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http://www.ncbi.nlm.nih.gov/pubmed/23153939 | 1. Urology. 2013 Jan;81(1):209.e1-7. doi: 10.1016/j.urology.2012.08.044. Epub
2012 Nov 13.
Inducing cell proliferation inhibition, apoptosis, and motility reduction by
silencing long noncoding ribonucleic acid metastasis-associated lung
adenocarcinoma transcript 1 in urothelial carcinoma of the bladder.
Han Y(1), Liu Y, Nie L, Gui Y, Cai Z.
Author information:
(1)Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking
University Shenzhen Hospital, Shenzhen, China.
OBJECTIVE: To study the expression patterns of long noncoding ribonucleic acid
(RNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the
cell proliferation inhibition, apoptosis, and motility changes induced by
silencing MALAT1 in urothelial carcinoma of the bladder.
MATERIALS AND METHODS: The expression levels of MALAT1 were determined using
real-time quantitative polymerase chain reaction in cancerous tissues and paired
normal tissues in a total of 36 patients with urothelial carcinoma of the
bladder. Expression differences were analyzed according to the grade and stage.
Bladder urothelial carcinoma T24 and 5637 cells were transfected with MALAT1
small interfering RNA or negative control small interfering RNA. The cell
proliferation changes of the transfected bladder urothelial carcinoma cells were
determined using the MTT assay. Apoptosis caused by silencing MALAT1 was
evaluated using the flow cytometry assay and enzyme-linked immunosorbent assay.
The motility changes induced by silencing MALAT1 were measured using the wound
healing assay.
RESULTS: MALAT1 was upregulated in bladder urothelial carcinoma compared with
matched normal urothelium (P=.008). The MALAT1 expression levels were greater in
high-grade carcinomas than in low-grade carcinoma (P=.001). The MALAT1
expression levels were greater in invasive carcinoma than in noninvasive
carcinoma (P=.018). Cell proliferation inhibition, increased apoptosis, and
decreased motility were observed in MALAT1 small interfering RNA-transfected
bladder urothelial carcinoma T24 and 5637 cells.
CONCLUSION: MALAT1 plays an oncogenic role in urothelial carcinoma of the
bladder. Silencing MALAT1 is a potential novel therapeutic approach for this
cancer.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.urology.2012.08.044
PMID: 23153939 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21239804 | 1. Hematology Am Soc Hematol Educ Program. 2010;2010:265-70. doi:
10.1182/asheducation-2010.1.265.
Signal transduction inhibitor therapy for lymphoma.
Witzig TE(1), Gupta M.
Author information:
(1)Division of Hematology, Department of Internal Medicine, Mayo Clinic College
of Medicine and Mayo Foundation, Rochester, MN 55905, USA. [email protected]
Current research in lymphoma is focused on two areas of lymphoma biology-the
signal transduction pathways used to maintain the growth of malignant
lymphocytes and the role of the tumor microenvironment in lymphoma growth and
survival. This review focuses on three signaling pathways: the
phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway,
the B-cell receptor/spleen tyrosine kinase (BCR/Syk) pathway, and the protein
kinase C-beta (PKC-β) pathway, known to be important to lymphoma cells. The mTOR
inhibitors temsirolimus and everolimus have demonstrated antitumor activity in
all types of lymphoma, the Syk inhibitor fostamatinib has activity in diffuse
large B-cell lymphoma and chronic lymphocytic leukemia, and the PKC-β inhibitor
enzastaurin is being used as consolidation therapy after remission in diffuse
large B-cell lymphoma. This review discusses the biology behind the development
of each new agent and the results of initial clinical trials. The goal is to
provide the hematologist/oncologist background information on these new agents
and understand their current and potential role in the management of patients.
DOI: 10.1182/asheducation-2010.1.265
PMCID: PMC3626402
PMID: 21239804 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures Conflict-of-interest disclosure: TEW
has been an uncompensated advisory committee member for Novartis and Celgene
(with compensation to the Mayo Clinic) and has from both entities received
research funding and patent royalties. Off-label drug use: Temsirolimus and
everolimus are both FDA approved for renal cell cancer in the United States but
are not approved currently for mantle cell lymphoma. Revlimid is approved for
myeloma but not lymphoma. |
http://www.ncbi.nlm.nih.gov/pubmed/23267367 | 1. Front Genet. 2012 Dec 21;3:299. doi: 10.3389/fgene.2012.00299. eCollection
2012.
Identifying putative breast cancer-associated long intergenic non-coding RNA
loci by high density SNP array analysis.
Jiang Z(1), Zhou Y, Devarajan K, Slater CM, Daly MB, Chen X.
Author information:
(1)Cancer Biology Program, Fox Chase Cancer Center Philadelphia, PA, USA.
Recent high-throughput transcript discoveries have yielded a growing recognition
of long intergenic non-coding RNAs (lincRNAs), a class of arbitrarily defined
transcripts (>200 nt) that are primarily produced from the intergenic space.
lincRNAs have been increasingly acknowledged for their expressional dynamics and
likely functional associations with cancers. However, differential gene dosage
of lincRNA genes between cancer genomes is less studied. By using the
high-density Human Omni5-Quad BeadChips (Illumina), we investigated genomic copy
number aberrations in a set of seven tumor-normal paired primary human mammary
epithelial cells (HMECs) established from patients with invasive ductal
carcinoma. This Beadchip platform includes a total of 2,435,915 SNP loci
dispersed at an average interval of ~700 nt throughout the intergenic region of
the human genome. We mapped annotated or putative lincRNA genes to a subset of
332,539 SNP loci, which were included in our analysis for lincRNA-associated
copy number variations (CNV). We have identified 122 lincRNAs, which were
affected by somatic CNV with overlapped aberrations ranging from 0.14% to 100%
in length. lincRNA-associated aberrations were detected predominantly with copy
number losses and preferential clustering to the ends of chromosomes.
Interestingly, lincRNA genes appear to be less susceptible to CNV in comparison
to both protein-coding and intergenic regions (CNV affected segments in
percentage: 1.8%, 37.5%, and 60.6%, respectively). In summary, our study
established a novel approach utilizing high-resolution SNP array to identify
lincRNA candidates, which could functionally link to tumorigenesis, and provide
new strategies for the diagnosis and treatment of breast cancer.
DOI: 10.3389/fgene.2012.00299
PMCID: PMC3528021
PMID: 23267367 |
http://www.ncbi.nlm.nih.gov/pubmed/23078058 | 1. Expert Rev Clin Immunol. 2012 Sep;8(7):609-15. doi: 10.1586/eci.12.63.
The status of fostamatinib in the treatment of rheumatoid arthritis.
Morales-Torres J(1).
Author information:
(1)Department of Rheumatology, Hospital Aranda de la Parra, Hidalgo 329-704,
León 37000, GTO, Mexico. [email protected]
Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on
oral administration. This (known as R406) is a potent inhibitor of spleen
tyrosine kinase, required for the expression of a number of proinflammatory
cytokines. Fostamatinib has shown significantly superior efficacy (when compared
with placebo) in the control of patients with rheumatoid arthritis not
responding to methotrexate in Phase II clinical trials. Treatment emergent
adverse events with a higher frequency than in those on placebo included
diarrhea, hypertension, urinary tract infections, neutropenia and elevated
transaminases. The studied doses have shown a linear pharmacokinetic pattern and
the administration of methotrexate does not affect it. Fostamatinib may have a
role in the therapy of patients with rheumatoid arthritis with poor response to
conventional therapy. If these results are confirmed once Phase III studies are
completed, it may find a place in the evolving treatment algorithm for
rheumatoid arthritis.
DOI: 10.1586/eci.12.63
PMID: 23078058 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23011794 | 1. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16708-13. doi:
10.1073/pnas.1205414109. Epub 2012 Sep 24.
Small-molecule histone methyltransferase inhibitors display rapid antimalarial
activity against all blood stage forms in Plasmodium falciparum.
Malmquist NA(1), Moss TA, Mecheri S, Scherf A, Fuchter MJ.
Author information:
(1)Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris,
France.
Epigenetic factors such as histone methylation control the developmental
progression of malaria parasites during the complex life cycle in the human
host. We investigated Plasmodium falciparum histone lysine methyltransferases as
a potential target class for the development of novel antimalarials. We
synthesized a compound library based upon a known specific inhibitor (BIX-01294)
of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its
derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC(50)
values of ~100 nM, values at least 22-fold more potent than their apparent
IC(50) toward two human cell lines and one mouse cell line. These compounds
irreversibly arrested parasite growth at all stages of the intraerythrocytic
life cycle. Decrease in parasite viability (>40%) was seen after a 3-h
incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a
12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain
infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced
parasitemia the following day. Importantly, treatment of P. falciparum parasites
in culture with BIX-01294 or TM2-115 resulted in significant reductions in
histone H3K4me3 levels in a concentration-dependent and exposure time-dependent
manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit
malaria parasite histone methyltransferases, resulting in rapid and irreversible
parasite death. Our data position histone lysine methyltransferases as a
previously unrecognized target class, and BIX-01294 as a promising lead
compound, in a presently unexploited avenue for antimalarial drug discovery
targeting multiple life-cycle stages.
DOI: 10.1073/pnas.1205414109
PMCID: PMC3478629
PMID: 23011794 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/26448890 | 1. Case Rep Oncol Med. 2015;2015:737389. doi: 10.1155/2015/737389. Epub 2015 Sep
10.
PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV.
Davar D(1), Wilson M(1), Pruckner C(1), Kirkwood JM(1).
Author information:
(1)Division of Hematology-Oncology, Department of Medicine, University of
Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
On the basis of remarkable antitumor activity, programmed death receptor-1
(PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of
advanced melanoma in the second-line setting following progression on either
CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma).
Given hypothesized risk of triggering exacerbations of autoimmune diseases
and/or chronic viral infections, clinical trials (including regulatory studies)
evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients
with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human
immunodeficiency virus (HIV) infections. Herein, we describe two patients with
advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor
pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of
pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with
initial partial response. HCV viral load remained stable after 9 cycles of
pembrolizumab following which 12-week course of HCV-directed therapy was
commenced, resulting in prompt reduction of HCV viral load below detectable
levels. Response is ongoing and HCV viral load remains undetectable. In both
patients, no significant toxicities were observed when pembrolizumab was
initiated. We argue for the further investigation of checkpoint inhibition in
cancer patients with underlying chronic viral infections in the context of
carefully designed clinical trials.
DOI: 10.1155/2015/737389
PMCID: PMC4581502
PMID: 26448890 |
http://www.ncbi.nlm.nih.gov/pubmed/9305655 | 1. Hum Mol Genet. 1997 Sep;6(9):1505-11. doi: 10.1093/hmg/6.9.1505.
Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC
International Consortium on Myotubular Myopathy. European Neuro-Muscular Center.
Laporte J(1), Guiraud-Chaumeil C, Vincent MC, Mandel JL, Tanner SM,
Liechti-Gallati S, Wallgren-Pettersson C, Dahl N, Kress W, Bolhuis PA, Fardeau
M, Samson F, Bertini E.
Author information:
(1)IGBMC, CNRS/INSERM/ULP, Illkirch, France.
X-linked recessive myotubular myopathy (XLMTM) is characterized by severe
hypotonia and generalized muscle weakness, with impaired maturation of muscle
fibres. The gene responsible, MTM1, was identified recently by positional
cloning, and encodes a protein (myotubularin) with a tyrosine phosphatase domain
(PTP). Myotubularin is highly conserved through evolution and defines a new
family of putative tyrosine phosphatases in man. We report the identification of
MTM1 mutations in 55 of 85 independent patients screened by single-strand
conformation polymorphism for all the coding sequence. Large deletions were
observed in only three patients. Five point mutations were found in multiple
unrelated patients, accounting for 27% of the observed mutations. The
possibility of detecting mutations and determining carrier status in a disease
with a high proportion of sporadic cases is of importance for genetic
counselling. More than half of XLMTM mutations are expected to inactivate the
putative enzymatic activity of myotubularin, either by truncation or by missense
mutations affecting the predicted PTP domain. Additional mutations are missenses
clustered in two regions of the protein. Most of these affect amino acids
conserved in the homologous yeast and Caenorhabditis elegans proteins, thus
indicating the presence of other functional domains.
DOI: 10.1093/hmg/6.9.1505
PMID: 9305655 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26029270 | 1. Ther Adv Musculoskelet Dis. 2015 Jun;7(3):88-102. doi:
10.1177/1759720X15579189.
Effects of denosumab on bone density, mass and strength in women with
postmenopausal osteoporosis.
Törring O(1).
Author information:
(1)Institution for Clinical Science and Education, Södersjukhuset, Karolinska
Institutet, Sjukhusbacken 10, Stockholm 11883, Sweden.
Denosumab is a human monoclonal antibody which specifically blocks receptor
activator of nuclear factor κB ligand and is a very potent antiresorptive drug.
Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has
been proven in a large prospective, randomized multicenter study of 7808
postmenopausal women with osteoporosis [Fracture Reduction Evaluation of
Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes
somewhat greater increases in bone mineral density (BMD) than the class of
bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass
and bone strength in the spine, ultradistal and diaphysis of the radius,
proximal tibia and the hip. Recently long-term treatment with denosumab has been
shown to cause a continued almost linear increase in total hip and femoral neck
BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ
from the bisphosphonate group in which the rate of improvement of BMD diminishes
and for some drugs becomes negative after 3-4 years when the process of
secondary mineralization flattens out. This unique property of an antiresorptive
drug points towards mechanisms of action which differ from the bisphosphonate
group. Both types of antiresorptives decrease cortical porosity but contrary to
bisphosphonates the reduction in cortical porosity continues with denosumab
which, in addition, also seems to cause a slight continuous modeling-based
formation of new bone despite suppression of bone remodeling. The net effect is
an increase in cortical thickening and bone mass, and increased strength of
cortical bone. This may contribute substantially to the significant further
reduction of the nonvertebral fracture risk which was found in the long-term
denosumab arm of the FREEDOM extension trial during years 4-7.
DOI: 10.1177/1759720X15579189
PMCID: PMC4426099
PMID: 26029270
Conflict of interest statement: Conflict of interest statement: OT has been
lecturer and consultant for the Swedish National Board of Health and Welfare and
The Swedish Medical Products Agency. OT has received fees from Amgen, GSK,
Lilly, Nycomed, MEDA and Takeda as lecturer, consultant and/or scientific
advisor. |
http://www.ncbi.nlm.nih.gov/pubmed/12390644 | 1. Headache. 2002 Sep;42(8):796-803. doi: 10.1046/j.1526-4610.2002.02183.x.
Prophylaxis of migraine, transformed migraine, and cluster headache with
topiramate.
Mathew NT(1), Kailasam J, Meadors L.
Author information:
(1)Houston Headache Clinic, Houston, Texas 77004, USA.
OBJECTIVE: To assess the efficacy and tolerability of topiramate for prophylaxis
of migraine and cluster headache via a retrospective chart analysis.
BACKGROUND: Topiramate has multiple mechanisms of action that could potentially
contribute to migraine prophylaxis. We conducted a retrospective chart review to
assess the efficacy of topiramate as add-on therapy in patients with transformed
migraine or cluster headache, and as first-line therapy in patients with
episodic migraine.
METHODS: Patients diagnosed with transformed migraine, episodic migraine, or
cluster headache, who received topiramate either as add-on therapy or
monotherapy were selected via retrospective chart review. Patients had begun
topiramate therapy at 25 mg/day for the first week and increased their dosage by
25 mg/week to a maximum of 200 mg/day. Topiramate was used as add-on therapy for
patients with transformed migraine and cluster headache, and as a first-line
monotherapy in patients with episodic migraine who had no previous prophylactic
therapy. The outcome parameters examined included a mean 28-day migraine
frequency, migraine severity, number of headache days/month, number of abortive
medication tablets/month, patient global evaluation, and the MIDAS scale.
RESULTS: One hundred seventy-eight patients (transformed migraine: n = 96;
episodic migraine: n = 70; and cluster headache: n = 12) were included in the
retrospective analysis. The mean dose of topiramate for all patients was 87.5
mg/day. For patients with transformed migraine, mean migraine frequency
decreased from 6.3/28 days to 3.7 (P = 0.005). Mean severity decreased from 7.1
to 3.8 on a 10-point scale, with 10 representing the most severe pain (P =
0.003). The mean number of headache days/month decreased from 22.1 to 9.6 (P =
0.001), and the mean number of abortive medication tablets decreased from
28.7/month to 10.6 (P = 0.001). Patient global evaluation indicated substantial
or moderate improvement in 53% of patients with transformed migraine who used
topiramate as add-on therapy. Mean MIDAS scale values decreased from 90.2 to
24.9 (P< 0.0001). The 70 episodic migraine patients who were administered
topiramate as first-line therapy exhibited a decrease in mean migraine frequency
(5.8/28 days to 1.9, P = 0.001), while mean migraine severity decreased from 8.1
to 2.0 (P = 0.003). Sixty-one percent of patients reported marked improvement.
Nine of the 12 cluster headache patients exhibited substantial or moderate
improvement in symptoms, whereas three had no improvement. The most common
adverse effects were paresthesias (12%), cognitive effects (11%), and dizziness
(6%). Eight patients discontinued topiramate due to adverse effects; cognitive
effects were the most common reason. No patient discontinued topiramate
treatment due to lack of efficacy. Twelve percent of patients lost more than 5
lbs during treatment (a range of 5-120 lbs).
CONCLUSION: For both patients with transformed migraine (add-on therapy) and
patients with episodic migraine (first-line monotherapy), topiramate yielded
significant reductions in migraine frequency, migraine severity, number of
headache days/month, and use of abortive medications. Topiramate also appears to
be well tolerated and useful in the adjunctive treatment of cluster headache.
Prospective double-blind, placebo-controlled trials will be required to confirm
our results.
DOI: 10.1046/j.1526-4610.2002.02183.x
PMID: 12390644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20459811 | 1. Arthritis Res Ther. 2010;12(3):R81. doi: 10.1186/ar3006. Epub 2010 May 11.
Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells
from patients with rheumatoid arthritis.
Li J(1), Wan Y, Guo Q, Zou L, Zhang J, Fang Y, Zhang J, Zhang J, Fu X, Liu H, Lu
L, Wu Y.
Author information:
(1)Institute of Immunology, PLA, Third Military Medical University, 30#
Gaotanyan Street, District Shipingba, Chongqing 400038, PR China.
Comment in
Nat Rev Rheumatol. 2010 Aug;6(8):436. doi: 10.1038/nrrheum.2010.112.
INTRODUCTION: Increasing evidence indicates that microRNAs (miRNAs) play a
critical role in the pathogenesis of inflammatory diseases. The aim of the study
was to investigate the expression pattern and function of miRNAs in CD4+ T cells
from patients with rheumatoid arthritis (RA).
METHODS: The expression profile of miRNAs in CD4+ T cells from synovial fluid
(SF) and peripheral blood of 33 RA patients was determined by microarray assay
and validated by qRT-PCR analysis. The correlation between altered expression of
miRNAs and cytokine levels was determined by linear regression analysis. The
role of miR-146a overexpression in regulating T cell apoptosis was evaluated by
flow cytometry. A genome-wide gene expression analysis was further performed to
identify miR-146a-regulated genes in T cells.
RESULTS: miRNA expression profile analysis revealed that miR-146a expression was
significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T
cells of RA patients. The level of miR-146a expression was positively correlated
with levels of tumor necrosis factor-alpha (TNF-alpha), and in vitro studies
showed TNF-alpha upregulated miR-146a expression in T cells. Moreover, miR-146a
overexpression was found to suppress Jurkat T cell apoptosis. Finally,
transcriptome analysis of miR-146a overexpression in T cells identified Fas
associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically
involved in modulating T cell apoptosis.
CONCLUSIONS: We have detected increased miR-146a in CD4+ T cells of RA patients
and its close correlation with TNF-alpha levels. Our findings that miR-146a
overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA
pathogenesis and provide potential novel therapeutic targets.
DOI: 10.1186/ar3006
PMCID: PMC2911863
PMID: 20459811 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23937680 | 1. Pediatr Int. 2014 Feb;56(1):24-30. doi: 10.1111/ped.12201.
Association of problem behavior with sleep problems and gastroesophageal reflux
symptoms.
Sakaguchi K(1), Yagi T, Maeda A, Nagayama K, Uehara S, Saito-Sakoguchi Y,
Kanematsu K, Miyawaki S.
Author information:
(1)Department of Orthodontics, Field of Developmental Medicine, Health Research
Course, Graduate School of Medical and Dental Sciences, Kagoshima University,
Kagoshima, Japan.
BACKGROUND: There are few large-scale epidemiologic studies examining the
associations between sleep problems, gastroesophageal reflux disease (GERD)
symptoms, lifestyle and food habits and problem behaviors (PB) in adolescents.
The aim of this study was to evaluate the associations among these factors in
Japanese adolescents.
METHODS: A cross-sectional survey of 1840 junior high school students was
carried out using questionnaires. The subjects were classified into PB or normal
behavior (NB) groups using the Pediatric Symptom Checklist (PSC). The scores of
the sleep-related factors, sleep bruxism, lifestyle and food habits, and GERD
symptoms were compared. Logistic regression analysis was used to determine the
factors related to PB.
RESULTS: Mean subject age was 13.3 ± 1.8 years. The PB group had significantly
longer sleep latency and higher GERD symptom score (P < 0.001). Furthermore, the
PB group was significantly more likely to experience absence of the mother at
dinner time, skip breakfast, and have <30 min of conversation among family at
dinner time. The PB group had significantly higher frequencies of sleep bruxism,
difficulty falling asleep within 30 min, nightmares, feeling of low sleep
quality, daytime somnolence, and daytime lack of motivation. Feelings of low
sleep quality had the strongest association with PB, with an adjusted odds ratio
of 12.88 (95% confidence interval: 8.99-18.46).
CONCLUSIONS: PB in adolescents are associated with sleep problems, including
sleep bruxism, as well as lifestyle and food habits and GERD symptoms.
© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.
DOI: 10.1111/ped.12201
PMID: 23937680 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17483413 | 1. Genetics. 2007 Jul;176(3):1417-29. doi: 10.1534/genetics.107.072876. Epub 2007
May 4.
