.16.7510
PMID: 18981465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24746173 | 1. Expert Opin Investig Drugs. 2014 Jun;23(6):875-82. doi:
10.1517/13543784.2014.909407. Epub 2014 Apr 19.
Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of
type 1 diabetes.
Lamos EM(1), Younk LM, Davis SN.
Author information:
(1)University of Maryland School of Medicine , 660 West Redwood Street, Howard
Hall 469, Baltimore, MD 21201 , USA.
INTRODUCTION: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is
currently restricted to insulin, pramlintide, and pancreas or islet cell
transplantation. The imperfect replication of normal insulin secretion and
glucose control has been a driver for development of other anti-hyperglycemic
agents for this population. Empagliflozin, a sodium glucose co-transporter 2
(SGLT2) inhibitor, is currently under investigation as an add-on therapy to
insulin in T1DM.
AREAS COVERED: Within the drug evaluation, the authors describe the mechanism of
action of SGLT2 inhibitors and preliminary results from studies investigating
treatment in rodent models and in individuals with T1DM.
EXPERT OPINION: Studies on adjunct therapeutic effects of empagliflozin in
individuals with T1DM are limited, but initial reports show favorable effects on
reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events.
Intriguingly, this drug may confer a degree of renal protection by reducing
glomerular hyperfiltration that can arise in the diabetic state. Currently, the
primary concern seems to be the presence of ketone levels indicating an
under-insulinized state. Long-term effects can only be inferred from studies in
type 2 diabetes mellitus at this time. Empagliflozin represents a novel
non-insulin-mediated therapy that warrants further investigation.
DOI: 10.1517/13543784.2014.909407
PMID: 24746173 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24950857 | 1. Arch Pharm Res. 2014 Aug;37(8):957-66. doi: 10.1007/s12272-014-0419-0. Epub
2014 Jun 21.
Clinical implication of SGLT2 inhibitors in type 2 diabetes.
Kim GW(1), Chung SH.
Author information:
(1)Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung
Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
Treatment of type 2 diabetes mellitus (T2DM) continues to present challenges,
with many patients failing to achieve glycemic targets. Despite the availability
of many oral and injectable anti-diabetic agents, therapeutic efficacy is often
offset by undesirable side effects such as hypoglycemia, weight gain and
cardiovascular complications. Therefore, the search for new therapeutic agents
with an improved benefit-risk profile continues. Recent research has focused on
the kidney as a potential therapeutic target, especially because maximal renal
glucose reabsorption is increased in T2DM. Under normal physiological
conditions, nearly all filtered glucose is reabsorbed in the proximal tubule of
the nephron via the sodium/glucose co-transporter 2 (SGLT2). SGLT2-inhibitors
are a new class of oral anti-diabetes, which reduce hyperglycemia by increasing
urinary glucose excretion independently of insulin secretion or action.
Canagliflozin and dapagliflozin in US market, and ipragliflozin and
luseogliflozin in Japan market are now available for glycemic control in type 2
diabetics. There are several phase III clinical ongoing trials involving this
new class of medications. This review examines some of the key efficacy and
safety data from clinical trials of the SGLT2 inhibitors approved, and their
future perspectives in the treatment of T2DM.
DOI: 10.1007/s12272-014-0419-0
PMID: 24950857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11597323 | 1. Breast Cancer Res. 2001;3(5):328-31. doi: 10.1186/bcr316. Epub 2001 Aug 7.
Hypoxia and oxidative stress. Tumour hypoxia--therapeutic considerations.
Williams KJ(1), Cowen RL, Stratford IJ.
Author information:
(1)Department of Pharmacy and Pharmaceutical Sciences, University of Manchester,
Manchester, UK.
Conclusive research has shown that regions of acute/chronic hypoxia, which exist
within the majority of solid tumours, have a profound influence on the
therapeutic outcome of cancer chemotherapy and radiotherapy and are a strong
prognostic factor of disease progression and survival. A strong argument
therefore exists for assessing the hypoxic fraction of tumours, prior to patient
treatment, and to tailor this treatment accordingly. Tumour hypoxia also
provides a powerful physiological stimulus that can be exploited as a
tumour-specific condition, allowing for the rationale design of
hypoxia-activated anticancer drugs or novel hypoxia-regulated gene therapy
strategies.
DOI: 10.1186/bcr316
PMCID: PMC138697
PMID: 11597323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23259508 | 1. BMC Musculoskelet Disord. 2012 Dec 23;13:259. doi: 10.1186/1471-2474-13-259.
Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood
and microarray analysis of vitamin D responsive genes expression in
paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients.
Nowak R(1), Szota J, Mazurek U.
Author information:
(1)Orthopaedics Clinic Medical University of Silesia, Wojewódzki Szpital
Specjalistyczny nr5 41-200 Sosnowiec, Pl. Medyków 1, Poland. [email protected]
BACKGROUND: VDR may be considered as a candidate gene potentially related to
idiopathic scoliosis susceptibility and natural history. Transcriptional profile
of VDR mRNA isoforms might be changed in the structural tissues of the scoliotic
spine and potentially influence the expression of VDR responsive genes. The
purpose of the study was to determine differences in mRNA abundance of VDR
isoforms in bone, cartilage and paravertebral muscles between tissues from curve
concavity and convexity, between JIS and AIS and to identify VDR responsive
genes differentiating juvenile and adolescent idiopathic scoliosis in
paravertebral muscles.
METHODS: In a group of 29 patients with JIS and AIS, specimens of bone,
cartilage, paravertebral muscles were harvested at the both sides of the curve
apex together with peripheral blood samples. Extracted total RNA served as a
matrix for VDRs and VDRl mRNA quantification by QRT PCR. Subsequent microarray
analysis of paravertebral muscular tissue samples was performed with HG U133A
chips (Affymetrix). Quantitative data were compared by a nonparametric Mann
Whitney U test. Microarray results were analyzed with GeneSpring 11GX
application. Matrix plot of normalized log-intensities visualized the degree of
differentiation between muscular tissue transcriptomes of JIS and AIS group.
Fold Change Analysis with cutoff of Fold Change ≥2 identified differentially
expressed VDR responsive genes in paravertebral muscles of JIS and AIS.
RESULTS: No significant differences in transcript abundance of VDR isoforms
between tissues of the curve concavity and convexity were found. Statistically
significant difference between JIS and AIS group in mRNA abundance of VDRl
isoform was found in paravertebral muscles of curve concavity. Higher degree of
muscular transcriptome differentiation between curve concavity and convexity was
visualized in JIS group. In paravertebral muscles Tob2 and MED13 were selected
as genes differentially expressed in JIS and AIS group.
CONCLUSIONS: In Idiopathic Scolioses transcriptional activity and alternative
splicing of VDR mRNA in osseous, cartilaginous, and paravertebral muscular
tissues are tissue specific and equal on both sides of the curve. The number of
mRNA copies of VDRl izoform in concave paravertebral muscles might be one of the
factors differentiating JIS and AIS. In paravertebral muscles Tob2 and Med13
genes differentiate Adolescent and Juvenile type of Idiopathic Scoliosis.
DOI: 10.1186/1471-2474-13-259
PMCID: PMC3532837
PMID: 23259508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24038971 | 1. Am J Med Genet A. 2013 Dec;161A(12):3042-8. doi: 10.1002/ajmg.a.36154. Epub
2013 Aug 16.
Neuromotor synapses in Escobar syndrome.
Robinson KG(1), Viereck MJ, Margiotta MV, Gripp KW, Abdul-Rahman OA, Akins RE.
Author information:
(1)Nemours Biomedical Research, Alfred I. duPont Hospital for Children,
Wilmington, Delaware.
The Escobar variant of multiple pterygium syndrome (OMIM #265000) is a rare,
autosomal recessive disorder associated with mutations in the γ-subunit of the
nicotinic acetylcholine receptor (CHRNG). CHRNG is expressed in fetal muscle
during motor development and contributes to the formation of neuromuscular
junctions (NMJs). Anomalies in NMJ structure and function have not been
investigated in patients with Escobar syndrome. We report five patients
identified as having Escobar syndrome, from four families. In three families,
the same mutation (c.459dupA) was identified in CHRNG. A biopsy from
brachioradialis muscle was collected from a patient from one of these families
and analyzed for NMJ organization using fluorescence microscopy. Compared to
spinalis muscle from control patients with idiopathic scoliosis or cerebral
palsy (CP), the patient with Escobar syndrome had a significantly higher degree
of acetylcholine receptor present outside acetylcholinesterase and significantly
less acetylcholinesterase outside acetylcholine receptors. Given the role of the
acetylcholine receptor γ-subunit in fetal neuromuscular signal transduction and
in establishing the primary encounter of muscle and motor nerve terminal, the
CHRNG mutations described in Escobar syndrome may cause a broader disruption of
postsynaptic proteins and result in aberrant development of the NMJ due to
impaired prenatal neuromuscular transmission and/or abnormal neuromuscular
synaptogenesis.
