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http://www.ncbi.nlm.nih.gov/pubmed/24799061 | 1. Future Oncol. 2014 Apr;10(5):803-11. doi: 10.2217/fon.14.35.
Orteronel for the treatment of prostate cancer.
Van Hook K(1), Huang T, Alumkal JJ.
Author information:
(1)Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon
Health & Science University, Portland, OR 97239, USA.
Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently
in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20
lyase activity of the enzyme CYP17A1, which is important for androgen synthesis
in the testes, adrenal glands and prostate cancer cells. Preclinical studies
demonstrate that orteronel treatment suppresses androgen levels and causes
shrinkage of androgen-dependent organs, such as the prostate gland. Early
reports of clinical studies demonstrate that orteronel treatment leads to
reduced prostate-specific antigen levels, a marker of prostate cancer tumor
burden, and more complete suppression of androgen synthesis than conventional
androgen deprivation therapies that act in the testes alone. Treatment with
single-agent orteronel has been well tolerated with fatigue as the most common
adverse event, while febrile neutropenia was the dose-limiting toxicity in a
combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III
clinical trial in patients with advanced-stage prostate cancer who had received
prior docetaxel was unblinded as the overall survival primary end point was not
achieved. However, additional Phase III orteronel trials are ongoing in men with
earlier stages of prostate cancer.
DOI: 10.2217/fon.14.35
PMCID: PMC4148348
PMID: 24799061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19101078 | 1. Clin Neurol Neurosurg. 2009 May;111(4):352-3. doi:
10.1016/j.clineuro.2008.11.009. Epub 2008 Dec 20.
Impact of the lunar cycle on the incidence of aneurysmal subarachnoid
haemorrhage: myth or reality?
Lahner D(1), Marhold F, Gruber A, Schramm W.
Author information:
(1)Department of Anaesthesia, General Intensive Care Medicine and Pain
Management, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna,
Austria. [email protected]
OBJECTIVE: To investigate the impact of the lunar cycle on the incidence of
aneurysmal subarachnoid haemorrhages.
METHODS: We retrospectively identified all patients admitted to the department
of neurosurgery during 1992 and 2004 suffering from aneurysmal subarachnoid
haemorrhage. The onset of bleeding was compared with the lunar phase.
RESULTS: We did not observe any significant impact of the lunar cycle on the
incidence of aneurysmal subarachnoid haemorrhage in 717 consecutive patients
(p=0.84).
CONCLUSION: The impact of the lunar cycle on aneurysmal subarachnoid haemorrhage
is a myth rather than reality.
DOI: 10.1016/j.clineuro.2008.11.009
PMID: 19101078 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18672707 | 1. Vojnosanit Pregl. 2008 Jun;65(6):485-7. doi: 10.2298/vsp0806485m.
Acrokeratosis paraneoplastica Bazex syndrome associated with esophageal
squamocellular carcinoma.
Medenica L(1), Gajić-Veljić M, Skiljević D, Pesko P.
Author information:
(1)Clinical Center of Serbia, Institute of Dermatology and Venerology, Belgrade,
Serbia. [email protected]
BACKGROUND: Acrokeratosis paraneoplastica Bazex (APB) is a very rare disease in
the group of obligate paraneoplastic dermatoses, associated mostly with squamous
cell carcinoma of the upper aerodigestive tract and metastatic cervical
lymphadenopathy. The disease is characterized by violaceous erythemosquamous
changes on the acral regions. This entity was first reported by Bazex in 1965.
About 160 cases have been presented so far.
CASE REPORT: We presented a patient with a three-month history of violaceous
erythema, edema, erosions and scaling on the acral regions, elbows and knees and
severe nail dystrophy. When the diagnosis was established, he did not have any
symptom of internal malignancy. Esophagogastroscopy revealed ulcerovegetant
lesion of the esophagus, while histology showed squamocellular invasive
carcinoma. Surgical tumor removal resulted in significant improvement of skin
changes in 15 days. Unfortunately, four months later, extensive skin lesions
pointed to metastasis of squamous cell carcinoma.
CONCLUSION: Skin changes can precede a few years the first manifestations of
neoplasia. The course of the disease in our patient proved that APB is a
specific marker of underlying malignancy.
DOI: 10.2298/vsp0806485m
PMID: 18672707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20388189 | 1. Alzheimers Res Ther. 2010 Apr 9;2(2):5. doi: 10.1186/alzrt28.
Can novel therapeutics halt the amyloid cascade?
Prins ND(1), Visser PJ, Scheltens P.
Author information:
(1)Alzheimer Center, VU University Medical Center, Boelelaan 1118, Amsterdam,
The Netherlands. [email protected].
The amyloid hypothesis provides a basis for the development of new therapeutic
strategies in Alzheimer's disease. Two large trials have recently been
published. The first is a phase 2 study of passive immunotherapy with
bapineuzumab, a humanized anti-Abeta monoclonal antibody directed against the
N-terminus of Abeta. This trial showed no differences within dose cohorts on the
primary efficacy analysis. Exploratory analyses showed potential treatment
differences on cognitive and functional endpoints in study completers and
apolipoprotein E epsilon4 noncarriers. A safety concern was the occurrence of
reversible vasogenic edema. The second study is a phase 3 trial of tarenflurbil,
a modulator of the activity of gamma-secretase. Tarenflurbil had no beneficial
effect on the primary or secondary outcomes. The tarenflurbil group had a small
increase in frequency of dizziness, anemia, and infections. Possible
explanations for the negative results of these trials may be related to the
study design or the choice of dosage. However, it may also be that these
negative findings reflect our still incomplete understanding of, at least part
of, the pathogenesis of Alzheimer's disease.
DOI: 10.1186/alzrt28
PMCID: PMC2876783
PMID: 20388189 |
http://www.ncbi.nlm.nih.gov/pubmed/20560046 | 1. J Cardiovasc Transl Res. 2010 Jun;3(3):251-5. doi: 10.1007/s12265-010-9169-7.
Epub 2010 May 1.
MicroRNA-21 in cardiovascular disease.
Cheng Y(1), Zhang C.
Author information:
(1)RNA and Cardiovascular Research Laboratory, Department of Anesthesiology, New
Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185
South Orange Avenue, MSB-E548, Newark, NJ 07101, USA.
MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular
system. Recent studies have revealed that its expression is deregulated in heart
and vasculature under cardiovascular disease conditions such as proliferative
vascular disease, cardiac hypertrophy and heart failure, and ischemic heart
disease. miR-21 is found to play important roles in vascular smooth muscle cell
proliferation and apoptosis, cardiac cell growth and death, and cardiac
fibroblast functions. Accordingly, miR-21 is proven to be involved in the
pathogenesis of the above-mentioned cardiovascular diseases as demonstrated by
both loss-of-function and gain-of-function approaches. Programmed cell death 4
(PDCD4), phosphatase and tensin homology deleted from chromosome 10 (PTEN),
sprouty1 (SPRY1), and sprouty2 (SPRY2) are the current identified target genes
of miR-21 that are involved in miR-21-mediated cardiovascular effects. miR-21
might be a novel therapeutic target in cardiovascular diseases. This review
article summarizes the research progress regarding the roles of miR-21 in
cardiovascular disease.
DOI: 10.1007/s12265-010-9169-7
PMCID: PMC3611957
PMID: 20560046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11820058 | 1. Ned Tijdschr Geneeskd. 2002 Jan 12;146(2):63-6.
[From gene to disease; craniosynostosis syndromes due to FGFR2-mutation].
[Article in Dutch]
van Ravenswaaij-Arts CM(1), van den Ouweland AM, Hoogeboom AJ, Herbergs J, Pals
G.
Author information:
(1)Universitair Medisch Centrum St Radboud, afd. Antropogenetica 417, Postbus
9101, 6500 HB Nijmegen. [email protected]
One of the genes involved in craniosynostosis syndromes is the fibroblast growth
factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene. Upon ligand
binding the FGFR2 receptors dimerise, and this is followed by activation of the
intracellular tyrosine kinase domains. This initiates a cascade of signals that
influence cell division and differentiation. FGFR2 mutations have been found in
the Apert, Crouzon and Pfeiffer craniosynostosis syndromes. Most mutations are
gain of function mutations, inducing ligand-independent receptor activation or
altered ligand binding. With the exception of Apert syndrome, there is no clear
genotype-phenotype correlation. Many different mutations have been found in
Pfeiffer and Crouzon syndrome, but all of the mutations occur in the same
extracellular region of the receptor. Identical mutations have been found in
Pfeiffer and Crouzon syndrome. So within one family, both Crouzon and Pfeiffer
syndrome may occur. Mutations in other FGFR-genes have also been found in
craniosynostosis syndromes.
PMID: 11820058 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23340574 | 1. Nat Rev Mol Cell Biol. 2013 Feb;14(2):98-112. doi: 10.1038/nrm3512.
Caveolae as plasma membrane sensors, protectors and organizers.
Parton RG(1), del Pozo MA.
Author information:
(1)Institute for Molecular Bioscience and Centre for Microscopy and
Microanalysis, University of Queensland, Brisbane, QLD 4072, Australia.
[email protected]
Caveolae are submicroscopic, plasma membrane pits that are abundant in many
mammalian cell types. The past few years have seen a quantum leap in our
understanding of the formation, dynamics and functions of these enigmatic
structures. Caveolae have now emerged as vital plasma membrane sensors that can
respond to plasma membrane stresses and remodel the extracellular environment.
Caveolae at the plasma membrane can be removed by endocytosis to regulate their
surface density or can be disassembled and their structural components degraded.
Coat proteins, called cavins, work together with caveolins to regulate the
formation of caveolae but also have the potential to dynamically transmit
signals that originate in caveolae to various cellular destinations. The
importance of caveolae as protective elements in the plasma membrane, and as
membrane organizers and sensors, is highlighted by links between caveolae
dysfunction and human diseases, including muscular dystrophies and cancer.
DOI: 10.1038/nrm3512
PMID: 23340574 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15675355 | 1. No To Hattatsu. 2005 Jan;37(1):20-5.
[Molecular screening for moyamoya disease by use of expressed sequence tag on
chromosome 3p].
[Article in Japanese]
Yamamoto T(1), Akasaka Y, Ohtani K, Hayashi T, Kashiwagi S, Ichiyama T,
Nishikawa M, Kato M, Maegaki Y, Oka A, Ohno K.
Author information:
(1)Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama,
Kanagawa. [email protected]
Moyamoya disease is a well-known cerebrovascular disorder of unknown
pathogenesis affecting terminal portion of internal carotid arteries and causing
ischemic attacks. Its familial occurrence suggests genetic background. We
hypothesized that paternally imprinted gene might be associated with this
disorder. To identify the expressed sequence tags (ESTs) with monoallelic
expressions on chromosome 3, we used mouse A9 hybrid cells having human
chromosome 3. Two ESTs showed only maternal expression in mouse A9 hybrid cells,
and four showed non-expression in the lymphocytes derived from moyamoya
patients. Although these ESTs are clustered on the same 150 kb region, we
finally failed to identify cDNA in this region.
PMID: 15675355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11920466 | 1. Cancer. 2002 Feb 15;94(4):980-6.
HER-2 profiling and targeting in prostate carcinoma.
Morris MJ(1), Reuter VE, Kelly WK, Slovin SF, Kenneson K, Verbel D, Osman I,
Scher HI.
Author information:
(1)Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
BACKGROUND: The clinical effects of targeting HER-2 in prostate carcinoma are
not known. This study explored the feasibility of molecular profiling to
determine the correlation between HER-2 expression, hormonal sensitivity, and
the antitumor effects of trastuzumab and paclitaxel in patients with prostate
carcinoma.
METHODS: Patients with progressive androgen dependent (AD) and androgen
independent (AI) prostate carcinoma were eligible to participate in the study.
HER-2 expression was assessed on pretreatment tissue specimens, and patients
were then assigned to one of four treatment groups: AD HER-2 positive, AD HER-2
negative, AI HER-2 positive, and AI HER-2 negative. They were treated with
weekly trastuzumab at a dose of 2 mg/kg (after a 4 mg/kg loading dose) until
they experienced disease progression, when weekly paclitaxel at 100 mg/m(2) was
added.
RESULTS: The authors screened 130 patients for HER-2 expression. In total, 23
patients were treated. Six eligible patients had HER-2 positive disease;
therefore, only the AI HER-2 negative arm accrued to completion. All patients
(100%) experienced disease progression on trastuzumab alone at or before the
first 12 weeks of treatment. Fifteen patients received combined therapy: Seven
patients (47%) experienced disease progression, 5 patients (33%) had stable
disease, and 3 patients (20%) had a decline > or = 50% in prostate specific
antigen PSA level or in soft tissue disease. HER-2 overexpression was found in
significant proportions only in AI metastatic tissue samples (42% HER-2
positive; 95% confidence interval, 14-60%). In three of nine matched pairs, the
AD prostate biopsy was HER-2 negative, and the AI metastatic sample was HER-2
positive.
CONCLUSIONS: Trastuzumab is not effective as a single agent for the treatment of
patients with AI HER-2 negative tumors. HER-2 expression varies by clinical
state in patients with prostate carcinoma: Accurate HER-2 profiling requires
sampling metastatic tissue in patients with metastatic disease. Further
development of trastuzumab for the treatment of patients with metastatic
prostate carcinoma is not feasible until more reliable and practical methods of
sampling metastatic disease are developed to identify patients with HER-2
positive tumors.
Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10339
PMID: 11920466 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23089711 | 1. Clin Chem Lab Med. 2012 Oct 1;50(10):1809-18. doi: 10.1515/cclm-2011-0823.
Increased concentrations of growth factors and activation of the EGFR system in
breast cancer.
Olsen DA(1), Bechmann T, Østergaard B, Wamberg PA, Jakobsen EH, Brandslund I.
Author information:
(1)Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
[email protected]
BACKGROUND: In this study the total and phosphorylated amount of epidermal
growth factor receptor 1 (EGFR) and 2 (HER2) were measured together with EGFR
ligands in tissue samples of breast cancer patients in order to investigate
interrelations and possible prognostic values.
METHODS: Samples of malignant and non-cancer autologous reference tissue were
collected from 415 breast cancer patients. The tissue samples were cut and
either paraffin-embedded or homogenized in a lysis buffer to extract the
proteins. HER2 was measured using both immunohistochemistry (IHC)/fluorescence
in situ hybridization (FISH) and ADVIA Centaur. Phosphorylated HER2 and EGFR
(pHER2, pEGFR), total EGFR and the ligands: epidermal growth factor (EGF),
transforming growth factor-α (TGFα), amphiregulin (AREG), heparin-binding
EGF-like growth factor (HB-EGF), betacellulin (BTC) and epiregulin (EREG) were
measured using the Luminex.
RESULTS: The HER2 positivity rate was determined to be 25.2% by the Centaur
method vs. 15.8% by IHC and FISH. HER2, HB-EGF, TGFα and AREG were upregulated
in cancer tissue as compared with autologous reference tissue while EGFR, pEGFR
and EGF were downregulated (p<10-6). pEGFR in autologous reference tissue was
negatively correlated to the number of positive lymph nodes and to the tumor
size (p=0.0007 and p=0.001, respectively) and furthermore, decreased in the
group of mastectomy operated patients as compared with the lumpectomy group
(p<10-6). HB-EGF in cancer tissue was positively associated with high grade
tumors (p<10-6) and pHER2, HB-EGF and BTC were associated with poor disease free
survival (p=0.017, p=0.012 and p=0.0026, respectively).
CONCLUSIONS: Our study demonstrated a profound activation of the EGFR system.
HB-EGF was increased by factor 10 in cancer tissue and related to the biological
aggressiveness of the tumors, and pHER2, HB-EGF and BTC were associated with
poor clinical outcome.
DOI: 10.1515/cclm-2011-0823
PMID: 23089711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20851221 | 1. N Biotechnol. 2010 Dec 31;27(6):755-65. doi: 10.1016/j.nbt.2010.09.005. Epub
2010 Sep 17.
Assessment of protein domain fusions in human protein interaction networks
prediction: application to the human kinetochore model.
Morilla I(1), Lees JG, Reid AJ, Orengo C, Ranea JA.
Author information:
(1)Department of Molecular Biology and Biochemistry, University of Malaga,
Malaga, Spain. [email protected]
In order to understand how biological systems function it is necessary to
determine the interactions and associations between proteins. Some proteins,
involved in a common biological process and encoded by separate genes in one
organism, can be found fused within a single protein chain in other organisms.
By detecting these triplets, a functional relationship can be established
between the unfused proteins. Here we use a domain fusion prediction method to
predict these protein interactions for the human interactome. We observed that
gene fusion events are more related to physical interaction between proteins
than to other weaker functional relationships such as participation in a common
biological pathway. These results suggest that domain fusion is an appropriate
method for predicting protein complexes. The most reliable fused domain
predictions were used to build protein-protein interaction (PPI) networks. These
predicted PPI network models showed the same topological features as real
biological networks and different features from random behaviour. We built the
PPI domain fusion sub-network model of the human kinetochore and observed that
the majority of the predicted interactions have not yet been experimentally
characterised in the publicly available PPI repositories. The study of the human
kinetochore domain fusion sub-network reveals undiscovered kinetochore proteins
with presumably relevant functions, such as hubs with many connections in the
kinetochore sub-network. These results suggest that experimentally hidden
regions in the predicted PPI networks contain key functional elements,
associated with important functional areas, still undiscovered in the human
interactome. Until novel experiments shed light on these hidden regions; domain
fusion predictions provide a valuable approach for exploring them.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nbt.2010.09.005
PMID: 20851221 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17101786 | 1. Mol Cell Biol. 2007 Jan;27(2):453-65. doi: 10.1128/MCB.01576-06. Epub 2006 Nov
13.