Genetic dissection of parallel sister-chromatid cohesion pathways.
Xu H(1), Boone C, Brown GW.
Author information:
(1)Banting and Best Department of Medical Research, University of Toronto,
Toronto, Ontario M5S 1A8, Canada.
Sister-chromatid cohesion, the process of pairing replicated chromosomes during
mitosis and meiosis, is mediated through the essential cohesin complex and a
number of nonessential cohesion genes, but the specific roles of these
nonessential genes in sister-chromatid cohesion remain to be clarified. We
analyzed sister-chromatid cohesion in double mutants of mrc1Delta, tof1Delta,
and csm3Delta and identified additive cohesion defects that indicated the
existence of at least two pathways that contribute to sister-chromatid cohesion.
To understand the relationship of other nonessential cohesion genes with respect
to these two pathways, pairwise combinations of deletion and
temperature-sensitive alleles were tested for cohesion defects. These data
defined two cohesion pathways, one containing CSM3, TOF1, CTF4, and CHL1, and
the second containing MRC1, CTF18, CTF8, and DCC1. Furthermore, we found that
the nonessential genes are not important for the maintenance of cohesion at
G(2)/M. Thus, our data suggest that nonessential cohesion genes make critical
redundant contributions to the establishment of sister-chromatid cohesion and
define two cohesion pathways, thereby establishing a framework for understanding
the role of nonessential genes in sister-chromatid cohesion.
DOI: 10.1534/genetics.107.072876
PMCID: PMC1931553
PMID: 17483413 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20713356 | 1. J Biol Chem. 2010 Oct 22;285(43):33037-33044. doi: 10.1074/jbc.M110.155283.
Epub 2010 Aug 16.
Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase.
Bélanger F(1), Stepinski J(2), Darzynkiewicz E(2), Pelletier J(3).
Author information:
(1)From the Departments of Biochemistry and Oncology and The Rosalind and Morris
Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6,
Canada.
(2)Division of Biophysics, Institute of Experimental Physics, Faculty of
Physics, University of Warsaw, 02-089 Warsaw, Poland.
(3)From the Departments of Biochemistry and Oncology and The Rosalind and Morris
Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6,
Canada. Electronic address: [email protected].
Cellular eukaryotic mRNAs are capped at their 5' ends with a 7-methylguanosine
nucleotide, a structural feature that has been shown to be important for
conferring mRNA stability, stimulating mRNA biogenesis (splicing, poly(A)
addition, nucleocytoplasmic transport), and increasing translational efficiency.
Whereas yeast mRNAs have no additional modifications to the cap, called cap0,
higher eukaryotes are methylated at the 2'-O-ribose of the first or the first
and second transcribed nucleotides, called cap1 and cap2, respectively. In the
present study, we identify the methyltransferase responsible for cap1 formation
in human cells, which we call hMTr1 (also known as FTSJD2 and ISG95). We show in
vitro that hMTr1 catalyzes specific methylation of the 2'-O-ribose of the first
nucleotide of a capped RNA transcript. Using siRNA-mediated knockdown of hMTr1
in HeLa cells, we demonstrate that hMTr1 is responsible for cap1 formation in
vivo.
DOI: 10.1074/jbc.M110.155283
PMCID: PMC2963352
PMID: 20713356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15073769 | 1. Pharmacoepidemiol Drug Saf. 1997 Sep;6(5):337-45. doi:
10.1002/(SICI)1099-1557(199709/10)6:5<337::AID-PDS298>3.0.CO;2-P.
The standardized prescribing ratio--a new method for comparing prescribing
between GPs, controlling for patient age and sex.
Johnson Z(1), Hayes C, Dack P.
Author information:
(1)Eastern Health Board, Regional Drug Unit, Dr Steevens Hospital, Dublin 8,
Ireland.
OBJECTIVES: To develop a method for comparing the proportion of patients on any
drug or group of drugs for individual GP patient panels in Ireland, taking
account of the age and sex structure of the panel.
DESIGN: Calculations based on prescribing data for the fourth-quarter of 1995
supplied by the Irish General Medical Services Payments Board for the Eastern
Health Board area.Setting-Five hundred and fifty Irish general practices serving
355,000 persons entitled to free medical care under the General Medical Services
Scheme in the Eastern Health Board area (28% of the population).
MAIN OUTCOME MEASURES: Weightings for number of persons prescribed each of four
drug groups, and all drugs combined, for 22 age/sex groupings, leading to a
single age/sex adjusted prescribing index-the standardized prescribing ratio
(SPR) for each GPs practice population.
RESULTS: The SPRs showed a large amount of variation from the average figure of
100 for practices of 1000 or more patients for all drugs and for each of the
four drug groups studied: all drugs 54-125, antibiotics 52-165, H(2)
antagonists/proton pump inhibitors 38-197, antidepressants 13-213 and thyroxine
33-175. Practices with above average SPRs for all drugs, antibiotics and H(2)
antagonists/proton pump inhibitors were significantly larger than those with
below-average SPRs. Practices with below average SPRs for thyroxine were
significantly larger than those with above-average SPRs.
CONCLUSIONS: The SPR provides a useful age/sex adjusted method of comparing
prescribing between GPs and it can be applied to any drug or group of drugs.
Copyright 1997 John Wiley & Sons, Ltd.
DOI: 10.1002/(SICI)1099-1557(199709/10)6:5<337::AID-PDS298>3.0.CO;2-P
PMID: 15073769 |
http://www.ncbi.nlm.nih.gov/pubmed/24513384 | 1. J Fr Ophtalmol. 2014 Feb;37(2):89-92. doi: 10.1016/j.jfo.2013.05.026. Epub
2014 Feb 7.
[Ataxia with ophthalmoplegia: Miller-Fisher syndrome with anti-GQ1b antibody
positivity].
[Article in French]
Guilloton L(1), Camarasa C(2), Agard E(3), Tondeur G(2), Dot C(3), Drouet A(2).
Author information:
(1)Service de neurologie, HIA Desgenettes, 108, boulevard Pinel, 69275 Lyon
cedex 03, France. Electronic address: [email protected].
(2)Service de neurologie, HIA Desgenettes, 108, boulevard Pinel, 69275 Lyon
cedex 03, France.
(3)Service d'ophtalmologie, HIA Desgenettes, 108, boulevard Pinel, 69275 Lyon
cedex 03, France.
Miller-Fisher syndrome is defined as ophthalmoplegia, ataxia and areflexia.
Considered as a variant of Guillain-Barré syndrome, it differs in its clinical
presentation and by anti-GQ1b antibody positivity. The authors report a case of
Miller-Fisher syndrome characterized by ataxia and complete ophthalmoplegia.
Through this example, the range of ophthalmologic clinical manifestations are
discussed.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.jfo.2013.05.026
PMID: 24513384 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16024819 | 1. Genome Res. 2005 Aug;15(8):1034-50. doi: 10.1101/gr.3715005. Epub 2005 Jul 15.
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast
genomes.
Siepel A(1), Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson
H, Spieth J, Hillier LW, Richards S, Weinstock GM, Wilson RK, Gibbs RA, Kent WJ,
Miller W, Haussler D.
Author information:
(1)Center for Biomolecular Science and Engineering, University of California,
Santa Cruz, Santa Cruz, California 95064, USA. [email protected]
We have conducted a comprehensive search for conserved elements in vertebrate
genomes, using genome-wide multiple alignments of five vertebrate species
(human, mouse, rat, chicken, and Fugu rubripes). Parallel searches have been
performed with multiple alignments of four insect species (three species of
Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven
species of Saccharomyces. Conserved elements were identified with a computer
program called phastCons, which is based on a two-state phylogenetic hidden
Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by
maximum likelihood, subject to constraints designed to calibrate the model
across species groups, and then predicting conserved elements based on this
model. The predicted elements cover roughly 3%-8% of the human genome (depending
on the details of the calibration procedure) and substantially higher fractions
of the more compact Drosophila melanogaster (37%-53%), Caenorhabditis elegans
(18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to
vertebrates, in order of increasing genome size and general biological
complexity, increasing fractions of conserved bases are found to lie outside of
the exons of known protein-coding genes. In all groups, the most highly
conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases
long. These elements share certain properties with ultraconserved elements, but
they tend to be longer and less perfectly conserved, and they overlap genes of
somewhat different functional categories. In vertebrates, HCEs are associated
with the 3' UTRs of regulatory genes, stable gene deserts, and megabase-sized
regions rich in moderately conserved noncoding sequences. Noncoding HCEs also
show strong statistical evidence of an enrichment for RNA secondary structure.
DOI: 10.1101/gr.3715005
PMCID: PMC1182216
PMID: 16024819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23479439 | 1. Subcell Biochem. 2013;66:105-28. doi: 10.1007/978-94-007-5940-4_5.
Proteolytic regulation of stress response pathways in Escherichia coli.
Micevski D(1), Dougan DA.
Author information:
(1)Department of Biochemistry, La Trobe Institute for Molecular Science (LIMS),
La Trobe University, Melbourne, 3086, Australia.
Maintaining correct cellular function is a fundamental biological process for
all forms of life. A critical aspect of this process is the maintenance of
protein homeostasis (proteostasis) in the cell, which is largely performed by a
group of proteins, referred to as the protein quality control (PQC) network.
This network of proteins, comprised of chaperones and proteases, is critical for
maintaining proteostasis not only during favourable growth conditions, but also
in response to stress. Indeed proteases play a crucial role in the clearance of
unwanted proteins that accumulate during stress, but more importantly, in the
activation of various different stress response pathways. In bacteria, the cells
response to stress is usually orchestrated by a specific transcription factor
(sigma factor). In Escherichia coli there are seven different sigma factors,
each of which responds to a particular stress, resulting in the rapid expression
of a specific set of genes. The cellular concentration of each transcription
factor is tightly controlled, at the level of transcription, translation and
protein stability. Here we will focus on the proteolytic regulation of two sigma
factors (σ(32) and σ(S)), which control the heat and general stress response
pathways, respectively. This review will also briefly discuss the role
proteolytic systems play in the clearance of unwanted proteins that accumulate
during stress.
DOI: 10.1007/978-94-007-5940-4_5
PMID: 23479439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24853856 | 1. Acta Haematol. 2014;132(2):240-3. doi: 10.1159/000358292.
Successful treatment of refractory Guillain-Barré syndrome with alemtuzumab in a
patient with chronic lymphocytic leukemia.
Tzachanis D, Hamdan A, Uhlmann EJ, Joyce RM.
Comment in
Acta Haematol. 2014;132(2):237-9. doi: 10.1159/000359949.
This is the case of a 79-year-old man with chronic lymphocytic leukemia who
presented with Guillain-Barré syndrome with features overlapping with the Miller
Fisher syndrome and Bickerstaff brainstem encephalitis and positive
antiganglioside GQ1b antibody about 6 months after treatment with bendamustine
and rituximab. His clinical and neurologic condition continued to deteriorate
despite sequential treatment with corticosteroids, intravenous immunoglobulin
and plasmapheresis, but in the end, he had a complete and durable response to
treatment with alemtuzumab.
DOI: 10.1159/000358292
PMID: 24853856 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23510020 | 1. Alzheimers Res Ther. 2013 Mar 18;5(2):11. doi: 10.1186/alzrt165. eCollection
2013.
Have we learnt all we need to know from genetic studies - is genetics over in
Alzheimer's disease?
Hampel H(1), Lista S(2).
Author information:
(1)Department of Psychiatry, University of Frankfurt, Heinrich-Hoffmann-Str. 10,
60528 - Frankfurt am Main, Germany ; Department of Neurology, University of
Belgrade, Dr Subotića Str. 8, 11000 - Belgrade, Serbia.
(2)DZNE, German Center for Neurodegenerative Diseases Rostock/Greifswald,
Gehlsheimer Str. 20, 18147 - Rostock, Germany.
BACKGROUND: Alzheimer's disease (AD) pathophysiology is mostly (>95%) not
inherited in a Mendelian fashion. Such sporadic AD (sAD) forms do not exhibit
familial aggregation and are characterized by complex genetic inheritance.
Growing evidence indicates that multiple genes contribute to sAD-characteristic
endophenotypes, molecular mechanisms, signaling pathways and biomarker
signatures either individually or through complex gene-gene interactions,
lifestyle and the environment.
DISCUSSION: Under the hypothesis that low-prevalence variants showing
moderate-to-high effect size may be associated with risk for sAD, two
independent research groups have demonstrated that a rare variant (rs75932628,
encoding a substitution of arginine by histidine at residue 47 (R47H), in the
TREM2 gene, which encodes the triggering receptor expressed on myeloid cells 2)
is significantly associated with an increased susceptibility to sAD. Another
study has provided intriguing evidence that a low-frequency variant (rs63750847)
in the APP gene is associated with a reduced risk of developing AD and a lower
likelihood of age-related cognitive decline in elderly subjects without AD.
SUMMARY: Recent years have witnessed tremendous development in genetics
technology that has allowed full individualized genome-wide or genomic screening
embracing all of the risk and protective variants for sAD, both across
populations and within individuals. Hopefully, the integration of neurogenetics
with systems biology and high-throughput genotyping will further pave the way to
decipher all of the related causes, mechanisms, and biomarkers across the
spectrum of distinct AD forms. After an almost lost apprentice decade in AD
therapy development, the epoch of individualized asymptomatic screening and
progress in primary and secondary prevention of sAD is probably at its dawn.
Even though we are more at the beginning than at the end of sAD genetics, there
is some reason for optimism given the recent identification of novel risk or
protective variants (such as rare TREM2 and APP mutations) showing strong
statistical associations with sAD.
DOI: 10.1186/alzrt165
PMCID: PMC3706946
PMID: 23510020 |
http://www.ncbi.nlm.nih.gov/pubmed/25759527 | 1. World J Gastroenterol. 2015 Mar 7;21(9):2605-13. doi: 10.3748/wjg.v21.i9.2605.
Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis.
Liu GX(1), Xi HQ(1), Sun XY(1), Wei B(1).
Author information:
(1)Guo-Xiao Liu, Hong-Qing Xi, Xiao-Yan Sun, Bo Wei, Department of General
Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853,
China.
The extracellular matrix component periostin is a secreted protein that
functions as both a cell attachment protein and an autocrine or paracrine factor
that signals through the cell adhesion molecule integrins αvβ3 and αvβ5.
Periostin participates in normal physiological activities such as cardiac
development, but is also involved in pathophysiological processes in vascular
diseases, wound repair, bone formation, and tumor development. It is of
increasing interest in tumor biology because it is frequently overexpressed in a
variety of epithelial carcinomas and is functionally involved in multiple steps
of metastasis progression. These include the maintenance of stemness, niche
formation, EMT, the survival of tumor cells, and angiogenesis, all of which are
indispensable for gastric cancer metastasis. Periostin has been reported to
activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote
metastasis. Therefore, periostin represents a potentially promising candidate
for the inhibition of metastasis. In this review article, we summarize recent
advances in knowledge concerning periostin, its antagonist PNDA-3, and their
influence on such key processes in cancer metastasis as maintenance of stemness,
niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and
angiogenesis. In particular, we focus our attention on the role of periostin in
gastric cancer metastasis, speculate as to the usefulness of periostin as a
therapeutic and diagnostic target for gastric cancer metastasis, and consider
potential avenues for future research.
DOI: 10.3748/wjg.v21.i9.2605
PMCID: PMC4351209
PMID: 25759527 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23366158 | 1. Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:1386-9. doi:
10.1109/EMBC.2012.6346197.
Cardiac optogenetics.
Abilez OJ(1).
Author information:
(1)Bio-X Program, Stanford University, Stanford, CA 94305, USA.
[email protected]
For therapies based on human induced pluripotent stem cell (hiPSC)-derived
cardiomyocytes (CM) to be effective, arrhythmias must be avoided. Towards
achieving this goal, light-activated channelrhodopsin-2 (ChR2), a cation channel
activated with 480 nm light, and a first generation halorhodopsin (NpHR1.0), an
anion pump activated by 580 nm light, have been introduced into hiPSC. By using
in vitro approaches, hiPSC-CM are able to be optogenetically activated and
inhibited. ChR2 and NpHR1.0 are stably transduced into undifferentiated hiPSC
via a lentiviral vector. Via directed differentiation, both wildtype hiPSC-CM
(hiPSC(WT)-CM) and hiPSC(ChR2/NpHR)-CM are produced and subjected to both
electrical and optical stimulation. Both hiPSC(WT)-CM and hiPSC(ChR2/NpHR)-CM
respond to traditional electrical stimulation and produce similar contractility
features but only hiPSC(ChR2/NpHR)-CM can be synchronized and inhibited by
optical stimulation. Here it is shown that light sensitive proteins can enable
in vitro optical control of hiPSC-CM. For future therapy, in vivo optical
stimulation could allow precise and specific synchronization of implanted
hiPSC-CM with patient cardiac rates and rhythms.
DOI: 10.1109/EMBC.2012.6346197
PMID: 23366158 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9541111 | 1. J Med Genet. 1998 Mar;35(3):241-3. doi: 10.1136/jmg.35.3.241.
Extensive germinal mosaicism in a family with X linked myotubular myopathy
simulates genetic heterogeneity.
Vincent MC(1), Guiraud-Chaumeil C, Laporte J, Manouvrier-Hanu S, Mandel JL.
Author information:
(1)Laboratoire de Génétique Moleculaire Humaine, Faculté de Médecine et CHRU,
Illkirch, Strasbourg, France.
A family with two male cousins affected with myotubular myopathy (MTM) was
referred to us for genetic counselling. Linkage analysis appeared to exclude the
Xq28 region. As a gene for X linked MTM was recently identified in Xq28, we
screened the obligatory carrier mothers for mutation. We found a 4 bp deletion
in exon 4 of the MTM1 gene, which originated from the grandfather of the
affected children and which was transmitted to three daughters. This illustrates
the importance of mutation detection to avoid pitfalls in linkage analysis that
may be caused by such cases of germinal mosaicism.
DOI: 10.1136/jmg.35.3.241
PMCID: PMC1051250
PMID: 9541111 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24509078 | 1. J Clin Invest. 2014 Mar;124(3):1114-29. doi: 10.1172/JCI69050. Epub 2014 Feb
10.
Optogenetic stimulation of the auditory pathway.
Hernandez VH, Gehrt A, Reuter K, Jing Z, Jeschke M, Mendoza Schulz A, Hoch G,
Bartels M, Vogt G, Garnham CW, Yawo H, Fukazawa Y, Augustine GJ, Bamberg E,
Kügler S, Salditt T, de Hoz L, Strenzke N, Moser T.
Auditory prostheses can partially restore speech comprehension when hearing
fails. Sound coding with current prostheses is based on electrical stimulation
of auditory neurons and has limited frequency resolution due to broad current
spread within the cochlea. In contrast, optical stimulation can be spatially
confined, which may improve frequency resolution. Here, we used animal models to
characterize optogenetic stimulation, which is the optical stimulation of
neurons genetically engineered to express the light-gated ion channel
channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons
(SGNs) activated the auditory pathway, as demonstrated by recordings of single
neuron and neuronal population responses. Furthermore, optogenetic stimulation
of SGNs restored auditory activity in deaf mice. Approximation of the spatial
spread of cochlear excitation by recording local field potentials (LFPs) in the
inferior colliculus in response to suprathreshold optical, acoustic, and
electrical stimuli indicated that optogenetic stimulation achieves better
frequency resolution than monopolar electrical stimulation. Virus-mediated
expression of a ChR2 variant with greater light sensitivity in SGNs reduced the
amount of light required for responses and allowed neuronal spiking following
stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic
stimulation of the auditory pathway in rodents and lays the groundwork for
future applications of cochlear optogenetics in auditory research and
prosthetics.
DOI: 10.1172/JCI69050
PMCID: PMC3934189
PMID: 24509078 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23443164 | 1. Int J Mol Sci. 2013 Feb 26;14(3):4655-69. doi: 10.3390/ijms14034655.
Long non-coding RNA in cancer.
Hauptman N(1), Glavač D.
Author information:
(1)Department of Molecular Genetics, Institute of Pathology, University of
Ljubljana, SI-1000 Ljubljana, Slovenia. [email protected].
Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are
emerging as new players in tumorigenesis due to their various functions in
transcriptional, posttranscriptional and epigenetic mechanisms of gene
regulation. LncRNAs are deregulated in a number of cancers, demonstrating both
oncogenic and tumor suppressive roles, thus suggesting their aberrant expression
may be a substantial contributor in cancer development. In this review, we will
summarize their emerging role in human cancer and discuss their perspectives in
diagnostics as potential biomarkers.
DOI: 10.3390/ijms14034655
PMCID: PMC3634483
PMID: 23443164 |
http://www.ncbi.nlm.nih.gov/pubmed/22961106 | 1. Nat Med. 2012 Oct;18(10):1575-9. doi: 10.1038/nm.2897. Epub 2012 Sep 9.
Sarcolipin is a newly identified regulator of muscle-based thermogenesis in
mammals.
Bal NC(1), Maurya SK, Sopariwala DH, Sahoo SK, Gupta SC, Shaikh SA, Pant M,
Rowland LA, Bombardier E, Goonasekera SA, Tupling AR, Molkentin JD, Periasamy M.
Author information:
(1)Department of Physiology and Cell Biology, Ohio State University, College of
Medicine, Columbus, Ohio, USA.
Erratum in
Nat Med. 2012 Dec;18(12):1857. Tupling, A Russell [added]; Bombardier, Eric
[added].
Comment in
Nat Med. 2012 Oct;18(10):1458-9. doi: 10.1038/nm.2956.
The role of skeletal muscle in nonshivering thermogenesis (NST) is not well
understood. Here we show that sarcolipin (Sln), a newly identified regulator of
the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for
muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice
were not able to maintain their core body temperature (37 °C) and developed
hypothermia. Surgical ablation of brown adipose tissue and functional knockdown
of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln
in the Sln-null background fully restored muscle-based thermogenesis, suggesting
that Sln is the basis for Serca-mediated heat production. We show that ryanodine
receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for
Serca-activated heat generation. Here we present data to suggest that Sln can
continue to interact with Serca in the presence of Ca(2+), which can promote
uncoupling of the Serca pump and cause futile cycling. We further show that loss
of Sln predisposes mice to diet-induced obesity, which suggests that
Sln-mediated NST is recruited during metabolic overload. These data collectively
suggest that SLN is an important mediator of muscle thermogenesis and whole-body
energy metabolism.