© 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.36154
PMCID: PMC5600816
PMID: 24038971 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23154884 | 1. J Radiat Res. 2013 Mar 1;54(2):268-76. doi: 10.1093/jrr/rrs105. Epub 2012 Nov
14.
Placental extract protects bone marrow-derived stem/progenitor cells against
radiation injury through anti-inflammatory activity.
Kawakatsu M(1), Urata Y, Goto S, Ono Y, Li TS.
Author information:
(1)Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki
University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki
852-8523, Japan.
Placental extracts have been reported to have anti-oxidative and
anti-inflammatory activities. Because there is increasing evidence that ionizing
radiation induces the release of reactive oxygen species (ROS) and inflammatory
cytokines, we examined the protective effects of a placental extract against
radiation injury. C57BL/6 mice were exposed to 1 Gy of γ-ray radiation every day
for 5 days, and placental extract (1 mg/day) was administrated orally soon after
each exposure. At 2 days after the last irradiation, mice were euthanized to
examine the numbers, colony-forming capacity, and DNA damage of stem/progenitor
cells in the peripheral blood and bone marrow. To understand the related
mechanisms, we also measured the levels of intracellular and mitochondrial ROS,
and 8-OHdG in the plasma and urine, and IL-6 and TNF-α in the plasma. Compared
with the placebo treatment, oral administration of placental extract
significantly increased the number and colony-forming capacity, but decreased
the DNA damage of bone marrow stem/progenitor cells. However, neither the levels
of intracellular and mitochondrial ROS in bone marrow cells, nor the levels of
8-OHdG in the urine and plasma significantly differed between groups.
Interestingly, in comparison with the placebo treatment, placental extract
significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α
in the plasma. Placental extract significantly attenuated the acute radiation
injury to bone marrow-derived stem/progenitor cells, and this protection is
likely to be related to the anti-inflammatory activity of the placental extract.
DOI: 10.1093/jrr/rrs105
PMCID: PMC3589942
PMID: 23154884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22310283 | 1. Oncogene. 2012 Nov 29;31(48):5007-18. doi: 10.1038/onc.2012.8. Epub 2012 Feb
6.
Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in
hematopoiesis and leukemogenesis.
Li Y(1), Deng C, Hu X, Patel B, Fu X, Qiu Y, Brand M, Zhao K, Huang S.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Florida
College of Medicine, Gainesville, FL, USA.
TAL1/SCL is a hematopoietic-specific oncogene and its activity is regulated by
associated transcriptional co-activators and corepressors. Dysregulation of TAL1
activity has been associated with T-cell leukemogenesis. However, it remains
unclear how the interactions between TAL1 and corepressors versus co-activators
are properly regulated. Here, we reported that protein kinase A (PKA)-mediated
phosphorylation regulates TAL1 interaction with the lysine-specific demethylase
(LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails.
Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1
interaction leading to promoter H3K4 hypermethylation and activation of target
genes that have been suppressed in normal and malignant hematopoiesis. Knockdown
of TAL1 or LSD1 led to a derepression of the TAL1 target genes in T-cell acute
lymphoblast leukemia (T-ALL) Jurkat cells, which is accompanied by elevating
promoter H3K4 methylation. Similarly, treatment of PKA activator forskolin
resulted in derepression of target genes by reducing its interaction with LSD1
while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels.
Consistent with the dual roles of TAL1 in transcription, TAL1-associated LSD1 is
decreased while recruitment of hSET1 is increased at the TAL1 targets during
erythroid differentiation. This process is accompanied by a dramatic increase in
H3K4 methylation. Thus, our data revealed a novel interplay between PKA
phosphorylation and TAL1-mediated epigenetic regulation that regulates
hematopoietic transcription and differentiation programs during hematopoiesis
and leukemogenesis.
DOI: 10.1038/onc.2012.8
PMCID: PMC3510314
PMID: 22310283 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest The authors declare no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/16894358 | 1. Cell Res. 2006 Aug;16(8):681-92. doi: 10.1038/sj.cr.7310086.
Heme: a versatile signaling molecule controlling the activities of diverse
regulators ranging from transcription factors to MAP kinases.
Mense SM(1), Zhang L.
Author information:
(1)Department of Environmental Health Sciences, Columbia University, Mailman
School of Public Health, New York, NY 10032, USA.
Heme (iron protoporphyrin IX) is an essential molecule for numerous living
organisms. Not only does it serve as a prosthetic group in enzymes, it also acts
as a signaling molecule that controls diverse molecular and cellular processes
ranging from signal transduction to protein complex assembly. Deficient heme
synthesis or function impacts the hematopoietic, hepatic and nervous systems in
humans. Recent studies have revealed a series of heme-regulated transcription
factors and signal transducers including Hap1, a heme-activated transcription
factor that mediates the effects of oxygen on gene transcription in the yeast
Saccharomyces cerevisiae; Bach1, a transcriptional repressor that is negatively
regulated by heme in mammalian cells; IRR, an iron regulatory protein that
mediates the iron-dependant regulation of heme synthesis in the bacterium
Bradyrhizobium japonicum; and heme-regulated inhibitor, an eucaryotic initiation
factor 2alpha kinase that coordinates protein synthesis with heme availability
in reticulocytes. In this review, we summarize the current knowledge about how
heme controls the activity of these transcriptional regulators and signal
transducers, and discuss diseases associated with defective heme synthesis,
degradation and function.
DOI: 10.1038/sj.cr.7310086
PMID: 16894358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7952245 | 1. Curr Opin Neurol. 1994 Aug;7(4):353-7. doi: 10.1097/00019052-199408000-00013.
Neuroleptic malignant syndrome.
Kornhuber J(1), Weller M.
Author information:
(1)Department of Psychiatry, University of Würzburg, Germany.
Neuroleptic malignant syndrome (NMS) was first recognized as a life-threatening
complication of dopamine receptor antagonists characterized by extrapyramidal
disturbances, hyperthermia, and elevated serum creatine kinase levels. Concepts
of NMS have changed because medications other than classic neuroleptic drugs
have been implicated as triggering agents and because syndromes identical to NMS
have been observed in patients with Parkinson's disease withdrawn from their
medication or suffering akinetic hyperthermic parkinsonian crisis. The
neurochemical key features in all these conditions are probably functional
dopamine deficiency and ensuing hyperactivity of excitatory amino acid
neurotransmission in the basal ganglia and hypothalamus. Recognition of NMS is
the most important step in its management; the outcome is good if causative
drugs are discontinued or if parkinsonian therapy is readjusted. Supportive care
includes management of hyperthermia and fluid replacement. Controversial
therapeutic measures include the application of dopamine receptor agonists,
excitatory amino acid antagonists, or dantrolene. Psychiatric patients with a
history of NMS and psychotic relapse necessitating neuroleptic drugs do not
commonly redevelop NMS when reexposed to dopamine receptor antagonists but may
be treated most safely with atypical neuroleptic drugs such as clozapine.
DOI: 10.1097/00019052-199408000-00013
PMID: 7952245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17582433 | 1. J Mol Cell Cardiol. 2007 Aug;43(2):187-96. doi: 10.1016/j.yjmcc.2007.05.005.
Epub 2007 May 18.
T75M-KCNJ2 mutation causing Andersen-Tawil syndrome enhances inward
rectification by changing Mg2+ sensitivity.
Tani Y(1), Miura D, Kurokawa J, Nakamura K, Ouchida M, Shimizu K, Ohe T,
Furukawa T.
Author information:
(1)Department of Bio-Informational Pharmacology, Medical Research Institute,
Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo
101-0062, Japan.
Andersen-Tawil syndrome (ATS) is a multisystem inherited disease exhibiting
periodic paralysis, cardiac arrhythmias, and dysmorphic features. In this study,
we characterized the KCNJ2 channels with an ATS mutation (T75M) which is
associated with cardiac phenotypes of bi-directional ventricular tachycardia,
syncope, and QT(c) prolongation. Confocal imaging of GFP-KCNJ2 fusion proteins
showed that the T75M mutation impaired membrane localization of the channel
protein, which was restored by co-expression of WT channels with T75M channels.