HP1 binding to chromatin methylated at H3K9 is enhanced by auxiliary factors.
Eskeland R(1), Eberharter A, Imhof A.
Author information:
(1)Histone Modifications Group, Adolf-Butenandt Institut, University of Munich,
Schillerstrasse 44, 80336 Munich, Germany.
A large portion of the eukaryotic genome is packaged into transcriptionally
silent heterochromatin. Several factors that play important roles during the
establishment and maintenance of this condensed form have been identified.
Methylation of lysine 9 within histone H3 and the subsequent binding of the
chromodomain protein heterochromatin protein 1 (HP1) are thought to initiate
heterochromatin formation in vivo and to propagate a heterochromatic state
lasting through several cell divisions. For the present study we analyzed the
binding of HP1 to methylated chromatin in a fully reconstituted system. In
contrast to its strong binding to methylated peptides, HP1 binds only weakly to
methylated chromatin. However, the addition of recombinant SU(VAR) protein, such
as ACF1 or SU(VAR)3-9, facilitates HP1 binding to chromatin methylated at lysine
9 within the H3 N terminus (H3K9). We propose that HP1 has multiple target sites
that contribute to its recognition of chromatin, only one of them being
methylated at H3K9. These findings have implications for the mechanisms of
recognition of specific chromatin modifications in vivo.
DOI: 10.1128/MCB.01576-06
PMCID: PMC1800810
PMID: 17101786 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23402716 | 1. Appetite. 2013 Jul;66:26-33. doi: 10.1016/j.appet.2013.01.017. Epub 2013 Feb
10.
Effects of different modes of exercise on appetite and appetite-regulating
hormones.
Kawano H(1), Mineta M, Asaka M, Miyashita M, Numao S, Gando Y, Ando T, Sakamoto
S, Higuchi M.
Author information:
(1)Faculty of Sport Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa,
Saitama 359-1192, Japan. [email protected]
The present study determined the changes in appetite and appetite-regulating gut
hormones during and following bouts of both rope skipping exercise
(weight-bearing) and bicycle ergometer exercise (non-weight-bearing). After a
12-h fast, 15 young men (mean ± SD, age 24.4 ± 1.7 yrs, maximal oxygen uptake
47.0 ± 6.5 mL/kg/min) participated in three 160 min trials: (1) rope skipping
exercise (295 ± 40 kcal, 3 sets × 10 min with 5-min interval, then rested for
120 min); (2) bicycle ergometer exercise (288 ± 36 kcal, 3 sets × 10 min with
5-min interval, then rested for 120 min); (3) control (rested for 160 min).
Ratings of perceived hunger and acylated ghrelin were suppressed and total
peptide YY (PYY) were increased during and immediately after exercise in both
exercise trials, but glucagon liked peptide-1 was not changed. Furthermore,
suppressed hunger during rope skipping exercise was greater than that during
bicycle ergometer exercise, but there were no differences in acylated ghrelin
and total PYY. These results indicate that weight-bearing exercise has a greater
exercise-induced appetite suppressive effect compared with non-weight-bearing
exercise, and both forms of exercise lowered acylated ghrelin and increased
total PYY, but the changes did not differ significantly between exercise modes.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.appet.2013.01.017
PMID: 23402716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22131258 | 1. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):47-51. doi:
10.1002/bdra.22863. Epub 2011 Dec 1.
Functional analyses of RET mutations in Chinese Hirschsprung disease patients.
Leon TY(1), So MT, Lui VC, Hofstra RM, Tam PK, Ngan ES, Garcia-Barceló MM.
Author information:
(1)Division of Paediatric Surgery, Department of Surgery, The University of Hong
Kong, Hong Kong, Special Administrative Region, China.
BACKGROUND: Hirschsprung disease (HSCR) is a congenital disease characterized by
the absence of ganglion cells in various length of distal digestive tract. The
rearranged during transfection gene (RET) is considered the major gene in HSCR.
Although an increasing number of HSCR-associated RET coding sequence (CDS)
mutations have been identified in recent years, not many have been investigated
for functional consequence on the RET protein.
METHODS AND RESULTS: We examined the functional implications of the de novo
RET-CDS mutations V145G, Y483X, V636fsX1, and F961L that we first identified in
sporadic Chinese patients with HSCR. The V145G disrupted RET glycosylation and
F961L RET phosphorylation. Presumably, the truncation mutations would affect the
translocation or the anchoring of the RET protein onto the cellular membrane.
CONCLUSION: The study of RET-CDS mutations that appear de novo is essential not
only for understanding the mechanistic of the disease but also for penetrance
and recurrence risk estimations, being the ultimate goal for the improvement in
disease management and counseling.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/bdra.22863
PMID: 22131258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10519379 | 1. Cancer Res. 1999 Oct 1;59(19):4761-4.
Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and
-independent human xenograft models.
Agus DB(1), Scher HI, Higgins B, Fox WD, Heller G, Fazzari M, Cordon-Cardo C,
Golde DW.
Author information:
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New
York 10021, USA. [email protected]
Antibody to the Her-2/neu gene product has been shown to inhibit the growth of
breast cancer cells overexpressing Her-2/neu and to have clinical utility in
treating breast cancer. We studied a recombinant, humanized anti-Her-2/neu
antibody (Herceptin) in preclinical models of human prostate cancer. The
androgen-dependent CWR22 and LNCaP human prostate cancer xenograft models and
androgen-independent sublines of CWR22 were used. Her-2/neu staining of the
parental, androgen-dependent, and androgen-independent CWR22 tumors and LNCaP
tumors demonstrated variable Her-2/neu expression. Herceptin was administered
i.p. at a dose of 20 mg/kg twice weekly after the xenograft had been
established. No effect of Herceptin on tumor growth was observed in any of the
androgen-independent tumors; however, significant growth inhibition was observed
in both of the androgen-dependent xenograft models, CWR22 (68% growth inhibition
at the completion of the experiment; P = 0.03 for trajectories of the average
tumor volume of the groups) and LNCaP (89% growth inhibition; P = 0.002). There
was a significant increase in prostate-specific antigen (PSA) index (ng PSA/ml
serum/mm3 tumor) in Herceptin-treated androgen-dependent groups compared with
control (CWR22, 18-fold relative to pretreatment value versus 1.0-fold, P =
0.0001; LNCaP, 2.35-fold relative to pretreatment value versus 0.6-fold, P =
0.001). When paclitaxel (6.25 mg/kg s.c., five times/week) was given to animals
with androgen-dependent and -independent tumors, there was growth inhibition in
each group. Paclitaxel and Herceptin cotreatment led to greater growth
inhibition than was seen for the agents individually. Thus, in these prostate
cancer model systems, Herceptin alone has clinical activity only in the
androgen-dependent tumor and has at least an additive effect on growth, in
combination with paclitaxel, in both androgen-dependent and androgen-independent
tumors. Response to Herceptin did not correlate with the PSA levels, because the
PSA index markedly increased in the Herceptin-treated group, whereas it remained
constant in the control group. These results suggest the utility of Herceptin in
the treatment of human prostate cancer.
PMID: 10519379 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23728749 | 1. Scott Med J. 2013 May;58(2):64-8. doi: 10.1177/0036933013482631.
There are calls for a national screening programme for prostate cancer: what is
the evidence to justify such a national screening programme?
Green A(1), Tait C, Aboumarzouk O, Somani BK, Cohen NP.
Author information:
(1)School of Medicine and Dentistry, University of Aberdeen, Foresterhill,
Aberdeen, UK. [email protected]
INTRODUCTION: Prostate cancer is the commonest cancer in men and a major health
issue worldwide. Screening for early disease has been available for many years,
but there is still no national screening programme established in the United
Kingdom.
OBJECTIVE: To assess the latest evidence regarding prostate cancer screening and
whether it meets the necessary requirements to be established as a national
programme for all men.
METHODS: Electronic databases and library catalogues were searched
electronically and manual retrieval was performed. Only primary research results
were used for the analysis.
RESULTS: In recent years, several important randomised controlled trials have
produced varied outcomes. In Europe the largest study thus far concluded that
screening reduced prostate cancer mortality by 20%. On the contrary, a large
American trial found no reduction in mortality after 7-10 years follow-up. Most
studies comment on the adverse effects of screening - principally those of
overdiagnosis and subsequent overtreatment.
DISCUSSION: Further information about the natural history of prostate cancer and
accuracy of screening is needed before a screening programme can be truly
justified. In the interim, doctors and patients should discuss the risks,
benefits and sequelae of taking part in voluntary screening for prostate cancer.
DOI: 10.1177/0036933013482631
PMID: 23728749 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18429952 | 1. Cancer Sci. 2008 Jun;99(6):1139-46. doi: 10.1111/j.1349-7006.2008.00814.x.
Epub 2008 Apr 21.
Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated
transcriptionally by beta-catenin/TCF.
Torisu Y(1), Watanabe A, Nonaka A, Midorikawa Y, Makuuchi M, Shimamura T,
Sugimura H, Niida A, Akiyama T, Iwanari H, Kodama T, Zeniya M, Aburatani H.
Author information:
(1)Genome Science Division, Research Center for Advanced Science and Technology,
The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a
secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative
analysis of the gene expression profiles in primary human hepatocellular
carcinomas (HCC) and normal organs, we observed that the human ortholog of
Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed
rarely in adult normal tissues. Immunoblotting confirmed the overexpression of
NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein
were significantly associated with intracellular (nuclear or cytoplasmic)
accumulation of beta-catenin protein: all 10 HCC with high intracellular
beta-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%)
without intracellular beta-catenin had high NOTUM expression (P < 0.00001).
NOTUM expression in HepG2 cells was downregulated significantly by induction of
a dominant-negative mutant of TCF4, a beta-catenin partner. In vivo binding of
the beta-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin
immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is
activated constitutively. These findings provide evidence that NOTUM is a novel
target of beta-catenin/TCF4 and is upregulated in Wnt/beta-catenin
signaling-activated HCC.
DOI: 10.1111/j.1349-7006.2008.00814.x
PMCID: PMC11158900
PMID: 18429952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25339210 | 1. Neurology. 2014 Nov 18;83(21):1898-905. doi: 10.1212/WNL.0000000000001002.
Epub 2014 Oct 22.
Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.
Wolf NI(1), Vanderver A(2), van Spaendonk RM(2), Schiffmann R(2), Brais B(2),
Bugiani M(2), Sistermans E(2), Catsman-Berrevoets C(2), Kros JM(2), Pinto PS(2),
Pohl D(2), Tirupathi S(2), Strømme P(2), de Grauw T(2), Fribourg S(2), Demos
M(2), Pizzino A(2), Naidu S(2), Guerrero K(2), van der Knaap MS(2), Bernard
G(2); 4H Research Group.
Collaborators: Benko W, Boltshauser E, Bonkowsky J, Brouwer OF, Brozova K,
Champaigne NL, Cimas I, Clough C, Cohen A, Collins A, Corenblum B, Dai L, Dolan
G, Faletra F, Fernandez R, Eugenia Garcia Garcia M, Gasparini P, Gburek-Augustat
J, Gibson W, Gonzalez Moron D, Guo Y, Hakonarson H, Hamati A, Harms N, Harting
I, Hertzberg C, Hill A, Hobson G, Innes M, Kauffman M, Keating BJ, Kluger G,
Kolditz P, Kotzaeridou U, Krägeloh-Mann I, La Piana R, Liu X, Marques Lourenço
C, Martos-Moreno GÁ, Matalon R, Mazzeo R, McClintock W, McKenzie F, Mierzewska
H, Mohnish S, Muschke P, Nickel M, Orcesi S, Padiath QS, Patzer S, Pedro H,
Pineda Marfa M, Plecko B, Poll-Thé BT, Potic A, Rating D, Rankin J, Raymond G,
Ronan A, Rosendahl Østergaard J, Rossignol E, Sanchez-Carpintero R, Schossig A,
Sébire G, Senbil N, Swisher CN, Synofzik M, Sønderberg Roos LK, Stevens C,
Sylvain M, Tibussek D, Tonduti D, Tran L, van Hove JL, Vázquez López M, Wang F,
Wang J, Wasling P, Wassmer E, Wiegand G, Wolff A, Zhang J.
Author information:
(1)From the Departments of Child Neurology (N.I.F., M.B., M.S.v.d.K.), Clinical
Genetics (R.M.L.v.S., E.S.), and Pathology (M.B.), Neuroscience Campus (N.I.F.,
M.B., M.S.v.d.K.), and the Department of Functional Genomics, Center for
Neurogenomics and Cognitive Research (M.S.v.d.K.), VU University Medical Center,
Amsterdam, the Netherlands; the Center for Genetic Medicine Research, Department
of Neurology (A.V., A.P.), Children's National Medical Center, Washington, DC;
the Institute of Metabolic Disease (R.S.), Baylor Research Institute, Dallas,
TX; the Departments of Neurology and Neurosurgery and Human Genetics (B.B.),
Montreal Neurological Institute, Canada; the Department of Paediatric Neurology
(C.C.-B.), Erasmus University Hospital-Sophia Children's Hospital; the
Department of Pathology (J.M.K.), Erasmus Medical Center, Rotterdam, the
Netherlands; the Neuroradiology Department (P.S.P.), Centro Hospitalar do Porto,
Portugal; the Division of Neurology (D.P.), Children's Hospital of Eastern
Ontario, University of Ottawa, Canada; the Department of Paediatric Neurology
(S.T.), Royal Belfast Hospital for Sick Children, UK; the Department of Clinical
Neurosciences for Children (P.S.), Oslo University Hospital, Ullevål; University
of Oslo (P.S.), Norway; the Department of Neurology (T.d.G.), Cincinnati School
of Medicine and Cincinnati Children's Hospital Medical Center, OH; INSERM-IECB
(S.F.), Pessac, France; the Department of Pediatric Neurology (M.D.), University
of British Columbia and British Columbia Children's Hospital, Vancouver, Canada;
Kennedy Krieger Institute/Johns Hopkins Medical Institutions (S.N.), Baltimore,
MD; and the Departments of Pediatrics, Neurology, and Neurosurgery, Division of
Pediatric Neurology (K.G., G.B.), Montreal Children's Hospital, McGill
University Health Center, Montreal, Canada. [email protected].
(2)From the Departments of Child Neurology (N.I.F., M.B., M.S.v.d.K.), Clinical
Genetics (R.M.L.v.S., E.S.), and Pathology (M.B.), Neuroscience Campus (N.I.F.,
M.B., M.S.v.d.K.), and the Department of Functional Genomics, Center for
Neurogenomics and Cognitive Research (M.S.v.d.K.), VU University Medical Center,
Amsterdam, the Netherlands; the Center for Genetic Medicine Research, Department
of Neurology (A.V., A.P.), Children's National Medical Center, Washington, DC;
the Institute of Metabolic Disease (R.S.), Baylor Research Institute, Dallas,
TX; the Departments of Neurology and Neurosurgery and Human Genetics (B.B.),
Montreal Neurological Institute, Canada; the Department of Paediatric Neurology
(C.C.-B.), Erasmus University Hospital-Sophia Children's Hospital; the
Department of Pathology (J.M.K.), Erasmus Medical Center, Rotterdam, the
Netherlands; the Neuroradiology Department (P.S.P.), Centro Hospitalar do Porto,
Portugal; the Division of Neurology (D.P.), Children's Hospital of Eastern
Ontario, University of Ottawa, Canada; the Department of Paediatric Neurology
(S.T.), Royal Belfast Hospital for Sick Children, UK; the Department of Clinical
Neurosciences for Children (P.S.), Oslo University Hospital, Ullevål; University
of Oslo (P.S.), Norway; the Department of Neurology (T.d.G.), Cincinnati School
of Medicine and Cincinnati Children's Hospital Medical Center, OH; INSERM-IECB
(S.F.), Pessac, France; the Department of Pediatric Neurology (M.D.), University
of British Columbia and British Columbia Children's Hospital, Vancouver, Canada;
Kennedy Krieger Institute/Johns Hopkins Medical Institutions (S.N.), Baltimore,
MD; and the Departments of Pediatrics, Neurology, and Neurosurgery, Division of
Pediatric Neurology (K.G., G.B.), Montreal Children's Hospital, McGill
University Health Center, Montreal, Canada.
Comment in
Neurology. 2014 Nov 18;83(21):1884-5. doi: 10.1212/WNL.0000000000001010.
OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype
correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism)
leukodystrophy caused by mutations in POLR3A or POLR3B.
METHODS: We performed a multinational cross-sectional observational study of the
clinical, radiologic, and molecular characteristics of 105 mutation-proven
cases.