DOI: 10.1038/nm.2897
PMCID: PMC3676351
PMID: 22961106 [Indexed for MEDLINE]
Conflict of interest statement: COMPETING FINANCIAL INTERESTS The authors
declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/7831320 | 1. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):507-11. doi:
10.1073/pnas.92.2.507.
Reaction in alphavirus mRNA capping: formation of a covalent complex of
nonstructural protein nsP1 with 7-methyl-GMP.
Ahola T(1), Kääriäinen L.
Author information:
(1)Institute of Biotechnology, University of Helsinki, Finland.
After the start of transcription, the 5' ends of eukaryotic mRNA molecules are
modified by the addition of a guanylyl residue to form a cap structure,
G(5')ppp(5')N. The guanylyltransferase (GTP:mRNA guanylyltransferase, EC
2.7.7.50) reaction responsible for cap formation usually proceeds via a covalent
enzyme-GMP intermediate. We have studied the alphavirus-specific
guanylyltransferase by incubating lysates from Semliki Forest and Sindbis
virus-infected cells with [alpha-32P]GTP, using vaccinia virus and mock-infected
cells as controls. One additional 32P-labeled protein was detected in
alphavirus-infected cells but only in the presence of S-adenosylmethionine. This
protein was identified as the nonstructural protein nsP1. The properties of the
covalent enzyme-guanylate complex were studied with Semliki Forest virus nsP1
expressed in recombinant baculovirus-infected cells. S-Adenosylmethionine and
divalent cations were required for the complex formation. The reaction was
specific for guanylate nucleotides (GTP, dGTP) and was inhibited by
pyrophosphate. nsP1 could be labeled with S-adenosyl[methyl-3H]methionine but
only under conditions in which the nsP1-guanylate complex was formed.
7-Methyl-GMP was released from the nsP1-guanylate complex by treatment with acid
or acidic hydroxylamine. Similar treatment of vaccinia virus capping enzyme
released GMP. These findings suggest that in the capping of alphavirus mRNAs the
guanine is methylated before linkage to the mRNA molecule.
DOI: 10.1073/pnas.92.2.507
PMCID: PMC42770
PMID: 7831320 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21070773 | 1. FEBS Lett. 2010 Dec 1;584(23):4731-4. doi: 10.1016/j.febslet.2010.11.003. Epub
2010 Nov 9.
Per3, a circadian gene, is required for Chk2 activation in human cells.
Im JS(1), Jung BH, Kim SE, Lee KH, Lee JK.
Author information:
(1)Department of Biology Education, Seoul National University, Seoul, Republic
of Korea.
PER3 is a member of the PERIOD genes, but does not play essential roles in the
circadian clock. Depletion of Per3 by siRNA almost completely abolished
activation of checkpoint kinase 2 (Chk2) after inducing DNA damage in human
cells. In addition, Per3 physically interacted with ATM and Chk2. Per3
overexpression induced Chk2 activation in the absence of exogenous DNA damage,
and this activation depended on ATM. Per3 overexpression also led to the
inhibition of cell proliferation and apoptotic cell death. These combined
results suggest that Per3 is a checkpoint protein that plays important roles in
checkpoint activation, cell proliferation and apoptosis.
Copyright © 2010 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.febslet.2010.11.003
PMID: 21070773 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12441204 | 1. Early Hum Dev. 2002 Dec;70(1-2):47-54. doi: 10.1016/s0378-3782(02)00073-7.
The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia
due to 21-hydroxylase deficiency.
Okten A(1), Kalyoncu M, Yariş N.
Author information:
(1)Department of Paediatrics, Karadeniz Technical University, Trabzon, Turkey.
[email protected]
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in
excessive androgen exposure in the gestational period and various degrees of
masculinization of the external genitalia in female foetuses. Intrauterine
gonadal steroids are not only essential for the development of the genital
organs but also affect some other extragenital organ development. The second to
fourth digit (2D/4D) ratio shows a sexually dimorphic pattern with longer fourth
digit from second digit in men compared to women. A low 2D/4D ratio is
associated with high sperm count, testosterone levels and reproductive success
in men. A high 2D/4D ratio is associated with high oestrogen levels in women.
Second and fourth digit ratio has also found to be correlated with sexual
orientation, left hand preference autism and some adult onset diseases such as
breast cancer and myocardial infarction. We found lower 2D/4D ratio in female
patients with 21-hydroxylase deficiency compared to healthy girls (p=0.000) and
equal 2D/4D ratio for female patients when compared to male controls. Male
patients with 21-hydroxylase deficiency had significantly lower 2D/4D ratio than
female and male controls in the right hand. Healthy boys had lower 2D/4D ratio
than healthy girls. It is concluded that 2D/4D ratio established by intrauterine
androgen levels influences the sexually dimorphic digit pattern.
DOI: 10.1016/s0378-3782(02)00073-7
PMID: 12441204 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18081313 | 1. Biochemistry. 2008 Jan 8;47(1):3-13. doi: 10.1021/bi701668v. Epub 2007 Dec 15.
Structural and dynamic basis of phospholamban and sarcolipin inhibition of
Ca(2+)-ATPase.
Traaseth NJ(1), Ha KN, Verardi R, Shi L, Buffy JJ, Masterson LR, Veglia G.
Author information:
(1)Department of Chemistry, University of Minnesota, Minneapolis, Minnesota
55455, USA.
Phospholamban (PLN) and sarcolipin (SLN) are two single-pass membrane proteins
that regulate Ca2+-ATPase (SERCA), an ATP-driven pump that translocates calcium
ions into the lumen of the sarcoplasmic reticulum, initiating muscle relaxation.
Both proteins bind SERCA through intramembrane interactions, impeding calcium
translocation. While phosphorylation of PLN at Ser-16 and/or Thr-17
reestablishes calcium flux, the regulatory mechanism of SLN remains elusive.
SERCA has been crystallized in several different states along the enzymatic
reaction coordinates, providing remarkable mechanistic information; however, the
lack of high-resolution crystals in the presence of PLN and SLN limits the
current understanding of the regulatory mechanism. This brief review offers a
survey of our hybrid structural approach using solution and solid-state NMR
methodologies to understand SERCA regulation from the point of view of PLN and
SLN. These results have improved our understanding of the calcium translocation
process and are the basis for designing new therapeutic approaches to ameliorate
muscle malfunctions.
DOI: 10.1021/bi701668v
PMCID: PMC2699759
PMID: 18081313 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9736772 | 1. Hum Mol Genet. 1998 Oct;7(11):1703-12. doi: 10.1093/hmg/7.11.1703.
Characterization of the myotubularin dual specificity phosphatase gene family
from yeast to human.
Laporte J(1), Blondeau F, Buj-Bello A, Tentler D, Kretz C, Dahl N, Mandel JL.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire,
CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex, France.
X-linked myotubular myopathy (XLMTM) is a severe congenital muscle disorder due
to mutations in the MTM1 gene. The corresponding protein, myotubularin, contains
the consensus active site of tyrosine phosphatases (PTP) but otherwise shows no
homology to other phosphatases. Myotubularin is able to hydrolyze a synthetic
analogue of tyrosine phosphate, in a reaction inhibited by orthovanadate, and
was recently shown to act on both phosphotyrosine and phosphoserine. This gene
is conserved down to yeast and strong homologies were found with human ESTs,
thus defining a new dual specificity phosphatase (DSP) family. We report the
presence of novel members of the MTM gene family in Schizosaccharomyces pombe,
Caenorhabditis elegans, zebrafish, Drosophila, mouse and man. This represents
the largest family of DSPs described to date. Eight MTM-related genes were found
in the human genome and we determined the chromosomal localization and
expression pattern for most of them. A subclass of the myotubularin homologues
lacks a functional PTP active site. Missense mutations found in XLMTM patients
affect residues conserved in a Drosophila homologue. Comparison of the various
genes allowed construction of a phylogenetic tree and reveals conserved residues
which may be essential for function. These genes may be good candidates for
other genetic diseases.
DOI: 10.1093/hmg/7.11.1703
PMID: 9736772 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16379031 | 1. Pituitary. 2005;8(2):115-22. doi: 10.1007/s11102-005-5227-6.
Stimulation of the hypothalamic-pituitary-adrenal axis with the opioid
antagonist nalmefene.
Geer EB(1), Landman RE, Wardlaw SL, Conwell IM, Freda PU.
Author information:
(1)Department of Medicine, Columbia University College of Physicians and
Surgeons, New York, NY 10032, USA. [email protected]
Nalmefene Stimulation of the HPA Axis.
BACKGROUND: The Hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in
the body's response to stress. The traditional gold standard for evaluating the
HPA axis, the insulin hypoglycemia test (IHT), has several known limitations,
and a second test, the standard ACTH stimulation test, can detect severe
deficiencies of cortisol, but often misses mild or early cases. Therefore, a
better test for the evaluation of the HPA axis is needed. This study evaluated
the opiate antagonist nalmefene as a stimulation test of the HPA axis.
METHODS: 25 healthy subjects were studied, 9 women and 16 men, mean age 30.4 yr.
(range 21-55), and mean BMI 24.1 kg/m2 (range 18.6-34.2). Subjects received one
of 3 doses of intravenously administered nalmefene: 2 mg (n = 6), 6 mg (n = 12),
or 10 mg (n = 7). Serum cortisol and plasma ACTH were measured before and
serially over two hours after the administration of nalmefene.
RESULTS: ACTH and cortisol levels rose significantly and similarly after the 10
mg dose and the 6 mg dose. After the 10 mg dose, mean peak ACTH was 82.4 +/-
22.6 pg/ml and mean peak cortisol was 25.2 +/- 1.8 microg/dl. After the 6 mg
dose, mean peak ACTH was 70.3 +/- 7.7 pg/ml and mean peak cortisol was 24.7 +/-
1.7 microg/dl. Cortisol levels rose above 18 microg/dl in all subjects receiving
10 mg of nalmefene, and in all but two of the subjects receiving 6 mg of
nalmefene. Side effects to nalmefene were of greater duration and intensity in
the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These
included most notably fatigue, lightheadedness, nausea and vomiting.
CONCLUSIONS: Of the nalmefene doses we studied, 6 mg achieved the best
combination of stimulation of ACTH and cortisol and fewest side effects. If
further studies show a concordance between nalmefene and IHT, nalmefene testing
could be used to assess the HPA axis in patients at risk for dysfunction of this
axis.
DOI: 10.1007/s11102-005-5227-6
PMID: 16379031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23689226 | 1. Onkologie. 2013;36(5):295-302. doi: 10.1159/000350625. Epub 2013 Apr 5.
Practical management of everolimus-related toxicities in patients with advanced
solid tumors.
Grünwald V(1), Weikert S, Pavel ME, Hörsch D, Lüftner D, Janni W, Geberth M,
Weber MM.
Author information:
(1)Klinik für Hämatologie, Hämostaseologie, Onkologie und
Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.
[email protected]
Everolimus is an orally administered inhibitor of the mammalian target of
rapamycin (mTOR), an intracellular protein kinase downstream of the
phosphatidylinositol 3-kinase/AKT pathway involved in key components of
tumorigenesis, including cell growth, proliferation, and angiogenesis. In the
advanced cancer setting, based on favorable results from phase III trials,
everolimus is indicated for the treatment of advanced renal cell carcinoma,
advanced neuroendocrine tumors of pancreatic origin, and advanced hormone
receptor-positive, human epidermal growth factor receptor 2-negative breast
cancer. Additional oncology indications for everolimus include renal
angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell
astrocytoma. Although it is generally well tolerated, with most adverse events
of mild to moderate severity and manageable, everolimus exhibits a distinct
adverse event profile that warrants guidance for proper diagnostic and medical
management. This guidance is particularly important given the potential for
widespread long-term use of everolimus. This review will focus on the most
relevant toxicities associated with mTOR inhibitors and on their management.
Practical treatment recommendations are presented for stomatitis, noninfectious
pneumonitis, rash, selected metabolic abnormalities, and infections. Provided
these events are rapidly identified and treated, the vast majority should
resolve with minimal effect on treatment outcomes and patients' quality of life.
Copyright © 2013 S. Karger AG, Basel.
DOI: 10.1159/000350625
PMID: 23689226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22931521 | 1. Drugs. 2012 Sep 10;72(13):1739-53. doi: 10.2165/11635730-000000000-00000.
New oral anticoagulants: a review of the literature with particular emphasis on
patients with impaired renal function.
Poulsen BK(1), Grove EL, Husted SE.
Author information:
(1)Department of Clinical Pharmacology, University Hospital of Aarhus, Aarhus,
Denmark. [email protected]
Oral anticoagulant therapy (OAT) is widely used to prevent and treat
thromboembolic events. Traditionally, warfarin has been the drug of choice and,
indeed, this drug is effective and provides a more than 60% reduction in stroke
risk in patients with atrial fibrillation. However, OAT entails an increased
bleeding risk, and management of this is challenging. Among other things, new
oral anticoagulant drugs offer fixed dosing, more predictable pharmacokinetics
and fewer interactions with drugs and food. Moreover, these drugs seem to
provide an improved benefit-risk ratio with respect to thromboembolic events and
bleeding complications in a broad patient population. The new drugs differ from
traditional OAT with respect to their mechanism of action and pharmacokinetics,
especially with respect to elimination through the kidneys. These drugs may
potentially cause bleeding complications in patients with reduced drug excretion
due to impaired renal function. Dabigatran etexilate and rivaroxaban carry the
highest risk due to a high degree of renal excretion, whereas the risk for
apixaban, edoxaban and betrixaban seems lower. Pharmacokinetic studies and data
from clinical studies have provided information on how to guide dosing in
patients with renal impairment. However, the risk of drug accumulation and
bleeding may be amplified by several drug-drug interactions. This article
provides a review of the literature on the pharmacology of new anticoagulant
drugs with particular focus on the impact of impaired renal function.
DOI: 10.2165/11635730-000000000-00000
PMID: 22931521 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23362265 | 1. J Biol Chem. 2013 Mar 22;288(12):8456-8467. doi: 10.1074/jbc.M112.446161. Epub
2013 Jan 29.
Sarco(endo)plasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is
encoded in its luminal tail.
Gorski PA(1), Glaves JP(2), Vangheluwe P(3), Young HS(4).
Author information:
(1)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada.
(2)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada; National Institute for Nanotechnology, University of Alberta, Edmonton,
Alberta T6G 2M9, Canada.
(3)Department of Cellular and Molecular Medicine, Katholieke Universiteit
Leuven, B3000 Leuven, Belgium.
(4)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada; National Institute for Nanotechnology, University of Alberta, Edmonton,
Alberta T6G 2M9, Canada. Electronic address: [email protected].
The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is regulated in a
tissue-dependent manner via interaction with the short integral membrane
proteins phospholamban (PLN) and sarcolipin (SLN). Although defects in SERCA
activity are known to cause heart failure, the regulatory mechanisms imposed by
PLN and SLN could have clinical implications for both heart and skeletal muscle
diseases. PLN and SLN have significant sequence homology in their transmembrane
regions, suggesting a similar mode of binding to SERCA. However, unlike PLN, SLN
has a conserved C-terminal luminal tail composed of five amino acids
((27)RSYQY), which may contribute to a distinct SERCA regulatory mechanism. We
have functionally characterized alanine mutants of the C-terminal tail of SLN
using co-reconstituted proteoliposomes of SERCA and SLN. We found that Arg(27)
and Tyr(31) are essential for SLN function. We also tested the effect of a
truncated variant of SLN (Arg(27)stop) and extended chimeras of PLN with the
five luminal residues of SLN added to its C terminus. The Arg(27)stop form of
SLN resulted in loss of function, whereas the PLN chimeras resulted in
superinhibition with characteristics of both PLN and SLN. Based on our results,
we propose that the C-terminal tail of SLN is a distinct, essential domain in
the regulation of SERCA and that the functional properties of the SLN tail can
be transferred to PLN.
DOI: 10.1074/jbc.M112.446161
PMCID: PMC3605661
PMID: 23362265 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1901428 | 1. S Afr Med J. 1991 Mar 2;79(5):271-4.
Katayama fever in scuba divers. A report of 3 cases.
Evans AC(1), Martin DJ, Ginsburg BD.
Author information:
(1)Research Institute for Diseases in a Tropical Environment, South Africa
Medical Research Council, Nelspruit, Tvl.
Katayama fever or acute schistosomiasis probably occurs more commonly than is
recorded. Interviews with a 3-man scuba diving team who had had contact with a
large dam in an endemic area of the eastern Transvaal Lowveld at the same time
and contact area on the same day during late summer of 1986 are discussed. Two,
who had not previously been exposed to infected water, presented with Katayama
fever, due to Schistosoma mansoni infection, 21 days after contact and it took
30-36 months for them to recover fully after several treatments. The third
patient, a keen water-sportsman and resident in the endemic area for a period of
10 years, presented with a mild infection, probably due to acquired immunity
initiated during previous contacts with infected water; he took about a year to
recover. The pathogenesis, clinical features, diagnosis and treatment of the 3
cases are described in the light of recent observations made elsewhere on
Katayama fever cases and the effects of chemotherapy on the course of illness.
The necessity of obtaining basic information on the travel and water-contact
activities of patients in order to make a diagnosis is emphasised.
PMID: 1901428 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23790601 | 1. Can J Cardiol. 2013 Jul;29(7 Suppl):S71-8. doi: 10.1016/j.cjca.2013.04.005.
Stroke prevention in atrial fibrillation patients with chronic kidney disease.
Hart RG(1), Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ.
Author information:
(1)Department of Medicine (Neurology), McMaster University, Hamilton, Ontario,
Canada. [email protected]
Chronic kidney disease (CKD) is prevalent in elderly patients with atrial
fibrillation and is an independent risk factor for stroke. Warfarin
anticoagulation is efficacious for stroke prevention in atrial fibrillation
patients with moderate CKD (stage III, estimated glomerular filtration rate
30-59 mL/min), but recent observational studies have challenged its value for
patients with end-stage renal disease requiring dialysis. The novel oral
anticoagulants (i.e., dabigatran, apixaban, rivaroxaban) all undergo renal
metabolism to varying degrees, and hence dosing, efficacy, and safety require
special consideration in CKD patients. In randomized trials to date involving
11,169 patients with moderate CKD, the novel oral anticoagulants performed well,
with similar efficacy and safety profiles as for non-CKD patients. For atrial
fibrillation patients with stage III CKD, the available data are strongest for
dabigatran 150 mg twice daily as superior to warfarin for stroke prevention and
for apixaban as superior to warfarin regarding reduced major hemorrhage. Renal
function should be monitored at least annually in patients receiving a novel
oral anticoagulant, and more often in elderly patients and those with underlying
CKD or comorbidities who are at special risk for dehydration and deterioration
of renal function. Much remains to be learned about the optimal use of the novel
oral anticoagulants in CKD patients; additional studies about optimal dosing of
the novel oral anticoagulants and frequency of monitoring renal function in CKD
patients with atrial fibrillation are needed. Anticoagulation options for
hemodialysis patients require testing in randomized trials.
Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.cjca.2013.04.005
PMID: 23790601 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23588999 | 1. JAMA Intern Med. 2013 May 27;173(10):866-73. doi:
10.1001/jamainternmed.2013.323.
Five-year downstream outcomes following prostate-specific antigen screening in
older men.
Walter LC(1), Fung KZ, Kirby KA, Shi Y, Espaldon R, O'Brien S, Freedland SJ,
Powell AA, Hoffman RM.
Author information:
(1)Division of Geriatrics, San Francisco VA Medical Center, Mail Code 181G, 4150
Clement St, San Francisco, CA 94121, USA. [email protected]
IMPORTANCE: Despite ongoing controversies surrounding prostate-specific antigen
(PSA) screening, many men 65 years or older undergo screening. However, few data
exist that quantify the chain of events following screening in clinical practice
to better inform decisions.
OBJECTIVE: To quantify 5-year downstream outcomes following a PSA screening
result exceeding 4.0 ng/mL in older men.
DESIGN AND SETTING: Longitudinal cohort study in the national Veterans Affairs
health care system.
PARTICIPANTS: In total, 295,645 men 65 years or older who underwent PSA
screening in the Veterans Affairs health care system in 2003 and were followed
up for 5 years using national Veterans Affairs and Medicare data.
MAIN OUTCOME MEASURES: Among men whose index screening PSA level exceeded 4.0
ng/mL, we determined the number who underwent prostate biopsy, were diagnosed as
having prostate cancer, were treated for prostate cancer, and were treated for
prostate cancer and were alive at 5 years according to baseline characteristics.
Biopsy and treatment complications were also assessed.
RESULTS: In total, 25,208 men (8.5%) had an index PSA level exceeding 4.0 ng/mL.
During the 5-year follow-up period, 8313 men (33.0%) underwent at least 1
prostate biopsy, and 5220 men (62.8%) who underwent prostate biopsy were
diagnosed as having prostate cancer, of whom 4284 (82.1%) were treated for
prostate cancer. Performance of prostate biopsy decreased with advancing age and
worsening comorbidity (P < .001), whereas the percentage treated for
biopsy-detected cancer exceeded 75% even among men 85 years or older, those with
a Charlson-Deyo Comorbidity Index of 3 or higher, and those having low-risk
cancer. Among men with biopsy-detected cancer, the risk of death from
non-prostate cancer causes increased with advancing age and worsening
comorbidity (P < .001). In total, 468 men (5.6%) had complications within 7 days
after prostate biopsy. Complications of prostate cancer treatment included new
urinary incontinence in 584 men (13.6%) and new erectile dysfunction 588 men
(13.7%).
CONCLUSIONS AND RELEVANCE: Performance of prostate biopsy is uncommon in older
men with abnormal screening PSA levels and decreases with advancing age and
worsening comorbidity. However, once cancer is detected on biopsy, most men
undergo immediate treatment regardless of advancing age, worsening comorbidity,
or low-risk cancer. Understanding downstream outcomes in clinical practice
should better inform individualized decisions among older men considering PSA
screening.