Whole-cell patch-clamp experiments in CHO-K1 cells showed that the T75M mutation
produced a loss-of-function of the channel. When both WT and the T75M were
co-expressed, the T75M mutation showed dominant-negative effects on inward
rectifier K+ current densities, with prominent suppression of outward currents
at potentials between 0 mV and +80 mV over the E(K). Inside-out patch
experiments in HEK293T cells revealed that co-expression of WT and the T75M
channels enhanced voltage-dependent block of the channels by internal Mg2+,
resulting in enhanced inward rectification at potentials 50 mV more positive
than the E(K). We suggest that the T75M mutation causes dominant-negative
suppression of the co-expressed WT KCNJ2 channels. In addition, the T75M
mutation caused alteration of gating kinetics of the mutated KCNJ2 channels,
i.e., increased sensitivity to intracellular Mg2+ and resultant enhancement of
inward rectification. The data presented suggest that the mutation may influence
clinical features, but it does not directly show this.
DOI: 10.1016/j.yjmcc.2007.05.005
PMID: 17582433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22357549 | 1. Biol Reprod. 2012 May 10;86(5):148, 1-11. doi: 10.1095/biolreprod.111.095307.
Print 2012 May.
In vitro transformation of mouse testis cells by oncogene transfection.
Morimoto H(1), Lee J, Tanaka T, Ishii K, Toyokuni S, Kanatsu-Shinohara M,
Shinohara T.
Author information:
(1)Department of Molecular Genetics, Graduate School of Medicine, Kyoto
University, Kyoto, Japan.
Germ cell tumors (GCTs) are unique in that they exhibit diverse biological
characteristics and pathological features. Although several in vivo GCT models
are available, studies on GCTs are hampered because in vivo development of GCTs
is time consuming and prevents a detailed molecular analysis of the
transformation process. Here we developed a novel strategy to transform mouse
testis cells in vitro. Lentivirus-mediated transfection of dominant negative
Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused
tumorigenic conversion in vitro. Although these cells resembled embryonic stem
(ES) cells, they were aneuploid and lacked Nanog expression, which is involved
in the maintenance of the undifferentiated state in ES cells. Euploid ES-like
cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and
Sox2) into the same cell population. Although these cells expressed Nanog, they
were distinct from ES cells in that they expressed CD44, a cancer stem cell
antigen. Both treatments induced similar changes in the DNA methylation patterns
in differentially methylated regions of imprinted genes. Moreover, despite the
differences in their phenotype and karyotype, both cell types similarly produced
mixed GCTs on transplantation, which were composed of teratomas, seminomas, and
embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an
analysis of the GCT formation process, and our results also suggest the close
similarity between GCT formation and reprogramming.
DOI: 10.1095/biolreprod.111.095307
PMID: 22357549 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15050829 | 1. J Mol Biol. 2004 Apr 16;338(1):139-48. doi: 10.1016/j.jmb.2004.02.046.
Two homologous domains of similar structure but different stability in the yeast
linker histone, Hho1p.
Ali T(1), Coles P, Stevens TJ, Stott K, Thomas JO.
Author information:
(1)Cambridge Centre for Molecular Recognition and Department of Biochemistry,
University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
The Saccharomyces cerevisiae homologue of the linker histone H1, Hho1p, has two
domains that are similar in sequence to the globular domain of H1 (and variants
such as H5). It is an open question whether both domains are functional and
whether they play similar structural roles. Preliminary structural studies
showed that the two isolated domains, GI and GII, differ significantly in
stability. In 10 mM sodium phosphate (pH 7), the GI domain, like the globular
domains of H1 and H5, GH1 and GH5, was stably folded, whereas GII was largely
unstructured. However, at high concentrations of large tetrahedral anions
(phosphate, sulphate, perchlorate), which might mimic the charge-screening
effects of DNA phosphate groups, GII was folded. In view of the potential
significance of these observations in relation to the role of Hho1p, we have now
determined the structures of its GI and GII domains by NMR spectroscopy under
conditions in which GII (like GI) is folded. The backbone r.m.s.d. over the
ordered residues is 0.43 A for GI and 0.97 A for GII. Both structures show the
"winged-helix" fold typical of GH1 and GH5 and are very similar to each other,
with an r.m.s.d. over the structured regions of 1.3 A, although there are
distinct differences. The potential for GII to adopt a structure similar to that
of GI when Hho1p is bound to chromatin in vivo suggests that both globular
domains might be functional. Whether Hho1p performs a structural role by
bridging two nucleosomes remains to be determined.
DOI: 10.1016/j.jmb.2004.02.046
PMID: 15050829 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25301180 | 1. Expert Opin Pharmacother. 2014 Nov;15(16):2429-41. doi:
10.1517/14656566.2014.966078.
Empagliflozin for the treatment of type 2 diabetes.
Jahagirdar V(1), Barnett AH.
Author information:
(1)Heart of England NHS Foundation Trust, Department of Diabetes and
Endocrinology , Birmingham , UK.
INTRODUCTION: Despite the availability of numerous anti-diabetes drugs and
treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not
reach recommended targets for glycemic control. There remains an unmet need for
effective and well-tolerated anti-diabetes agents that can be used as
monotherapy or in combination with other therapies to improve glycemic control
in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a
new class of treatment for T2DM that reduce hyperglycemia by reducing renal
glucose reabsorption and thereby increasing urinary glucose excretion.
AREAS COVERED: This paper reviews the pharmacokinetic and pharmacodynamic
properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials
investigating the efficacy of empagliflozin given as monotherapy or as add-on
therapy on glycemic control, body weight, and blood pressure in patients with
T2DM, and the safety and tolerability profile of empagliflozin.
EXPERT OPINION: Empagliflozin offers good glycemic efficacy, weight loss, blood
pressure reduction, and a low risk of hypoglycemia. These attributes, coupled
with the ability to be used in virtually any combination with other
anti-diabetes agents and at any stage in the disease process, provide a welcome
new agent to our armamentarium of drugs to help manage T2DM.
DOI: 10.1517/14656566.2014.966078
PMID: 25301180 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17534848 | 1. Yeast. 2007 Sep;24(9):767-75. doi: 10.1002/yea.1504.
Bimolecular fluorescence complementation analysis system for in vivo detection
of protein-protein interaction in Saccharomyces cerevisiae.
Sung MK(1), Huh WK.
Author information:
(1)School of Biological Sciences and Research Centre for Functional Cellulomics,
Institute of Microbiology, Seoul National University, Seoul 151-747, Republic of
Korea.
The bimolecular fluorescence complementation (BiFC) assay has been widely
accepted for studying in vivo detection of protein-protein interactions in
several organisms. To facilitate the application of the BiFC assay to yeast
research, we have created a series of plasmids that allow single-step, PCR-based
C- or N-terminal tagging of yeast proteins with yellow fluorescent protein
fragments for BiFC assay. By examination of several interacting proteins
(Sis1-Sis1, Net1-Sir2, Cet1-Cet1 and Pho2-Pho4), we demonstrate that the BiFC
assay can be used to reliably analyse the occurrence and subcellular
localization of protein-protein interactions in living yeast cells. The
sequences for the described plasmids were submitted to the GenBank under
Accession Nos: EF210802, pFA6a-VN-His3MX6; EF210803, pFA6a-VC-His3MX6; EF210804,
pFA6a-VN-TRP1; EF210807, pFA6a-VC-TRP1; EF210808, pFA6a-VN-kanMX6; EF210809,
pFA6a-VC-kanMX6; EF210810, pFA6a-His3MX6-P(GAL1)-VN; EF210805,
pFA6a-His3MX6-P(GAL1)-VC; EF210806, pFA6a-TRP1-P(GAL1)-VN; EF210811,
pFA6a-TRP1-P(GAL1)-VC; EF210812, pFA6a-kanMX6-P(GAL1)-VN; EF210813,
pFA6a-kanMX6-P(GAL1)-VC; EF521883, pFA6a-His3MX6-P(CET1)-VN; EF521884,
pFA6a-His3MX6-P(CET1)-VC; EF521885, pFA6a-TRP1-P(CET1)-VN; EF521886,
pFA6a-TRP1-P(CET1)-VC; EF521887, pFA6a-kanMX6-P(CET1)-VN; EF521888,
pFA6a-kanMX6-P(CET1)-VC.