RESULTS: The majority of patients presented before 6 years with gross motor
delay or regression. Ten percent had an onset beyond 10 years. The disease
course was milder in patients with POLR3B than in patients with POLR3A
mutations. Other than the typical neurologic, dental, and endocrine features,
myopia was seen in almost all and short stature in 50%. Dental and hormonal
findings were not invariably present. Mutations in POLR3A and POLR3B were
distributed throughout the genes. Except for French Canadian patients, patients
from European backgrounds were more likely to have POLR3B mutations than other
populations. Most patients carried the common c.1568T>A POLR3B mutation on one
allele, homozygosity for which causes a mild phenotype. Systematic MRI review
revealed that the combination of hypomyelination with relative T2 hypointensity
of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate
nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the
diagnosis.
CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are
present. Mutations in POLR3A are associated with a more severe clinical course.
MRI characteristics are helpful in addressing the diagnosis, especially if
patients lack the cardinal non-neurologic features.
© 2014 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000001002
PMCID: PMC4248461
PMID: 25339210 [Indexed for MEDLINE]
Conflict of interest statement: N. Wolf serves as communicating editor of the
Journal of Inherited Metabolic Disease and as editor for Neuropediatrics, both
without payment. A. Vanderver has acted on an advisory board for Shire
Pharmaceuticals as well as an unpaid consultant for Stem Cells Inc. R. van
Spaendonk reports no disclosures relevant to the manuscript. R. Schiffmann has
received honoraria and grant support from Shire and Amicus Therapeutics. B.
Brais, M. Bugiani, E. Sistermans, C. Catsman-Berrevoets, J. Kros, and P.S. Pinto
report no disclosures relevant to the manuscript. D. Pohl has received
compensation from Biogen Idec, Merck Serono, Bayer Schering, Teva, and
Sanofi-Aventis (speaker's honoraria and for serving on scientific advisory
boards). S. Tirupathi, P. Strømme, T. de Grauw, S. Fribourg, M. Demos, A.
Pizzino, S. Naidu, K. Guerrero, and M. van der Knaap report no disclosures
relevant to the manuscript. G. Bernard has received compensation from Actelion
Pharmaceuticals, Genzyme, Shire, and Santhera Pharmaceuticals (speaker's
honoraria and for serving on scientific advisory boards). Go to Neurology.org
for full disclosures. |
http://www.ncbi.nlm.nih.gov/pubmed/9636146 | 1. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7316-21. doi:
10.1073/pnas.95.13.7316.
Interaction of SP100 with HP1 proteins: a link between the promyelocytic
leukemia-associated nuclear bodies and the chromatin compartment.
Seeler JS(1), Marchio A, Sitterlin D, Transy C, Dejean A.
Author information:
(1)Unité de Recombinaison et Expression Génétique, Institut National de la Santé
et de la Recherche Médicale U163, Institut Pasteur, 28 rue du Dr. Roux, 75724
Paris Cedex 15.
The PML/SP100 nuclear bodies (NBs) were first described as discrete subnuclear
structures containing the SP100 protein. Subsequently, they were shown to
contain the PML protein which is part of the oncogenic PML-RARalpha hybrid
produced by the t(15;17) chromosomal translocation characteristic of acute
promyelocytic leukemia. Yet, the physiological role of these nuclear bodies
remains unknown. Here, we show that SP100 binds to members of the
heterochromatin protein 1 (HP1) families of non-histone chromosomal proteins.
Further, we demonstrate that a naturally occurring splice variant of SP100, here
called SP100-HMG, is a member of the high mobility group-1 (HMG-1) protein
family and may thus possess DNA-binding potential. Both HP1 and SP100-HMG
concentrate in the PML/SP100 NBs, and overexpression of SP100 leads to enhanced
accumulation of endogenous HP1 in these structures. When bound to a promoter,
SP100, SP100-HMG and HP1 behave as transcriptional repressors in transfected
mammalian cells. These observations present molecular evidence for an
association between the PML/SP100 NBs and the chromatin nuclear compartment.
They support a model in which the NBs may play a role in certain aspects of
chromatin dynamics.
DOI: 10.1073/pnas.95.13.7316
PMCID: PMC22602
PMID: 9636146 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8149913 | 1. Development. 1994 Feb;120(2):347-60. doi: 10.1242/dev.120.2.347.
dishevelled is required during wingless signaling to establish both cell
polarity and cell identity.
Theisen H(1), Purcell J, Bennett M, Kansagara D, Syed A, Marsh JL.
Author information:
(1)Developmental Biology Center, University of California Irvine 92717.
The dishevelled gene of Drosophila is required to establish coherent arrays of
polarized cells and is also required to establish segments in the embryo. Here,
we show that loss of dishevelled function in clones, in double heterozygotes
with wingless mutants and in flies bearing a weak dishevelled transgene leads to
patterning defects which phenocopy defects observed in wingless mutants alone.
Further, polarized cells in all body segments require dishevelled function to
establish planar cell polarity, and some wingless alleles and dishevelled;
wingless double heterozygotes exhibit bristle polarity defects identical to
those seen in dishevelled alone. The requirement for dishevelled in establishing
polarity in cell autonomous. The dishevelled gene encodes a novel intracellular
protein that shares an amino acid motif with several other proteins that are
found associated with cell junctions. Clonal analysis of dishevelled in leg
discs provides a unique opportunity to test the hypothesis that the wingless
dishevelled interaction species at least one of the circumferential positional
values predicted by the polar coordinate model. We propose that dishevelled
encodes an intracellular protein required to respond to a wingless signal and
that this interaction is essential for establishing both cell polarity and cell
identity.
DOI: 10.1242/dev.120.2.347
PMID: 8149913 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19803925 | 1. Womens Health (Lond). 2006 Jan;2(1):43-51. doi: 10.2217/17455057.2.1.43.
Paroxetine use in the treatment of premenstrual dysphoric disorder.
Misri S(1), Kendrick K.
Author information:
(1)University of British Columbia, 2329 West Mall, Vancouver, BC, B6T 1Z4,
Canada. [email protected].
Premenstrual dysphoric disorder, which affects 3-8% of women of reproductive
age, is characterized by a combination of symptoms that may include depressed
mood, irritability, anxiety and/or physical symptoms. These symptoms occur
during the luteal phase of the menstrual cycle, with remission generally
occurring within 3 days after the onset of menses. Presently, treatment
guidelines for premenstrual dysphoric disorder focus on lifestyle management and
psychopharmacologic interventions, with selective serotonin reuptake inhibitors
being considered the first line of medication intervention. The US Food and Drug
Administration and Health Canada recently approved paroxetine for the treatment
of premenstrual dysphoric disorder. This article reviews the properties of this
medication and its use in the treatment of premenstrual dysphoric disorder.
DOI: 10.2217/17455057.2.1.43
PMID: 19803925 |
http://www.ncbi.nlm.nih.gov/pubmed/15975091 | 1. Biochem J. 2005 Oct 15;391(Pt 2):417-24. doi: 10.1042/BJ20050717.
Generation of protein kinase Ck1alpha mutants which discriminate between
canonical and non-canonical substrates.
Bustos VH(1), Marin O, Meggio F, Cesaro L, Allende CC, Allende JE, Pinna LA.
Author information:
(1)Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas,
Facultad de Medicina, Universidad de Chile, Casilla 70086, Santiago 7, Chile.
Protein kinase CK1 denotes a family of pleiotropic serine/threonine protein
kinases implicated in a variety of cellular functions. Typically, CK1 acts as a
'phosphate-directed' kinase whose targeting is primed by a single phosphorylated
side chain at position n-3 or n-4 relative to serine/threonine, but increasing
evidence is accumulating that CK1 can also engage some of its substrates at
sites that do not conform to this canonical consensus. In the present paper, we
show that CK1a phosphorylates with the same efficiency phosphopeptides primed by
a phosphoserine residue at either n-3 [pS(-3)] or n-4 [pS(-4)] positions. The
phosphorylation efficiency of the pS(-4) peptide, and to a lesser extent that of
the pS(-3) peptide, is impaired by the triple mutation of the lysine residues in
the K229KQK232 stretch to alanine residues, promoting 40-fold and 6-fold
increases of Km respectively. In both cases, the individual mutation of Lys232
is as detrimental as the triple mutation. A kinetic alanine-scan analysis with a
series of substituted peptide substrates in which the priming phosphoserine
residue was effectively replaced by a cluster of four aspartate residues was
also consistent with a crucial role of Lys232 in the recognition of the acidic
determinant at position n-4. In sharp contrast, the phosphorylation of b-catenin
and of a peptide including the non-canonical b-catenin site (Ser45) lacking
acidic/phosphorylated determinants upstream is not significantly affected by
mutations in the KKQK stretch. These data provide a molecular insight into the
structural features that underlie the site specificity of CK1a and disclose the
possibility of developing strategies for the preferential targeting of subsets
of CK1 substrates.
DOI: 10.1042/BJ20050717
PMCID: PMC1276941
PMID: 15975091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21571355 | 1. Gynecol Oncol. 2011 Aug;122(2):366-71. doi: 10.1016/j.ygyno.2011.04.033. Epub
2011 May 14.
MicroRNA let-7a: a potential marker for selection of paclitaxel in ovarian
cancer management.
Lu L(1), Schwartz P, Scarampi L, Rutherford T, Canuto EM, Yu H, Katsaros D.
Author information:
(1)Department of Epidemiology and Public Health, Yale Cancer Center, Yale
University School of Medicine, New Haven, CT 06520-8034, USA.
OBJECTIVES: Let-7 is a family of small non-coding RNAs regulating the expression
of many genes that control important cellular activities. Let-7 is shown in
vitro to sensitize cancer cells to platinum, but induce ovarian cancer
resistance to paclitaxel. This study aims to investigate the effect of let-7a
expression on survival outcomes of epithelial ovarian cancer (EOC) patients
treated with different chemotherapy.
METHODS: Let-7a expression was measured with qRT-PCR in ovarian tumors of 178
EOC patients who received platinum-based chemotherapy with and without
paclitaxel after surgery. Survival analysis was performed to assess the effects
of let-7a and chemotherapy on disease outcomes.
RESULTS: Let-7a expression was detectable in the EOC samples, but the expression
was not associated with disease stage, tumor grade, histology and debulking
results. Patients who responded to platinum with paclitaxel had significantly
lower let-7a than those who did not. Survival analyses showed that patients with
high let-7a had better survival compared to those with low let-7a when they were
treated with platinum without paclitaxel. The hazards ratios (HRs) for death and
disease progression were 0.52 (95% CI: 0.29-0.96) and 0.48 (0.26-0.89) for high
let-7a when compared to low let-7a, respectively. However, when patients were
treated with platinum and paclitaxel, high let-7a was associated with worse
progression-free and overall survival. The HRs for death and disease progression
were 3.87 (95% CI: 1.28-11.66) and 3.48 (95% CI: 1.25-9.67) for high let-7a when
compared to low let-7a, respectively. Further studies showed that among patients
with low let-7a, those treated with paclitaxel in addition to platinum survived
better than those treated without paclitaxel [adjusted-HRs were 0.31 (95% CI:
0.15-0.66) for death and 0.40 (95% CI: 0.22-0.75) for disease], while among
those with high let-7a, the two types of treatment made no difference in patient
survival.
CONCLUSIONS: The study suggests that the beneficial impact of the addition of
paclitaxel on EOC survival was significantly linked to let-7a levels, and that
miRNAs such as let-7a may be a useful marker for selection of chemotherapeutic
agents in EOC management.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygyno.2011.04.033
PMID: 21571355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18629289 | 1. Comp Funct Genomics. 2003;4(3):337-41. doi: 10.1002/cfg.287.
Mapping functional associations in the entire genome of Drosophila melanogaster
using fusion analysis.
Iliopoulos I(1), Enright AJ, Poullet P, Ouzounis CA.
Author information:
(1)INA-EKETA, Thessaloniki GR-57001, Greece.
We have previously shown that the detection of gene fusion events can contribute
towards the elucidation of functional associations of proteins within entire
genomes. Here we have analysed the entire genome of Drosophila melanogaster
using fusion analysis and two additional constraints that improve the
reliability of the predictions, viz. low sequence similarity and low degree of
paralogy of the component proteins involved in a fusion event. Imposing these
constraints, the total number of unique component pairs is reduced from 18 654
to a mere 220 cases, which are expected to represent some of the most reliably
detected functionally associated proteins. Using additional information from
sequence databases, we have been able to detect pairs of functionally associated
proteins with important functions in cellular and developmental pathways, such
as spermatogenesis and programmed cell death.
DOI: 10.1002/cfg.287
PMCID: PMC2448454
PMID: 18629289 |
http://www.ncbi.nlm.nih.gov/pubmed/16100656 | 1. Tuberk Toraks. 2005;53(2):177-80.
[Association of combined small cell and large cell lung cancer with
Lambert-Eaton myasthenic syndrome: case report].
[Article in Turkish]
Tokat AO(1), Yüksel C, Ozdemir Kumbasar O, Güngör A.
Author information:
(1)Ankara Education and Research Hospital, Ankara, Turkey. [email protected]
Lambert-Eaton myasthenic syndrome (LEMS) is a rare type of neuromusculer
conduction disorder. This disease can be seen with lung cancer and, it is
associated with otoimmunity. Among the symptoms of lung cancer LEMS can be seen,
but it is very rare. In this case, LEMS symptoms were analyzed before lung
cancer symptoms. The localization of the tumor was near the pulmonary artery. By
the early diagnose, the patient had the chance of cure.
PMID: 16100656 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24126422 | 1. Acta Reumatol Port. 2012 Oct-Dec;37(4):302-13.
Denosumab: recent update in postmenopausal osteoporosis.
Silva I, Branco JC.
Postmenopausal osteoporosis is a major concern to public health. Fractures are
the major clinical consequence of osteoporosis and are associated with
substantial morbidity, mortality and health care costs. Bone strength
determinants such as bone mineral density and bone quality parameters are
determined by life-long remodeling of skeletal tissue. Receptor activator of
nuclear factor-kB ligand (RANKL) is a cytokine essential for osteoclast
differentiation, activation and survival. Denosumab (Prolia®) is a fully human
monoclonal antibody for RANKL, which selectively inhibits osteoclastogenesis,
being recently approved for the treatment of postmenopausal osteoporosis in
women at a high or increased risk of fracture by the FDA in the United States
and by the European Medicines Agency in Europe since June 2010. FREEDOM, DECIDE
and STAND are the phase 3 trials comparing denosumab with placebo and
alendronate in postmenopausal osteoporosis. The authors aim to update denosumab
role in postmenopausal osteoporosis with a physiopathological review.
PMID: 24126422 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19297413 | 1. Development. 2009 May;136(9):1433-42. doi: 10.1242/dev.028472. Epub 2009 Mar
18.
C. elegans mig-6 encodes papilin isoforms that affect distinct aspects of DTC
migration, and interacts genetically with mig-17 and collagen IV.
Kawano T(1), Zheng H, Merz DC, Kohara Y, Tamai KK, Nishiwaki K, Culotti JG.
Author information:
(1)Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, M5G
1X5, Canada.
The gonad arms of C. elegans hermaphrodites acquire invariant shapes by guided
migrations of distal tip cells (DTCs), which occur in three phases that differ
in the direction and basement membrane substrata used for movement. We found
that mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the
extracellular matrix protein papilin, each required for distinct aspects of DTC
migration. Both MIG-6 isoforms have a predicted N-terminal papilin cassette,
lagrin repeats and C-terminal Kunitz-type serine proteinase inhibitory domains.
We show that mutations affecting MIG-6L specifically and cell-autonomously
decrease the rate of post-embryonic DTC migration, mimicking a post-embryonic
collagen IV deficit. We also show that MIG-6S has two separable functions - one
in embryogenesis and one in the second phase of DTC migration. Genetic data
suggest that MIG-6S functions in the same pathway as the MIG-17/ADAMTS
metalloproteinase for guiding phase 2 DTC migrations, and MIG-17 is abnormally
localized in mig-6 class-s mutants. Genetic data also suggest that MIG-6S and
non-fibrillar network collagen IV play antagonistic roles to ensure normal phase
2 DTC guidance.
DOI: 10.1242/dev.028472
PMCID: PMC2674254
PMID: 19297413 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21606361 | 1. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9566-71. doi:
10.1073/pnas.1019391108. Epub 2011 May 23.
CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of
the Igh locus and antisense transcription in pro-B cells.
Degner SC(1), Verma-Gaur J, Wong TP, Bossen C, Iverson GM, Torkamani A,
Vettermann C, Lin YC, Ju Z, Schulz D, Murre CS, Birshtein BK, Schork NJ,
Schlissel MS, Riblet R, Murre C, Feeney AJ.
Author information:
(1)Department of Immunology and Microbial Science, The Scripps Research
Institute, La Jolla, CA 92037, USA.