DOI: 10.1001/jamainternmed.2013.323
PMCID: PMC3712749
PMID: 23588999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16675552 | 1. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7694-9. doi:
10.1073/pnas.0511243103. Epub 2006 May 4.
The bundling activity of vasodilator-stimulated phosphoprotein is required for
filopodium formation.
Schirenbeck A(1), Arasada R, Bretschneider T, Stradal TE, Schleicher M, Faix J.
Author information:
(1)Department of Cell Biology, Ludwig Maximilians University, 80336 München,
Germany.
Filopodia are highly dynamic finger-like cell protrusions filled with parallel
bundles of actin filaments. Previously we have shown that Diaphanous-related
formin dDia2 is involved in the formation of filopodia. Another key player for
the formation of filopodia across many species is vasodilator-stimulated
phosphoprotein (VASP). It has been proposed that the essential role of VASP for
formation of filopodia is its competition with capping proteins for filament
barbed-end interaction. To better understand the function of VASP in filopodium
formation, we analyzed the in vitro and in vivo properties of Dictyostelium VASP
(DdVASP) and extended our findings to human VASP. Recombinant VASP from both
species nucleated and bundled actin filaments, but did not compete with capping
proteins or block depolymerization from barbed ends. Together with the finding
that DdVASP binds to the FH2 domain of dDia2, these data indicate that the
crucial role of VASP in filopodium formation is different from uncapping of
actin filaments. To identify the activity of DdVASP required in this process,
rescue experiments of DdVASP-null cells with mutant DdVASP constructs were
performed. Only WT DdVASP, but not a mutant lacking the F-actin bundling
activity, could rescue the ability of these cells to form WT-like filopodia. Our
data suggest that DdVASP is complexed with dDia2 in filopodial tips and support
formin-mediated filament elongation by bundling nascent actin filaments.
DOI: 10.1073/pnas.0511243103
PMCID: PMC1457090
PMID: 16675552 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: No conflicts
declared. |
http://www.ncbi.nlm.nih.gov/pubmed/9416973 | 1. Biochem Pharmacol. 1997 Dec 1;54(11):1225-31. doi:
10.1016/s0006-2952(97)00327-4.
Effects of proton pump inhibitors on thyroid hormone metabolism in rats: a
comparison of UDP-glucuronyltransferase induction.
Masubuchi N(1), Hakusui H, Okazaki O.
Author information:
(1)Drug Metabolism and Analytical Chemistry Research Laboratory, Daiichi
Pharmaceutical Co., Ltd., Tokyo, Japan. [email protected]
The effects of proton pump inhibitors on thyroid hormone metabolism in rats were
examined. Pantoprazole, omeprazole, and lansoprazole were administered
repeatedly to female SD rats at doses of 5, 50, and 300 mg/kg/day for 1 week,
and changes in UDP-glucuronyltransferase activities were examined. Increases in
o-aminophenol UDP-glucuronyltransferase activity, which was measured as that
responsible for the glucuronidation of thyroxine, were evident following 7-day
high-dose administration of all the proton pump inhibitors tested. Of the three
proton pump inhibitors investigated, o-aminophenol UDP-glucuronyltransferase
activity was greatest following the high-dose administration of omeprazole.
Androsterone UDP-glucuronyltransferase activity in rats treated with the proton
pump inhibitors increased significantly, but these increases were smaller than
those of o-aminophenol UDP-glucuronyltransferase. Pantoprazole and omeprazole
treatment did not affect plasma T4 or T3 significantly, whereas lansoprazole
treatment produced marked reductions in plasma T4 but did not affect plasma T3
significantly. After administration of 125I-labeled thyroid hormone to rats
treated with the proton pump inhibitors, biliary excretion of radioactivity
increased significantly in omeprazole- and lansoprazole-treated rats; these
increases were attributed to induction of liver thyroxine
UDP-glucuronyltransferase activities. The order of biliary excretion of
radioactivity, as well as the o-aminophenol UDP-glucuronyltransferase activity,
in the treated animals was: omeprazole > lansoprazole > pantoprazole. Therefore,
repeated administration of the proton pump inhibitors increased
thyroxine-metabolizing activity via induction of UDP-glucuronyltransferase, and
this induction by pantoprazole was less pronounced than that by omeprazole or
lansoprazole.
DOI: 10.1016/s0006-2952(97)00327-4
PMID: 9416973 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22358266 | 1. Rev Bras Cir Cardiovasc. 2011 Oct-Dec;26(4):525-31. doi:
10.5935/1678-9741.20110041.
On-pump coronary artery bypass graft surgery: biochemical, hormonal and cellular
features.
[Article in English, Portuguese]
Gabriel EA(1), Locali RF, Matsuoka PK, Cherbo T, Buffolo E.
Author information:
(1)Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
[email protected]
OBJECTIVE: The authors sought to assess biochemical, hormonal and cellular
repercussions from use of cardiopulmonary bypass (CPB) in coronary artery bypass
graft (CABG) surgery.
METHODS: Eighteen patients underwent on-pump CABG surgery. Mean time of CPB was
80.3 minutes. Hormonal, biochemical and cellular measurements were taken in some
time points - preoperatively, immediately after coming off CPB, 24 and 48 hours
postoperatively. Friedman and Wilcoxon tests were applied based on significance
level of 5%.
RESULTS: There was activation and significant elevation of total leukocytes and
neutrophils count over CPB, remaining this way up to 48 hours postoperatively.
Total platelets count, in turn, was marked by relevant reduction immediately
after coming off CPB as well as in two postoperative time points. Serum levels
of total proteins and albumin, immediately after coming off CPB and also in two
postoperative time points, were significantly decreased comparing with
preoperative status. There was remarkable reduction of total T3, free T3 and
total T4 particularly up to first 24 hours postoperatively.
CONCLUSION: In on-pump CABG surgery, inflammatory effects encompass activation
of total leukocytes, neutrophils and platelets, reduction of serum level of
total proteins and albumin and decreased thyroid hormones levels, especially
within first postoperative 24 hours.
DOI: 10.5935/1678-9741.20110041
PMID: 22358266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12893884 | 1. Mol Endocrinol. 2003 Nov;17(11):2340-54. doi: 10.1210/me.2003-0207. Epub 2003
Jul 31.
Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase
(immune response gene 1) in the uterine epithelium during implantation through
the protein kinase C pathway.
Chen B(1), Zhang D, Pollard JW.
Author information:
(1)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, New York, New York 10461, USA. [email protected]
Implantation requires coordination between development of the blastocyst and the
sex steroid hormone-regulated differentiation of the uterus. Under the influence
of these hormones, the uterine luminal epithelium becomes receptive to
attachment of the hatched blastocyst. In this study we sought to identify genes
regulated by progesterone (P4) in the uterine epithelium. This resulted in the
identification of one novel P4-regulated gene that had been previously found in
lipopolysaccharide-stimulated macrophages and called immune response gene-1
(Irg1) and which is the mammalian ortholog of the bacterial gene encoding
methylcitrate dehydratase. In adult mice Irg1 expression was limited to the
uterine luminal epithelium where it is expressed only during pregnancy with a
peak coinciding with implantation. Irg1 mRNA expression is regulated
synergistically by P4 and estradiol (E2) but not by E2 alone. In macrophages
Irg1 is induced by lipopolysaccharide through a protein kinase C (PKC)-regulated
pathway. Now we demonstrate that the PKC pathway is induced in the uterine
epithelium at implantation by the synergistic action of P4 and E2 and is
responsible for the hormone induction of Irg1. These results suggest that the
PKC pathway plays an important role in modulating steroid hormone responsiveness
in the uterine luminal epithelium during the implantation window and that Irg1
will be an important marker of this window and may play an important role in
implantation.
DOI: 10.1210/me.2003-0207
PMID: 12893884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18325099 | 1. Int Semin Surg Oncol. 2008 Mar 6;5:7. doi: 10.1186/1477-7800-5-7.
Uterine PEComa: appraisal of a controversial and increasingly reported
mesenchymal neoplasm.
Fadare O(1).
Author information:
(1)Department of Pathology, Wilford Hall Medical Center, Lackland Air Force
Base, San Antonio, TX 78236, USA. [email protected].
In recent years, a group of tumors that have been designated "perivascular
epithelioid cell tumors" (PEComa) have been reported with increasing frequency
from a wide variety of anatomic locations. The uterus and retroperitoneum appear
to be the most frequent sites of origin for these lesions. PEComas belong to an
identically named family of tumors comprised of conventional angiomyolipomas,
clear cell sugar tumors, lymphangiomyomatosis and clear cell myomelanocytic
tumor of the falciform ligament/ligament teres, and are also known as
PEComa-NOS. This article is a primer for clinicians on the most salient
clinicopathologic features of uterine PEComas, as most of the debate and
discussion have taken place in the pathologic literature. The author appraises
in detail the current state of knowledge on PEComas of the uterus based on a
review of published data on the 44 previously reported cases, and comments on
areas of controversy. The latter are centered predominantly on the significant
morphologic and immunophenotypic overlap that exists between uterine PEComa and
some smooth muscle tumors of the uterus. The clinicopathologic features of cases
reported as epithelioid smooth muscle tumors and cases reported as uterine
PEComas are compared and contrasted, and a practical approach to their reporting
is proposed.
DOI: 10.1186/1477-7800-5-7
PMCID: PMC2278149
PMID: 18325099 |
http://www.ncbi.nlm.nih.gov/pubmed/17939863 | 1. BMC Bioinformatics. 2007 Oct 16;8:392. doi: 10.1186/1471-2105-8-392.
Improved human disease candidate gene prioritization using mouse phenotype.
Chen J(1), Xu H, Aronow BJ, Jegga AG.
Author information:
(1)Division of Biomedical Informatics, Cincinnati Children's Hospital Medical
Center, Cincinnati, USA. [email protected]
BACKGROUND: The majority of common diseases are multi-factorial and modified by
genetically and mechanistically complex polygenic interactions and environmental
factors. High-throughput genome-wide studies like linkage analysis and gene
expression profiling, tend to be most useful for classification and
characterization but do not provide sufficient information to identify or
prioritize specific disease causal genes.
RESULTS: Extending on an earlier hypothesis that the majority of genes that
impact or cause disease share membership in any of several functional
relationships we, for the first time, show the utility of mouse phenotype data
in human disease gene prioritization. We study the effect of different data
integration methods, and based on the validation studies, we show that our
approach, ToppGene http://toppgene.cchmc.org, outperforms two of the existing
candidate gene prioritization methods, SUSPECTS and ENDEAVOUR.
CONCLUSION: The incorporation of phenotype information for mouse orthologs of
human genes greatly improves the human disease candidate gene analysis and
prioritization.
DOI: 10.1186/1471-2105-8-392
PMCID: PMC2194797
PMID: 17939863 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24282181 | 1. J Child Neurol. 2014 Dec;29(12):NP168-70. doi: 10.1177/0883073813509120. Epub
2013 Nov 25.
Mowat-Wilson syndrome: deafness in the first Egyptian case who was conceived by
intracytoplasmic sperm injection.
Abdalla EM(1), Zayed LH(2).
Author information:
(1)Department of Human Genetics, Medical Research Institute, Alexandria
University, Alexandria, Egypt [email protected].
(2)Department of Obstetrics and Gynecology, Alexandria Faculty of Medicine,
Alexandria, Egypt.
Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or
deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome
is characterized by typical facial features, moderate-to-severe mental
retardation, epilepsy and variable congenital malformations, including
Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of
the corpus callosum, and eye defects. The prevalence of Mowat-Wilson syndrome is
currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed,
particularly in patients without Hirschsprung disease. We report here the first
Egyptian case of Mowat-Wilson syndrome who was conceived by intracytoplasmic
sperm injection. The patient manifested bilateral sensorineural hearing loss--a
new feature not previously reported in cases of Mowat-Wilson syndrome. This
report describes the first Egyptian patient of Mowat-Wilson syndrome who was
conceived after intracytoplasmic sperm injection, and provides a new evidence
for the inclusion of deafness among the congenital defects of the syndrome.
© The Author(s) 2013.
DOI: 10.1177/0883073813509120
PMID: 24282181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21699738 | 1. BioData Min. 2011 Jun 24;4:19. doi: 10.1186/1756-0381-4-19.
DADA: Degree-Aware Algorithms for Network-Based Disease Gene Prioritization.
Erten S(1), Bebek G, Ewing RM, Koyutürk M.
Author information:
(1)Department of Electrical Engineering and Computer Science, Case Western
Reserve University, Cleveland, OH, USA. [email protected].
BACKGROUND: High-throughput molecular interaction data have been used
effectively to prioritize candidate genes that are linked to a disease, based on
the observation that the products of genes associated with similar diseases are
likely to interact with each other heavily in a network of protein-protein
interactions (PPIs). An important challenge for these applications, however, is
the incomplete and noisy nature of PPI data. Information flow based methods
alleviate these problems to a certain extent, by considering indirect
interactions and multiplicity of paths.
RESULTS: We demonstrate that existing methods are likely to favor highly
connected genes, making prioritization sensitive to the skewed degree
distribution of PPI networks, as well as ascertainment bias in available
interaction and disease association data. Motivated by this observation, we
propose several statistical adjustment methods to account for the degree
distribution of known disease and candidate genes, using a PPI network with
associated confidence scores for interactions. We show that the proposed methods
can detect loosely connected disease genes that are missed by existing
approaches, however, this improvement might come at the price of more false
negatives for highly connected genes. Consequently, we develop a suite called
DADA, which includes different uniform prioritization methods that effectively
integrate existing approaches with the proposed statistical adjustment
strategies. Comprehensive experimental results on the Online Mendelian
Inheritance in Man (OMIM) database show that DADA outperforms existing methods
in prioritizing candidate disease genes.
CONCLUSIONS: These results demonstrate the importance of employing accurate
statistical models and associated adjustment methods in network-based disease
gene prioritization, as well as other network-based functional inference
applications. DADA is implemented in Matlab and is freely available at
http://compbio.case.edu/dada/.
DOI: 10.1186/1756-0381-4-19
PMCID: PMC3143097
PMID: 21699738 |
http://www.ncbi.nlm.nih.gov/pubmed/22727621 | 1. Mol Cell. 2012 Jul 27;47(2):242-52. doi: 10.1016/j.molcel.2012.05.019. Epub
2012 Jun 21.
Transient sequestration of TORC1 into stress granules during heat stress.
Takahara T(1), Maeda T.
Author information:
(1)Institute of Molecular and Cellular Biosciences, The University of Tokyo,
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Comment in
Mol Cell. 2012 Jul 27;47(2):155-7. doi: 10.1016/j.molcel.2012.07.005.
The target of rapamycin complex 1 (TORC1) is a central kinase that coordinates
nutrient availability with eukaryotic cell growth. Although TORC1 signaling is
repressed by various stresses in yeast, the underlying mechanisms remain
elusive. Here we report that TORC1 signaling upon heat stress is regulated by
stress granules (SGs), which are cytoplasmic foci formed under certain stresses.
Ectopic formation of SGs achieved by Pbp1 overexpression in unstressed cells
sequesters TORC1 in this compartment, thereby blunting TORC1 signaling. Upon
heat stress, a physiological SG-inducing condition, TORC1 is also recruited to
SGs, which delays reactivation of TORC1 signaling during recovery from heat
stress. Moreover, TORC1 reactivation is directed through SG disassembly,
suggesting that SGs act as a key determinant for TORC1 reactivation during
recovery from heat stress. Furthermore, this mechanism contributes to reduction
of heat-induced mutations. Thus, TORC1 signaling is coupled to heat-induced SGs
to protect cells from DNA damage.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2012.05.019
PMID: 22727621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20576703 | 1. Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20. doi:
10.1093/nar/gkq537.
The GeneMANIA prediction server: biological network integration for gene
prioritization and predicting gene function.
Warde-Farley D(1), Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M,
Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright
G, Bader GD, Morris Q.
Author information:
(1)Department of Computer Science, University of Toronto, Toronto, Ontario,
Canada.
GeneMANIA (http://www.genemania.org) is a flexible, user-friendly web interface
for generating hypotheses about gene function, analyzing gene lists and
prioritizing genes for functional assays. Given a query list, GeneMANIA extends
the list with functionally similar genes that it identifies using available
genomics and proteomics data. GeneMANIA also reports weights that indicate the
predictive value of each selected data set for the query. Six organisms are
currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila
melanogaster, Mus musculus, Homo sapiens and Saccharomyces cerevisiae) and
hundreds of data sets have been collected from GEO, BioGRID, Pathway Commons and
I2D, as well as organism-specific functional genomics data sets. Users can
select arbitrary subsets of the data sets associated with an organism to perform
their analyses and can upload their own data sets to analyze. The GeneMANIA
algorithm performs as well or better than other gene function prediction methods
on yeast and mouse benchmarks. The high accuracy of the GeneMANIA prediction
algorithm, an intuitive user interface and large database make GeneMANIA a
useful tool for any biologist.
DOI: 10.1093/nar/gkq537
PMCID: PMC2896186
PMID: 20576703 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10519426 | 1. Br J Obstet Gynaecol. 1999 Oct;106(10):1023-8. doi:
10.1111/j.1471-0528.1999.tb08108.x.
Non-invasive RNA-based determination of fetal Rhesus D type: a prospective study
based on 96 pregnancies.
Cunningham J(1), Yates Z, Hamlington J, Mason G, Mueller R, Miller D.
Author information:
(1)Cytogenetics, Pathology Department, Ninewells Hospital and Medical School,
Dundee, UK.
OBJECTIVES: To develop a non-invasive method for determining fetal RhD status in
order to provide improved care for women most at risk.
DESIGN: A prospective study.
METHODS: Fetal erythroblasts were enriched from the peripheral circulation of 96
RhD negative women with pregnancies at various stages in gestation using
discontinuous density gradients. Amplification of RhD-specific mRNAs was carried
out by reverse transcription-polymerase chain reaction assay. RNA, rather than
DNA, was selected for amplification because it rarely contaminates samples, thus
resulting in fewer false positives; moreover, its presence in multiple copies
per cell should enhance the sensitivity of the assay, resulting in fewer false
negatives. The study was prospective, relying on postnatal serological
confirmation of RhD phenotype.
RESULTS: The assay was 75% accurate at predicting fetal RhD status, comparing
favourably with standard genomic DNA-based assays. However, we found that
accuracy dropped from 85% (29/34) in the third trimester of pregnancy, to 82%
(32/39) in the second and 48% (11/23) in the first trimester. Discordant data
were due to false negatives in the majority (78%) of cases.
CONCLUSIONS: We suggest that reverse transcription may be a useful and perhaps
more sensitive alternative to standard genomic polymerase chain reaction in the
majority of cases. However, under certain circumstances the absence or reduction
of fetal erythroblasts or possibly RhD mRNA in some preparations may compromise
the accuracy of the assay.
DOI: 10.1111/j.1471-0528.1999.tb08108.x
PMID: 10519426 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19712596 | 1. Farm Hosp. 2009 May-Jun;33(3):125-33.
[Pharmacokinetics and pharmacodynamics of the new oral anticoagulants dabigatran
and rivaroxaban].
[Article in Spanish]
Ordovás Baines JP(1), Climent Grana E, Jover Botella A, Valero García I.
Author information:
(1)Servicio de Farmacia, Hospital General Universitario de Alicante, Alicante,
España. [email protected]
Comment in
Farm Hosp. 2009 May-Jun;33(3):123-4. doi: 10.1016/s1130-6343(09)71153-5.
Farm Hosp. 2010 Mar-Apr;34(2):101. doi: 10.1016/j.farma.2009.09.009.
Dabigatran is the first available oral direct thrombin inhibitor anticoagulant.
Absorption of the prodrug, dabigatran etexilate and its conversion to dabigatran
is rapid (peak plasma concentrations are reached 4-6 hours following surgery,
and a further 2 hours later). Its oral bioavailability is low, but shows reduced
interindividual variability. Dabigatran specifically and reversibly inhibits
thrombin, the key enzyme in the coagulation cascade. Studies both in healthy
volunteers and in patients undergoing major orthopaedic surgery show a
predictable pk/pd profile that allows for fixed-dose regimens. The anticoagulant
effect correlates adequately with the plasma concentrations of the drug,
demonstrating effective anticoagulation combined with a low risk of bleeding.
Dabigatran is mainly eliminated by renal excretion (a fact which affects the
dosage in elderly and in moderate-severe renal failure patients), and no hepatic
metabolism by cytochrome P450 isoenzymes has been observed, showing a good
interaction profile. Rivaroxaban will probably be the first available oral
factor Xa (FXa) direct inhibitor anticoagulant drug. It produces a reversible
and predictable inhibition of FXa activity with potential to inhibit clot-bound
FXa. Its pharmacokinetic characteristics include rapid absorption, high oral
availability, high plasma protein binding and a half-life of aprox. 8 hours.
Rivaroxaban elimination is mainly renal, but also through faecal matter and by
hepatic metabolism. Although the drug has demonstrated moderate potential to
interact with strong CYP3A4 inhibitors, it does not inhibit or induce any major
CYP450 enzyme.
PMID: 19712596 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24092421 | 1. Childs Nerv Syst. 2013 Dec;29(12):2151-5. doi: 10.1007/s00381-013-2283-5. Epub
2013 Oct 3.
Mowat-Wilson syndrome: the first report of an association with central nervous
system tumors.
Valera ET(1), Ferraz ST, Brassesco MS, Zhen X, Shen Y, dos Santos AC, Neder L,
Oliveira RS, Scrideli CA, Tone LG.
Author information:
(1)Division of Pediatric Oncology, Department of Pediatrics; Faculty of Medicine
of Ribeirão Preto, University of São Paulo, São Paulo, Brazil,
[email protected].
Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and
multiple congenital anomalies including Hirschsprung's disease, intellectual
disability, and prominent facial features are present. At molecular level, MWS
is characterized by many different described mutations in the zinc finger E-box
protein 2 (ZEB2) gene, ultimately leading to loss of gene function. This report
is the first to describe the association of MWS with two different asynchronous
malignant brain tumors (medulloblastoma and glioblastoma) occurring in a child.