Copyright (c) 2007 John Wiley & Sons, Ltd.
DOI: 10.1002/yea.1504
PMID: 17534848 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18687885 | 1. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11703-8. doi:
10.1073/pnas.0709403105. Epub 2008 Aug 7.
Yeast linker histone Hho1p is required for efficient RNA polymerase I
processivity and transcriptional silencing at the ribosomal DNA.
Levy A(1), Eyal M, Hershkovits G, Salmon-Divon M, Klutstein M, Katcoff DJ.
Author information:
(1)The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University,
Ramat Gan 52900, Israel.
Nucleosome core particles in eukaryotes are linked by a stretch of DNA that is
usually associated with a linker histone. Here, we show in yeast, that the
presence of yeast linker histone Hho1p represses expression of a pol II
transcribed gene (MET15) embedded in the rDNA. In vivo deletions of Hho1p
sequences showed that the second globular domain is sufficient for that
repression, whereas the presence of the N terminus is required for its
derepression. In contrast, a run-on assay confirmed by a ChIP experiment showed
that Hho1p is required for maximal pol I processivity during rDNA transcription.
Psoralen accessibility experiments indicated that Hho1p is necessary for normal
rDNA compaction. DNA array expression analysis comparing RNA transcripts in
wild-type and hho1 strains before and after a heat-shock showed that Hho1p is
necessary to achieve wild-type mRNA levels of transcripts that encode ribosomal
components. Taken together, our results suggest that Hho1p is involved in rDNA
compaction, and like core histones, is required for efficient rDNA transcription
by pol I.
DOI: 10.1073/pnas.0709403105
PMCID: PMC2575252
PMID: 18687885 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/11786427 | 1. Am J Pathol. 2002 Jan;160(1):339-45. doi: 10.1016/S0002-9440(10)64377-5.
Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer.
Savinainen KJ(1), Saramäki OR, Linja MJ, Bratt O, Tammela TL, Isola JJ,
Visakorpi T.
Author information:
(1)Laboratory of Cancer Genetics, Institute of Medical Technology, University of
Tampere, Tampere, Finland.
An anti-ERBB2 antibody, trastuzumab, has been shown to be highly efficient in
the treatment of metastatic breast cancers overexpressing the ERBB2 gene. It has
been suggested that overexpression and even amplification of ERBB2 may play a
role in the development of prostate cancer. Here, we have analyzed gene copy
number and expression of the ERBB2 gene in both androgen-dependent primary and
metastatic tumors, as well as recurrent hormone-refractory tumors. The
expression levels were compared to the expression of ERBB2 in breast cancers
with or without ERBB2 gene amplification. Of 126 prostate tumors, chromogenic in
situ hybridization (CISH) revealed only 1 case containing borderline (six to
eight copies) amplifications of ERBB2. This hormone-refractory tumor, however,
did not express ERBB2 protein. Immunohistochemical staining of ERBB2 protein was
negative (0 or 1+ intensity) in all prostate samples (n = 124) analyzed. To
quantitate the level of ERBB2 mRNA expression in prostate tumors (n = 34) and
cell lines (n = 3), as well as in breast tumors (n = 30) and cell lines (n =
16), real-time reverse transcriptase-polymerase chain reaction (LightCycler)
methodology was used. The expression level was similar in all prostate tumor
types and corresponded to the level of expression in breast carcinomas without
ERBB2 amplification. Breast tumors with ERBB2 amplification expressed, on
average, approximately 20 times (P < 0.001) higher mRNA levels than prostate
tumors or breast carcinomas without the gene amplification. In conclusion, the
expression of ERBB2 in prostate cancer is relatively low, and is not altered
during disease progression. Thus, it is unlikely that treatment modalities
relying on the overexpression of ERBB2 gene will be useful in treating prostate
cancer.
DOI: 10.1016/S0002-9440(10)64377-5
PMCID: PMC1867117
PMID: 11786427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22380004 | 1. Org Med Chem Lett. 2012 Mar 1;2(1):7. doi: 10.1186/2191-2858-2-7.
In silico identification of novel lead compounds with AT1 receptor antagonist
activity: successful application of chemical database screening protocol.
Pal M(1), Paliwal S.
Author information:
(1)Department of Pharmacy, Banasthali University, Banasthali, Tonk, Rajasthan,
India. [email protected].
BACKGROUND: AT1 receptor antagonists are clinically effective drugs for the
treatment of hypertension, cardiovascular, and related disorders. In an attempt
to identify new AT1 receptor antagonists, a pharmacophore-based virtual
screening protocol was applied. The pharmacophore models were generated from 30
training set compounds. The best model was chosen on the basis of squared
correlation coefficient of training set and internal test set. The validity of
the developed model was also ensured using catScramble validation method and
external test set prediction.
RESULTS: The final model highlighted the importance of hydrogen bond acceptor,
hydrophobic aliphatic, hydrophobic, and ring aromatic features. The model
satisfied all the statistical criteria such as cost function analysis and
correlation coefficient. The result of estimated activity for internal and
external test set compounds reveals that the generated model has high prediction
capability. The validated pharmacophore model was further used for mining of
56000 compound database (MiniMaybridge). Total 141 hits were obtained and all
the hits were checked for druggability, this led to the identification of two
active druggable AT1 receptor antagonists with diverse structure.
CONCLUSION: A highly validated pharmacophore model generated in this study
identified two novel druggable AT1 receptor antagonists. The developed model can
also be further used for mining of other virtual database.
DOI: 10.1186/2191-2858-2-7
PMCID: PMC3349973
PMID: 22380004 |
http://www.ncbi.nlm.nih.gov/pubmed/23982114 | 1. Pflugers Arch. 2014 Mar;466(3):517-27. doi: 10.1007/s00424-013-1335-8. Epub
2013 Aug 28.
The organic cation transporter 3 (OCT3) as molecular target of psychotropic
drugs: transport characteristics and acute regulation of cloned murine OCT3.
Massmann V(1), Edemir B, Schlatter E, Al-Monajjed R, Harrach S, Klassen P, Holle
SK, Sindic A, Dobrivojevic M, Pavenstädt H, Ciarimboli G.
Author information:
(1)Experimental Nephrology, Department of Internal Medicine D, University of
Münster, Albert-Schweitzer-Campus 1 (A14), 48149, Münster, Germany.
The organic cation transporter 3 (OCT3) is a widely expressed transporter for
endogenous and exogenous organic cations. Of particular interest is OCT3
expression and function in the brain, where it plays a role in serotonin
clearance and influences mood and behavior. Protein kinase signaling mediates
rapid modulation of cerebral processes, but little is known about acute
regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3)
and generated a human embryonic kidney cell line stably expressing the
transporter to study transport characteristics, acute regulation by protein
kinases, and interaction with psychotropic drugs. Uptake measurement was
performed using the fluorescent cation
4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+), 1 μM) as a
substrate. The translational value of these findings was determined by comparing
results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is
membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and
human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium,
tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by
the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory
concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine
are significantly different. Diazepam is a non-transported inhibitor.
Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56
(lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated
renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT
present, confirmed this regulation pathway. Only the activity of hOCT3 is
regulated by calmodulin. These findings suggest that even though many transport
properties of mOCT3 and hOCT3 are similar, there are also species-specific
aspects of OCT3 function.
DOI: 10.1007/s00424-013-1335-8
PMID: 23982114 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21473739 | 1. Free Radic Res. 2011 Jun;45(6):717-27. doi: 10.3109/10715762.2011.574287. Epub
2011 Apr 8.
Suppression of indomethacin-induced apoptosis in the small intestine due to
Bach1 deficiency.
Harusato A(1), Naito Y, Takagi T, Uchiyama K, Mizushima K, Hirai Y, Yamada S,
Tuji T, Yoriki H, Horie R, Inoue K, Fukumoto K, Handa O, Ishikawa T, Kokura S,
Minamiyama Y, Ichikawa H, Muto A, Igarashi K, Yoshikawa T.
Author information:
(1)Molecular Gastroenterology and Hepatology, Graduate School of Medical
Science, Kyoto Prefectural University of Medicine, Kawaramachi-hirokoji,
Kamigyo-ku, Kyoto 602-8566, Japan.
Erratum in
Free Radic Res. 2012 Nov;46(11):1420-1.
Free Radic Res. 2013 Dec;47(12):1088.
BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme
oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role
in the indomethacin-induced apoptosis in the case of small-intestinal mucosal
injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient
C57BL/6 mice were included in this study. Mucosal injuries induced by
subcutaneously administering indomethacin were evaluated macroscopically,
histologically and biochemically. Indomethacin-induced injuries were improved in
Bach1-deficient mice. Immunohistochemistry showed an increase in the number of
HO-1-positive cells, which were mainly F4/80 positive macrophages, in
Bach1-deficient mice. Indomethacin administration increased the expression of
HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal
deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining
showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In
conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed
mucosal injury, indicating that Bach1 is a novel therapeutic target for
indomethacin-induced intestinal injury.
DOI: 10.3109/10715762.2011.574287
PMID: 21473739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14559878 | 1. J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51. doi: 10.1093/jnci/djg072.
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi
anemia.
Offit K(1), Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider
H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H,
Auerbach AD.
Author information:
(1)Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York,
NY 10021, USA. [email protected]
Fanconi anemia is an inherited disease characterized by bone marrow failure,
congenital malformations, and predisposition to cancer. The breast cancer
susceptibility gene BRCA2 was recently found to be associated with Fanconi
anemia complementation group D1 (FA-D1). We examined four kindreds afflicted
with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred,
of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast
cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and
had Fanconi anemia and brain tumors. In another kindred of Ashkenazi Jewish and
Lithuanian Catholic ancestry, a child with Fanconi anemia and a medulloblastoma
was a BRCA2*6174delT/886delGT compound heterozygote. Two other kindreds each
contained a Fanconi anemia-afflicted child who developed medulloblastoma; one
child was of Latin American ancestry and a compound heterozygote for
BRCA2*I2490T/ 5301insA and the other was African American and a compound
heterozygote for BRCA2*Q3066X/E1308X. Median age of the Fanconi anemia-afflicted
children at brain tumor diagnosis was 3.5 years. The co-occurrence of brain
tumors, Fanconi anemia, and breast cancer observed in one of these kindreds
constitutes a new syndromic association. Individuals who carry a germline BRCA2
mutation and who plan to have children with a partner of Ashkenazi Jewish
descent should consider undergoing genetic counseling.
DOI: 10.1093/jnci/djg072
PMID: 14559878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15919668 | 1. J Biol Chem. 2005 Jul 29;280(30):27544-51. doi: 10.1074/jbc.M411626200. Epub
2005 May 26.
Inhibition of platelet-derived growth factor-induced cell growth signaling by a
short interfering RNA for EWS-Fli1 via down-regulation of phospholipase D2 in
Ewing sarcoma cells.
Nozawa S(1), Ohno T, Banno Y, Dohjima T, Wakahara K, Fan DG, Shimizu K.
Author information:
(1)Department of Orthopaedic Surgery, Gifu University School of Medicine, 1-1
Yanagido, Gifu 501-1194, Japan.
EWS-Fli1, a fusion gene resulting from a chromosomal translocation t(11;22,
q24;q12) and found in Ewing sarcoma and primitive neuroectodermal tumors,
encodes a transcriptional activator and promotes cellular transformation.
However, the precise biological functions of its products remain unknown. To
investigate the role of EWS-Fli1 in cell growth signaling, we transfected Ewing
sarcoma TC-135 cells with short interfering RNAs for EWS-Fli1. EWS-Fli1
knockdown reduced cell growth and platelet-derived growth factor
(PDGF)-BB-induced activation of the growth signaling enzymes. Interestingly,
phospholipase D2 (but not the PDGF-BB receptor) showed marked down-regulation in
the EWS-Fli1-knocked down TC-135 cells compared with the control cells. In Ewing
sarcoma TC-135 cells, the PDGF-BB-induced phosphorylation of growth signaling
involving extracellular signal-regulated kinase, Akt, p70S6K, and the expression
of cyclin D3 were markedly inhibited by transfection with short interfering RNA
phospholipase (PL)-D2. The PDGF-BB-induced activation of growth signaling was
also suppressed by 1-butanol, which prevents the production of phosphatidic acid
by phospholipase D (but not by t-butyl alcohol), thereby implicating PLD2 in
PDGF-BB-mediated signaling in TC-135 cells. These results suggest that EWS-Fli1
may play a role in the regulation of tumor proliferation-signaling enzymes via
PLD2 expression in Ewing sarcoma cells.
DOI: 10.1074/jbc.M411626200
PMID: 15919668 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19033200 | 1. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18976-81. doi:
10.1073/pnas.0800466105. Epub 2008 Nov 24.
Organic cation transporter 3: Keeping the brake on extracellular serotonin in
serotonin-transporter-deficient mice.
Baganz NL(1), Horton RE, Calderon AS, Owens WA, Munn JL, Watts LT,
Koldzic-Zivanovic N, Jeske NA, Koek W, Toney GM, Daws LC.
Author information:
(1)Department of Physiology, University of Texas Health Science Center, 7703
Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Mood disorders cause much suffering and are the single greatest cause of lost
productivity worldwide. Although multiple medications, along with behavioral
therapies, have proven effective for some individuals, millions of people lack
an effective therapeutic option. A common serotonin (5-HT) transporter
(5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression
in vivo and elevates risk for multiple mood disorders including anxiety,
alcoholism, and major depression. Importantly, this variant is also associated
with reduced responsiveness to selective 5-HT reuptake inhibitor
antidepressants. We hypothesized that a reduced antidepressant response in
individuals with a constitutive reduction in 5-HTT expression could arise
because of the compensatory expression of other genes that inactivate 5-HT in
the brain. A functionally upregulated alternate transporter for 5-HT may prevent
extracellular 5-HT from rising to levels sufficiently high enough to trigger the
adaptive neurochemical events necessary for therapeutic benefit. Here we
demonstrate that expression of the organic cation transporter type 3 (OCT3,
SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with
constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22
diminishes 5-HT clearance and exerts antidepressant-like effects in these mice
but not in WT animals. OCT3 may be an important transporter mediating
serotonergic signaling when 5-HTT expression or function is compromised.
DOI: 10.1073/pnas.0800466105
PMCID: PMC2596260
PMID: 19033200 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23139422 | 1. J Biol Chem. 2012 Dec 14;287(51):42835-45. doi: 10.1074/jbc.M112.407718. Epub
2012 Nov 8.
The plasma membrane sialidase NEU3 regulates the malignancy of renal carcinoma
cells by controlling β1 integrin internalization and recycling.
Tringali C(1), Lupo B, Silvestri I, Papini N, Anastasia L, Tettamanti G,
Venerando B.
Author information:
(1)Department of Medical Biotechnology, University of Milan, Segrate, 20090
Milan, Italy.
The human plasma membrane sialidase NEU3 is a key enzyme in the catabolism of
membrane gangliosides, is crucial in the regulation of cell surface processes,
and has been demonstrated to be significantly up-regulated in renal cell
carcinomas (RCCs). In this report, we show that NEU3 regulates β1 integrin
trafficking in RCC cells by controlling β1 integrin recycling to the plasma
membrane and controlling activation of the epidermal growth factor receptor
(EGFR) and focal adhesion kinase (FAK)/protein kinase B (AKT) signaling. NEU3
silencing in RCC cells increased the membrane ganglioside content, in particular
the GD1a content, and changed the expression of key regulators of the integrin
recycling pathway. In addition, NEU3 silencing up-regulated the Ras-related
protein RAB25, which directs internalized integrins to lysosomes, and
down-regulated the chloride intracellular channel protein 3 (CLIC3), which
induces the recycling of internalized integrins to the plasma membrane. In this
manner, NEU3 silencing enhanced the caveolar endocytosis of β1 integrin, blocked
its recycling and reduced its levels at the plasma membrane, and, consequently,
inhibited EGFR and FAK/AKT. These events had the following effects on the
behavior of RCC cells: they (a) decreased drug resistance mediated by the block
of autophagy and the induction of apoptosis; (b) decreased metastatic potential
mediated by down-regulation of the metalloproteinases MMP1 and MMP7; and (c)
decreased adhesion to collagen and fibronectin. Therefore, our data identify
NEU3 as a key regulator of the β1 integrin-recycling pathway and FAK/AKT
signaling and demonstrate its crucial role in RCC malignancy.
DOI: 10.1074/jbc.M112.407718
PMCID: PMC3522280
PMID: 23139422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10834782 | 1. Reg Anesth Pain Med. 2000 May-Jun;25(3):274-8. doi:
10.1016/s1098-7339(00)90010-5.
Ziconotide, a new N-type calcium channel blocker, administered intrathecally for
acute postoperative pain.