Compaction and looping of the ~2.5-Mb Igh locus during V(D)J rearrangement is
essential to allow all V(H) genes to be brought in proximity with D(H)-J(H)
segments to create a diverse antibody repertoire, but the proteins directly
responsible for this are unknown. Because CCCTC-binding factor (CTCF) has been
demonstrated to be involved in long-range chromosomal interactions, we
hypothesized that CTCF may promote the contraction of the Igh locus. ChIP
sequencing was performed on pro-B cells, revealing colocalization of CTCF and
Rad21 binding at ~60 sites throughout the V(H) region and 2 other sites within
the Igh locus. These numerous CTCF/cohesin sites potentially form the bases of
the multiloop rosette structures at the Igh locus that compact during Ig heavy
chain rearrangement. To test whether CTCF was involved in locus compaction, we
used 3D-FISH to measure compaction in pro-B cells transduced with CTCF shRNA
retroviruses. Reduction of CTCF binding resulted in a decrease in Igh locus
compaction. Long-range interactions within the Igh locus were measured with the
chromosomal conformation capture assay, revealing direct interactions between
CTCF sites 5' of DFL16 and the 3' regulatory region, and also the intronic
enhancer (Eμ), creating a D(H)-J(H)-Eμ-C(H) domain. Knockdown of CTCF also
resulted in the increase of antisense transcription throughout the D(H) region
and parts of the V(H) locus, suggesting a widespread regulatory role for CTCF.
Together, our findings demonstrate that CTCF plays an important role in the 3D
structure of the Igh locus and in the regulation of antisense germline
transcription and that it contributes to the compaction of the Igh locus.
DOI: 10.1073/pnas.1019391108
PMCID: PMC3111298
PMID: 21606361 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/22668124 | 1. CNS Drugs. 2012 Jul 1;26(7):613-36. doi: 10.2165/11634020-000000000-00000.
A review of neuroprotection pharmacology and therapies in patients with acute
traumatic brain injury.
McConeghy KW(1), Hatton J, Hughes L, Cook AM.
Author information:
(1)UK Healthcare Pharmacy Services, Lexington, KY, USA.
Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury
severity impacts the overall outcome and likelihood for survival. Current
treatment of acute TBI includes surgical intervention and supportive care
therapies. Treatment of elevated intracranial pressure and optimizing cerebral
perfusion are cornerstones of current therapy. These approaches do not directly
address the secondary neurological sequelae that lead to continued brain injury
after TBI. Depending on injury severity, a complex cascade of processes are
activated and generate continued endogenous changes affecting cellular systems
and overall outcome from the initial insult to the brain. Homeostatic cellular
processes governing calcium influx, mitochondrial function, membrane stability,
redox balance, blood flow and cytoskeletal structure often become dysfunctional
after TBI. Interruption of this cascade has been the target of numerous
pharmacotherapeutic agents investigated over the last two decades. Many agents
such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol
were ineffective in clinical trials. While progesterone and ciclosporin have
shown promise in phase II studies, success in larger phase III, randomized,
multicentre, clinical trials is pending. Consequently, no neuroprotective
treatment options currently exist that improve neurological outcome after TBI.
Investigations to date have extended understanding of the injury mechanisms and
sites for intervention. Examination of novel strategies addressing both
pathological and pharmacological factors affecting outcome, employing novel
trial design methods and utilizing biomarkers validated to be reflective of the
prognosis for TBI will facilitate progress in overcoming the obstacles
identified from previous clinical trials.
DOI: 10.2165/11634020-000000000-00000
PMID: 22668124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21787602 | 1. Environ Toxicol Pharmacol. 2010 May;29(3):195-201. doi:
10.1016/j.etap.2010.01.006. Epub 2010 Feb 2.
Neurotoxic effects in patients poisoned with organophosphorus pesticides.
Jokanović M(1), Kosanović M.
Author information:
(1)Faculty of Medicine, University of Nish, Nish, Serbia; Academy of Sciences
and Arts of Republic Srpska, Banja Luka, Bosnia and Herzegovina.
In this paper we review neurotoxic disorders appearing in patients poisoned with
organophosphorus pesticides. These compounds cause four important neurotoxic
effects in humans: the cholinergic syndrome, the intermediate syndrome,
organophosphate-induced delayed polyneuropathy (OPIDP) and chronic
organophosphate-induced neuropsychiatric disorder (COPIND). Compared to the
cholinergic syndrome, that causes millions of cases of poisoning each year,
other disorders involve much smaller numbers of patients. The review is focused
on the neurotoxic effects appearing after acute and chronic exposure to
organophosphates with emphasis on clinical presentation, pathogenesis, molecular
mechanisms, and possibilities for prevention/therapy.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.etap.2010.01.006
PMID: 21787602 |
http://www.ncbi.nlm.nih.gov/pubmed/24096230 | 1. Kathmandu Univ Med J (KUMJ). 2013 Apr-Jun;11(42):175-8. doi:
10.3126/kumj.v11i2.12498.
Burning mouth syndrome: an enigmatic disorder.
Javali MA(1).
Author information:
(1)Department of PDS, Division of periodontics, King Khalid University, College
of Dentistry, Abha.KSA.
Burning mouth syndrome (BMS) is a chronic oral pain or burning sensation
affecting the oral mucosa, often unaccompanied by mucosal lesions or other
evident clinical signs. It is observed principally in middle-aged patients and
postmenopausal women and may be accompanied by xerostomia and altered taste.
Burning mouth syndrome is characterized by an intense burning or stinging
sensation, preferably on the tongue or in other areas of mouth. This disorder is
one of the most common, encountered in the clinical practice. This condition is
probably of multifactorial origin; however the exact underlying etiology remains
uncertain. This article discusses several aspects of BMS, updates current
knowledge about the etiopathogenesis and describes the clinical features as well
as the diagnosis and management of BMS patients.
DOI: 10.3126/kumj.v11i2.12498
PMID: 24096230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21713343 | 1. Biomedica. 2010 Jul-Sep;30(3):410-20.
[Genetic and bioenvironmental factors associated with warfarin response in
Colombian patients].
[Article in Spanish]
Isaza C(1), Beltrán L, Henao J, Porras G, Pinzón A, Vallejos A, Machado J.
Author information:
(1)Facultad de Ciencias de la Salud, Universidad Tecnológica de Pereira,
Colombia. [email protected]
INTRODUCTION: Warfarin is an anticoagulant that is difficult to administer
because of its narrow therapeutic margin and the numerous factors that influence
patient response.
OBJECTIVE: Demographic, clinical and genetic variables were characterized to
establish the appropriate maintenance dosages of warfarin.
MATERIALS AND METHODS: The Colombian patients consisted of 145 adults of both
sexes. They were in stable anticoagulation status with international normalized
ratio between 2 and 3 for at least two months, and without changes in the
warfarin commercial preparation or in the dosage. After signing the informed
consent, the following data was recorded for each volunteer: age, gender,
weight, height, smoker status, co-morbidity, co-medication, International
Normalized Ratio (INR), warfarin dose, and commercial brand. Each patient was
typed for genes CYP2C9, VKORC1, CYP4F2 and PROC; for 59 patients, the serum
levels of warfarin were quantified. The genotyping and the blood quantification
were performed by mini-sequencing and HPLC methods, respectively.
RESULTS: Age, co-medication with enzymatic inhibitors (amiodarone, sertraline,
fluoxetine) or inducers (phenytoin, carbamazepine), and the alleles rs1799853
(*2) and rs1057910 (*3) of the CYP2C9 gene, as well as rs9923231 of the VKORC1
gene were associated with warfarin dose required to achieve anticoagulation with
INR of 2-3. These variables were included in a multiple linear regression model
for predicting the optimum dose/week of warfarin. This resulted in an algorithm
that explained 47.4% of the variability in the dose responses.
CONCLUSION: Clinical and pharmacogenetic variables provided a basis for
improving the safety and effective dosage of warfarin; however, the use of a
pharmacogenetic algorithm will require patient data obtained during clinical
trials.
PMID: 21713343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1867260 | 1. Am J Med Genet. 1991 Apr 1;39(1):28-33. doi: 10.1002/ajmg.1320390108.
Characterization of the calcitonin/CGRP gene in Williams syndrome.
Russo AF(1), Chamany K, Klemish SW, Hall TM, Murray JC.
Author information:
(1)Department of Physiology, University of Iowa, Iowa City 52242.
We have investigated the possibility of mutations in the calcitonin/calcitonin
gene related peptide (CGRP) gene in children with Williams syndrome. Involvement
of the calcitonin/CGRP gene in Williams syndrome is postulated on the basis that
Williams syndrome children often have infantile hypercalcemia and deficient
expression of calcitonin, a hormone that lowers serum calcium levels. To test
the hypothesis that mutations in the calcitonin/CGRP gene might be responsible
for the reduced calcitonin levels, we examined the calcitonin/CGRP gene
structure in Williams syndrome children. Analysis of white blood cell DNA by
Southern blot hybridizations in 5 individuals did not show any detectable large
deletions or rearrangements in the calcitonin/CGRP gene locus. The possibility
of small deletions or point mutations within the exon encoding the mature
calcitonin hormone is unlikely based on ribonuclease protection assays with
patient DNA amplified by the polymerase chain reaction (PCR) technique. These
findings suggest that the calcitonin deficiency might be due either to mutations
elsewhere in the gene or to defects in the cellular machinery needed for
calcitonin synthesis and/or secretion.
DOI: 10.1002/ajmg.1320390108
PMID: 1867260 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20470249 | 1. Med Chem. 2010 Mar;6(2):70-8. doi: 10.2174/157340610791321514.
Styrylbenzimidazoles. Synthesis and biological activity - part 3.
Vitale G(1), Corona P, Loriga M, Carta A, Paglietti G, Ibba C, Giliberti G,
Loddo R, Marongiu E, La Colla P.
Author information:
(1)Dipartimento Farmaco Chimico Tossicologico, University of Sassari, Via
Muroni, 23-07100 Sassari, Italy.
As a follow up of an anti-Flaviviridae project, a new series of variously
substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for
biological activity. Compounds were tested in cell-based assays against viruses
representative of: i) two of the three genera of the Flaviviridae family, i.e.
Pestiviruses and Flaviviruses; ii) other RNA virus families, such as
Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae;
iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for
cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and
Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and
RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the
concentration range 1.7-16 microM; among them, compound 17 was the most active,
with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against
CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active
against RSV with EC(50)= 1 microM and represents a new lead compound.
DOI: 10.2174/157340610791321514
PMID: 20470249 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18344568 | 1. N Engl J Med. 2008 Mar 20;358(12):1215-28. doi: 10.1056/NEJMoa070812. Epub
2008 Mar 16.
Treatment of patients with the hypereosinophilic syndrome with mepolizumab.
Rothenberg ME(1), Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, Schwartz
LB, Rosenwasser LJ, Ring J, Griffin EF, Haig AE, Frewer PI, Parkin JM, Gleich
GJ; Mepolizumab HES Study Group.
Collaborators: Singh A, Joske D, Coyle L, Taylor K, Szer J, Blockmans D, Verhoef
G, Carey W, Denburg J, Padmos A, Shear N, Taraska V, Blétry O, Hatron PY, Ganser
A, Gross W, Baccarani M, Braathen LR, Assa'ad A, Busse W, Butterfield J,
Leiferman K, Murray J, Hagaman D, Ramsdell J, Sheikh J, Talar-Williams CA,
Verstovsek S, Weber R.
Author information:
(1)Division of Allergy and Immunology, Department of Pediatrics, Cincinnati
Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH
45229, USA. [email protected]
Erratum in
N Engl J Med. 2008 Jun 5;358(23): 2530.
Comment in
N Engl J Med. 2008 Mar 20;358(12):1293-4. doi: 10.1056/NEJMe0800524.
N Engl J Med. 2008 Jun 26;358(26):2838-9; author reply 2839-40. doi:
10.1056/NEJMc080856.
N Engl J Med. 2008 Jun 26;358(26):2838; author reply 2839-40.
N Engl J Med. 2008 Jun 26;358(26):2839; author reply 2839-40.
J Allergy Clin Immunol. 2010 Jun;125(6):1245-6. doi:
10.1016/j.jaci.2010.04.022.
BACKGROUND: The hypereosinophilic syndrome is a group of diseases characterized
by persistent blood eosinophilia, defined as more than 1500 cells per microliter
with end-organ involvement and no recognized secondary cause. Although most
patients have a response to corticosteroids, side effects are common and can
lead to considerable morbidity.
METHODS: We conducted an international, randomized, double-blind,
placebo-controlled trial evaluating the safety and efficacy of an
anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the
hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion
gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a
stable clinical status and a blood eosinophil count of less than 1000 per
microliter. Patients received either intravenous mepolizumab or placebo while
the prednisone dose was tapered. The primary end point was the reduction of the
prednisone dose to 10 mg or less per day for 8 or more consecutive weeks.
RESULTS: The primary end point was reached in 84% of patients in the mepolizumab
group, as compared with 43% of patients in the placebo group (hazard ratio,
2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in
clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of
less than 600 per microliter for 8 or more consecutive weeks was achieved in 95%
of patients receiving mepolizumab, as compared with 45% of patients receiving
placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse
events occurred in seven patients receiving mepolizumab (14 events, including
one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five
patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6
months).
CONCLUSIONS: Our study shows that treatment with mepolizumab, an agent designed
to target eosinophils, can result in corticosteroid-sparing for patients
negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome.
(ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov].).
Copyright 2008 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa070812
PMID: 18344568 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11301401 | 1. Cancer. 2001 Apr 15;91(8):1525-9. doi:
10.1002/1097-0142(20010415)91:8<1525::aid-cncr1161>3.0.co;2-p.
Serum endostatin levels are elevated in patients with soft tissue sarcoma.
Feldman AL(1), Pak H, Yang JC, Alexander HR Jr, Libutti SK.
Author information:
(1)Surgery Branch, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland 20892, USA.
BACKGROUND: Solid tumors are angiogenesis dependent, and elevated levels of
proangiogenic cytokines have been reported in a variety of histologies.
Endostatin is an antiangiogenic fragment of the basement membrane protein,
collagen XVIII. Because antiangiogenic protein fragments may be generated by
tumor-derived proteases, the authors sought to determine whether circulating
levels of endostatin were elevated in patients with localized soft tissue
sarcoma.
METHODS: The authors analyzed preoperative serum levels of endostatin, vascular
endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in
25 patients (14 males and 11 females; mean age, 44 years) with soft tissue
sarcoma. For each serum sample, two aliquots were assayed in duplicate using a
competitive enzyme immunoassay. Serum levels were compared with levels from 34
age-matched and gender-matched volunteer blood donors.
RESULTS: Endostatin levels were significantly higher in sera from sarcoma
patients than in sera from healthy controls (43.0 ng/mL vs. 25.8 ng/mL,
respectively; P = 0.0002; Mann-Whitney U test). Significant elevations also were
noted in VEGF and bFGF levels (P = 0.0002 and P = 0.0001, respectively).
Furthermore, endostatin levels > 2 standard deviations above the control mean
(55 ng/mL) were associated with an increased risk of tumor recurrence after
resection (P = 0.047; log-rank test).
CONCLUSIONS: Serum endostatin, VEGF, and bFGF levels are elevated in patients
with soft tissue sarcoma. Elevated endostatin levels appear to be associated
with tumor aggressiveness. The role of these cytokines in sarcoma angiogenesis
and as potential targets for therapy warrants further study.
Copyright 2001 American Cancer Society.
DOI: 10.1002/1097-0142(20010415)91:8<1525::aid-cncr1161>3.0.co;2-p
PMID: 11301401 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23559085 | 1. J Clin Endocrinol Metab. 2013 Jun;98(6):2256-66. doi: 10.1210/jc.2012-3818.
Epub 2013 Apr 4.
Is subclinical hypothyroidism a cardiovascular risk factor in the elderly?
Pasqualetti G(1), Tognini S, Polini A, Caraccio N, Monzani F.
Author information:
(1)Geriatrics Unit, Department of Clinical and Experimental Medicine, University
of Pisa, Via Roma 67, 56126 Pisa, Italy.
CONTEXT: The negative impact of subclinical hypothyroidism (sHT) on
cardiovascular risk, widely recognized in young adults (aged <55-60 y), is still
debated in the elderly (>65 y), especially in the oldest olds (>80 y).
EVIDENCE ACQUISITION: We searched Medline for reports published with the
following search terms: "hypothyroidism," "subclinical hypothyroidism,"
"ageing," "elderly," "L-thyroxin," "thyroid," "guidelines," "treatment,"
"quality of life," "cardiovascular risk," "heart failure," "coronary heart
disease" (CHD), "atherosclerosis," and "endothelial dysfunction." We limited our
search to reports in English published after 1980, although we incorporated some
reports published before 1980. We supplemented the search with records from
personal files, textbooks, and relevant articles. Analyzed parameters included
the epidemiology of thyroid failure, the effect of thyroid hormone on the aging
process, cardiovascular function, and CHD risk factors. We also included the
potential benefits of L-T4 therapy on the quality of life, cardiovascular
events, and survival.
EVIDENCE SYNTHESIS: TSH levels increase with age, even in older people without
thyroid disease. Most longitudinal studies show an increased risk for CHD events
and mortality in sHT participants. This increase is less evident in the elderly,
mainly in cases of serum TSH values above 10 mIU/L. Lower mortality rate in a
cohort of the oldest olds (>85 y) has been reported.
CONCLUSIONS: sHT in older people should be not regarded as a unique condition,
and moderately old patients (aged <70-75 y) could be considered clinically
similar to the adult population, albeit with a higher optimal TSH target value.