DOI: 10.1007/s00381-013-2283-5
PMID: 24092421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17433057 | 1. Epilepsia. 2007 Jul;48(7):1406-8. doi: 10.1111/j.1528-1167.2007.01074.x. Epub
2007 Apr 13.
Neurologic improvement in a type 3 Gaucher disease patient treated with
imiglucerase/miglustat combination.
Capablo JL(1), Franco R, de Cabezón AS, Alfonso P, Pocovi M, Giraldo P.
Author information:
(1)Department of Neurology, Miguel Servet University Hospital, Zaragoza, Spain.
PURPOSE: Gaucher disease (GD) is an autosomal recessive lysosomal disorder
caused by a deficiency of glucocerebrosidase. The neurologic manifestations of
GD patients have to date been refractory to any treatment approach. We present a
report of a neuronopathic GD patient whose myoclonic epilepsy improved after
combination therapy with imiglucerase and miglustat.
METHODS: In an adult type 3 GD patient who, despite good visceral and analytic
response to ERT, developed progressive neurologic deterioration with marked
myoclonic epilepsy and dystonia, we added miglustat to the enzyme-replacement
therapy.
RESULTS: After 2 years of combined miglustat (200 mg, 3 t.i.d.) and imiglucerase
(60 IU/kg every 2 weeks), generalized tonic-clonic seizures decreased, speech
improved, and the general neurologic clinical picture improved markedly. The EEG
showed a reduction in focal and generalized paroxysmal discharges. No
significant adverse effects were observed.
CONCLUSIONS: Combined imiglucerase and miglustat therapy may be beneficial for
some neuronopathic forms of GD.
DOI: 10.1111/j.1528-1167.2007.01074.x
PMID: 17433057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25499213 | 1. Neoplasia. 2014 Dec;16(12):993-1006. doi: 10.1016/j.neo.2014.10.001.
In vivo Mn-enhanced MRI for early tumor detection and growth rate analysis in a
mouse medulloblastoma model.
Suero-Abreu GA(1), Praveen Raju G(2), Aristizábal O(1), Volkova E(1), Wojcinski
A(3), Houston EJ(1), Pham D(4), Szulc KU(1), Colon D(1), Joyner AL(3), Turnbull
DH(5).
Author information:
(1)Skirball Institute of Biomolecular Medicine and Department of Radiology, NYU
School of Medicine, New York, NY, USA.
(2)Developmental Biology Department, Memorial Sloan-Kettering Cancer Center, New
York, NY, USA; Department of Pediatrics, Weill Cornell Medical College, New
York, NY, USA.
(3)Developmental Biology Department, Memorial Sloan-Kettering Cancer Center, New
York, NY, USA.
(4)Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
(5)Skirball Institute of Biomolecular Medicine and Department of Radiology, NYU
School of Medicine, New York, NY, USA. Electronic address:
[email protected].
Mouse models have increased our understanding of the pathogenesis of
medulloblastoma (MB), the most common malignant pediatric brain tumor that often
forms in the cerebellum. A major goal of ongoing research is to better
understand the early stages of tumorigenesis and to establish the genetic and
environmental changes that underlie MB initiation and growth. However, studies
of MB progression in mouse models are difficult due to the heterogeneity of
tumor onset times and growth patterns and the lack of clinical symptoms at early
stages. Magnetic resonance imaging (MRI) is critical for noninvasive,
longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is
limited in resolution and sensitivity for imaging early MBs in mice. In this
study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15
minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early
detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout
(CKO) model. The high tissue contrast obtained with MEMRI revealed detailed
cerebellar morphology and enabled detection of MBs over a wide range of stages
including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes
close to 0.1 mm(3). Furthermore, longitudinal MEMRI allowed noninvasive
monitoring of tumors and demonstrated that lesions within and between
individuals have different tumorigenic potentials. 3D volumetric studies allowed
quantitative analysis of MB tumor morphology and growth rates in individual
Ptch1-CKO mice. These results show that MEMRI provides a powerful method for
early in vivo detection and longitudinal imaging of MB progression in the mouse
brain.
Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.neo.2014.10.001
PMCID: PMC4309249
PMID: 25499213 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2431391 | 1. Nucleic Acids Res. 1986 Nov 11;14(21):8279-90. doi: 10.1093/nar/14.21.8279.
Green light induces transcription of the phycoerythrin operon in the
cyanobacterium Calothrix 7601.
Mazel D, Guglielmi G, Houmard J, Sidler W, Bryant DA, Tandeau de Marsac N.
Phycobilisomes, the major light-harvesting complexes of cyanobacteria are
multimolecular structures made up of chromophoric proteins called
phycobiliproteins and non chromophoric linker polypeptides. We report here the
isolation and nucleotide sequence of the genes, cpeA and cpeB, which in
Calothrix PCC 7601 encode the alpha and beta subunits of phycoerythrin, one of
the major phycobiliproteins. In Calothrix PCC 7601, modulation of the
polypeptide composition of the phycobilisomes occurs in response to changes of
the light wavelength, a phenomenon known as complementary chromatic adaptation.
Under green illumination, cells synthesize phycoerythrin and its two
specifically associated linker polypeptides (LR35 and LR36), while under red
illumination none of these proteins are detected. Using specific probes, a
single transcript (1450 nucleotide long) corresponding to the cpe genes was
detected but only in green-light-grown cells, establishing the occurrence of
transcriptional regulation for the expression of this operon in response to
light wavelength changes. The size of this transcript excludes the possibility
that the phycoerythrin-associated LR35 and LR36 could be cotranscribed with the
cpeA and cpeB genes.
DOI: 10.1093/nar/14.21.8279
PMCID: PMC311859
PMID: 2431391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9291508 | 1. Neurotoxicology. 1997;18(2):589-602.
Methamidophos: an anticholinesterase without significant effects on postsynaptic
receptors or transmitter release.
Camara AL(1), Braga MF, Rocha ES, Santos MD, Cortes WS, Cintra WM, Aracava Y,
Maelicke A, Albuguergue EX.
Author information:
(1)Laboratory of Molecular Pharmacology II, Institute of Biophysics, Carlos
Chagas Filho, UFRJ, Rio de Janeiro, Brazil.
Methamidophos (O,S-dimethyl phosphoroamidothiolate, Tamaron), an organophosphate
(OP) anticholinesterase of limited toxicity, is widely used as an insecticide
and acaricide. To provide additional insight into the molecular basis of its
action, we have used electrophysiological and biochemical techniques to study
the effects of methamidophos on the neuromuscular junction of rat and frog and
on the central nervous system of rat. Methamidophos has a relatively weak
inhibitory action on cholinesterases in rat diaphragm muscle, brain and
hippocampal homogenates, with IC50 values on the order of 20-20 microM. An even
weaker anticholinesterase activity was found in frog muscle homogenates, with
the IC50 being above 300 microM. As further evidence of anticholinesterase
activity, methamidophos (1-100 microM) was able to reverse the blockade by
d-tubocurarine (0.5-0.7 microM) of neuromuscular transmission in rat phrenic
nerve-hemidiaphragm preparations. Inhibition of cholinesterase activity by
methamidophos was long lasting, which is consistent with the formation by the
agent of a covalent bond with the enzyme's active serine residue. The action was
also slowly reversible, which suggests spontaneous reactivation of the enzyme.
electrophysiological studies at the rat neuromuscular junction showed that, due
to its anticholinesterase activity, methamidophos increased the amplitude and
prolonged the decay phase of nerve-evoked and spontaneous miniature end-plate
potentials. In contrast to other OP compounds, e.g., paraoxon (Rocha et al.,
1996a), methamidophos did not affect neurotransmitter release, nor did it
interact directly with the muscle nicotinic acetylcholine receptor. Moreover, it
contrast to paraoxon, methamidophos did not affect the whole-cell currents
induced by application of acetylcholine, glutamate or gamma-aminobutyric acid
recorded to cultured hippocampal neurons. Based on these data, methamidophos
appears to have a selective effect on cholinesterase.
PMID: 9291508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16088920 | 1. Am J Med Genet A. 2005 Sep 1;137A(3):302-4. doi: 10.1002/ajmg.a.30896.
Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation.
McGaughran J(1), Sinnott S, Dastot-Le Moal F, Wilson M, Mowat D, Sutton B,
Goossens M.
Author information:
(1)Queensland Clinical Genetics Service, Royal Children's Hospital, Brisbane,
Queensland, Australia. [email protected]
Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with
distinctive facial features, microcephaly, epilepsy, and a variable spectrum of
congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the
corpus callosum, genitourinary abnormalities, and congenital heart disease.
Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1)
[OMIM 605802] have recently been found to cause MWS. There have previously been
no reports of a sibling recurrence of this syndrome. A brother and sister are
described with clinical features of MWS, where both have the same truncating
mutation in exon 8 of ZFHX1B. As their parents are phenotypically normal and do
not have the mutation in lymphocyte-derived DNA, the most likely explanation is
germ-line mosaicism.
(c) 2005 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.30896
PMID: 16088920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17209571 | 1. Biochemistry. 2007 Jan 16;46(2):610-21. doi: 10.1021/bi062165b.
Carboxyl terminus of hsc70-interacting protein (CHIP) can remodel mature aryl
hydrocarbon receptor (AhR) complexes and mediate ubiquitination of both the AhR
and the 90 kDa heat-shock protein (hsp90) in vitro.
Morales JL(1), Perdew GH.
Author information:
(1)Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The
Pennsylvania State University, University Park, Pennsylvania 16802, USA.
The regulation of the aryl hydrocarbon receptor (AhR) protein levels has been an
area of keen interest, given its important role in mediating the cellular
adaptation and toxic response to several environmental pollutants. The carboxyl
terminus of hsc70-interacting protein (CHIP) ubiquitin ligase was previously
associated with the regulation of the aryl hydrocarbon receptor, although the
mechanisms were not directly demonstrated. In this study, we established that
CHIP could associate with the AhR at cellular levels of these two proteins,
suggesting a potential role for CHIP in the regulation of the AhR complex. The
analysis of the sucrose-gradient-fractionated in vitro translated AhR complexes
revealed that CHIP can mediate hsp90 ubiquitination while cooperating with
unidentified factors to promote the ubiquitination of mature unliganded AhR
complexes. In addition, the immunophilin-like protein XAP2 was able to partially
protect the AhR from CHIP-mediated ubiquitination in vitro. This protection
required the direct interaction of the XAP2 with the AhR complex. Surprisingly,
CHIP silencing in Hepa-1c1c7 cells by siRNA methods did not reveal the function
of CHIP in the AhR complex, because it did not affect well-characterized
activities of the AhR nor affect its steady-state protein levels. However, the
presence of potential compensatory mechanisms may be confounding this particular
observation. Our results suggest a model where the E3 ubiquitin ligase CHIP
cooperates with other ubiquitination factors to remodel native AhR-hsp90
complexes and where co-chaperones such as the XAP2 may affect the ability of
CHIP to target AhR complexes for ubiquitination.
DOI: 10.1021/bi062165b
PMCID: PMC2527729
PMID: 17209571 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24063013 | 1. Biomed Res Int. 2013;2013:742859. doi: 10.1155/2013/742859. Epub 2013 Aug 26.
Recent developments in production and biotechnological applications of
C-phycocyanin.
Kuddus M(1), Singh P, Thomas G, Al-Hazimi A.
Author information:
(1)Department of Biochemistry, College of Medicine, University of Hail, Hail
2440, Saudi Arabia.
An extensive range of pigments including phycobiliproteins are present in algae.
C-phycocyanin (C-PC), a phycobiliprotein, is one of the key pigments of
Spirulina, a microalgae used in many countries as a dietary supplement. Algal
pigments have massive commercial value as natural colorants in nutraceutical,
cosmetics, and pharmaceutical industries, besides their health benefits. At
present, increasing awareness of harmful effects of synthetic compounds and
inclination of community towards the usage of natural products have led to the
exploitation of microalgae as a source of natural pigments/colors. This review
describes recent findings about the sources and production of C-PC, with
emphasis on specific techniques for extraction and purification, along with
potential industrial applications in diagnostics, foods, cosmetics, and
pharmaceutical industries.
DOI: 10.1155/2013/742859
PMCID: PMC3770014
PMID: 24063013 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17525527 | 1. Cell Cycle. 2007 Jun 1;6(11):1393-402. doi: 10.4161/cc.6.11.4296. Epub 2007
Jun 13.
Low dose geldanamycin inhibits hepatocyte growth factor and hypoxia-stimulated
invasion of cancer cells.
Koga F(1), Tsutsumi S, Neckers LM.
Author information:
(1)Urologic Oncology Branch, Center for Cancer Research, National Cancer
Institute, Bethesda, Maryland 20892-1107, USA.
Hepatocyte growth factor (HGF) receptor Met and hypoxia-inducible factor-1
(HIF-1) signaling pathways are commonly activated in aggressive tumors and
promote progression. Since both Met and HIF-1alpha proteins are heat shock
protein (Hsp) 90 clients, Hsp90 inhibitors might be expected to positively
impact tumor progression. Here, we systematically evaluated the inhibitory
effects of the prototypical Hsp90 inhibitor geldanamycin (GA) on cellular
processes involved in invasion and angiogenesis in T24 bladder cancer cells
stimulated with HGF and chemical hypoxia. First, we demonstrated the positive
feedback loop between Met and HIF-1 pathways, which serves to sustain and
amplifies their signaling in T24 cells. GA downregulated Met by inhibiting new
protein maturation, thereby dampening HGF signaling. HGF and chemical hypoxia
with CoCl2 cooperatively promoted in vitro invasion and vascular endothelial
growth factor (VEGF) secretion, while CoCl2 but not HGF activated urokinase-type
plasminogen activator and matrix metalloproteinase 2, both of which promote
invasion and angiogenesis. Low dose GA (100 nmol/L) inhibited these processes by
suppressing both HGF and HIF-1 pathways. Notably, brief GA pretreatment
inhibited in vitro invasion and VEGF secretion induced by HGF as effectively as
did continuous treatment. Moreover, we found that GA inhibited activation of
focal adhesion kinase, focal adhesion assembly, and actin reorganization induced
by HGF and integrin engagement by extracellular matrix. Thus, GA widely
suppresses extrinsic stimuli-induced signaling that contribute to tumor invasion
and angiogenesis in this bladder carcinoma model, suggesting the utility of
Hsp90 inhibitors in preventing tumor progression and metastasis.
DOI: 10.4161/cc.6.11.4296
PMID: 17525527 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22814427 | 1. Ann Rheum Dis. 2012 Dec;71(12):2044-50. doi: 10.1136/annrheumdis-2012-201400.
Epub 2012 Jul 19.
Prostaglandin I(2) analogues enhance already exuberant Th17 cell responses in
systemic sclerosis.
Truchetet ME(1), Allanore Y, Montanari E, Chizzolini C, Brembilla NC.
Author information:
(1)Division of Immunology and Allergy, University Hospital and School of
Medicine, Geneva, Switzerland.
OBJECTIVE: Among pleiotropic effects, the capacity of prostaglandin I(2)
(PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The
purpose of this study was to assess whether PGI(2) analogues could affect T
helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy
donors (HD).
METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 33
patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell
cultures were quantified by immunoassays. The frequencies of interleukin
(IL)-17A, IL-22, interferon γ (IFNγ) and IL-4-producing CD4 T cells were
assessed by multiparametric flow cytometry. Selective receptor antagonists,
cytokine blocking antibodies and signalling protein inhibitors were used to
identify the receptors and signalling pathways mediating PGI(2) analogue
effects.
RESULTS: Th17 and Th22 cells were more abundant in individuals with SSc than in
HD. PGI(2) analogues (iloprost, treprostinil and beraprost) significantly
increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc
and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and
inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased
IL-23 production by monocytes, involved the IP prostacyclin receptor and
required protein kinase A activation. Importantly, in vivo administration of
iloprost in individuals with SSc presenting with digital ulcers resulted in a
significant increase in the frequency of Th17 cells.
CONCLUSIONS: These findings demonstrate that PGI(2) analogues affect Th cell
differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell
responses in SSc. The impact of these changes on the disease course needs to be
taken into consideration and further exploited to improve SSc.
DOI: 10.1136/annrheumdis-2012-201400
PMID: 22814427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19224391 | 1. Photosynth Res. 2009 Apr;100(1):7-17. doi: 10.1007/s11120-009-9412-8. Epub
2009 Feb 18.
Phycobiliprotein diffusion in chloroplasts of cryptophyte Rhodomonas CS24.
Mirkovic T(1), Wilk KE, Curmi PM, Scholes GD.
Author information:
(1)Department of Chemistry, Institute for Optical Sciences, Centre for Quantum
Information and Quantum Control, University of Toronto, 80 St. George Street,
Toronto, Ontario, Canada.
Unicellular cryptophyte algae employ antenna proteins with phycobilin
chromophores in their photosynthetic machinery. The mechanism of light
harvesting in these organisms is significantly different than the energy
funneling processes in phycobilisomes utilized by cyanobacteria and red algae.
One of the most striking features of cryptophytes is the location of the
water-soluble phycobiliproteins, which are contained within the intrathylakoid
spaces and are not on the stromal side of the lamellae as in the red algae and
cyanobacteria. Studies of mobility of phycobiliproteins at the lumenal side of
the thylakoid membranes and how their diffusional behavior may influence the
energy funneling steps in light harvesting are reported. Confocal microscopy and
fluorescence recovery after photobleaching (FRAP) are used to measure the
diffusion coefficient of phycoerythrin 545 (PE545), the primary light harvesting
protein of Rhodomonas CS24, in vivo. It is concluded that the diffusion of PE545
in the lumen is inhibited, suggesting possible membrane association or
aggregation as a potential source of mobility hindrance.
DOI: 10.1007/s11120-009-9412-8
PMID: 19224391 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9447621 | 1. Semin Pediatr Neurol. 1997 Dec;4(4):282-91. doi:
10.1016/s1071-9091(97)80014-9.
Neuropathology of pediatric brain tumors.
Yachnis AT(1).
Author information:
(1)Department of Pathology, Immunology, and Laboratory Medicine, University of
Florida Brain Institute, Gainesville, USA.
Pediatric central nervous system neoplasms include a spectrum of both glial and
nonglial tumors that differ significantly in location and biological behavior
from those of adults. Brain tumors in infants and children most often arise from
central neuroepithelial tissue, whereas a significant number of adult tumors
arise from central nervous system coverings (e.g., meningioma), adjacent tissue
(e.g., pituitary adenoma), or metastases. Most adult brain tumors are
supratentorial malignant gliomas, whereas the most common malignant pediatric
brain tumor is the cerebellar primitive neuroectodermal tumor (medulloblastoma).
This article reviews neuropathological characteristics of the more common
pediatric brain tumors. Entities, such as the brainstem glioma, and less common
neoplasms like the desmoplastic infantile ganglioglioma and the central nervous
system atypical teratoid/rhabdoid tumor are reviewed because they occur almost
exclusively in children. Known cytogenetic and molecular characteristics of
childhood brain tumors are also reviewed.
DOI: 10.1016/s1071-9091(97)80014-9
PMID: 9447621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25134955 | 1. Can J Microbiol. 2014 Sep;60(9):557-68. doi: 10.1139/cjm-2014-0209. Epub 2014
Jul 14.
New evidence on the relationship between Microsporidia and Fungi: a genome-wide
analysis by DarkHorse software.
Xiang H(1), Zhang R, De Koeyer D, Pan G, Li T, Liu T, Zhou Z.
Author information:
(1)a College of Animal Science and Technology, Southwest University, Beibei,
Chongqing 400715, People's Republic of China.
Microsporidia are a group of obligate intracellular eukaryotic parasites that
infect a wide variety of species, including humans. Phylogenetic analysis
indicates a relationship between the Microsporidia and the Fungi. However, most
results are based on the analysis of relatively few genes. DarkHorse analysis
involves the transformation of BLAST results into a lineage probability index
(LPI) value and allows for the comparison of genes for an entire genome with
those of other genomes. Thus, we can see which genes from the microsporidia
score most closely based on the LPI with other eukaryotic organisms. In this
analysis, we calculated the LPI for each gene from the genomes of 7
Microsporidia, Antonospora locustae, Enterocytozoon bieneusi, Encephalitozoon
cuniculi, Encephalitozoon intestinalis, Nosema bombycis, Nosema ceranae, and
Nematocida parisii, to analyze the genetic relationships between Microsporidia
and other species. It was found that many (91%) genes were most closely
correlated with genes from other microsporidial genomes and had the highest mean
LPI (0.985), indicating a monophyletic origin of the Microsporidia. In a
subsequent analysis, we excluded the other Microsporidia from the analysis to
look for relationships before the divergence of Microsporidia, and found that
43% of the microsporidial genes scored highest with fungal genes, and a higher
mean LPI was found with Fungi than with other kingdoms, suggesting that
Microsporidia is closely related to Fungi at the genomic level. Microsporidial
genes were functionally clustered based on the KOG (Eukaryotic COG) database,
and the possible lineages for each gene family were discussed in concert with
the DarkHorse results.
DOI: 10.1139/cjm-2014-0209
PMID: 25134955 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20674093 | 1. Neurobiol Aging. 2011 Dec;32(12):2323.e27-40. doi:
10.1016/j.neurobiolaging.2010.06.010. Epub 2010 Jul 31.
Nuclear localization sequence of FUS and induction of stress granules by ALS
mutants.
Gal J(1), Zhang J, Kwinter DM, Zhai J, Jia H, Jia J, Zhu H.
Author information:
(1)Department of Molecular and Cellular Biochemistry, College of Medicine,
University of Kentucky, Lexington, KY 40536, USA.