Atanassoff PG(1), Hartmannsgruber MW, Thrasher J, Wermeling D, Longton W, Gaeta
R, Singh T, Mayo M, McGuire D, Luther RR.
Author information:
(1)Department of Anesthesiology, Yale University School of Medicine, New Haven,
Connecticut 06520-8051, USA. [email protected]
BACKGROUND AND OBJECTIVES: Voltage-sensitive calcium channel conductance is
essential for the nervous system to signal a painful event. However, intrathecal
administration of L-type calcium channel blockers does not provide analgesia.
The present investigation was designed to assess the safety and analgesic
efficacy of ziconotide, a new N-type calcium channel blocker, when administered
intrathecally to patients with acute postoperative pain.
METHODS: This randomized, double-blind, pilot study included patients undergoing
elective total abdominal hysterectomy, radical prostatectomy, or total hip
replacement. After intrathecal injection of local anesthetic and before surgical
incision, a continuous intrathecal infusion of either placebo or 1 of 2 doses of
ziconotide (0.7 microg/h or 7.0 microg/h) was started and continued for 48 to 72
hours postoperatively. Primary and secondary efficacy variables were the mean
daily patient controlled analgesia (PCA) morphine equivalent consumption and
visual analog pain intensity (VASPI) scores, respectively.
RESULTS: Thirty patients received study drug; 26 were evaluable for efficacy.
Mean daily PCA morphine equivalent consumption was less in patients receiving
ziconotide than in placebo-treated patients, and the difference was
statistically significant between 24 and 48 hours (P = .040). VASPI scores
during the first 8 hours postoperatively were markedly lower in
ziconotide-treated than in placebo-treated patients. In 4 of 6 patients
receiving the high-dose of ziconotide (7 microg/h), adverse events, such as
dizziness, blurred vision, nystagmus, and sedation contributed to study drug
being discontinued after 24 hours. After ziconotide discontinuation, these
symptoms resolved.
CONCLUSIONS: Ziconotide showed analgesic activity, as shown by decreased PCA
morphine equivalent consumption and lower VASPI scores. Because of a favorable
trend of decreased morphine consumption with an acceptable side-effect profile
in the low-dose ziconotide group, 0.7 microg/h may be closer to the ideal dose
than 7 microg/h. Large-scale studies are required to clarify this issue.
DOI: 10.1016/s1098-7339(00)90010-5
PMID: 10834782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21953455 | 1. J Biol Chem. 2011 Dec 9;286(49):42337-42348. doi: 10.1074/jbc.M111.277335.
Epub 2011 Sep 26.
Evidence for ATP-dependent structural rearrangement of nuclease catalytic site
in DNA mismatch repair endonuclease MutL.
Yamamoto T(1), Iino H(1), Kim K(2), Kuramitsu S(3), Fukui K(4).
Author information:
(1)RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun,
Hyogo 679-5148, Japan.
(2)Department of Biological Sciences, Graduate School of Science, Osaka
University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.
(3)RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun,
Hyogo 679-5148, Japan; Department of Biological Sciences, Graduate School of
Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043,
Japan.
(4)RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun,
Hyogo 679-5148, Japan. Electronic address: [email protected].
DNA mismatch repair (MMR) greatly contributes to genome integrity via the
correction of mismatched bases that are mainly generated by replication errors.
Postreplicative MMR excises a relatively long tract of error-containing
single-stranded DNA. MutL is a widely conserved nicking endonuclease that
directs the excision reaction to the error-containing strand of the duplex by
specifically nicking the daughter strand. Because MutL apparently exhibits
nonspecific nicking endonuclease activity in vitro, the regulatory mechanism of
MutL has been argued. Recent studies suggest ATP-dependent conformational and
functional changes of MutL, indicating that the regulatory mechanism involves
the ATP binding and hydrolysis cycle. In this study, we investigated the effect
of ATP binding on the structure of MutL. First, a cross-linking experiment
confirmed that the N-terminal ATPase domain physically interacts with the
C-terminal endonuclease domain. Next, hydrogen/deuterium exchange mass
spectrometry clarified that the binding of ATP to the N-terminal domain induces
local structural changes at the catalytic sites of MutL C-terminal domain.
Finally, on the basis of the results of the hydrogen/deuterium exchange
experiment, we successfully identified novel regions essential for the
endonuclease activity of MutL. The results clearly show that ATP modulates the
nicking endonuclease activity of MutL via structural rearrangements of the
catalytic site. In addition, several Lynch syndrome-related mutations in human
MutL homolog are located in the position corresponding to the newly identified
catalytic region. Our data contribute toward understanding the relationship
between mutations in MutL homolog and human disease.
DOI: 10.1074/jbc.M111.277335
PMCID: PMC3234979
PMID: 21953455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21992243 | 1. Neuromodulation. 2011 May-Jun;14(3):219-24; discussion 224. doi:
10.1111/j.1525-1403.2011.00334.x. Epub 2011 Mar 1.
Psychiatric predisposition to autonomic and abnormal perception side-effects of
ziconotide: a case series study.
Poli P(1), Ciaramella A.
Author information:
(1)Pain Therapy Unit, Azienda Ospedaliero-Universitaria Pisana-Department of
Oncology, Pisa, Italy.
INTRODUCTION: Ziconotide is a reversible blocker of the N-type neuronal
voltage-sensitive calcium channels with analgesic effects. The main adverse
effects of ziconotide are ataxia, dizziness, gait disorder, confusion,
hallucinations, and gastrointestinal symptoms.
METHODS: Eighteen chronic pain patients with intrathecal ziconotide treatment
were investigated using the Mini International Neuropsychiatric Interview for
psychiatric disorders according to the DSM IV.
RESULTS: Ten patients showed good pain relief (ΔVAS ≥ 50%) after one year of
treatment. Patients without psychiatric comorbidity exhibited better outcomes,
without autonomic side-effects. Eight patients with panic disorder (always
comorbid with other psychiatric disorders) showed the greatest number of
side-effects during treatment with ziconotide.
DISCUSSION: Emotional and cognitive symptoms of panic disorder are associated
with autonomic symptoms resulting from parasympathetic activation. Dysfunction
of both cholinergic and N-type calcium channel activity was found.
CONCLUSION: A psychiatric disorder with cholinergic-noradrenergic system
impairment could increase some side-effects of treatment with N-type calcium
channel blockers.
© 2011 International Neuromodulation Society.
DOI: 10.1111/j.1525-1403.2011.00334.x
PMID: 21992243 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15702403 | 1. J Inherit Metab Dis. 2005;28(1):21-33. doi: 10.1007/s10545-005-4415-x.
Monitoring enzyme replacement therapy in Fabry disease--role of urine
globotriaosylceramide.
Whitfield PD(1), Calvin J, Hogg S, O'Driscoll E, Halsall D, Burling K, Maguire
G, Wright N, Cox TM, Meikle PJ, Deegan PB.
Author information:
(1)Biochemical Genetics Unit, Addenbrooke's NHS Trust, Cambridge, UK.
Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder
characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and
the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)),
the main substrate of the defective enzyme. Enzyme replacement therapy (ERT)
offers a specific treatment for patients with Fabry disease, though monitoring
of treatment is hampered by a lack of surrogate markers of response. In this
study, the efficacy of long-term ERT in six Fabry hemizygotes and two
symptomatic heterozygotes has been evaluated. Patients were administered
recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy
of ERT was assessed by monitoring symptomatology and renal function. Urinary
glycolipid concentration was estimated by a novel tandem mass spectrometric
method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively
on ERT where patients were hemizygotes and in the absence of renal
transplantation. In heterozygotes and in a recipient of a renal allograft,
elevations and changes in urine glycolipids were less pronounced. In one
patient, after several months of ERT, there was a transient increase in Gb(3)
concentrations to baseline (pre-ERT) levels, associated with the presence of
antibodies to the recombinant alpha-galactosidase A. The marked decline in urine
Gb(3) on ERT, and its subsequent increase in association with an inhibitory
antibody response, suggest that this analyte deserves further investigation as a
potential marker of disease severity and response to treatment.
DOI: 10.1007/s10545-005-4415-x
PMID: 15702403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24719112 | 1. J Neurosci. 2014 Apr 9;34(15):5342-54. doi: 10.1523/JNEUROSCI.2728-13.2014.
The serine/threonine kinase Ndr2 controls integrin trafficking and
integrin-dependent neurite growth.
Rehberg K(1), Kliche S, Madencioglu DA, Thiere M, Müller B, Meineke BM, Freund
C, Budinger E, Stork O.