Conversely, the oldest old subjects should be carefully followed with a
wait-and-see strategy, generally avoiding hormonal treatment. The decision to
treat elderly people is still an unresolved clinical challenge--first, due to a
lack of appropriately powered randomized controlled trials of L-T4 in sHT
patients, examining cardiovascular hard endpoints in various classes of age; and
second, because of the negative effects of possible overtreatment.
DOI: 10.1210/jc.2012-3818
PMID: 23559085 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23185328 | 1. PLoS One. 2012;7(11):e49405. doi: 10.1371/journal.pone.0049405. Epub 2012 Nov
20.
Effects of acute organophosphorus poisoning on function of peripheral nerves: a
cohort study.
Jayasinghe SS(1), Pathirana KD, Buckley NA.
Author information:
(1)Department of Pharmacology, Faculty of Medicine, University of Ruhuna, Galle,
Sri Lanka. [email protected]
BACKGROUND: Following acute organophosphorus (OP) poisoning patients complain of
numbness without objective sensory abnormalities or other features of OP induced
delayed polyneuropathy. The aim of this study was to measure peripheral nerve
function after acute exposure to OP.
METHODS: A cohort study was conducted with age, gender and occupation matched
controls. Motor nerve conduction velocity (MNCV), amplitude and area of compound
muscle action potential (CMAP), sensory nerve conduction velocity (SNCV), F-
waves and electromyography (EMG) on the deltoid and the first dorsal
interosseous muscles on the dominant side were performed, following acute OP
poisoning. All neurophysiological assessments except EMG were performed on the
controls. Assessments were performed on the day of discharge from the hospital
(the first assessment) and six weeks (the second assessment) after the exposure.
The controls were assessed only once.
RESULTS: There were 70 patients (50 males) and 70 controls. Fifty-three patients
attended for the second assessment. In the first assessment MNCV of all the
motor nerves examined, CMAP amplitude and SNCV of ulnar nerve, median and ulnar
F-wave occurrence in the patients were significantly reduced compared to the
controls. In the second assessment significant reduction was found in SNCV of
both sensory nerves examined, MNCV of ulnar nerve, CMAP amplitude of common
peroneal nerve, F-wave occurrence of median and ulnar nerves. No abnormalities
were detected in the patients when compared to the standard cut-off values of
nerve conduction studies except F-wave occurrence. EMG studies did not show any
abnormality.
CONCLUSION: There was no strong evidence of irreversible peripheral nerve damage
following acute OP poisoning, however further studies are required.
DOI: 10.1371/journal.pone.0049405
PMCID: PMC3502513
PMID: 23185328 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/20301331 | 1. Achondroplasia.
Legare JM(1).
In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW,
Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of
Washington, Seattle; 1993–2024.
1998 Oct 12 [updated 2023 May 11].
Author information:
(1)School of Medicine and Public Health, University of Wisconsin, Madison,
Wisconsin
CLINICAL CHARACTERISTICS: Achondroplasia is the most common cause of
disproportionate short stature. Affected individuals have rhizomelic shortening
of the limbs, macrocephaly, and characteristic facial features with frontal
bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition
of developmental motor milestones is often both aberrant in pattern and delayed.
Intelligence and life span are usually near normal, although craniocervical
junction compression increases the risk of death in infancy. Additional
complications include obstructive sleep apnea, middle ear dysfunction, kyphosis,
and spinal stenosis.
DIAGNOSIS/TESTING: Achondroplasia can be diagnosed by characteristic clinical
and radiographic findings in most affected individuals. In individuals in whom
there is diagnostic uncertainty or who have atypical findings, identification of
a heterozygous pathogenic variant in FGFR3 can establish the diagnosis.
MANAGEMENT: Treatment of manifestations: Vosoritide, a C-type natriuretic
peptide (CNP) analog, was recently approved to enhance height in individuals
with achondroplasia from age five years until growth plates close.
Ventriculoperitoneal shunt may be required for increased intracranial pressure;
suboccipital decompression as indicated for signs and symptoms of craniocervical
junction compression; adenotonsillectomy, positive airway pressure, and, rarely,
tracheostomy to correct obstructive sleep apnea; pressure-equalizing tubes for
middle ear dysfunction; monitor and treat obesity; evaluation and treatment by
an orthopedist if progressive bowing of the legs arises; spinal surgery may be
needed for severe, persistent kyphosis; surgery to correct spinal stenosis in
symptomatic adults; modification in the school and work setting to optimize
function; educational support in socialization and school adjustment.
Surveillance: Monitor height, weight, and head circumference in childhood using
growth curves standardized for achondroplasia; evaluation of developmental
milestones throughout infancy and childhood using achondroplasia-specific
standards; baseline neuroimaging of craniocervical junction and brain in
infancy; neurologic examinations monitoring for signs of cervical myelopathy;
monitor for signs and symptoms of sleep apnea; hearing evaluation as a newborn
and tympanometric and behavioral audiometric evaluation by age approximately one
year; monitor for middle ear problems or evidence of hearing loss in childhood;
clinical assessment for kyphosis and bowed legs, with radiographic evaluation
and referral to an orthopedist if necessary; in adults, clinical history and
neurologic examination to screen for spinal stenosis with development of any new
signs or symptoms or at least every three to five years; discuss social
adjustment at each visit with primary care provider. Agents/circumstances to
avoid: Rear-facing car seats should be used as long as possible to avoid injury
from motor vehicle accident. Avoid soft-back infant seats and front carriers
without a firm back. Avoid activities in which there is risk of injury to the
craniocervical junction, such as collision sports; use of a trampoline; diving
from diving boards; vaulting in gymnastics; and hanging upside down from the
knees or feet on playground equipment (due to risk of falling onto the head or
neck). Pregnancy management: Pregnant women with achondroplasia must undergo
cesarean section delivery because of small pelvic size.
GENETIC COUNSELING: Achondroplasia is inherited in an autosomal dominant manner.
Around 80% of individuals with achondroplasia have parents with average stature
and have achondroplasia as the result of a de novo pathogenic variant. Such
parents have a very low risk of having another child with achondroplasia. An
individual with achondroplasia who has a reproductive partner with average
stature is at 50% risk in each pregnancy of having a child with achondroplasia.
When both parents have achondroplasia, the risk to their offspring of having
average stature is 25%; of having achondroplasia, 50%; and of having homozygous
achondroplasia (a lethal condition), 25%. If the proband and the proband's
reproductive partner are affected with different dominantly inherited skeletal
dysplasias, genetic counseling becomes more complicated because of the risk of
inheriting two dominant skeletal dysplasias. If the FGFR3 pathogenic variant has
been identified in the affected parent or parents, prenatal testing for a
pregnancy at increased risk for achondroplasia is possible.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a
registered trademark of the University of Washington, Seattle. All rights
reserved.
PMID: 20301331 |
http://www.ncbi.nlm.nih.gov/pubmed/20308065 | 1. J Biol Chem. 2010 Jun 4;285(23):17896-906. doi: 10.1074/jbc.M109.096578. Epub
2010 Mar 22.
TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6.
Tokési N(1), Lehotzky A, Horváth I, Szabó B, Oláh J, Lau P, Ovádi J.
Author information:
(1)Institute of Enzymology, Biological Research Center, Hungarian Academy of
Sciences, Karolina u 29, H-1113, Budapest, Hungary.
TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured
protein that induces microtubule polymerization in vitro and is aligned along
the microtubule network in transfected mammalian cells. In normal human brain,
TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is
proved to be crucial for their differentiation process. Here we demonstrated
that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10
cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of
alpha-tubulin at residue Lys-40, whereas its down-regulation by specific small
interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10
cells decreased the acetylation level of alpha-tubulin. Our results indicate
that TPPP/p25 binds to HDAC6 (histone deacetylase 6), an enzyme responsible for
tubulin deacetylation. Moreover, we demonstrated that the direct interaction of
these two proteins resulted in the inhibition of the deacetylase activity of
HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce
almost complete (90%) inhibition at 3 microM concentration. In addition,
treatment of the cells with nocodazole, vinblastine, or cold exposure revealed
that microtubule acetylation induced by trichostatin A, a well known HDAC6
inhibitor, does not cause microtubule stabilization. In contrast, the
microtubule bundling activity of TPPP/p25 was able to protect the microtubules
from depolymerization. Finally, we demonstrated that, similarly to other HDAC6
inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the
growth velocity of the microtubule plus ends and also affects cell motility as
demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is
a multiple effector of the microtubule organization.
DOI: 10.1074/jbc.M109.096578
PMCID: PMC2878552
PMID: 20308065 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24119843 | 1. Cell. 2013 Nov 7;155(4):934-47. doi: 10.1016/j.cell.2013.09.053. Epub 2013 Oct
10.
Super-enhancers in the control of cell identity and disease.
Hnisz D(1), Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young
RA.
Author information:
(1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
MA 02142, USA.
Super-enhancers are large clusters of transcriptional enhancers that drive
expression of genes that define cell identity. Improved understanding of the
roles that super-enhancers play in biology would be afforded by knowing the
constellation of factors that constitute these domains and by identifying
super-enhancers across the spectrum of human cell types. We describe here the
population of transcription factors, cofactors, chromatin regulators, and
transcription apparatus occupying super-enhancers in embryonic stem cells and
evidence that super-enhancers are highly transcribed. We produce a catalog of
super-enhancers in a broad range of human cell types and find that
super-enhancers associate with genes that control and define the biology of
these cells. Interestingly, disease-associated variation is especially enriched
in the super-enhancers of disease-relevant cell types. Furthermore, we find that
cancer cells generate super-enhancers at oncogenes and other genes important in
tumor pathogenesis. Thus, super-enhancers play key roles in human cell identity
in health and in disease.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2013.09.053
PMCID: PMC3841062
PMID: 24119843 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14988723 | 1. EMBO J. 2004 Mar 10;23(5):1178-87. doi: 10.1038/sj.emboj.7600113. Epub 2004
Feb 26.
The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and
ATR-NBS1-FANCD2 pathways.
Pichierri P(1), Rosselli F.
Author information:
(1)UPR 2169 du CNRS, Institut Gustave Roussy PR2, Villejuif Cedex, France.
The genetic syndrome Fanconi anemia (FA) is characterized by aplastic anemia,
cancer predisposition and hypersensitivity to DNA interstrand crosslinks (ICLs).
FA proteins (FANCs) are thought to work in pathway(s) essential for dealing with
crosslinked DNA. FANCs interact with other proteins involved in both DNA repair
and S-phase checkpoint such as BRCA1, ATM and the RAD50/MRE11/NBS1 (RMN)
complex. We deciphered the previously undefined pathway(s) leading to the
ICLs-induced S-phase checkpoint and the role of FANCs in this process. We found
that ICLs activate a branched pathway downstream of the ATR kinase: one branch
depending on CHK1 activity and the other on the FANCs-RMN complex. The transient
slow-down of DNA synthesis was abolished in cells lacking ATR, whereas
CHK1-siRNA-treated cells, NBS1 or FA cells showed partial S-phase arrest. CHK1
RNAi in NBS1 or FA cells abolished the S-phase checkpoint, suggesting that CHK1
and FANCs/NBS1 proteins work on parallel pathways. Furthermore, we found that
ICLs trigger ATR-dependent FANCD2 phosphorylation and FANCD2/ATR colocalization.
This study demonstrates a novel relationship between the FA pathway(s) and the
ATR kinase.
DOI: 10.1038/sj.emboj.7600113
PMCID: PMC380971
PMID: 14988723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11490597 | 1. Nestle Nutr Workshop Ser Clin Perform Programme. 1999;1:67-76; discussion 77.
doi: 10.1159/000062949.
Anorexia of aging, leptin, and the Mini Nutritional Assessment.
Morley JE(1), Miller DK, Perry HM 3rd, Patrick P, Guigoz Y, Vellas B.
Author information:
(1)GRECC, St. Louis VAMC, and Division of Geriatric Medicine, Saint Louis
University, Saint Louis, Mo., USA.
In this chapter we have reviewed the evidence for physiological anorexia of
aging and stressed that its pathophysiology involves both central and peripheral
mechanisms. Early satiation in the older person appears to involve signals
predominantly arising in the stomach. The increased feeling of satiety in older
persons is mainly related to changes in the central feeding drive, in particular
a decrease in the opioid rewarding properties for fatty foods. Increased
cytokines, secondary to inflammatory conditions which are common in old age, may
further increase the anorexia seen in older persons. Leptin, the fat hormone, is
an excellent indicator of fat mass in women, in whom leptin concentrations
correlate with the MNA. In men, testosterone inhibits leptin, and the fall in
testosterone with age results in an increase in leptin concentrations. In males
the MNA is not related to leptin concentrations. Finally, we have examined the
interrelation of two nutritional screening indices, MNA and SCALES. The two
indices were well correlated and were both predictive of poor basic function. We
conclude that the MNA is an excellent predictor of nutritional status. These
findings suggest that malnutrition is a major predictor of frailty or the
"failure to thrive" syndrome in older persons. Depression is a major cause of
poor nutritional status in older persons.
DOI: 10.1159/000062949
PMID: 11490597 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20382953 | 1. J Child Neurol. 2010 Apr;25(4):490-3. doi: 10.1177/0883073809357937.
Andersen cardiodysrhythmic periodic paralysis with KCNJ2 mutations: a novel
mutation in the pore selectivity filter residue.
Lim BC(1), Kim GB, Bae EJ, Noh CI, Hwang H, Kim KJ, Hwang YS, Ko TS, Chae JH.
Author information:
(1)Department of Pediatrics, Seoul National University College of Medicine,
Seoul, Korea.
Andersen cardiodysrhythmic periodic paralysis or Andersen-Tawil syndrome
includes the distinct clinical features of periodic paralysis, cardiac
arrhythmia, and facial and skeletal dysmorphisms and exhibits autosomal dominant
inheritance. Mutations in the KCNJ2 gene, which encodes the human inward
rectifier potassium channel Kir2.1, have been identified in the majority of
cases. Despite well-established clinical and molecular characteristics,
treatment is still case oriented, and timely diagnosis could be delayed because
of the low incidence and phenotypic heterogeneity of this disease. This article
describes the clinical and molecular features of 3 cases of Andersen-Tawil
syndrome in 2 families. One of the mutations (G144D) was located in the pore
selectivity filter residue (which is mutated recurrently) and was considered
novel. Intermittent muscle weakness in childhood warrants careful evaluation of
cardiac dysrhythmia and skeletal anomalies.
DOI: 10.1177/0883073809357937
PMID: 20382953 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25186601 | 1. Immunotherapy. 2014;6(6):679-90. doi: 10.2217/imt.14.21.
Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma
multiforme.
Swartz AM(1), Li QJ, Sampson JH.
Author information:
(1)Duke University Medical Center, Department of Surgery, Division of
Neurosurgery, DUMC Box 3050 Durham, NC 27710, USA.
Glioblastoma multiforme (GBM) is the most common and aggressive glial
cell-derived primary tumor. Current standard of care for patients with GBM
includes maximal tumor resection plus adjuvant radiotherapy and temozolomide
chemotherapy, increasing median overall survival to a mere 15 months from
diagnosis. Because these therapies are inherently nonspecific, there is an
increased likelihood of off-target and incomplete effects; therefore, targeted
modalities are required for enhanced safety and efficacy. Rindopepimut is
emerging as a safe and potentially effective drug for the treatment of GBM.
Rindopepimut consists of a 14-mer peptide that spans the length of EGF receptor
variant III, a mutant variant of EGF receptor found on approximately 30% of
primary GBM, conjugated to the carrier protein keyhole limpet hemocyanin.
Vaccination with rindopepimut has been shown to specifically eliminate cells
expressing EGF receptor variant III. Phase II clinical trials have suggested
that vaccination of newly diagnosed GBM patients with rindopepimut plus adjuvant
granulocyte-macrophage colony-stimulating factor results in prolonged
progression-free and overall survival with minimal toxicity. This review will
outline the development of rindopepimut, as well as the current status of this
vaccine.
DOI: 10.2217/imt.14.21
PMCID: PMC4524671
PMID: 25186601 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15304085 | 1. J Invest Dermatol. 2004 Sep;123(3):470-3. doi:
10.1111/j.0022-202X.2004.23228.x.
Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese
pedigrees with Dyskeratosis congenita.
Ding YG(1), Zhu TS, Jiang W, Yang Y, Bu DF, Tu P, Zhu XJ, Wang BX.
Author information:
(1)Department of Dermatology and Venereology, Peking University First Hospital,
Beijing 100 034, China.
Dyskeratosis congenita (DKC) is a rare and fatal congenital syndrome
characterized by the triad of reticular skin pigmentation, nail dystrophy and
mucosal leukoplakia, and the predisposition to bone marrow failure and
malignancies. Mutations in DKC1 gene encoding dyskerin are responsible for the
X-linked dyskeratosis congenita. Here we report mutation analysis of two Chinese
pedigrees with dyskeratosis congenita. The 15 coding exons of DKC1 and their
flanking regions were amplified from genomic DNA by PCR. DNA sequencing and
restriction endonuclease digestion were used for mutation detection. Transition
mutation of 1226C-->T (P409L) found in the first pedigree is a novel mutation.