Mutations in fused in sarcoma (FUS) have been reported to cause a subset of
familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly
localized in the nuclei of neurons, but the ALS mutants are partly mislocalized
in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32
amino acid residues of FUS constitute an effective nuclear localization sequence
(NLS) as it targeted beta-galactosidase (LacZ, 116 kDa) to the nucleus. Deletion
of or the ALS mutations within the NLS caused cytoplasmic mislocalization of
FUS. Moreover, we identified the poly-A binding protein (PABP1), a stress
granule marker, as an interacting partner of FUS. Large PABP1-positive
cytoplasmic foci (i.e. stress granules) colocalized with the mutant FUS
inclusions but were absent in wild-type FUS-expressing cells. Processing bodies,
which are functionally related to stress granules, were adjacent to but not
colocalized with the mutant FUS inclusions. Our results suggest that the ALS
mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic
inclusions and stress granules, and potentially perturb RNA metabolism.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2010.06.010
PMCID: PMC2997923
PMID: 20674093 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16637459 | 1. Vnitr Lek. 2006 Mar;52 Suppl 1:119-22.
Emerging anticoagulants: mechanism of action and future potential.
Klement P(1), Rak J.
Author information:
(1)Henderson Research Centre and McMaster University, Hamilton, Canada.
[email protected]
Medical needs associated with diverse thromboembolic conditions are not fully
met by currently available anticoagulants. Of those, unfractionated heparin
(UFH) is gradually replaced by low molecular weight heparin (LMWH) for
prevention and treatment of venous thromboembolism and acute coronary syndromes,
along with supportive treatment with oral anticoagulants, such as warfarin
derivatives. While generally effective these agents have several shortcomings
involving compliance, delivery, efficacy and safety considerations in various
disease settings, and for these reasons new anticoagulants are sought, to target
more specifically the critical effectors and steps in the blood coagulation
process, namely: (i) initiation, (ii) propagation and (iii) the phase of
thrombin activity. The emerging agents that block tissue factor/factor
VIIa-dependent initiation phase of the coagulation cascade, include: recombinant
tissue factor pathway inhibitor (rTFPI), nematode anticoagulant peptide (NAPc2),
active site-blocked factor VIIa (FVIIai) and TF targeting antibodies. Some of
them are currently evaluated in clinical trials with promising results.
Propagation phase of thrombus formation (e.g. the activity of factors IXa, Xa,
VIIIa or Va) is targeted mainly by various indirect, direct and bimodal
inhibitors, such as fondaparinux, indraparinux, tick anticoagulant peptide
(TAP), antistatin (ANT) and antithrombin-heparin covalent complex (ATH), all
endowed mostly with an anti-Xa activity. Although promising, some of these
agents (TAP, ANT and ATH) have not progressed beyond animal testing while others
(fondaparinux) was already assessed for prevention and treatment of venous
thromboembolism and for treatment of arterial thrombosis. Lastly, inhibitors of
thrombin activity are composed of either indirect (UFH, LMWH), or direct
thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran,
ximelagatran, dabigatran, and bivalirudin. These agents are either in advanced
development or already approved for clinical use. Bimodal FIIa inhibitory
activity of ATH was demonstrated in animal models of venous and arterial
thrombosis, but is in need of further development. In conclusion, while some of
these emerging anticoagulants, such as fondaparinux, idraparinux, ximelagatran
and ATH appear to possess superior efficacy-safety profile, as compared to their
conventional predecessors (UFH, LMWH and warfarin), their cost-effectiveness,
side effects and antidote availability have to be considered. More importantly,
coagulation factors that are targets of these inhibitory activities also affect
coagulation independent processes, such as wound healing, inflammation,
angiogenesis, mitogenesis and cell survival. Thus the consequences of both
coagulation-dependent and -independent effects of new agents should be carefully
considered before proper clinical indications are established.
PMID: 16637459 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8042665 | 1. Am J Med Genet. 1994 Apr 15;50(3):228-33. doi: 10.1002/ajmg.1320500304.
Emery-Dreifuss syndrome: genetic and clinical varieties.
Rudenskaya GE(1), Ginter EK, Petrin AN, Djomina NA.
Author information:
(1)Research Centre of Medical Genetics, Academy of Medical Sciences, Moscow,
Russia.
Two familial and 2 sporadic cases of Emery-Dreifuss syndrome are reported. One
family presented a rare autosomal dominant variant of Emery-Dreifuss muscular
dystrophy, another with X-linked recessive inheritance showed unusual
intrafamilial variability. One of sporadic cases closely resembled rigid spine
syndrome, the other was clinically intermediate between Emery-Dreifuss muscular
dystrophy and rigid spine syndrome, showing that they are not distinct
disorders.
DOI: 10.1002/ajmg.1320500304
PMID: 8042665 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16585054 | 1. Brain. 2006 May;129(Pt 5):1260-8. doi: 10.1093/brain/awl062. Epub 2006 Apr 3.
Disease severity in dominant Emery Dreifuss is increased by mutations in both
emerin and desmin proteins.
Muntoni F(1), Bonne G, Goldfarb LG, Mercuri E, Piercy RJ, Burke M, Yaou RB,
Richard P, Récan D, Shatunov A, Sewry CA, Brown SC.
Author information:
(1)Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital,
London, UK. [email protected]
Individuals with the same genetic disorder often show remarkable differences in
clinical severity, a finding generally attributed to the genetic background. We
identified two patients with genetically proven Emery-Dreifuss muscular
dystrophy (EDMD) who followed an unusual course and had uncommon
clinicopathological findings. We hypothesized digenic inheritance and looked for
additional molecular explanations. Mutations in additional separate genes were
identified in both patients. The first patient was a member of a family with
molecularly proven X-linked EDMD. However, the clinical features were unusually
severe for this condition in the propositus: he presented at 2.5 years with
severe proximal weakness and markedly elevated serum creatine kinase. Muscle
weakness rapidly progressed, leading to loss of independent ambulation by the
age of 12. In addition, the patient developed cardiac conduction system disease
requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early
teens. Despite pacing, he had several syncopal episodes attributed to
ventricular dysrhythmias. As these resemble the cardiac features of patients
with the autosomal dominant variant of EDMD, we examined the lamin A/C gene,
identifying a de-novo mutation in the propositus. The second patient had a
cardioskeletal myopathy, similar to his mother who had died more than 20 years
previously. Because of the dominant family history, a laminopathy was suspected
and a mutation in exon 11 of the LMNA gene was identified. This mutation,
however, was not present in his mother, but instead, surprisingly, was
identified in his virtually asymptomatic father. Unusual accumulations of desmin
found in the cardiac muscle of the propositus prompted us to examine the desmin
gene in this patient, and in so doing, we identified a desmin mutation, in
addition to the LMNA mutation in the propositus. These cases suggest that
separate mutations in related proteins that are believed to interact, or that
represent different parts of a presumed functional pathway, may synergistically
contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic
inheritance may well contribute to the clinical severity of many other
neuromuscular disorders.
DOI: 10.1093/brain/awl062
PMID: 16585054 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12416885 | 1. J Chromatogr A. 2002 Oct 4;972(2):269-76. doi: 10.1016/s0021-9673(02)01085-3.
Separation and quantitation of phycobiliproteins using phytic acid in capillary
electrophoresis with laser-induced fluorescence detection.
Viskari PJ, Colyer CL.
The similar electrophoretic mobilities and sizes of several of the
phycobiliproteins, which are derived from the photosynthetic apparatus of
cyanobacteria and eukaryotic algae, render their separation and quantitation a
challenging problem. However, we have developed a suitable capillary
electrophoresis (CE) method that employs a phytic acid-boric acid buffer and
laser-induced fluorescence (LIF) detection with a single 594 nm He-Ne laser.
This method takes advantage of the remarkably high quantum yields of these
naturally fluorescent proteins, which can be attributed to their linear
tetrapyrrole chromophores covalently bound to cysteinyl residues. As such,
limits of detection of 1.18 x 10(-14), 5.26 x 10(-15), and 2.38 x 10(-15) mol/l
were obtained for R-phycoerythrin, C-phycocyanin, and allophycocyanin proteins,
respectively, with a linear dynamic range of eight orders of magnitude in each
case. Unlike previously published CE-LIF methods, this work describes the
separation of all three major classes of phycobiliproteins in under 5 min. Very
good recoveries, ranging from 93.2 to 105.5%, were obtained for a standard
mixture of the phycobiliproteins, based on seven-point calibration curves for
both peak height and peak area. It is believed that this development will prove
useful for the determination of phycobiliprotein content in naturally occurring
cyanobacteria populations, thus providing a useful tool for understanding
biological and chemical oceanographic processes.
DOI: 10.1016/s0021-9673(02)01085-3
PMID: 12416885 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18062815 | 1. Genome Biol. 2007;8(12):R259. doi: 10.1186/gb-2007-8-12-r259.
Diversity and evolution of phycobilisomes in marine Synechococcus spp.: a
comparative genomics study.
Six C(1), Thomas JC, Garczarek L, Ostrowski M, Dufresne A, Blot N, Scanlan DJ,
Partensky F.
Author information:
(1)UMR 7144 Université Paris VI and CNRS, Station Biologique, Groupe Plancton
Océanique, F-29682 Roscoff cedex, France. [email protected]
BACKGROUND: Marine Synechococcus owe their specific vivid color (ranging from
blue-green to orange) to their large extrinsic antenna complexes called
phycobilisomes, comprising a central allophycocyanin core and rods of variable
phycobiliprotein composition. Three major pigment types can be defined depending
on the major phycobiliprotein found in the rods (phycocyanin, phycoerythrin I or
phycoerythrin II). Among strains containing both phycoerythrins I and II, four
subtypes can be distinguished based on the ratio of the two chromophores bound
to these phycobiliproteins. Genomes of eleven marine Synechococcus strains
recently became available with one to four strains per pigment type or subtype,
allowing an unprecedented comparative genomics study of genes involved in
phycobilisome metabolism.
RESULTS: By carefully comparing the Synechococcus genomes, we have retrieved
candidate genes potentially required for the synthesis of phycobiliproteins in
each pigment type. This includes linker polypeptides, phycobilin lyases and a
number of novel genes of uncharacterized function. Interestingly, strains
belonging to a given pigment type have similar phycobilisome gene complements
and organization, independent of the core genome phylogeny (as assessed using
concatenated ribosomal proteins). While phylogenetic trees based on concatenated
allophycocyanin protein sequences are congruent with the latter, those based on
phycocyanin and phycoerythrin notably differ and match the Synechococcus pigment
types.
CONCLUSION: We conclude that the phycobilisome core has likely evolved together
with the core genome, while rods must have evolved independently, possibly by
lateral transfer of phycobilisome rod genes or gene clusters between
Synechococcus strains, either via viruses or by natural transformation, allowing
rapid adaptation to a variety of light niches.
DOI: 10.1186/gb-2007-8-12-r259
PMCID: PMC2246261
PMID: 18062815 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10744320 | 1. J Chromatogr B Biomed Sci Appl. 2000 Feb 28;739(1):117-23. doi:
10.1016/s0378-4347(99)00433-8.
One-step purification of R-phycoerythrin from the red macroalga Palmaria palmata
using preparative polyacrylamide gel electrophoresis.
Galland-Irmouli AV(1), Pons L, Luçon M, Villaume C, Mrabet NT, Guéant JL,
Fleurence J.
Author information:
(1)Laboratoire de Pathologie Cellulaire et Moléculaire en Nutrition, EP CNRS
0616, Faculté de Médecine, BP 184, Vandoeuvre lès Nancy, France.
Phycoerythrin is a major light-harvesting pigment of red algae and cyanobacteria
widely used as a fluorescent probe. In this study, phycoerythrin of the red
macroalga Palmaria palmata was extracted by grinding the algal sample in liquid
nitrogen, homogenisation in phosphate buffer and centrifugation. Phycoerythrin
was then purified from this crude extract using preparative polyacrylamide gel
electrophoresis (PAGE) with a continuous elution system and detected by its pink
colour and fluorescence. The pigment presented a typical spectrum of
R-phycoerythrin, with three absorbance maxima at 499, 545 and 565 nm, and
displayed a fluorescence maximum at 578 nm. The absorbance ratio A565/A280, a
criterion for purity, was 3.2. A single protein of relative molecular mass
240,000 was detected on native-PAGE with silver staining. Sodium dodecyl
sulphate-PAGE demonstrated the presence of two major subunits with Mr 20,000 and
21,000, respectively, and a very minor subunit of Mr 30,000. These observations
are consistent with the (alphabeta)6gamma subunit composition characteristic of
R-phycoerythrin. Phycoerythrin of Palmaria palmata was determined to be present
in larger amounts in autumn and showed a good stability up to 60 degrees C and
between pH 3.5 and 9.5. In conclusion, phycoerythrin of Palmaria palmata was
purified in a single-step using preparative PAGE. Obtaining pure R-phycoerythrin
of Palmaria palmata will allow one to evaluate its fluorescence properties for
future applications in biochemical techniques.
DOI: 10.1016/s0378-4347(99)00433-8
PMID: 10744320 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11731280 | 1. Neuromuscul Disord. 2002 Jan;12(1):19-25. doi: 10.1016/s0960-8966(01)00239-5.
Autosomal dominant Emery-Dreifuss muscular dystrophy: a new family with late
diagnosis.
Colomer J(1), Iturriaga C, Bonne G, Schwartz K, Manilal S, Morris GE, Puche M,
Fernández-Alvarez E.
Author information:
(1)Servei de Neurologia, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2,
08950 Esplugues, Barcelona, Spain. [email protected]
Emery-Dreifuss muscular dystrophy is characterized by the clinical triad of
early onset contractures of elbows, Achilles tendons and spine, wasting and
weakness with a predominantly humero-peroneal distribution and life-threatening
cardiac conduction defects and/or cardiomyopathy. Two main types of inheritance
have been described: the X-linked form is caused by mutations in the STA gene on
locus Xq28 and the gene for the autosomal dominant form (LMNA gene) has been
localized on chromosome 1q11-q23. Recently, mutations in this LMNA gene have
been also found to be responsible for the less frequent autosomal recessive form
of the disease. Although all forms share a similar clinical presentation, some
differences appear to exist between them as has been described recently in a
large number of patients. We present the first documented Spanish family
genetically confirmed to have autosomal dominant Emery-Dreifuss muscular
dystrophy. Clinical, pathological and genetic data are described. We emphasize
the difficulties in diagnosis, especially in sporadic cases or young patients in
whom the clinical picture is not completely established.
DOI: 10.1016/s0960-8966(01)00239-5
PMID: 11731280 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16791377 | 1. Arq Neuropsiquiatr. 2006 Jun;64(2A):314-7. doi:
10.1590/s0004-282x2006000200027. Epub 2006 Jun 9.
[Emery-Dreifuss muscular dystrophy: case report].
[Article in Portuguese]
Carsten AL(1), Lorenzoni PJ, Scola RH, Werneck LC.
Author information:
(1)Serviço de Doenças Neuromusculares, Hospital de Clínicas, Universidade
Federal do Paraná, Curitiba, PR, Brazil.
The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that
frequently presents early contractures and cardiac conduction defects, caused by
emerin deficiency in the inner nuclear membrane of the muscular fibers. A
19-years-old man it presented muscle weakness and hypotrophy in the proximal
upper and lower limbs, dysphagia and early contractures in elbows and ankles,
with familiar history compatible with X-linked inheritance form. The
investigation showed increased serum creatinekinase levels electrocardiogram had
a first degree atrioventricular block and right bundle branch block normal
electromyography and nerve conduction study muscle biopsy disclosed myopathic
characteristics and nuclear protein immunohystochemical analysis showed
deficiency of emerin. The clinical and genetics manifestations, laboratorial and
electromyography changes, as well as, the study of the pattern of inheritance
for genetic counseling are discussed.
DOI: 10.1590/s0004-282x2006000200027
PMID: 16791377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21795750 | 1. Genome Biol Evol. 2011;3:974-84. doi: 10.1093/gbe/evr072. Epub 2011 Jul 27.
The Anolis lizard genome: an amniote genome without isochores.
Fujita MK(1), Edwards SV, Ponting CP.
Author information:
(1)Museum of Comparative Zoology, Department of Organismic and Evolutionary
Biology, Harvard University, Cambridge, Massachusetts, USA.
[email protected]
Isochores are large regions of relatively homogeneous nucleotide composition and
are present in the genomes of all mammals and birds that have been sequenced to
date. The newly sequenced genome of Anolis carolinensis provides the first
opportunity to quantify isochore structure in a nonavian reptile. We find Anolis
to have the most compositionally homogeneous genome of all amniotes sequenced
thus far, a homogeneity exceeding that for the frog Xenopus. Based on a Bayesian
algorithm, Anolis has smaller and less GC-rich isochores compared with human and
chicken. Correlates generally associated with GC-rich isochores, including
shorter introns and higher gene density, have all but disappeared from the
Anolis genome. Using genic GC as a proxy for isochore structure so as to compare
with other vertebrates, we found that GC content has substantially decreased in
the lineage leading to Anolis since diverging from the common ancestor of
Reptilia ∼275 Ma, perhaps reflecting weakened or reversed GC-biased gene
conversion, a nonadaptive substitution process that is thought to be important
in the maintenance and trajectory of isochore evolution. Our results demonstrate
that GC composition in Anolis is not associated with important features of
genome structure, including gene density and intron size, in contrast to
patterns seen in mammal and bird genomes.
DOI: 10.1093/gbe/evr072
PMCID: PMC3184785
PMID: 21795750 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23810808 | 1. Exp Eye Res. 2013 Oct;115:113-22. doi: 10.1016/j.exer.2013.06.007. Epub 2013
Jun 28.
Regulation of Na,K-ATPase β1-subunit in TGF-β2-mediated
epithelial-to-mesenchymal transition in human retinal pigmented epithelial
cells.
Mony S(1), Lee SJ, Harper JF, Barwe SP, Langhans SA.
Author information:
(1)Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Rockland
Center I, 1701 Rockland Road, Wilmington, DE 19803, USA. Electronic address:
[email protected].
Proliferative vitreo retinopathy (PVR) is associated with extracellular matrix
membrane (ECM) formation on the neural retina and disruption of the multilayered
retinal architecture leading to distorted vision and blindness. During disease
progression in PVR, retinal pigmented epithelial cells (RPE) lose cell-cell
adhesion, undergo epithelial-to-mesenchymal transition (EMT), and deposit ECM
leading to tissue fibrosis. The EMT process is mediated via exposure to vitreous
cytokines and growth factors such as TGF-β2. Previous studies have shown that
Na,K-ATPase is required for maintaining a normal polarized epithelial phenotype
and that decreased Na,K-ATPase function and subunit levels are associated with
TGF-β1-mediated EMT in kidney cells. In contrast to the basolateral localization
of Na,K-ATPase in most epithelia, including kidney, Na,K-ATPase is found on the
apical membrane in RPE cells. We now show that EMT is also associated with
altered Na,K-ATPase expression in RPE cells. TGF-β2 treatment of ARPE-19 cells
resulted in a time-dependent decrease in Na,K-ATPase β1 mRNA and protein levels
while Na,K-ATPase α1 levels, Na,K-ATPase activity, and intracellular sodium
levels remained largely unchanged. In TGF-β2-treated cells reduced Na,K-ATPase
β1 mRNA inversely correlated with HIF-1α levels and analysis of the Na,K-ATPase
β1 promoter revealed a putative hypoxia response element (HRE). HIF-1α bound to
the Na,K-ATPase β1 promoter and inhibiting the activity of HIF-1α blocked the
TGF-β2 mediated Na,K-ATPase β1 decrease suggesting that HIF-1α plays a potential
role in Na,K-ATPase β1 regulation during EMT in RPE cells. Furthermore,
knockdown of Na,K-ATPase β1 in ARPE-19 cells was associated with a change in
cell morphology from epithelial to mesenchymal and induction of EMT markers such
as α-smooth muscle actin and fibronectin, suggesting that loss of Na,K-ATPase β1
is a potential contributor to TGF-β2-mediated EMT in RPE cells.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.exer.2013.06.007
PMCID: PMC3796007
PMID: 23810808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25657347 | 1. Genetics. 2015 Feb;199(2):293-306. doi: 10.1534/genetics.114.172510.
Brainbow: new resources and emerging biological applications for multicolor
genetic labeling and analysis.
Weissman TA(1), Pan YA(2).
Author information:
(1)Department of Biology, Lewis and Clark College, Portland, Oregon 97219
[email protected] [email protected].
(2)Department of Neuroscience and Regenerative Medicine, Medical College of
Georgia, Georgia Regents University, Augusta, Georgia 30912 Department of
Neurology, Medical College of Georgia, Georgia Regents University, Augusta,
Georgia 30912 James and Jean Culver Vision Discovery Institute, Medical College
of Georgia, Georgia Regents University, Augusta, Georgia 30912
[email protected] [email protected].
Brainbow is a genetic cell-labeling technique where hundreds of different hues
can be generated by stochastic and combinatorial expression of a few spectrally
distinct fluorescent proteins. Unique color profiles can be used as cellular
identification tags for multiple applications such as tracing axons through the
nervous system, following individual cells during development, or analyzing cell
lineage. In recent years, Brainbow and other combinatorial expression strategies
have expanded from the mouse nervous system to other model organisms and a wide
variety of tissues. Particularly exciting is the application of Brainbow in
lineage tracing, where this technique has been instrumental in parsing out
complex cellular relationships during organogenesis. Here we review recent
findings, new technical improvements, and exciting potential genetic and genomic
applications for harnessing this colorful technique in anatomical,
developmental, and genetic studies.
Copyright © 2015 by the Genetics Society of America.
DOI: 10.1534/genetics.114.172510
PMCID: PMC4317644
PMID: 25657347 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18792103 | 1. Cell Motil Cytoskeleton. 2008 Dec;65(12):935-44. doi: 10.1002/cm.20315.
Inflammatory cytokines augments TGF-beta1-induced epithelial-mesenchymal
transition in A549 cells by up-regulating TbetaR-I.
Liu X(1).