Author information:
(1)Department of Genetics and Molecular Neurobiology, Institute of Biology, and
Institute for Molecular and Clinical Immunology, Medical Faculty,
Otto-von-Guericke University, 39120 Magdeburg, Germany, Department of
Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität
Berlin, 14195 Berlin, Germany, Protein Engineering Group, Leibniz-Institute for
Molecular Pharmacology, 13125 Berlin, Germany, Department of Auditory Learning
and Speech, Leibniz-Institute for Neurobiology, 39118 Magdeburg, Germany, and
Center for Behavioral Brain Sciences, 39106 Magdeburg, Germany.
Integrins have been implicated in various processes of nervous system
development, including proliferation, migration, and differentiation of neuronal
cells. In this study, we show that the serine/threonine kinase Ndr2 controls
integrin-dependent dendritic and axonal growth in mouse hippocampal neurons. We
further demonstrate that Ndr2 is able to induce phosphorylation at the activity-
and trafficking-relevant site Thr(788/789) of β1-integrin to stimulate the PKC-
and CaMKII-dependent activation of β1-integrins, as well as their exocytosis.
Accordingly, Ndr2 associates with integrin-positive early and recycling
endosomes in primary hippocampal neurons and the surface expression of activated
β1-integrins is reduced on dendrites of Ndr2-deficient neurons. The role of Ndr2
in dendritic differentiation is also evident in vivo, because Ndr2-null mutant
mice show arbor-specific alterations of dendritic complexity in the hippocampus.
This indicates a role of Ndr2 in the fine regulation of dendritic growth; in
fact, treatment of primary neurons with Semaphorin 3A rescues Ndr2
knock-down-induced dendritic growth deficits but fails to enhance growth beyond
control level. Correspondingly, Ndr2-null mutant mice show a Semaphorin
3A(-/-)-like phenotype of premature dendritic branching in the hippocampus. The
results of this study show that Ndr2-mediated integrin trafficking and
activation are crucial for neurite growth and guidance signals during neuronal
development.
DOI: 10.1523/JNEUROSCI.2728-13.2014
PMCID: PMC6609001
PMID: 24719112 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10547097 | 1. J Neurotrauma. 1999 Oct;16(10):879-92. doi: 10.1089/neu.1999.16.879.
Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on
calcium-45 accumulation following fluid-percussion injury.
Samii A(1), Badie H, Fu K, Luther RR, Hovda DA.
Author information:
(1)Brain Research Institute, UCLA School of Medicine, Los Angeles, California
90095-7039, USA.
Accumulation of calcium following experimental traumatic brain injury (TBI) has
been demonstrated to be a prominent pathophysiological component that can
compromise mitochondrial functioning and threaten cell survival. The
omega-conopeptide SNX-111, also known as Ziconotide, is a potent antagonist of
the voltage-gated N-type calcium channel and has demonstrated significant
neuroprotective effects against ischemia-induced neuronal injury. To determine
whether this compound would be effective in reducing calcium accumulation
associated with TBI, SNX-111 was administered intravenously to rats 1 hour
following a moderate (2.2 to 2.75 atm) lateral fluid-percussion injury (or sham)
at doses of 1 (n = 30), 3 (n = 31), or 5 (n = 30) mg/kg; another group received
0.9% saline solution (n = 35). Brains were processed for calcium 45 (45Ca)
autoradiography at 6, 12, 24, 48, and 96 hours following insult. Optical density
measurements of 20 cortical and subcortical regions were analyzed. Injured
animals administered saline solution exhibited a significant increase in 45Ca
uptake within 12 regions ipsilateral to the site of injury. The most prominent
increases were evident throughout the ipsilateral cerebral cortex. SNX-111
reduced the injury-induced calcium accumulation within the ipsilateral cortex in
a dose-response fashion when measured at 6, 12, and 48 hours after insult. These
drug-induced reductions in calcium accumulation were as high as 75% in the
ipsilateral cerebral cortex, and up to 50% in other ipsilateral regions
(including thalamus and hippocampus). Consequently, the results suggest that
posttraumatic blocking of the voltage-gated N-type calcium channel after injury
reduces prolonged, trauma-induced calcium accumulation.
DOI: 10.1089/neu.1999.16.879
PMID: 10547097 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20188724 | 1. Eur J Pharmacol. 2010 May 25;634(1-3):40-5. doi: 10.1016/j.ejphar.2010.02.025.
Epub 2010 Feb 25.
Spinal mechanism of standard analgesics: evaluation using mouse models of
allodynia.
Tsukamoto M(1), Kiso T, Shimoshige Y, Aoki T, Matsuoka N.
Author information:
(1)Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka,
Tsukuba, Ibaraki 305-8585, Japan. [email protected]
Spinal neurotransmission plays an important role in the perception of pain
signaling. In the present study, we investigated the spinal anti-nociceptive
mechanism of current standard analgesics in mouse models of tactile allodynia
induced by intrathecal administration of N-methyl-D-aspartic acid (NMDA),
prostaglandin E2 (PGE2), and bicuculline. NMDA-induced allodynia is induced by
postsynaptic NMDA receptor activation, while PGE2-induced allodynia is triggered
by the enhancement of presynaptic glutamate release via EP1 receptor activation.
In contrast, bicuculline induces allodynia by the blockade of gamma-aminobutyric
acid (GABA)A receptor-mediated inhibitory system. As the clinically available
analgesics, pregabalin (alpha2delta-subunit calcium channel ligand), ziconotide
(N-type calcium channel blocker), mexiletine (sodium channel blocker), and
duloxetine (serotonin and norepinephrine reuptake inhibitors) were evaluated in
these neurochemically-induced allodynia models. Pregabalin almost completely
alleviated NMDA-, PGE2-, and bicuculline-induced allodynia. Despite being
classified as an agent with a similar molecular target mechanism, ziconotide
could only alleviate PGE2-induced allodynia, but not NMDA- or
bicuculline-induced allodynia, as did mexiletine and duloxetine. These results
taken together suggest that ziconotide, mexiletine, and duloxetine suppress
spinal hyperactivity via the presynaptic site mechanism. In contrast, pregabalin
could suppress via the downstream step during spinal hyperactivation such as
postsynaptic NMDA activation or dysfunction of GABAergic control in addition to
presynaptic mechanism. In conclusion, present findings provide implication that
the spinal anti-nociceptive mechanistic site of pregabalin is different from
that of ziconotide, mexiletine, and duloxetine, and pregabalin could have a
broader anti-nociceptive mechanism other than N-type calcium channel blockade.
Copyright 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2010.02.025
PMID: 20188724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16564056 | 1. J Mol Biol. 2006 May 12;358(4):1041-50. doi: 10.1016/j.jmb.2006.02.047. Epub
2006 Mar 7.
Effects of Ser16 phosphorylation on the allosteric transitions of
phospholamban/Ca(2+)-ATPase complex.
Traaseth NJ(1), Thomas DD, Veglia G.
Author information:
(1)Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase
1 modulate the inhibitory activity of phospholamban (PLN), the endogenous
regulator of the sarco(endo)plasmic reticulum calcium Ca(2+) ATPase (SERCA).
This cyclic mechanism constitutes the driving force for calcium reuptake from
the cytoplasm into the myocite lumen, regulating cardiac contractility. PLN
undergoes a conformational transition between a relaxed (R) and tense (T) state,
an equilibrium perturbed by the addition of SERCA. Here, we show that the single
phosphoryl transfer at Ser16 induces a more pronounced conformational switch to
the R state in phosphorylated PLN (pPLN). The binding affinity of PLN to SERCA
is not affected (K(d) values for the transmembrane domains of pPLN and PLN are
approximately 60 microM), supporting the hypothesis that phosphorylation at
Ser16 does not dissociate PLN from SERCA. However, the binding surface and
dynamics in domain Ib (residues 22-31) change substantially upon
phosphorylation. Since PLN can be singly or doubly phosphorylated at Ser16 and
Thr17, we propose that these sites remotely control the conformation of domain
Ib. These findings constitute a paradigm for how post-translational
modifications such as phosphorylation in the cytoplasmic portion of membrane
proteins control intramembrane protein-protein interactions.
DOI: 10.1016/j.jmb.2006.02.047
PMID: 16564056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19830044 | 1. Cases J. 2009 Jul 22;2:8018. doi: 10.4076/1757-1626-2-8018.
Dental erosion caused by gastroesophageal reflux disease: a case report.