In the second pedigree, the proband's mother phenotypically normal carried a de
novo transition mutation of 1058C-->T (A353 V) in one allele, and transmitted
the mutant allele to her two sons who had typical manifestations of dyskeratosis
congenita.
DOI: 10.1111/j.0022-202X.2004.23228.x
PMID: 15304085 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19282658 | 1. Tohoku J Exp Med. 2009 Mar;217(3):223-9. doi: 10.1620/tjem.217.223.
Bach1 deficiency ameliorates hepatic injury in a mouse model.
Iida A(1), Inagaki K, Miyazaki A, Yonemori F, Ito E, Igarashi K.
Author information:
(1)Japan Tobacco Inc., Central Pharmaceutical Research Institute, Osaka, Japan.
Bach1 is a basic region-leucine zipper (bZip) protein that forms heterodimers
with the small Maf proteins and functions as a repressor of gene expression. One
of the target genes of Bach1 is Hmox-1 that encodes heme oxygenase-1 (HO-1).
HO-1 degrades heme into carbon monoxide (CO), biliverdin, and iron. HO-1 is
strongly induced by various stresses as well as its substrate heme, and protects
cells and tissues against insults through diverse cytoprotective functions of
the reaction products CO and biliverdin. Bach1-deficiency in mice leads to
higher expression of Hmox-1 in various tissues. Here we investigated the effects
of Bach1-deficiency in mice on tissue injuries: hepatic injury induced by
D-galactosamine (GalN) and lipopolysaccharide (LPS), and mouse paw edema induced
by carrageenin, polysaccharide derived from various seaweeds. Bach1-deficiency
suppressed induction of plasma alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) activities in response to the GalN/LPS-treatment.
However, production of tumor necrosis factor alpha (TNF-alpha) and nitric oxide
(NO), both being cytotoxic mediators in LPS-induced hepatic injury, in
Bach1-deficient mice and their peritoneal macrophages was similar to wild type
controls. In contrast, Bach1-deficiency did not affect extent of mouse paw edema
induced by carrageenin, which enhances vascular permeability by activating kinin
release. These results indicate that Bach1 plays an inhibitory role in the
cytoprotection of LPS-induced liver injury but not in the kinin-mediated
inflammatory edema. The inhibitory role for Bach1 may stem from its activity to
repress gene expression including HO-1.
DOI: 10.1620/tjem.217.223
PMID: 19282658 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24130305 | 1. Bioinformatics. 2014 Mar 1;30(5):644-51. doi: 10.1093/bioinformatics/btt591.
Epub 2013 Oct 15.
ORMAN: optimal resolution of ambiguous RNA-Seq multimappings in the presence of
novel isoforms.
Dao P(1), Numanagić I, Lin YY, Hach F, Karakoc E, Donmez N, Collins C, Eichler
EE, Sahinalp SC.
Author information:
(1)School of Computing Science, Simon Fraser University, Burnaby, BC, Canada,
Department of Genome Sciences, University of Washington, Seattle, WA, USA,
Vancouver Prostate Centre & Department of Urologic Sciences, University of
British Columbia, Vancouver, BC, Canada and Division of Computer Science, School
of Informatics and Computing, Indiana University, Bloomington, IN, USA.
MOTIVATION: RNA-Seq technology is promising to uncover many novel alternative
splicing events, gene fusions and other variations in RNA transcripts. For an
accurate detection and quantification of transcripts, it is important to resolve
the mapping ambiguity for those RNA-Seq reads that can be mapped to multiple
loci: >17% of the reads from mouse RNA-Seq data and 50% of the reads from some
plant RNA-Seq data have multiple mapping loci. In this study, we show how to
resolve the mapping ambiguity in the presence of novel transcriptomic events
such as exon skipping and novel indels towards accurate downstream analysis. We
introduce ORMAN ( O ptimal R esolution of M ultimapping A mbiguity of R N A-Seq
Reads), which aims to compute the minimum number of potential transcript
products for each gene and to assign each multimapping read to one of these
transcripts based on the estimated distribution of the region covering the read.
ORMAN achieves this objective through a combinatorial optimization formulation,
which is solved through well-known approximation algorithms, integer linear
programs and heuristics.
RESULTS: On a simulated RNA-Seq dataset including a random subset of transcripts
from the UCSC database, the performance of several state-of-the-art methods for
identifying and quantifying novel transcripts, such as Cufflinks, IsoLasso and
CLIIQ, is significantly improved through the use of ORMAN. Furthermore, in an
experiment using real RNA-Seq reads, we show that ORMAN is able to resolve
multimapping to produce coverage values that are similar to the original
distribution, even in genes with highly non-uniform coverage.
AVAILABILITY: ORMAN is available at http://orman.sf.net
DOI: 10.1093/bioinformatics/btt591
PMID: 24130305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23531534 | 1. Int J Mol Sci. 2013 Mar 26;14(4):6690-719. doi: 10.3390/ijms14046690.
Aptamers and their potential to selectively target aspects of EGF, Wnt/β-catenin
and TGFβ-smad family signaling.
Conidi A(1), van den Berghe V, Huylebroeck D.
Author information:
(1)Laboratory of Molecular Biology (Celgen), Department of Development and
Regeneration, KU Leuven, Campus Gasthuisberg, Building Ond & Nav4 p.o.box 812,
room 05.313, Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium.
[email protected].
The smooth identification and low-cost production of highly specific agents that
interfere with signaling cascades by targeting an active domain in surface
receptors, cytoplasmic and nuclear effector proteins, remain important
challenges in biomedical research. We propose that peptide aptamers can provide
a very useful and new alternative for interfering with protein-protein
interactions in intracellular signal transduction cascades, including those
emanating from activated receptors for growth factors. By their targeting of
short, linear motif type of interactions, peptide aptamers have joined nucleic
acid aptamers for use in signaling studies because of their ease of production,
their stability, their high specificity and affinity for individual target
proteins, and their use in high-throughput screening protocols. Furthermore,
they are entering clinical trials for treatment of several complex, pathological
conditions. Here, we present a brief survey of the use of aptamers in signaling
pathways, in particular of polypeptide growth factors, starting with the
published as well as potential applications of aptamers targeting Epidermal
Growth Factor Receptor signaling. We then discuss the opportunities for using
aptamers in other complex pathways, including Wnt/β-catenin, and focus on
Transforming Growth Factor-β/Smad family signaling.
DOI: 10.3390/ijms14046690
PMCID: PMC3645661
PMID: 23531534 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24838573 | 1. Nucleic Acids Res. 2014 Jun;42(11):7473-85. doi: 10.1093/nar/gku402. Epub 2014
May 16.
CRISPR/Cas9 systems have off-target activity with insertions or deletions
between target DNA and guide RNA sequences.
Lin Y(1), Cradick TJ(1), Brown MT(1), Deshmukh H(1), Ranjan P(2), Sarode N(2),
Wile BM(1), Vertino PM(3), Stewart FJ(2), Bao G(4).
Author information:
(1)Department of Biomedical Engineering, Georgia Institute of Technology and
Emory University, Atlanta, GA 30332, USA.
(2)School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
(3)Department of Radiation Oncology, Emory University School of Medicine,
Atlanta, GA 30322, USA.
(4)Department of Biomedical Engineering, Georgia Institute of Technology and
Emory University, Atlanta, GA 30332, USA [email protected].
CRISPR/Cas9 systems are a versatile tool for genome editing due to the highly
efficient targeting of DNA sequences complementary to their RNA guide strands.
However, it has been shown that RNA-guided Cas9 nuclease cleaves genomic DNA
sequences containing mismatches to the guide strand. A better understanding of
the CRISPR/Cas9 specificity is needed to minimize off-target cleavage in large
mammalian genomes. Here we show that genomic sites could be cleaved by
CRISPR/Cas9 systems when DNA sequences contain insertions ('DNA bulge') or
deletions ('RNA bulge') compared to the RNA guide strand, and Cas9 nickases used
for paired nicking can also tolerate bulges in one of the guide strands.
Variants of single-guide RNAs (sgRNAs) for four endogenous loci were used as
model systems, and their cleavage activities were quantified at different
positions with 1- to 5-bp bulges. We further investigated 114 putative genomic
off-target loci of 27 different sgRNAs and confirmed 15 off-target sites, each
harboring a single-base bulge and one to three mismatches to the guide strand.
Our results strongly indicate the need to perform comprehensive off-target
analysis related to DNA and sgRNA bulges in addition to base mismatches, and
suggest specific guidelines for reducing potential off-target cleavage.
© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gku402
PMCID: PMC4066799
PMID: 24838573 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24576837 | 1. J Thorac Imaging. 2014 May;29(3):147-54. doi: 10.1097/RTI.0000000000000077.
Myocardial tissue characterization by magnetic resonance imaging: novel
applications of T1 and T2 mapping.
Ferreira VM(1), Piechnik SK, Robson MD, Neubauer S, Karamitsos TD.
Author information:
(1)Radcliffe Department of Medicine, Division of Cardiovascular Medicine,
University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR),
John Radcliffe Hospital, Oxford, UK.
Cardiac magnetic resonance (CMR) imaging is a well-established noninvasive
imaging modality in clinical cardiology. Its unsurpassed accuracy in defining
cardiac morphology and function and its ability to provide tissue
characterization make it well suited for the study of patients with cardiac
diseases. Late gadolinium enhancement was a major advancement in the development
of tissue characterization techniques, allowing the unique ability of CMR to
differentiate ischemic heart disease from nonischemic cardiomyopathies. Using
T2-weighted techniques, areas of edema and inflammation can be identified in the
myocardium. A new generation of myocardial mapping techniques are emerging,
enabling direct quantitative assessment of myocardial tissue properties in
absolute terms. This review will summarize recent developments involving
T1-mapping and T2-mapping techniques and focus on the clinical applications and
future potential of these evolving CMR methodologies.
DOI: 10.1097/RTI.0000000000000077
PMCID: PMC4252135
PMID: 24576837 [Indexed for MEDLINE]
Conflict of interest statement: US patent pending 61/387,591: Stefan K. Piechnik
and Matthew D. Robson. Systems and methods for shortened look-locker inversion
recovery (ShMOLLI) cardiac gated mapping of T1. September 29, 2010. All rights
sold exclusively to Siemens Medical Solutions. US patent pending 61/689,067:
Stefan K. Piechnik and Matthew D. Robson. Color map design method for immediate
assessment of the deviation from established normal population statistics and
its application to cardiovascular T1 mapping images. The remaining authors
declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24265855 | 1. Commun Integr Biol. 2013 Sep 1;6(5):e25429. doi: 10.4161/cib.25429. Epub 2013
Jun 25.
Intracellular Ca(2+) signaling: A novel player in the canonical mTOR-controlled
autophagy pathway.
Decuypere JP(1), Paudel RC, Parys J, Bultynck G.
Author information:
(1)Laboratory of Molecular and Cellular Signaling; Department of Cellular and
Molecular Medicine; KU Leuven; Leuven, Belgium ; Current affiliation: Laboratory
of Abdominal Transplant Surgery; Department of Microbiology and Immunology;
University Hospitals Leuven; KU Leuven; Leuven, Belgium.
Functional intracellular Ca(2+) signaling is essential for the upregulation of
the canonical mTOR-controlled autophagy pathway triggered by rapamycin or by
nutrient deprivation. Moreover, modifications in the Ca(2+)-signaling machinery
coincide with autophagy stimulation. This results in enhanced intracellular
Ca(2+) signaling essential for driving the autophagy process. Yet, the
mechanisms upstream (the players causing the changes in Ca(2+) signaling) and
downstream (the targets of the altered Ca(2+) signals) of this Ca(2+)-dependent
autophagy pathway remain elusive. Here, we speculate about these mechanisms
based on our current knowledge.
DOI: 10.4161/cib.25429
PMCID: PMC3829968
PMID: 24265855 |
http://www.ncbi.nlm.nih.gov/pubmed/24140975 | 1. J Proteomics. 2013 Dec 6;94:359-69. doi: 10.1016/j.jprot.2013.10.006. Epub
2013 Oct 17.
A novel angiotensin converting enzyme inhibitory peptide derived from
proteolytic digest of Chinese soft-shelled turtle egg white proteins.
Rawendra RD(1), Aisha, Chang CI, Aulanni'am, Chen HH, Huang TC, Hsu JL.
Author information:
(1)Department of Biological Science and Technology, National Pingtung University
of Science and Technology, Pingtung, Taiwan; Department of Food Science,
National Pingtung University of Science and Technology, 91201 Pingtung, Taiwan;
Department of Food Science, Faculty of Agricultural Technology, University of
Brawijaya, Malang, Indonesia.
In this study, soft-shelled turtle (Pelodiscus sinensis) egg white (SSTEW)
proteins were digested by thermolysin and the resulting small peptides were
further fractionated by reverse phase chromatography. Peptides with angiotensin
I-converting enzyme inhibitory (ACEI) activity from these fractions were
screened. A lysozyme-derived peptide, IW-11, from the fraction with the most
effective ACEI was identified by liquid chromatography-tandem mass spectrometry
(LC-MS/MS) and its purified form showed effective ACEI activity in vitro
(IC50=4.39±0.31μM). The Lineweaver-Burk plots indicated that the inhibition
towards ACE caused by this peptide is a competitive inhibition. The molecular
docking study further revealed that the ACEI activity of IW-11 is mainly
attributed to the formation of hydrogen bonds between the N-terminal residue of
IW-11 and the S1 pocket (Ala354 and Tyr523) and the S2' region (His513 and
His353) of ACE. Moreover, the digestion parameters were further optimized and
the target peptide (82% purity) was readily obtained (15% yield) without any
cumbersome purification procedure. Notably, lysozyme C is the most abundant
protein in SSTEW, which implies that an efficient production of this ACEI
peptide from SSTEW is promising.
BIOLOGICAL SIGNIFICANCE: Inhibition of ACE has proven to be an effective
strategy in prevention and treatment of hypertension and related diseases.
Unlike typical synthetic ACE inhibitors which exert well described side effects,
food-derived peptides with ACE inhibitory activity may be safer alternatives for
hypertension treatment. In this study, we comprehensively identified peptides
derived from SSTEW digest using a proteomic approach. IW-11, which is derived
from lysozyme, the most abundant protein in SSTEW, showed remarkable inhibition
towards ACE. This peptide has been demonstrated to have a competitive inhibitory
property which is able to bind to ACE active site and found to be a true
inhibitor against ACE according to Lineweaver-Burk plots. Using an optimized
thermolysin condition, IW-11 can be readily obtained without any complex
purification step, which will benefit its further application to prevention or
treatment of hypertension.
© 2013.
DOI: 10.1016/j.jprot.2013.10.006
PMID: 24140975 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9781539 | 1. Neurology. 1998 Oct;51(4):1116-20. doi: 10.1212/wnl.51.4.1116.
Early onset, autosomal recessive muscular dystrophy with Emery-Dreifuss
phenotype and normal emerin expression.
Taylor J(1), Sewry CA, Dubowitz V, Muntoni F.
Author information:
(1)Department of Paediatrics and Neonatal Medicine, MRC Clinical Sciences
Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
OBJECTIVE: To describe the clinical and histopathologic picture of a
childhood-onset, severe variant of scapuloperoneal MD with rigidity of the
spine.
BACKGROUND: Rigidity of the spine is a feature of numerous syndromes, including
X-linked Emery-Dreifuss MD, Bethlem myopathy, and the rigid spine syndrome.
These are, however, relatively static or very slowly progressive neuromuscular
disorders, usually associated with preserved ambulation into adult life.
PATIENTS AND METHODS: Five unrelated children (three boys and two girls)
presented in the first 2 years of life with poor neck control, waddling gait,
and frequent falls. Early wasting of the distal leg muscles, biceps, triceps,
and neck muscles was noted in all patients, and all had contractures and severe
rigidity of the spine. The condition progressed rapidly, and all patients lost
ambulation before the age of 8 years. Cardiac function was normal in all.
RESULTS: Creatine kinase was moderately elevated in all, and muscle biopsy
specimens showed nonspecific dystrophic changes with normal expression of
dystrophin, the sarcoglycans, and laminin alpha2, alpha5, beta1, and gamma1
chains. Emerin expression was normal in two of the boys whose tissue was
available for study.
CONCLUSIONS: The distribution of weakness, wasting, and contractures of the
patients described resembled Emery-Dreifuss MD, but the rapid progression of
weakness and contractures and the involvement of both sexes together with normal
emerin expression suggest that this form is not X-linked Emery-Dreifuss MD. We
suggest that these patients represent a severe MD characterized by early onset
distal wasting and severe rigidity of the spine, with probable autosomal
recessive inheritance.
DOI: 10.1212/wnl.51.4.1116
PMID: 9781539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21590310 | 1. Eur J Clin Pharmacol. 2011 Nov;67(11):1119-30. doi: 10.1007/s00228-011-1060-1.
Epub 2011 May 18.
Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9
genotypes, and clinical factors on warfarin response in Sudanese patients.
Shrif NE(1), Won HH, Lee ST, Park JH, Kim KK, Kim MJ, Kim S, Lee SY, Ki CS,
Osman IM, Rhman EA, Ali IA, Idris MN, Kim JW.