Author information:
(1)Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal
Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
[email protected]
Epithelial-mesenchymal transition (EMT) is believed to play an important role in
fibrosis and tumor invasion. EMT can be induced in vitro cell culture by various
stimuli including growth factors and matrix metalloproteinases. In this study,
we report that cytomix (a mixture of IL-1beta, TNF-alpha and IFN-gamma)
significantly enhances TGF-beta1-induced EMT in A549 cells as evidenced by
acquisition of fibroblast-like cell shape, loss of E-cadherin, and
reorganization of F-actin. IL-1beta or TNF-alpha alone can also augment
TGF-beta1-induced EMT. However, a combination of IL-1beta and TNF-alpha or the
cytomix is more potent to induce EMT. Cytomix, but not individual cytokine of
IL-1beta, TNF-alpha or IFN-gamma, significantly up-regulates expression of
TGF-beta receptor type I (TbetaR-I). Suppression of TbetaR-I, Smad2 or Smad3 by
siRNA partially blocks EMT induction by cytomix plus TGF-beta1, indicating
cytomix augments TGF-beta1-induced EMT through enhancing TbetaR-I and Smad
signaling. These results indicate that inflammatory cytokines together with
TGF-beta1 may play an important role in the development of fibrosis and tumor
progress via the mechanism of epithelial-mesenchymal transition.
Copyright 2008 Wiley-Liss, Inc.
DOI: 10.1002/cm.20315
PMID: 18792103 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11790801 | 1. J Cell Biol. 2002 Jan 21;156(2):299-313. doi: 10.1083/jcb.200109037. Epub 2002
Jan 14.
Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and
metastasis: dissection of Ras signaling pathways.
Janda E(1), Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H,
Grünert S.
Author information:
(1)Institute of Molecular Pathology, A-1030 Vienna, Austria.
Multistep carcinogenesis involves more than six discrete events also important
in normal development and cell behavior. Of these, local invasion and metastasis
cause most cancer deaths but are the least well understood molecularly. We
employed a combined in vitro/in vivo carcinogenesis model, that is, polarized
Ha-Ras-transformed mammary epithelial cells (EpRas), to dissect the role of Ras
downstream signaling pathways in epithelial cell plasticity, tumorigenesis, and
metastasis. Ha-Ras cooperates with transforming growth factor beta (TGFbeta) to
cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell
morphology, loss of epithelial markers, and induction of mesenchymal markers.
EMT requires continuous TGFbeta receptor (TGFbeta-R) and oncogenic Ras signaling
and is stabilized by autocrine TGFbeta production. In contrast, fibroblast
growth factors, hepatocyte growth factor/scatter factor, or TGFbeta alone induce
scattering, a spindle-like cell phenotype fully reversible after factor
withdrawal, which does not involve sustained marker changes. Using specific
inhibitors and effector-specific Ras mutants, we show that a hyperactive
Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas
activation of phosphatidylinositol 3-kinase (PI3K) causes scattering and
protects from TGFbeta-induced apoptosis. Hyperactivation of the PI3K pathway or
the Raf/MAPK pathway are sufficient for tumorigenesis, whereas EMT in vivo and
metastasis required a hyperactive Raf/MAPK pathway. Thus, EMT seems to be a
close in vitro correlate of metastasis, both requiring synergism between
TGFbeta-R and Raf/MAPK signaling.
DOI: 10.1083/jcb.200109037
PMCID: PMC2199233
PMID: 11790801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17998275 | 1. J Hered. 2008 Jan-Feb;99(1):73-80. doi: 10.1093/jhered/esm090. Epub 2007 Nov
12.
Evaluation of 15 candidate genes for dilated cardiomyopathy in the Newfoundland
dog.
Wiersma AC(1), Stabej P, Leegwater PA, Van Oost BA, Ollier WE, Dukes-McEwan J.
Author information:
(1)Small Animal Teaching Hospital, University of Liverpool, Leahurst, Chester
High Road, Neston, CH64 7TE, United Kingdom. [email protected]
Dilated cardiomyopathy (DCM) is a disease of the myocardium, which causes heart
failure and premature death. It has been described in humans and several
domestic animals. In the Newfoundland dog, DCM is an autosomal dominant disease
with late onset and reduced penetrance. We analyzed 15 candidate genes for their
involvement in DCM in the Newfoundland dog. Polymorphic microsatellite markers
and single Nucleotide Polymorphisms were genotyped in 4 families of Newfoundland
dogs segregating dilated cardiomyopathy for the genes encoding alpha-cardiac
actin (ACTC), caveolin (CAVI), cysteine-rich protein 3 (CSRP3), LIM-domain
binding factor 3 (LDB3), desmin (DES), lamin A/C (LMNA), myosin heavy
polypeptide 7 (MYH7), delta-sarcoglycan (SGCD), troponin I (TNNTI3), troponin T
(TNNT2), alpha-tropomyosin (TPMI), titin (TTN) and vinculin (VCL). A Logarithm
of the odds (LOD) score of less than -2.0 in 2-point linkage analysis indicated
exclusion of all but 2 genes, encoding CSRP3 and DES. A (LOD) score between -1.5
and -2.0 for CSRP3 and DES makes these genes unlikely causes of DCM in this dog
breed. For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation
screening approach was used. DNA sequence analysis of all exons showed no
evidence that these genes are involved in DCM in the Newfoundland dog.
DOI: 10.1093/jhered/esm090
PMID: 17998275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19888525 | 1. Thromb Haemost. 2009 Nov;102(5):892-9. doi: 10.1160/TH09-02-0134.
Direct inhibitors of coagulation proteins - the end of the heparin and
low-molecular-weight heparin era for anticoagulant therapy?
Laux V(1), Perzborn E, Heitmeier S, von Degenfeld G, Dittrich-Wengenroth E,
Buchmüller A, Gerdes C, Misselwitz F.
Author information:
(1)Global Drug Discovery, Bayer Schering Pharma AG, , 42096 Wuppertal, Germany.
[email protected]
Heparins, either unfractionated or low-molecular-weight (UFH and LMWHs), and
vitamin K antagonists (VKAs) are currently the anticoagulants of choice for the
prevention of post-operative venous thromboembolism (VTE) and for the treatment
of acute venous and arterial thromboembolism. While VKAs are widely used in the
US, LMWHs are the standard of care in the EU. Although efficacious, these agents
are associated with a number of drawbacks, such as the risk of heparin-induced
thrombocytopenia, the need for frequent coagulation monitoring in the case of
UFH and VKAs, and the parenteral mode of administration in the case of heparins,
which can lead to problems associated with patient compliance. There is a need
for new anticoagulants that overcome these limitations. Direct, small-molecule
inhibitors of coagulation proteins targeting a single enzyme in the coagulation
cascade - particularly thrombin or Factor Xa - have been developed in recent
years. Two agents, the direct thrombin inhibitor dabigatran and the direct
Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and
several other countries for the prevention of VTE after total hip or knee
replacement surgery. Here we will review data that suggest that the
antithrombin-independent mechanism of action of these agents, particularly that
of direct Factor Xa inhibitors, leads to increased efficacy with similar safety
profiles compared with the antithrombin-dependent heparins. Although the end of
the heparins era is not to be expected, the new anticoagulants presented in this
review potentially represent the future of anticoagulation.
DOI: 10.1160/TH09-02-0134
PMID: 19888525 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21542867 | 1. Mol Microbiol. 2011 Jul;81(1):232-48. doi: 10.1111/j.1365-2958.2011.07689.x.
Epub 2011 May 25.
The oxidative stress response in yeast cells involves changes in the stability
of Aft1 regulon mRNAs.
Castells-Roca L(1), Mühlenhoff U, Lill R, Herrero E, Bellí G.
Author information:
(1)Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida,
Montserrat Roig 2, 25008 Lleida, Spain.
Saccharomyces cerevisiae can import iron through a high-affinity system
consisting of the Ftr1/Fet3-mediated reductive pathway and the
siderophore-mediated non-reductive one. Expression of components of the
high-affinity system is controlled by the Aft1 transcriptional factor. In this
study we show that, upon oxidative stress, Aft1 is transitorily internalized
into the nucleus, followed by transcription activation of components of its
regulon. In these conditions, the mRNA levels of the genes of the non-reductive
pathway become increased, while those of FTR1 and FET3 remain low because of
destabilization of the mRNAs. Consequently, the respective protein levels also
remain low. Such mRNA destabilization is mediated by the general 5'-3' mRNA
decay pathway and is independent of the RNA binding protein Cth2. Yeast cells
are hypersensitive to peroxides in growth conditions where only the
high-affinity reductive pathway is functional for iron assimilation. On the
contrary, peroxide does not affect growth when iron uptake occurs exclusively
through the non-reductive pathway. This reinforces the idea that upon oxidative
stress S. cerevisiae cells redirect iron assimilation through the non-reductive
pathway to minimize oxidative damage by the ferrous ions, which are formed
during iron import through the Ftr1/Fet3 complexes.
© 2011 Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-2958.2011.07689.x
PMID: 21542867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7593195 | 1. J Cell Biol. 1995 Nov;131(3):761-73. doi: 10.1083/jcb.131.3.761.
pp60c-src is a positive regulator of growth factor-induced cell scattering in a
rat bladder carcinoma cell line.
Rodier JM(1), Vallés AM, Denoyelle M, Thiery JP, Boyer B.
Author information:
(1)UMR 144 CNRS, Institut Curie Section de Recherche, Paris, France.
The NBT-II rat carcinoma cell line exhibits two mutually exclusive responses to
FGF-1 and EGF, entering mitosis at cell confluency while undergoing an
epithelium-to-mesenchyme transition (EMT) when cultured at subconfluency. EMT is
characterized by acquisition of cell motility, modifications of cell morphology,
and cell dissociation correlating with the loss of desmosomes from cellular
cortex. The pleiotropic effects of EGF and FGF-1 on NBT-II cells suggest that
multiple signaling pathways may be activated. We demonstrate here that growth
factor activation is linked to at least two intracellular signaling pathways.
One pathway leading to EMT involves an early and sustained stimulation of
pp60c-src kinase activity, which is not observed during the growth
factor-induced entry into the cell cycle. Overexpression of normal c-src causes
a subpopulation of cells to undergo spontaneous EMT and sensitizes the rest of
the population to the scattering activity of EGF and FGF-1 without affecting
their mitogenic responsiveness. Addition of cholera toxin, a cAMP-elevating
agent, severely perturbs growth factor induction of EMT without altering
pp60c-src activation, therefore demonstrating that cAMP blockade takes place
downstream or independently of pp60c-src. On the other hand, overexpression of a
mutated, constitutively activated form of pp60c-src does not block cell
dispersion while strongly inhibiting growth factor-induced entry into cell
division. Moreover, stable transfection of a dominant negative mutant of c-src
inhibits the scattering response without affecting mitogenesis induced by the
growth factors. Altogether, these results suggest a role for pp60c-src in
epithelial cell scattering and indicate that pp60c-src might contribute
unequally to the two separate biological activities engendered by a single
signal.
DOI: 10.1083/jcb.131.3.761
PMCID: PMC2120611
PMID: 7593195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16868306 | 1. Am J Physiol Renal Physiol. 2006 Dec;291(6):F1323-31. doi:
10.1152/ajprenal.00480.2005. Epub 2006 Jul 25.
Prostaglandin E2 is a potent inhibitor of epithelial-to-mesenchymal transition:
interaction with hepatocyte growth factor.
Zhang A(1), Wang MH, Dong Z, Yang T.
Author information:
(1)Division of Nephrology, University of Utah and VA Medical Center, Salt Lake
City, UT 84148, USA.
Epithelial-to-mesenchymal transition (EMT) has emerged as a critical event in
the pathogenesis of tubulointerstitial fibrosis. EMT is typically induced by
transforming growth factor-beta1 (TGF-beta1) and inhibited by hepatocyte growth
factor (HGF). The present study was undertaken to evaluate the potential role of
cyclooxygenase (COX)-2-derived PGE2 in regulation of EMT in cultured Madin-Darby
canine kidney (MDCK) cells, in the setting of HGF treatment. Exposure to 50
ng/ml HGF significantly induced COX-2 protein expression and PGE2 release,
whereas other growth factors, including epidermal growth factor, the
insulin-like growth factor I protein, platelet-derived growth factor-BB, and
TGF-beta1, had no effects on COX-2 expression or PGE2 release. COX-2 induction
by HGF was preceded by activation of ERK1/2, and an ERK1/2-specific inhibitor,
U-0126 (10 microM), completely abolished HGF-induced COX-2 expression. Exposure
of MDCK cells to 10 ng/ml TGF-beta1 for 72 h induced EMT as evidenced by
conversion to the spindle-like morphology, loss of E-cadherin, and activation of
alpha-smooth muscle actin. In contrast, treatment with 1 microM PGE2 completely
blocked EMT, associated with a significant elevation of intracellular cAMP and
complete blockade of TGF-beta1-induced oxidant production. cAMP-elevating
agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated
oxidative stress induced by TGF-beta1, but inhibition of cAMP pathway with
Rp-cAMP, the cAMP analog, and H89, the protein kinase A (PKA) inhibitor, did not
block the effect of PGE2. The effect of HGF on EMT was inhibited by
approximately 50% in the presence of a COX-2 inhibitor SC-58635 (10 microM).
Therefore, our data suggest that PGE2 inhibits EMT via inhibition of oxidant
production and COX-2-derived PGE2 partially accounts for the antifibrotic effect
of HGF.
DOI: 10.1152/ajprenal.00480.2005
PMID: 16868306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6788711 | 1. Int Adv Surg Oncol. 1981;4:277-310.
Prolatin secreting pituitary adenomas.
Leavens ME, Samaan NA, Larson DL, Jesse RH, Byers RM.
Prolactin secreting adenomas are the most frequently (50%) occurring pituitary
adenoma. They occur more commonly in women than in men (4:1). Impairment of
gonadal function accounts for the predominant symptoms in both sexes. Forty
females and ten males with prolactin secreting adenomas were treated with
selective adenoma removal by transsphenoidal surgery. Duration of symptoms
varied from two months to 25 years. Twenty percent of the women and 100% of the
men had invasive adenomas, a tumor that is difficult or impossible to eradicate.
The chances of surgically correcting hyperprolactinemia in the female patient
was 75% if the preoperative basal prolactin was 200 ng/ml or less, or 71% if the
adenoma was non-invasive. The men were more difficult to treat because they all
had invasive adenoma. In 50% of the men, prolactin was normalized by surgery.
Early recognition of these patients before the adenomas become invasive is
needed.
PMID: 6788711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25547603 | 1. Nat Genet. 2015 Jan;47(1):8-12. doi: 10.1038/ng.3167.
What are super-enhancers?
Pott S(1), Lieb JD(1).
Author information:
(1)Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
Comment in
Nat Genet. 2015 Jan;47(1):1. doi: 10.1038/ng.3188.
The term 'super-enhancer' has been used to describe groups of putative enhancers
in close genomic proximity with unusually high levels of Mediator binding, as
measured by chromatin immunoprecipitation and sequencing (ChIP-seq). Here we
review the identification and composition of super-enhancers, describe links
between super-enhancers, gene regulation and disease, and discuss the functional
significance of enhancer clustering. We also provide our perspective regarding
the proposition that super-enhancers are a regulatory entity conceptually
distinct from what was known before the introduction of the term. Our opinion is
that there is not yet strong evidence that super-enhancers are a novel paradigm
in gene regulation and that use of the term in this context is not currently
justified. However, the term likely identifies strong enhancers that exhibit
behaviors consistent with previous models and concepts of transcriptional
regulation. In this respect, the super-enhancer definition is useful in
identifying regulatory elements likely to control genes important for cell type
specification.
DOI: 10.1038/ng.3167
PMID: 25547603 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9489705 | 1. Cell. 1998 Jan 9;92(1):117-29. doi: 10.1016/s0092-8674(00)80904-6.
Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch
recognition by complementary-strand interactions.
Barrett TE(1), Savva R, Panayotou G, Barlow T, Brown T, Jiricny J, Pearl LH.
Author information:
(1)Department of Biochemistry and Molecular Biology, University College London,
United Kingdom.
G:U mismatches resulting from deamination of cytosine are the most common
promutagenic lesions occurring in DNA. Uracil is removed in a base-excision
repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both
single- and double-stranded DNA. Recently, a biochemically distinct family of
DNA repair enzymes has been identified, which excises both uracil and thymine,
but only from mispairs with guanine. Crystal structures of the mismatch-specific
uracil DNA-glycosylase (MUG) from E. coli, and of a DNA complex, reveal a
remarkable structural and functional homology to UDGs despite low sequence
identity. Details of the MUG structure explain its thymine DNA-glycosylase
activity and the specificity for G:U/T mispairs, which derives from direct
recognition of guanine on the complementary strand.
DOI: 10.1016/s0092-8674(00)80904-6
PMID: 9489705 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25263595 | 1. Mol Cell. 2014 Oct 23;56(2):219-231. doi: 10.1016/j.molcel.2014.08.024. Epub
2014 Sep 25.
NF-κB directs dynamic super enhancer formation in inflammation and
atherogenesis.
Brown JD(#)(1), Lin CY(#)(2), Duan Q(#)(1)(3), Griffin G(4), Federation A(2),
Paranal RM(2), Bair S(4), Newton G(4), Lichtman A(4), Kung A(2)(5), Yang T(3),
Wang H(1), Luscinskas FW(4), Croce K(1), Bradner JE(2), Plutzky J(1).
Author information:
(1)Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA 02115, USA.
(2)Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical
School, Boston, MA 02115, USA.
(3)Cardiovascular Division, Xiangya Hospital, Central South University, 410078
Changsha, Hunan, PR China.
(4)Vascular Research Division, Department of Pathology, Harvard Medical School,
Boston, MA 02115, USA.
(5)Department of Pediatrics, Columbia University Medical Center, New York, NY
10032, USA.
(#)Contributed equally
Comment in
Trends Cell Biol. 2014 Nov;24(11):615-6. doi: 10.1016/j.tcb.2014.09.005.
Mol Cell. 2014 Oct 23;56(2):187-189. doi: 10.1016/j.molcel.2014.10.008.
Proinflammatory stimuli elicit rapid transcriptional responses via transduced
signals to master regulatory transcription factors. To explore the role of
chromatin-dependent signal transduction in the atherogenic inflammatory
response, we characterized the dynamics, structure, and function of regulatory
elements in the activated endothelial cell epigenome. Stimulation with tumor
necrosis factor alpha prompted a dramatic and rapid global redistribution of
chromatin activators to massive de novo clustered enhancer domains. Inflammatory
super enhancers formed by nuclear factor-kappa B accumulate at the expense of
immediately decommissioned, basal endothelial super enhancers, despite
persistent histone hyperacetylation. Mass action of enhancer factor
redistribution causes momentous swings in transcriptional initiation and
elongation. A chemical genetic approach reveals a requirement for BET
bromodomains in communicating enhancer remodeling to RNA Polymerase II and
orchestrating the transition to the inflammatory cell state, demonstrated in
activated endothelium and macrophages. BET bromodomain inhibition abrogates
super enhancer-mediated inflammatory transcription, atherogenic endothelial
responses, and atherosclerosis in vivo.
DOI: 10.1016/j.molcel.2014.08.024
PMCID: PMC4224636
PMID: 25263595 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17868323 | 1. J Neurochem. 2007 Dec;103(6):2177-88. doi: 10.1111/j.1471-4159.2007.04920.x.
Epub 2007 Sep 11.
Increased expression of lysosomal acid phosphatase in CLN3-defective cells and
mouse brain tissue.
Pohl S(1), Mitchison HM, Kohlschütter A, van Diggelen O, Braulke T, Storch S.
Author information:
(1)Department of Biochemistry, Children's Hospital, University Medical Center
Hamburg, Hamburg, Germany.
Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative
disorder caused by defective function of the lysosomal membrane glycoprotein
CLN3. The activity of the lysosomal acid phosphatase (LAP/ACP2) was found to be
significantly increased in the cerebellum and brain stem of Cln3-targeted mice
during the early stages of postnatal life. Histochemical localization studies
revealed an increased LAP/ACP2 staining intensity in neurons of the cerebral
cortex of 48-week-old Cln3-targeted mice as compared with controls.
Additionally, the expression of another lysosomal membrane protein LAMP-2 was
increased in all brain areas. Knockdown of CLN3 expression in HeLa cells by RNA
interference also resulted in increased LAP/ACP2 and LAMP-2 expression. Finally
in fibroblasts of two juvenile neuronal ceroid lipofuscinosis patients elevated
levels of LAP/ACP2 were found. Both activation of gene transcription and
increased protein half-life appear to contribute to increased LAP/ACP2 protein
expression in CLN3-deficient cells. The data suggest that lysosomal dysfunction
and accumulation of storage material require increased biogenesis of LAP/ACP2
and LAMP-2 positive membranes which makes LAP/ACP2 suitable as biomarker of
Batten disease.
DOI: 10.1111/j.1471-4159.2007.04920.x
PMID: 17868323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18092827 | 1. J Biomol Struct Dyn. 2008 Feb;25(4):327-36. doi:
10.1080/07391102.2008.10507181.
Biological implications of isochore boundaries in the human genome.
Zheng WX(1), Zhang CT.
Author information:
(1)Department of Physics, Tianjin University, Tianjin 300072, China.
The human genome is composed of large sequence segments with fairly homogeneous
GC content, namely isochores, which have been linked to many important
functions; biological implications of most isochore boundaries, however, remain
elusive, partly due to the difficulty in determining these boundaries at high
resolution. Using the segmentation algorithm based on the quadratic divergence,
we re-determined all 79 boundaries of previously identified human isochores at
single-nucleotide resolution, and then compared the boundary coordinates with
other genome features. We found that 55.7% of isochore boundaries coincide with
termini of repeat elements; 45.6% of isochore boundaries coincide with termini
of highly conserved sequences based on alignment of 17 vertebrate genomes, i.e.,
the highly conserved genome sequence switches to a less or non-conserved one at
the isochore boundary; some isochore boundaries coincide with abrupt change of
CpG island distribution (note that one boundary can associate with more than one
genome feature). In addition, sequences around isochore boundaries are highly
conserved. It seems reasonable to deduce that the boundaries of all the
isochores studied here would be replication timing sites in the human genome.
These results suggest possible key roles of the isochore boundaries and may
further our understanding of the human genome organization.
DOI: 10.1080/07391102.2008.10507181
PMID: 18092827 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16568545 | 1. J Bioinform Comput Biol. 2006 Feb;4(1):109-23. doi: 10.1142/s0219720006001722.
The use of functional domains to improve transmembrane protein topology
prediction.
Xu EW(1), Kearney P, Brown DG.