Cengiz S(1), Cengiz MI, Saraç YS.
Author information:
(1)Prosthetic Dentistry, Private Practice, Samsun, Turkey. [email protected]
INTRODUCTION: Chronic regurgitation of gastric acids in patients with
gastroesophageal reflux disease may cause dental erosion, which can lead in
combination with attrition or bruxism to extensive loss of coronal tooth tissue.
CASE PRESENTATION: This clinical report describes treatment of severe tooth wear
of a gastroesophageal reflux disease patient who is 54-year-old Turkish male
patient. After his medical treatment, severe tooth wear, bruxism and decreased
vertical dimensions were determined. The vertical dimension was re-established
and maxillary and mandibular anterior and posterior teeth were prepared for
metal-ceramic restorations. Metal-ceramic fixed partial dentures were fabricated
as full mouth restorations for both maxillary and mandibular arches because of
splinting all teeth. And then maxillary stabilization splint was fabricated for
his bruxism history.
CONCLUSION: Significant loss of coronal tooth structure must taken into
consideration. Gastroesophageal reflux disease by itself or in combination with
attrition, abrasion or bruxism may be responsible for the loss. An extensive
diagnostic evaluation is essential for the medical and dental effects of the
problem.
DOI: 10.4076/1757-1626-2-8018
PMCID: PMC2740145
PMID: 19830044 |
http://www.ncbi.nlm.nih.gov/pubmed/22033509 | 1. Dialogues Clin Neurosci. 2011;13(3):352-9. doi:
10.31887/DCNS.2011.13.2/dstein.
Is progesterone a worthy candidate as a novel therapy for traumatic brain
injury?
Stein DG(1).
Author information:
(1)Department of Emergency Medicine, Emory University, Atlanta, Georgia 30822,
USA. [email protected]
Although progesterone is critical to a healthy pregnancy, it is now known to
have other important functions as well. Recent research demonstrates that this
hormone is also a potent neurosteroid that can protect damaged cells in the
central and peripheral nervous systems and has rapid actions that go well beyond
its effects on the classical intranuclear progesterone receptor. Based on years
of preclinical research demonstrating its safety and effectiveness in animal
models of central nervous system injury the hormone was recently tested in two
Phase II clinical trials for traumatic brain injury (TBI). A US National
Institutes of Health-sponsored, nationwide Phase III clinical trial is now
evaluating progesterone for moderate-to-severe TBI in 1200 patients. An
industry-sponsored Phase III international trial is also under way, and planning
for a trial using progesterone to treat pediatric brain injury has begun.
Preclinical data suggest that progesterone may also be effective in stroke and
some neurodegenerative disorders.
Aunque se sabe que la progesterona es clave para un embarazo sano, ahora se le
reconocen otras importantes funciones. La investigación reciente demuesira que
esta hormona también es un potente neuroesteroide que puede protéger las células
dañadas en el sistema nervioso tanto central como periférico y tiene rápidas
acciones que van mucho más allá de sus efectos en el clásico receptor de
progesterona intranuclear. En base a años de investigación preclínica que ha
demostrado la seguridad y eficacia de la hormona en modelos animales de daño del
sistema nervioso central, ésta se probó recientemente en dos ensayos clínicos de
Fase II para daño cerebral traumático (DCT). En un estudio financiado por los
Institutes Nacionales de Salud de los EE.UU., actual mente se está evaluando la
progesterona para el DCT moderado a grave en 1200 pacientes en un ensayo clínico
de Fase III a nivel nacional. También está en desarrollo un ensayo internacional
de Fase III financiado por la industria y ha comenzado la planificación de un
ensayo que emplea progesterona para tratar daño cerebral pediátrico. Los datos
preclinicos sugieren que la progesterona también puede ser efectiva en los
accidentes vasculares y en algunos trastornos neurodegenerativos.
La progestérone est indispensable à la grossesse normale mais nous savons
maintenant qu'elle a aussi d'autres fonctions importantes. De récentes
recherches démontrent que cette hormone est aussi un puissant neurostéroïde
susceptible de protéger les cellules des systèmes nerveux périphérique et
central altérées, et qu'elle est capable d'action rapide allant bien au-delà de
ses effets sur le classique récepteur intranucléaire à la progestérone. Des
années de recherche préclinique ont démontré sa sécurité d'emploi et son
efficacité dans des modèles animaux de lésion du système nerveux central.
L'hormone a été récemment évaluée dans deux études cliniques de phase 2 pour les
lésions cérébrales traumatiques (LCT). Une étude clinique nationale de phase 3,
financée par les National Institutes of Health aux États-Unis, évalue maintenant
la progestérone dans les LCT modérées à sévères chez 1 200 patients. Une étude
internationale de phase 3 financée par l'industrie est également en cours ainsi
que la planification d'une étude utilisant la progestérone pour traiter les
lésions cérébrales chez l'enfant. Des données précliniques suggèrent que la
progestérone pourrait être aussi efficace dans les accidents vasculaires
cérébraux et certains troubles neurodégénératifs.
DOI: 10.31887/DCNS.2011.13.2/dstein
PMCID: PMC3182014
PMID: 22033509 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24036548 | 1. Cell Cycle. 2013 Oct 15;12(20):3317-28. doi: 10.4161/cc.26298. Epub 2013 Sep
9.
Autophagy modulates cell migration and β1 integrin membrane recycling.
Tuloup-Minguez V(1), Hamaï A, Greffard A, Nicolas V, Codogno P, Botti J.
Author information:
(1)INSERM UMR 984; University of Paris-Sud 11; Châtenay-Malabry, France.
Cell migration is dependent on a series of integrated cellular events including
the membrane recycling of the extracellular matrix receptor integrins. In this
paper, we investigate the role of autophagy in regulating cell migration. In a
wound-healing assay, we observed that autophagy was reduced in cells at the
leading edge than in cells located rearward. These differences in autophagy were
correlated with the robustness of MTOR activity. The spatial difference in the
accumulation of autophagic structures was not detected in rapamycin-treated
cells, which had less migration capacity than untreated cells. In contrast, the
knockdown of the autophagic protein ATG7 stimulated cell migration of HeLa
cells. Accordingly, atg3(-/-) and atg5(-/-) MEFs have greater cell migration
properties than their wild-type counterparts. Stimulation of autophagy increased
the co-localization of β1 integrin-containing vesicles with LC3-stained
autophagic vacuoles. Moreover, inhibition of autophagy slowed down the lysosomal
degradation of internalized β1 integrins and promoted its membrane recycling.
From these findings, we conclude that autophagy regulates cell migration, a
central mechanism in cell development, angiogenesis, and tumor progression, by
mitigating the cell surface expression of β1 integrins.
DOI: 10.4161/cc.26298
PMCID: PMC3885642
PMID: 24036548 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22195746 | 1. Immunity. 2011 Dec 23;35(6):908-18. doi: 10.1016/j.immuni.2011.09.020.
RIP kinase-dependent necrosis drives lethal systemic inflammatory response
syndrome.
Duprez L(1), Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V,
Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P.
Author information:
(1)Department for Molecular Biomedical Research, the Flanders Institute for
Biotechnology (VIB), 9052 Ghent, Belgium.
Comment in
Immunity. 2011 Dec 23;35(6):849-51. doi: 10.1016/j.immuni.2011.12.004.
Engagement of tumor necrosis factor receptor 1 signals two diametrically opposed
pathways: survival-inflammation and cell death. An additional switch decides,
depending on the cellular context, between caspase-dependent apoptosis and RIP
kinase (RIPK)-mediated necrosis, also termed necroptosis. We explored the
contribution of both cell death pathways in TNF-induced systemic inflammatory
response syndrome (SIRS). Deletion of apoptotic executioner caspases (caspase-3
or -7) or inflammatory caspase-1 had no impact on lethal SIRS. However, deletion
of RIPK3 conferred complete protection against lethal SIRS and reduced the
amounts of circulating damage-associated molecular patterns. Pretreatment with
the RIPK1 kinase inhibitor, necrostatin-1, provided a similar effect. These
results suggest that RIPK1-RIPK3-mediated cellular damage by necrosis drives
mortality during TNF-induced SIRS. RIPK3 deficiency also protected against cecal
ligation and puncture, underscoring the clinical relevance of RIPK kinase
inhibition in sepsis and identifying components of the necroptotic pathway that
are potential therapeutic targets for treatment of SIRS and sepsis.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2011.09.020
PMID: 22195746 [Indexed for MEDLINE] |