Author information:
(1)Department of Laboratory Medicine and Genetics, Samsung Medical Center,
Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Gangnam-gu, Seoul
135-710, South Korea.
OBJECTIVE: African populations, including the Sudanese, are underrepresented in
warfarin pharmacogenetic studies. We designed a study to determine the
associations between the polymorphisms and haplotype structures of CYP2C9 and
VKORC1 and warfarin dose response in Sudanese patients, one of the most
genetically diverse populations in Africa.
MATERIAL AND METHODS: The effect of the CYP2C9 polymorphisms (*2, *3, *5, *6,
*8, *9, and *11), 20 VKORC1 tag SNPs and haplotypes, and clinical covariates
were comprehensively assessed in 203 Sudanese warfarin-treated patients.
RESULTS: Patients with the CYP2C9*2,*5,*6, or *11 variant required a daily
warfarin dose that was 21% lower than those with CYP2C9*1/*1 (4.7 vs 5.8 mg/day,
P < 0.001). SNPs around the VKORC1 and POL3S genes were divided into two
haplotype blocks in Sudanese populations. According to multiple linear
regression results, rs8050984, rs7294, and rs7199949 in the VKORC1 and POL3S
genes (P <0.001, <0.001, <0.001, respectively), CYP2C9 genotype (*2, *5, *6,
*11; P < 0.001), body weight (P = 0.04), target INR (P = 0.007), and concurrent
medications (P = 0.029) could explain about 36.7% of the total warfarin dose
variation.
CONCLUSION: Our data revealed that VKORC1 and CYP2C9 polymorphisms are important
factors that influence warfarin dose response in Sudanese patients. Our data
suggest that combinations of the SNPs may improve predictions of warfarin dose
requirements.
DOI: 10.1007/s00228-011-1060-1
PMID: 21590310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12477530 | 1. Fertil Steril. 2002 Dec;78(6):1311-3. doi: 10.1016/s0015-0282(02)04342-x.
Exacerbation of ovarian hyperstimulation by leuprolide reveals a gonadotroph
adenoma.
Castelbaum AJ(1), Bigdeli H, Post KD, Freedman MF, Snyder PJ.
Author information:
(1)University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
19104-6149, USA.
OBJECTIVE: To report a case of a gonadotroph adenoma diagnosed after a dramatic
increase in estradiol level and ovarian hyperstimulation in response to a
gonadotropin-releasing hormone agonist.
DESIGN: Case report.
SETTING: Outpatient practice and university hospital.
PATIENT(S): A 35-year-old woman who presented with infertility, amenorrhea, and
an elevated basal estradiol concentration.
INTERVENTION(S): Ultrasonography, laparoscopy, endocrinologic assays, magnetic
resonance imaging, transsphenoidal surgery, and immunocytochemical staining.
MAIN OUTCOME MEASURE(S): Ultrasonography and laparoscopy demonstrated
bilaterally enlarged ovaries containing multiple preovulatory follicles, similar
in appearance in those women undergoing controlled ovarian hyperstimulation with
exogenous FSH. The serum estradiol level was moderately elevated, the FSH level
was within the normal range, and LH was suppressed. Administration of leuprolide
acetate resulted in very elevated estradiol concentrations and even larger
ovarian cysts. Magnetic resonance imaging demonstrated a sellar mass.
Examination of the tissue excised by transsphenoidal excision of the mass showed
a pituitary adenoma that stained strongly for FSH.
RESULT(S): Regular menses resumed soon after excision of the gonadotroph
adenoma, followed by a spontaneous pregnancy.
CONCLUSIONS: Gonadotroph adenoma should be suspected in a reproductive age woman
with oligomenorrhea or amenorrhea, infertility, multiple preovulatory follicles,
and a persistently elevated serum estradiol concentration. Exacerbation of the
ovarian hyperstimulation in response to a gonadotropin-releasing hormone agonist
in this setting also strongly suggests a gonadotroph adenoma but can be avoided
by recognizing the presenting features of this condition.
DOI: 10.1016/s0015-0282(02)04342-x
PMID: 12477530 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17158156 | 1. Nucleic Acids Res. 2007;35(1):165-74. doi: 10.1093/nar/gkl1033. Epub 2006 Dec
7.
Identification of functional, endogenous programmed -1 ribosomal frameshift
signals in the genome of Saccharomyces cerevisiae.
Jacobs JL(1), Belew AT, Rakauskaite R, Dinman JD.
Author information:
(1)Department of Cell Biology & Molecular Genetics, University of Maryland, 2135
Microbiology Building, College Park, MD 20742, USA.
In viruses, programmed -1 ribosomal frameshifting (-1 PRF) signals direct the
translation of alternative proteins from a single mRNA. Given that many basic
regulatory mechanisms were first discovered in viral systems, the current study
endeavored to: (i) identify -1 PRF signals in genomic databases, (ii) apply the
protocol to the yeast genome and (iii) test selected candidates at the bench.
Computational analyses revealed the presence of 10 340 consensus -1 PRF signals
in the yeast genome. Of the 6353 yeast ORFs, 1275 contain at least one strong
and statistically significant -1 PRF signal. Eight out of nine selected
sequences promoted efficient levels of PRF in vivo. These findings provide a
robust platform for high throughput computational and laboratory studies and
demonstrate that functional -1 PRF signals are widespread in the genome of
Saccharomyces cerevisiae. The data generated by this study have been deposited
into a publicly available database called the PRFdb. The presence of stable mRNA
pseudoknot structures in these -1 PRF signals, and the observation that the
predicted outcomes of nearly all of these genomic frameshift signals would
direct ribosomes to premature termination codons, suggest two possible mRNA
destabilization pathways through which -1 PRF signals could
post-transcriptionally regulate mRNA abundance.
DOI: 10.1093/nar/gkl1033
PMCID: PMC1802563
PMID: 17158156 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22898666 | 1. Semin Cell Dev Biol. 2012 Sep;23(7):770-84. doi: 10.1016/j.semcdb.2012.07.002.
Epub 2012 Aug 9.
Protein kinases of the Hippo pathway: regulation and substrates.
Avruch J(1), Zhou D, Fitamant J, Bardeesy N, Mou F, Barrufet LR.
Author information:
(1)Department of Molecular Biology, Massachusetts General Hospital, Boston, MA
02114, USA. [email protected]
The "Hippo" signaling pathway has emerged as a major regulator of cell
proliferation and survival in metazoans. The pathway, as delineated by genetic
and biochemical studies in Drosophila, consists of a kinase cascade regulated by
cell-cell contact and cell polarity that inhibits the transcriptional
coactivator Yorkie and its proliferative, anti-differentiation, antiapoptotic
transcriptional program. The core pathway components are the GC kinase Hippo,
which phosphorylates the noncatalytic polypeptide Mats/Mob1 and, with the
assistance of the scaffold protein Salvador, phosphorylates the ndr-family
kinase Lats. In turn phospho-Lats, after binding to phospho-Mats, autoactivates
and phosphorylates Yorkie, resulting in its nuclear exit. Hippo also uses the
scaffold protein Furry and a different Mob protein to control another ndr-like
kinase, the morphogenetic regulator Tricornered. Architecturally homologous
kinase cascades consisting of a GC kinase, a Mob protein, a scaffolding
polypeptide and an ndr-like kinase are well described in yeast; in Saccharomyces
cerevisiae, e.g., the MEN pathway promotes mitotic exit whereas the RAM network,
using a different GC kinase, Mob protein, scaffold and ndr-like kinase,
regulates cell polarity and morphogenesis. In mammals, the Hippo orthologs Mst1
and Mst2 utilize the Salvador ortholog WW45/Sav1 and other scaffolds to regulate
the kinases Lats1/Lats2 and ndr1/ndr2. As in Drosophila, murine Mst1/Mst2, in a
redundant manner, negatively regulate the Yorkie ortholog YAP in the epithelial
cells of the liver and gut; loss of both Mst1 and Mst2 results in
hyperproliferation and tumorigenesis that can be largely negated by reduction or
elimination of YAP. Despite this conservation, considerable diversification in
pathway composition and regulation is already evident; in skin, e.g., YAP
phosphorylation is independent of Mst1Mst2 and Lats1Lats2. Moreover, in lymphoid
cells, Mst1/Mst2, under the control of the Rap1 GTPase and independent of YAP,
promotes integrin clustering, actin remodeling and motility while restraining
the proliferation of naïve T cells. This review will summarize current knowledge
of the structure and regulation of the kinases Hippo/Mst1&2, their noncatalytic
binding partners, Salvador and the Rassf polypeptides, and their major
substrates Warts/Lats1&2, Trc/ndr1&2, Mats/Mob1 and FOXO.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcdb.2012.07.002
PMCID: PMC3489012
PMID: 22898666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8223759 | 1. Eur Heart J. 1993 Sep;14 Suppl E:73-9. doi: 10.1093/eurheartj/14.suppl_e.73.
The arrhythmogenic substrate of the long QT syndrome: genetic basis, pathology,
and pathophysiologic mechanisms.
Eggeling T(1), Höher M, Osterhues HH, Kochs M, Weismüller P, Hombach V.
Author information:
(1)Department of Cardiology, University of Ulm, Germany.
The Long QT syndrome (LQTS) is a relatively rare disorder. It has a major
clinical impact as affected individuals are prone to syncope and sudden
arrhythmogenic cardiac death. The LQTS comprises three groups of patients. The
Jervell-Lange-Nielsen syndrome is characterized by an autosomal recessive
pattern of inheritance and congenital neural deafness. The Romano-Ward syndrome
shows an autosomal dominant pattern of inheritance and normal hearing. Patients
with the sporadic form of LQTS have no evidence of familial transmission and
have normal hearing. Imbalance of sympathetic cardiac innervation with
predominance of the left stellate ganglion and an intrinsic myocardial defect
leading to early afterdepolarization are the two pathogenetic mechanisms of LQTS
discussed today. More recently a genetic basis for the Romano-Ward LQTS has been
reported. The genetic linkage to the Harvey ras-1 gene provides the basis for a
new hypothesis that an impairment of guanine nucleotide binding proteins is
responsible for symptoms observed in LQTS. This paper discusses the genetic
basis, pathology and pathophysiology of LQTS and tries to unify the different
theories.
DOI: 10.1093/eurheartj/14.suppl_e.73
PMID: 8223759 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2230849 | 1. J Neurol. 1990 Aug;237(5):316-9. doi: 10.1007/BF00314751.
Cardiac transplantation in female Emery-Dreifuss muscular dystrophy.
Merchut MP(1), Zdonczyk D, Gujrati M.
Author information:
(1)Department of Neurology, Loyola University Medical Center, Maywood, IL 60153.
A young woman with humeroperoneal muscular dystrophy and contractures received a
heart transplant for a severe dilated cardiomyopathy. Cardiac histopathology
consisted of myocyte hypertrophy, interstitial fibrosis, and nuclear
hyperchromaticity without mitochondrial abnormalities. Myopathy and heart
disease were not clinically evident in her family, although three relatives had
unexplained shortened Achilles tendons without weakness. Tendon contractures may
be a partial expression of this myopathic disorder, suggesting an autosomal
dominant inheritance with variable penetrance. A muscular dystrophy clinically
similar to that of the Emery-Dreifuss (EDMD) type can thus occur in women.
Rather than the cardiac arrhythmias typical of EDMD, a dilated cardiomyopathy
may occur and present with severe congestive heart failure. This is the first
report of cardiac transplantation in such a case.
DOI: 10.1007/BF00314751
PMID: 2230849 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22704664 | 1. J Plant Physiol. 2012 Sep 1;169(13):1311-6. doi: 10.1016/j.jplph.2012.05.010.
Epub 2012 Jun 15.
Assembly of NADPH: protochlorophyllide oxidoreductase complex is needed for
effective greening of barley seedlings.
Yuan M(1), Zhang DW, Zhang ZW, Chen YE, Yuan S, Guo YR, Lin HH.
Author information:
(1)College of Biology and Science, Sichuan Agricultural University, Ya'an
625014, China.
NADPH:protochlorophyllide (Pchlide) oxidoreductase (POR) is the key enzyme in
the light-induced greening of higher plants. A unique light-harvesting
POR:Pchlide complexes (LHPP) has been found in barley etioplasts, but not in
other plant species. Why PORs from barley, but not from other plants, can form
LHPP? And its function is not well understood. We modeled the barley and
Arabidopsis POR proteins and compared molecular surface. The results confirm the
idea that barley PORA can form a five-unit oligomer that interacts with a single
PORB. Chemical treatment experiments indicated that POR complex may be formed by
dithiol oxidation of cysteines of two adjacent proteins. We further showed that
LHPP assembly was needed for barley POR functions and seedling greening. On the
contrary, Arabidopsis POR proteins only formed dimers, which were not related to
the functions or the greening. Finally, POR complex assembly (including LHPP and
POR dimers) did not affect the formation of prolamellar bodies (PLBs) that
function for efficient capture of light energy for photo conversion in
etioplasts.
Copyright © 2012 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.jplph.2012.05.010
PMID: 22704664 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11504069 | 1. Electrophoresis. 2001 Jul;22(11):2327-35. doi:
10.1002/1522-2683(20017)22:11<2327::AID-ELPS2327>3.0.CO;2-J.
Determination of phycobiliproteins by capillary electrophoresis with
laser-induced fluorescence detection.
Viskari PJ(1), Kinkade CS, Colyer CL.
Author information:
(1)Wake Forest University, Winston-Salem, NC 27109, USA.
Phycobiliproteins are derived from the photosynthetic apparatus of cyanobacteria
and eukaryotic algae. They are composed of a protein backbone to which linear
tetrapyrrole chromophores are covalently bound. Furthermore, they are
water-soluble highly fluorescent, and relatively stable at room temperature and
neutral pH. For this reason, capillary electrophoresis-laser induced
fluorescence (CE-LIF) seems the idea method for determination of these important
proteins. The effects of buffer additives such as sodium dodecyl sulfate
(SDS)and putrescine on the separation of the three major phycobiliprotein types,
namely allophycocyanin, phycocyanin, and phycoerythrin, with excitation and
emission maxima at 652/660, 615/647, and 565(494)/575 nm, respectively, are
considered. Detection limits for these proteins by CE-LIF are some 60-500 times
better than by absorbance detection. The development of a fast and sensitive
CE-LIF assay such as this is of potential significance to our understand ing of
chemical and biological oceanographic processes.
DOI: 10.1002/1522-2683(20017)22:11<2327::AID-ELPS2327>3.0.CO;2-J
PMID: 11504069 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17958891 | 1. Orphanet J Rare Dis. 2007 Oct 24;2:42. doi: 10.1186/1750-1172-2-42.
Mowat-Wilson syndrome.
Garavelli L(1), Mainardi PC.
Author information:
(1)Clinical Genetics Unit, Obstetric and Pediatric Department, S, Maria Nuova
Hospital, Reggio Emilia, Italy. [email protected]
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome
characterized by a distinct facial phenotype (high forehead, frontal bossing,
large eyebrows, medially flaring and sparse in the middle part, hypertelorism,
deep set but large eyes, large and uplifted ear lobes, with a central
depression, saddle nose with prominent rounded nasal tip, prominent columella,
open mouth, with M-shaped upper lip, frequent smiling, and a prominent but
narrow and triangular pointed chin), moderate-to-severe intellectual deficiency,
epilepsy and variable congenital malformations including Hirschsprung disease
(HSCR), genitourinary anomalies (in particular hypospadias in males), congenital
heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence
of MWS is currently unknown, but 171 patients have been reported so far. It
seems probable that MWS is under-diagnosed, particularly in patients without
HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger
E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date,
over 100 deletions/mutations have been reported in patients with a typical
phenotype; they are frequently whole gene deletions or truncating mutations,
suggesting that haploinsufficiency is the main pathological mechanism. Studies
of genotype-phenotype analysis show that facial gestalt and delayed psychomotor
development are constant clinical features, while the frequent and severe
congenital malformations are variable. In a small number of patients, unusual
mutations can lead to an atypical phenotype. The facial phenotype is
particularly important for the initial clinical diagnosis and provides the
hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The
majority of MWS cases reported so far were sporadic, therefore the recurrence
risk is low. Nevertheless, rare cases of sibling recurrence have been observed.
Congenital malformations and seizures require precocious clinical investigation
with intervention of several specialists (including neonatologists and
pediatricians). Psychomotor development is delayed in all patients, therefore
rehabilitation (physical therapy, psychomotor and speech therapy) should be
started as soon as possible.
DOI: 10.1186/1750-1172-2-42
PMCID: PMC2174447
PMID: 17958891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18615229 | 1. J Nutr Health Aging. 2008 Aug-Sep;12(7):470-8. doi: 10.1007/BF02982708.
Target population for clinical trials on sarcopenia.
Cesari M(1), Pahor M.
Author information:
(1)Department of Aging and Geriatric Research, University of Florida - Institute
on Aging, Gainesville, FL 32611, USA. [email protected]
The term "sarcopenia" describes the progressive decline of muscle mass, strength
and function occurring with aging. It is not considered a disease, but the
direct consequence of the aging process on the skeletal muscle. Multiple
demographic (e.g. gender, race), biological (e.g. inflammatory status) and
clinical (e.g. diabetes, metabolic syndrome, congestive heart failure,
medications) factors are able to influence (positively or negatively) the
skeletal muscle quality and quantity. The extreme paucity of clinical trials on
sarcopenia in literature is mainly due to difficulties in designing studies able
to isolate the aging process from its multiple and interconnected consequences.