Author information:
(1)Department of Biochemistry and Molecular Biology, Faculty of Medicine,
University of Calgary, HS-1150, 3330 Hospital Drive NW, Calgary, AB T2N 4N1,
Canada. [email protected]
Transmembrane proteins affect vital cellular functions and pathogenesis, and are
a focus of drug design. It is difficult to obtain diffraction quality crystals
to study transmembrane protein structure. Computational tools for transmembrane
protein topology prediction fill in the gap between the abundance of
transmembrane proteins and the scarcity of known membrane protein structures.
Their prediction accuracy is still inadequate: TMHMM, the current
state-of-the-art method, has less than 52% accuracy in topology prediction on
one set of transmembrane proteins of known topology. Based on the observation
that there are functional domains that occur preferentially internal or external
to the membrane, we have extended the model of TMHMM to incorporate functional
domains, using a probabilistic approach originally developed for computational
gene finding. Our extension is better than TMHMM in predicting the topology of
transmembrane proteins. As prediction of functional domain improves, our
system's prediction accuracy will likely improve as well.
DOI: 10.1142/s0219720006001722
PMID: 16568545 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16432188 | 1. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93. doi:
10.1073/pnas.0510519103. Epub 2006 Jan 23.
A mutation in the human phospholamban gene, deleting arginine 14, results in
lethal, hereditary cardiomyopathy.
Haghighi K(1), Kolokathis F, Gramolini AO, Waggoner JR, Pater L, Lynch RA, Fan
GC, Tsiapras D, Parekh RR, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias
EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati
College of Medicine, Cincinnati, OH 45267, USA.
The sarcoplasmic reticulum Ca(2+)-cycling proteins are key regulators of cardiac
contractility, and alterations in sarcoplasmic reticulum Ca(2+)-cycling
properties have been shown to be causal of familial cardiomyopathies. Through
genetic screening of dilated cardiomyopathy patients, we identified a previously
uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the
phospholamban (PLN) gene in a large family with hereditary heart failure. No
homozygous individuals were identified. By middle age, heterozygous individuals
developed left ventricular dilation, contractile dysfunction, and episodic
ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice
overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy
exhibiting similar histopathologic abnormalities and premature death.
Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in
sarcoplasmic reticulum Ca(2+)-ATPase superinhibition. The dominant effect of the
PLN-R14Del mutation could not be fully removed, even upon phosphorylation by
protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum
Ca(2+)-ATPase activity, the nonreversible superinhibitory function of mutant
PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in
both humans and mice.
DOI: 10.1073/pnas.0510519103
PMCID: PMC1360586
PMID: 16432188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21112870 | 1. Nucleic Acids Res. 2011 Apr;39(7):2593-603. doi: 10.1093/nar/gkq913. Epub 2010
Nov 25.
Differential modes of DNA binding by mismatch uracil DNA glycosylase from
Escherichia coli: implications for abasic lesion processing and enzyme
communication in the base excision repair pathway.
Grippon S(1), Zhao Q, Robinson T, Marshall JJ, O'Neill RJ, Manning H, Kennedy G,
Dunsby C, Neil M, Halford SE, French PM, Baldwin GS.
Author information:
(1)Division of Molecular Biosciences, Sir Alexander Fleming Building, Chemical
Biology Centre, Imperial College London, South Kensington, London, SW7 2AZ, UK.
Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating
enzyme in the base-excision repair pathway. As with other DNA glycosylases, the
abasic product is potentially more harmful than the initial lesion. Since Mug is
known to bind its product tightly, inhibiting enzyme turnover, understanding how
Mug binds DNA is of significance when considering how Mug interacts with
downstream enzymes in the base-excision repair pathway. We have demonstrated
differential binding modes of Mug between its substrate and abasic DNA product
using both band shift and fluorescence anisotropy assays. Mug binds its product
cooperatively, and a stoichiometric analysis of DNA binding, catalytic activity
and salt-dependence indicates that dimer formation is of functional significance
in both catalytic activity and product binding. This is the first report of
cooperativity in the uracil DNA glycosylase superfamily of enzymes, and forms
the basis of product inhibition in Mug. It therefore provides a new perspective
on abasic site protection and the findings are discussed in the context of
downstream lesion processing and enzyme communication in the base excision
repair pathway.
DOI: 10.1093/nar/gkq913
PMCID: PMC3074160
PMID: 21112870 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19469713 | 1. Biochem J. 2009 Jul 29;422(1):181-91. doi: 10.1042/BJ20082399.
A novel function of Aft1 in regulating ferrioxamine B uptake: Aft1 modulates
Arn3 ubiquitination in Saccharomyces cerevisiae.
Jeong MY(1), Kang CM, Kim JH, Heo DH, Chang M, Baek IJ, Ro HS, Choi ID, Kim TH,
Yun CW.
Author information:
(1)School of Life Sciences and Biotechnology, Korea University Anam-Dong,
Sungbuk-Gu, Seoul, Republic of Korea.
Aft1 is a transcriptional activator in Saccharomyces cerevisiae that responds to
iron availability and regulates the expression of genes in the iron regulon,
such as FET3, FTR1 and the ARN family. Using a two-hybrid screen, we found that
Aft1 physically interacts with the FOB (ferrioxamine B) transporter Arn3. This
interaction modulates the ability of Arn3 to take up FOB. The interaction
between Arn3 and Aft1 was confirmed by beta-galactosidase,
co-immunoprecipitation and SPR (surface plasmon resonance) assays. Truncated
Aft1 had a stronger interaction with Arn3 and caused a higher FOB-uptake
activity than full-length Aft1. Interestingly, only full-length Aft1 induced the
correct localization of Arn3 in response to FOB. Furthermore, we found Aft1
affected Arn3 ubiquitination. These results suggest that Aft1 interacts with
Arn3 and may regulate the ubiquitination of Arn3 in the cytosolic compartment.
DOI: 10.1042/BJ20082399
PMID: 19469713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21651461 | 1. Anticancer Agents Med Chem. 2011 May 1;11(4):373-9. doi:
10.2174/187152011795677517.
Anti-cancer activity of nitrones and observations on mechanism of action.
Floyd RA(1), Chandru HK, He T, Towner R.
Author information:
(1)Merrick Foundation Chair in Aging Research, Head Experimental Therapeutics
Reasearch Program, Oklahoma Medical Research, Foundation, Oklahoma City, 73104
USA. [email protected]
The nitrone compound PBN, α-phenyl-tert-butylnitrone, and closely related
nitrones have anti-cancer activity in several experimental cancer models. The
three experimental models most extensively studied include A) the rat choline
deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse
APC(Min/+) colon cancer model. The two PBN-nitrones mostly studied are PBN and a
PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007
is a proprietary compound that has had extensive commercial development
(designated as NXY-059) for another indication, acute ischemic stroke, and after
extensive clinical studies was shown to lack efficacy for this indication but
was shown to be very safe for human use. This compound administered orally in
the rat glioma model has potent activity in treating fully formed gliomas. In
this report observations made on the PBN-nitrones in experimental cancer models
will be summarized. In addition the experimental results will be discussed in
the general framework of the properties of the compounds with a view to try to
understand the mechanistic basis of how the PBN-nitrones act as anti-cancer
agents. Possible mechanisms related to the suppression of NO production,
S-nitrosylation of critical proteins and inhibition of NF-κB activation are
discussed.
DOI: 10.2174/187152011795677517
PMCID: PMC3246679
PMID: 21651461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21835056 | 1. Thyroid Res. 2011 Aug 3;4 Suppl 1(Suppl 1):S9. doi: 10.1186/1756-6614-4-S1-S9.
Molecules important for thyroid hormone synthesis and action - known facts and
future perspectives.
Brix K(#)(1), Führer D(#)(2), Biebermann H(#)(3).
Author information:
(1)School of Engineering and Science, Jacobs University Bremen, Research II,
Campus Ring 6, 28759 Bremen, Germany.
(2)Universitätsklinikum Leipzig Medizinische Klinik III, 04103 Leipzig, Germany;
as of June 2011: Klinik für Endokrinologie, Zentrum für Innere Medizin, Bereich
Forschung und Lehre im Zentrallabor, 45147 Essen, Germany.
(3)Institute of Experimental Pediatric Endocrinology, Charité
Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
(#)Contributed equally
Thyroid hormones are of crucial importance for the functioning of nearly every
organ. Remarkably, disturbances of thyroid hormone synthesis and function are
among the most common endocrine disorders affecting approximately one third of
the working German population. Over the last ten years our understanding of
biosynthesis and functioning of these hormones has increased tremendously. This
includes the identification of proteins involved in thyroid hormone biosynthesis
like Thox2 and Dehal where mutations in these genes are responsible for certain
degrees of hypothyroidism. One of the most important findings was the
identification of a specific transporter for triiodothyronine (T3), the
monocarboxylate transporter 8 (MCT8) responsible for directed transport of T3
into target cells and for export of thyroid hormones out of thyroid epithelial
cells. Genetic disturbances of MCT8 in patients result in a biochemical
constellation of high T3 levels in combination with low or normal TSH and
thyroxine levels leading to a new syndrome of severe X-linked mental
retardation. Importantly mice lacking MCT8 presented only with a mild phenotype,
indicating that compensatory mechanisms exist in mice. Moreover, it has become
clear that not only genomic actions of T3 exist. T3 is also capable to activate
adhesion receptors and it signals via activation of PI3K and MAPK pathways. Most
recently, thyroid hormone derivatives were identified, the thyronamines which
are decarboxylated thyroid hormones initiating physiological actions like
lowering body temperature and heart rate, thereby acting in opposite direction
to the classical thyroid hormones. So far it is believed that thyronamines
function via the activation of a G-protein coupled receptor, TAAR1. The
objective of this review is to summarise the recent findings in thyroid hormone
synthesis and action and to discuss their implications for diagnosis of thyroid
disease and for treatment of patients.
DOI: 10.1186/1756-6614-4-S1-S9
PMCID: PMC3155115
PMID: 21835056 |
http://www.ncbi.nlm.nih.gov/pubmed/19324307 | 1. Heart Rhythm. 2009 Apr;6(4):480-6. doi: 10.1016/j.hrthm.2009.01.016. Epub 2009
Jan 18.
Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy
with attenuated electrocardiographic R amplitudes.
Posch MG(1), Perrot A, Geier C, Boldt LH, Schmidt G, Lehmkuhl HB, Hetzer R,
Dietz R, Gutberlet M, Haverkamp W, Ozcelik C.
Author information:
(1)Experimental and Clinical Research Center (ECRC), Berlin, Germany.
[email protected]
BACKGROUND: Familial dilated cardiomyopathy is a highly heterogeneous genetic
disease. Thus, identification of disease-causing mutations is a challenging and
time-consuming task. Genotype-phenotype associations may alleviate
identification of the underlying mutation.
OBJECTIVE: The purpose of this study was to investigate cardiac phenotypes
within a family harboring a familial dilated cardiomyopathy-related mutation in
the gene encoding phospholamban.
METHODS: Complete genetic and clinical analyses were performed in a family with
familial dilated cardiomyopathy due to the PLN-R14Del mutation. Family relatives
were studied by ECG, Holter ECG, echocardiography, ECG body surface potential
mapping, and cardiac magnetic resonance imaging.
RESULTS: A candidate gene approach resulted in identification of a heterozygous
deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del)
segregating with dilated cardiomyopathy in the family pedigree. Mutation
carriers suffered from familial dilated cardiomyopathy associated with cardiac
death between the ages of 26 and 50 years. Interestingly, all adult mutation
carriers revealed strikingly attenuated R amplitudes on standard ECG, regardless
of the absence or presence of echocardiographic abnormalities.
Gadolinium-enhanced cardiac magnetic resonance imaging showed late enhancement
in PLN-R14Del carriers with preserved ejection fraction. Late enhancement was
regionally related to areas of most pronounced R-amplitude attenuation as
assessed by body surface potential mapping.
CONCLUSION: Attenuated R amplitudes were identified as an early ECG phenotype in
a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation.
All adults harboring PLN-R14Del had attenuated R waves irrespective of
echocardiographic abnormalities. The study findings suggest a mutation-related
remodeling process preceding ventricular dysfunction.
DOI: 10.1016/j.hrthm.2009.01.016
PMID: 19324307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19631615 | 1. Brain Res. 2009 Oct 19;1294:144-52. doi: 10.1016/j.brainres.2009.07.035. Epub
2009 Jul 23.
Cerebrovascular protection as a possible mechanism for the protective effects of
NXY-059 in preclinical models: an in vitro study.
Culot M(1), Mysiorek C, Renftel M, Roussel BD, Hommet Y, Vivien D, Cecchelli R,
Fenart L, Berezowski V, Dehouck MP, Lundquist S.
Author information:
(1)Univ Lille-Nord de France, F59000 Lille, France. [email protected]
NXY-059, a polar compound with limited transport across the blood-brain barrier,
has demonstrated neuroprotection in several animal models of acute ischemic
stroke but failed to confirm clinical benefit in the second phase III trial
(SAINT-II). To improve the understanding of the mechanisms responsible for its
neuroprotective action in preclinical models a series of experiments was carried
out in an in vitro blood-brain barrier (BBB) model. A clinically attainable
concentration of 250 mumol/L of NXY-059 administered at the onset or up to 4 h
after oxygen glucose deprivation (OGD) produced a significant reduction in the
increased BBB permeability caused by OGD. Furthermore, OGD produced a huge
influx of tissue plasminogen activator across the BBB, which was substantially
reduced by NXY-059. This study suggests that the neuroprotective effects of
NXY-059 preclinically, may at least in part be attributed to its ability to
restore functionality of the brain endothelium.
DOI: 10.1016/j.brainres.2009.07.035
PMID: 19631615 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17019811 | 1. Novartis Found Symp. 2006;274:156-71; discussion 172-5, 272-6.
Phospholamban as a therapeutic modality in heart failure.
Chu G(1), Kranias EG.
Author information:
(1)Department of Internal Medicine, University of Cincinnati College of
Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
Increases in diastolic Ca2+ and impaired relaxation in failing hearts have been
suggested to reflect the deteriorated function of the sarcoplasmic reticulum
Ca-ATPase (SERCA2), whose activity is regulated by phospholamban (PLN). PLN is a
reversible inhibitor of SERCA2's Ca2+ affinity and cardiac contractility.
Studies in genetically altered mouse models have demonstrated that the levels
and the degree of PLN phosphorylation are critical in modulating basal Ca2+
handling and contractility. Correspondingly, the depressed contractility in
experimental and human heart failure is partially attributed to increased
inhibition by PLN due to: (a) increases in PLN/SERCA2; and (b) decreases in PLN
phosphorylation. The attenuated PLN phosphorylation is associated with increased
type 1 phosphatase, which reflects dephosphorylation or inactivation of its
inhibitor 1. Indeed PLN ablation was successful in rescuing cardiac remodelling
and dysfunction in several heart failure mouse models, and inhibition of the
phosphatase activity restored contractile parameters in failing rat hearts.
Recently, two human PLN mutations, associated with either absence or sustained
dephosphorylation of PLN, were linked to dilated cardiomyopathy. Thus, PLN
modulation appears to be of paramount importance in humans, and further
investigation into PLN function in higher mammalian species may provide insights
into its potential as a therapeutic modality in heart failure.
PMID: 17019811 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17096368 | 1. J Cell Physiol. 2007 Feb;210(2):378-84. doi: 10.1002/jcp.20845.
Cisplatin upregulates Saccharomyces cerevisiae genes involved in iron
homeostasis through activation of the iron insufficiency-responsive
transcription factor Aft1.
Kimura A(1), Ohashi K, Naganuma A.
Author information:
(1)Laboratory of Molecular and Biochemical Toxicology, Graduate School of
Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
The response of Saccharomyces cerevisiae to cisplatin was investigated by
examining variations in gene expression using cDNA microarrays and confirming
the results by reverse transcription polymerase chain reaction (RT-PCR). The
mRNA levels of 14 proteins involved in iron homeostasis were shown to be
increased by cisplatin. Interestingly, the expression of all 14 genes is known
to be regulated by Aft1, a transcription factor activated in response to iron
insufficiency. The promoter of one of these genes, FET3, has been relatively
well studied, so we performed a reporter assay using the FET3 promoter and
showed that an Aft1 binding site in the promoter region is indispensable for
induction of transcription by cisplatin. The active domain of Aft1 necessary for
activation of the FET3 promoter by cisplatin is identical to the one required
for activation by bathophenanthroline sulfonate, an inhibitor of cellular iron
uptake. Furthermore, we found that cisplatin inhibits the uptake of (55)Fe(II)
into yeast cells. These findings suggest that cisplatin activates Aft1 through
the inhibition of iron uptake into the cells, after which the expression of Aft1
target genes involved in iron uptake might be induced.
DOI: 10.1002/jcp.20845
PMID: 17096368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9794474 | 1. Endocrinology. 1998 Nov;139(11):4626-33. doi: 10.1210/endo.139.11.6323.
Direct measurement of the contributions of type I and type II 5'-deiodinases to
whole body steady state 3,5,3'-triiodothyronine production from thyroxine in the
rat.
Nguyen TT(1), Chapa F, DiStefano JJ 3rd.
Author information:
(1)Department of Computer Science, University of California, Los Angeles
90095-1596, USA.
Production of T3 from T4 in tissues is catalyzed by two 5'-deiodinases, type I
(D1) and type II (D2), but the quantitative contribution of each pathway to
whole body T3 production is not well established. In the presence of
propylthiouracil (PTU), D1, but not D2, can be effectively blocked, providing an
experimental probe for addressing this problem. Decades ago, this approach
provided indirect estimates ranging from 23-44% contribution by D2, based on
plasma T3 appearance rate comparisons (PAR3 = PCR3 [T3]p) in periodically
T4-injected athyreotic rats vs. controls. Two, more recent studies, using
constant infusions of T4 for replacement, achieved 22% and 65% estimates,
respectively, from PAR3 comparisons. We have revisited this problem more
directly and precisely, with two major differences in experiment design. We used
direct whole body steady state measurements of T3 production, instead of
indirect plasma-only data (PAR3). We also used (euthyroid) physiological doses
of both T4 (0.9 microg/day x 100 g BW) and T3 (0.15 microg/day x 100 g BW) for
replacement in two thyroidectomized rat groups, instead of T4 only, in a 7-day
constant steady state, dual tracer infusion protocol. The first group also had
chronically implanted 150-mg PTU pellets (TXR-PTU); the other had implanted 0.1
N NaOH placebo pellets (TXR-EU); each delivered their product at constant rates.
A third euthyroid intact group was used as the controls. The completeness of D1
inhibition was ascertained in a fourth group, identically treated with 150-mg
PTU pellets, in which negligible D1 activity was found in liver and kidney using
labeled rT3 as substrate for the 5'-D assays and minimal (1 mM) dithiothreitol
as cofactor. In the TXR-PTU group, the percentage of T4 converted to T3 was
11.8%, compared with 23.4% (P < 0.0005) in the TXR-EU group, and 22.7% (P = NS)
in controls. Thus, in euthyroid steady state, D2 contributes about half of the
T3 produced from T4.
DOI: 10.1210/endo.139.11.6323
PMID: 9794474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7768329 | 1. Mol Cell Endocrinol. 1995 Feb;107(2):173-80. doi:
10.1016/0303-7207(94)03440-5.
Investigation of type I and type III iodothyronine deiodinases in rat tissues
using N-bromoacetyl-iodothyronine affinity labels.
Schoenmakers CH(1), Pigmans IG, Visser TJ.
Author information:
(1)Department of Internal Medicine III, Erasmus University Medical School,
Rotterdam, The Netherlands.
In the present study the hypothesis was tested that
N-bromoacetyl-3,3',5-[125I]triiodothyronine (BrAc[125I]T3) is a useful affinity
label for both type I and type III iodothyronine deiodinases (ID-I and ID-III).
Therefore, the microsomal fractions of various rat tissues were tested for ID-I
and ID-III activities, and microsomal proteins were labeled with BrAc[125I]T3
and analyzed by SDS-PAGE. In agreement with previous observations, high ID-I
activities were found in liver, kidney and thyroid, and high ID-III activities
in brain, in particular fetal brain, and placenta. SDS-PAGE of
BrAc[125I]T3-labeled microsomes showed a prominent radioactive approximately 27
kDa protein (p27) in liver, kidney and thyroid, which was previously identified
as ID-I, and a approximately 32 kDa protein (p32) in brain, in particular fetal
brain, and placenta. A good correlation was found between the affinity labeling
of p32 and the inactivation of ID-III by BrAcT3, suggesting that p32 represents
ID-III or a subunit thereof. After treatment of microsomes with 0.05%
deoxycholate or carbonate buffer (pH 11.5) p32 was still labeled by
BrAc[125I]T3, indicating that p32 is a transmembrane protein. Although
3,3',5'-triiodothyronine (rT3) is not a substrate for ID-III, p32 was readily
labeled with BrAc[125I]rT3. Labeling of p32 in rat brain microsomes by
BrAc[125I]rT3 was not affected by addition of 100 microM unlabeled thyroxine
(T4) or T3, whereas deiodination of [125I]T3 by ID-III was inhibited by 91 and
96% in the presence of 1 microM T4 and T3, respectively.(ABSTRACT TRUNCATED AT
250 WORDS)
DOI: 10.1016/0303-7207(94)03440-5
PMID: 7768329 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12610310 | 1. Science. 2003 Feb 28;299(5611):1410-3. doi: 10.1126/science.1081578.
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
Schmitt JP(1), Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG,
MacLennan DH, Seidman JG, Seidman CE.
Author information:
(1)Department of Genetics, Harvard Medical School and Howard Hughes Medical
Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
Molecular etiologies of heart failure, an emerging cardiovascular epidemic
affecting 4.7 million Americans and costing 17.8 billion health-care dollars
annually, remain poorly understood. Here we report that an inherited human
dilated cardiomyopathy with refractory congestive heart failure is caused by a
dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban
(PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic
reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice
recapitulated human heart failure with premature death. Cellular and biochemical
studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit
SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked
PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of
calcium transients in myocytes. These results indicate that myocellular calcium
dysregulation can initiate human heart failure-a finding that may lead to
therapeutic opportunities.
DOI: 10.1126/science.1081578
PMID: 12610310 [Indexed for MEDLINE] |