In the present review, we present the major factors to consider as potential
sources of biased results when evaluating potential candidates for clinical
trials on sarcopenia. The development of clinical trials exploring the nature of
the sarcopenia process is urgent, but several controversial issues on this
hallmark of aging still need clarification.
DOI: 10.1007/BF02982708
PMCID: PMC4384436
PMID: 18615229 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15111065 | 1. J Mol Biol. 2004 May 14;338(5):1027-36. doi: 10.1016/j.jmb.2004.03.016.
A combined transmembrane topology and signal peptide prediction method.
Käll L(1), Krogh A, Sonnhammer EL.
Author information:
(1)Center for Genomics and Bioinformatics, Karolinska Institutet, SE-17 177
Stockholm, Sweden.
An inherent problem in transmembrane protein topology prediction and signal
peptide prediction is the high similarity between the hydrophobic regions of a
transmembrane helix and that of a signal peptide, leading to cross-reaction
between the two types of predictions. To improve predictions further, it is
therefore important to make a predictor that aims to discriminate between the
two classes. In addition, topology information can be gained when successfully
predicting a signal peptide leading a transmembrane protein since it dictates
that the N terminus of the mature protein must be on the non-cytoplasmic side of
the membrane. Here, we present Phobius, a combined transmembrane protein
topology and signal peptide predictor. The predictor is based on a hidden Markov
model (HMM) that models the different sequence regions of a signal peptide and
the different regions of a transmembrane protein in a series of interconnected
states. Training was done on a newly assembled and curated dataset. Compared to
TMHMM and SignalP, errors coming from cross-prediction between transmembrane
segments and signal peptides were reduced substantially by Phobius. False
classifications of signal peptides were reduced from 26.1% to 3.9% and false
classifications of transmembrane helices were reduced from 19.0% to 7.7%.
Phobius was applied to the proteomes of Homo sapiens and Escherichia coli. Here
we also noted a drastic reduction of false classifications compared to
TMHMM/SignalP, suggesting that Phobius is well suited for whole-genome
annotation of signal peptides and transmembrane regions. The method is available
at as well as at
DOI: 10.1016/j.jmb.2004.03.016
PMID: 15111065 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19273499 | 1. J Endocrinol. 2009 Jun;201(3):377-86. doi: 10.1677/JOE-09-0043. Epub 2009 Mar
9.
Central effects of thyronamines on glucose metabolism in rats.
Klieverik LP(1), Foppen E, Ackermans MT, Serlie MJ, Sauerwein HP, Scanlan TS,
Grandy DK, Fliers E, Kalsbeek A.
Author information:
(1)Laboratory of Endocrinology, Department of Endocrinology and Metabolism,
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
[email protected]
Thyronamines are naturally occurring, chemical relatives of thyroid hormone.
Systemic administration of synthetic 3-iodothyronamine (T(1)AM) and - to a
lesser extent - thyronamine (T(0)AM), leads to acute bradycardia, hypothermia,
decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize
that the central nervous system is among the principal targets of thyronamines.
We investigated whether a low dose i.c.v. infusion of synthetic thyronamines
recapitulates the changes in glucose metabolism that occur following i.p.
thyronamine administration. Plasma glucose, glucoregulatory hormones, and
endogenous glucose production (EGP) using stable isotope dilution were monitored
in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus
infusion of T(1)AM, T(0)AM, or vehicle. To identify the peripheral effects of
centrally administered thyronamines, drug-naive rats were also infused
intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T(1)AM rapidly
increased EGP and plasma glucose, increased plasma glucagon, and corticosterone,
but failed to change plasma insulin. Compared with i.p.-administered T(1)AM, a
100-fold lower dose administered centrally induced a more pronounced acute EGP
increase and hyperglucagonemia while plasma insulin tended to decrease. Both
systemic and central infusions of T(0)AM caused smaller increases in EGP, plasma
glucose, and glucagon compared with T(1)AM. Neither T(1)AM nor T(0)AM influenced
any of these parameters upon low dose i.v. administration. We conclude that
central administration of low-dose thyronamines suffices to induce the acute
alterations in glucoregulatory hormones and glucose metabolism following
systemic thyronamine infusion. Our data indicate that thyronamines can act
centrally to modulate glucose metabolism.
DOI: 10.1677/JOE-09-0043
PMID: 19273499 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15649888 | 1. J Biol Chem. 2005 Mar 18;280(11):10135-40. doi: 10.1074/jbc.M413731200. Epub
2005 Jan 13.
Activation of the iron regulon by the yeast Aft1/Aft2 transcription factors
depends on mitochondrial but not cytosolic iron-sulfur protein biogenesis.
Rutherford JC(1), Ojeda L, Balk J, Mühlenhoff U, Lill R, Winge DR.
Author information:
(1)University of Utah Health Sciences Center, Department of Medicine, Salt Lake
City, Utah 84132, USA.
Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in
Saccharomyces cerevisiae. These factors induce the expression of iron regulon
genes in iron-deficient yeast but are inactivated in iron-replete cells. Iron
inhibition of Aft1/Aft2 is abrogated in cells defective for Fe-S cluster
biogenesis within the mitochondrial matrix (Chen, O. S., Crisp, R. J.,
Valachovic, M., Bard, M., Winge, D. R., and Kaplan, J. (2004) J. Biol. Chem.
279, 29513-29518). To determine whether iron sensing by Aft1/Aft2 requires the
function of the mitochondrial Fe-S export and cytosolic Fe-S protein assembly
systems, we evaluated the expression of the iron regulon in cells depleted of
glutathione and in cells depleted of Atm1, Nar1, Cfd1, and Nbp35. The iron
regulon is induced in cells depleted of Atm1 with Aft1 largely responsible for
the induced gene expression. Aft2 is activated at a later time in Atm1-depleted
cells. Likewise, the iron regulon is induced in cells depleted of glutathione.
In contrast, repression of NAR1, CFD1, or NBP35 fails to induce the iron regulon
despite strong inhibition of cytosolic/nuclear Fe-S protein assembly. Thus, iron
sensing by Aft1/Aft2 is not linked to the maturation of cytosolic/nuclear Fe-S
proteins, but the mitochondrial inner membrane transporter Atm1 is important to
transport the inhibitory signal. Although Aft1 and Aft2 sense a signal emanating
from the Fe-S cluster biogenesis pathway, there is no indication that the
proteins are inhibited by direct binding of an Fe-S cluster.
DOI: 10.1074/jbc.M413731200
PMID: 15649888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12482242 | 1. Chem Res Toxicol. 2002 Dec;15(12):1595-601. doi: 10.1021/tx020062y.
Influence of local duplex stability and N6-methyladenine on uracil recognition
by mismatch-specific uracil-DNA glycosylase (Mug).
Valinluck V(1), Liu P, Burdzy A, Ryu J, Sowers LC.
Author information:
(1)Department of Biochemistry and Microbiology, School of Medicine, Loma Linda
University, Loma Linda, California 92350, USA.
To maintain genomic integrity, DNA repair enzymes continually remove damaged
bases and lesions resulting from endogenous and exogenous processes. These
repair enzymes must distinguish damaged bases from normal bases to prevent the
inadvertent removal of normal bases, which would promote genomic instability.
The mechanisms by which this high level of specificity is accomplished are as
yet unresolved. One member of the uracil-DNA glycosylase family of repair
enzymes, Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug), is
reported to distinguish U:G mispairs from U:A base pairs based upon specific
contacts with the mispaired guanine after flipping the target uracil out of the
duplex. However, recent studies suggest other mechanisms for base selection,
including local duplex stability. In this study, we used the modified base
N6-methyladenine to probe the effect of local helix perturbation on Mug
recognition of uracil. N6-Methyladenine is found in E. coli as part of both the
mismatch repair and restriction-modification systems. In its cis isomer,
N6-methyladenine destabilizes hydrogen bonding by interfering with
pseudo-Watson-Crick base pairing. It is observed that the selection of uracil by
Mug is sequence dependent and that uracil residues in sequences of reduced
thermostability are preferentially removed. The replacement of adenine by
N6-methyladenine increases the frequency of removal of the uracil residue paired
opposite the modified adenine. These results are in accord with suggestions that
local helix stability is an important determinant of base recognition by some
DNA repair enzymes and provide a potential strategy for identifying the sequence
location of modified bases in DNA.
DOI: 10.1021/tx020062y
PMID: 12482242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25404635 | 1. RNA. 2014 Dec;20(12):1829-42. doi: 10.1261/rna.047126.114.
Circular RNAs: diversity of form and function.
Lasda E(1), Parker R(2).
Author information:
(1)Department of Chemistry and Biochemistry, Howard Hughes Medical Institute,
University of Colorado, Boulder, Colorado 80309, USA.
(2)Department of Chemistry and Biochemistry, Howard Hughes Medical Institute,
University of Colorado, Boulder, Colorado 80309, USA [email protected].
It is now clear that there is a diversity of circular RNAs in biological
systems. Circular RNAs can be produced by the direct ligation of 5' and 3' ends
of linear RNAs, as intermediates in RNA processing reactions, or by
"backsplicing," wherein a downstream 5' splice site (splice donor) is joined to
an upstream 3' splice site (splice acceptor). Circular RNAs have unique
properties including the potential for rolling circle amplification of RNA, the
ability to rearrange the order of genomic information, protection from
exonucleases, and constraints on RNA folding. Circular RNAs can function as
templates for viroid and viral replication, as intermediates in RNA processing
reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA
sponges. Herein, we review the breadth of circular RNAs, their biogenesis and
metabolism, and their known and anticipated functions.
© 2014 Lasda and Parker; Published by Cold Spring Harbor Laboratory Press for
the RNA Society.
DOI: 10.1261/rna.047126.114
PMCID: PMC4238349
PMID: 25404635 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17408618 | 1. Exp Neurol. 2007 May;205(1):20-5. doi: 10.1016/j.expneurol.2007.03.003. Epub
2007 Mar 12.
A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a
need for more rigorous testing of neuroprotective agents in animal models of
stroke.
Savitz SI(1).
Author information:
(1)Department of Neurology, Beth Israel Deaconess Medical Center, Harvard
Medical School, 330 Brookline Avenue, Palmer 127, Boston, MA 02215, USA.
[email protected] <[email protected]>
Neuroprotection represents a failed strategy to improve outcome after acute
ischemic stroke (AIS). However, most neuroprotective drugs have been
inadequately studied in animal stroke models, which led to the creation of the
STAIR guidelines on preclinical and clinical testing of therapeutics for AIS.
NXY-059, a free radical spin trap agent, was felt by many to have followed these
criteria and it was recently shown to improve outcome in AIS patients in the
SAINT I trial. However, the repeat, SAINT II trial was a neutral study, the
results of which cast doubt on neuroprotection as a viable strategy for AIS. A
critical analysis of the NXY-059 preclinical data, however, reveals several
shortcomings that have not been addressed in the literature. This report
contends that the preclinical evaluation of NXY-059 lacked strenuous testing and
was not shown to reproducibly lead to robust protection in extended time windows
in clinically relevant stroke models, at several different academic research
laboratories. The clinical trials of NXY-059 were inadequately designed, in
part, because of inappropriate treatment windows and inclusion of diverse stroke
patients. Future neuroprotective agents need more rigorous testing in animal
models of focal cerebral ischemia and appropriate evaluation in clinical studies
that better match the preclinical data.
DOI: 10.1016/j.expneurol.2007.03.003
PMID: 17408618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25036098 | 1. PLoS One. 2014 Jul 18;9(7):e102738. doi: 10.1371/journal.pone.0102738.
eCollection 2014.
Specific interaction with cardiolipin triggers functional activation of
Dynamin-Related Protein 1.
Bustillo-Zabalbeitia I(1), Montessuit S(2), Raemy E(2), Basañez G(1), Terrones
O(1), Martinou JC(2).
Author information:
(1)Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular
Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
(2)Department of Cell Biology, University of Geneva, Geneva, Switzerland.
Dynamin-Related Protein 1 (Drp1), a large GTPase of the dynamin superfamily, is
required for mitochondrial fission in healthy and apoptotic cells. Drp1
activation is a complex process that involves translocation from the cytosol to
the mitochondrial outer membrane (MOM) and assembly into rings/spirals at the
MOM, leading to membrane constriction/division. Similar to dynamins, Drp1
contains GTPase (G), bundle signaling element (BSE) and stalk domains. However,
instead of the lipid-interacting Pleckstrin Homology (PH) domain present in the
dynamins, Drp1 contains the so-called B insert or variable domain that has been
suggested to play an important role in Drp1 regulation. Different proteins have
been implicated in Drp1 recruitment to the MOM, although how MOM-localized Drp1
acquires its fully functional status remains poorly understood. We found that
Drp1 can interact with pure lipid bilayers enriched in the
mitochondrion-specific phospholipid cardiolipin (CL). Building on our previous
study, we now explore the specificity and functional consequences of this
interaction. We show that a four lysine module located within the B insert of
Drp1 interacts preferentially with CL over other anionic lipids. This
interaction dramatically enhances Drp1 oligomerization and assembly-stimulated
GTP hydrolysis. Our results add significantly to a growing body of evidence
indicating that CL is an important regulator of many essential mitochondrial
functions.
DOI: 10.1371/journal.pone.0102738
PMCID: PMC4103857
PMID: 25036098 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/15220823 | 1. Adv Anat Pathol. 2004 Jul;11(4):202-10. doi:
10.1097/01.pap.0000131828.00189.29.
Pancreatic endocrine tumors: an update.
Chetty R(1), Asa SL.
Author information:
(1)Department of Pathology, University Health Network/Toronto Medical
Laboratories, University of Toronto, Toronto, Canada.
The morphology of pancreatic endocrine tumors (PETs) is similar to that of
endocrine tumors elsewhere in the body. PETs are usually encountered in adults.
They may be clinically functional and associated with various syndromes related
to hormone excess. However, it must be remembered that absence of obvious
clinical symptoms may not necessarily reflect true lack of clinical function,
and subtle clinical manifestations may be missed. Current thinking indicates
that PETs arise from totipotential stem cells as well as preexisting endocrine
cells. PETs may be hereditary or sporadic. The hereditary forms are associated
with multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome,
neurofibromatosis, and tuberous sclerosis. In sporadic PETs, the most consistent
and recurring chromosomal abnormality is allelic loss of chromosome 11q, which
includes the MEN-1 locus. Loss of a sex chromosome has been shown to be
associated with metastasis, local invasion, and poor survival.
DOI: 10.1097/01.pap.0000131828.00189.29
PMID: 15220823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2700889 | 1. Arch Stomatol (Napoli). 1989 Apr-Jun;30(2):453-60.
[Burning mouth syndrome].
[Article in Italian]
Serpico R, Del Core G, Laino G.
The analysis of etiopathogenetic and clinical aspects of burning mouth syndrome,
allow to suppose the participation of more factors in the determinism of
disease. Consequently, also the therapy, might to require the presence of many
specialist.
PMID: 2700889 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22278767 | 1. Plant Mol Biol. 2012 Mar;78(4-5):447-60. doi: 10.1007/s11103-012-9873-6. Epub
2012 Jan 26.
Arabidopsis light-dependent protochlorophyllide oxidoreductase A (PORA) is
essential for normal plant growth and development.
Paddock T(1), Lima D, Mason ME, Apel K, Armstrong GA.
Author information:
(1)Department of Plant Cellular and Molecular Biology, The Ohio State
University, Columbus, OH 43210-1293, USA. [email protected]
During skotomorphogenesis in angiosperms, NADPH:protochlorophyllide
oxidoreductase (POR) forms an aggregate of photolabile
NADPH-POR-protochlorophyllide (Pchlide) ternary complexes localized to the
prolamellar bodies within etioplasts. During photomorphogenesis, POR catalyzes
the light-dependent reduction of Pchlide a to chlorophyllide (Chlide) a, which
is subsequently converted to chlorophyll (Chl). In Arabidopsis there are three
structurally related POR genes, denoted PORA, PORB and PORC. The PORA and PORB
proteins accumulate during skotomorphogenesis. During illumination, PORA is only
transiently expressed, whereas PORB and PORC persist and are responsible for
bulk Chl synthesis throughout plant development. Here we have tested whether
PORA is important for skotomorphogenesis by assisting in etioplast development,
and normal photomorphogenic development. Using reverse genetic approaches, we
have identified the porA-1 null mutant, which contains an insertion of the maize
Dissociation transposable element in the PORA gene. Additionally, we have
characterized PORA RNAi lines. The porA-1 and PORA RNAi lines display severe
photoautotrophic growth defects, which can be partially rescued on
sucrose-supplemented growth media. Elimination of PORA during skotomorphogenesis
results in reductions in the volume and frequency of prolamellar bodies, and in
photoactive Pchlide conversion. The porA-1 mutant characterization thus
establishes a quantitative requirement for PORA in etioplast development by
demonstrating significant membrane ultrastructural and biochemical defects, in
addition to suggesting PORA-specific functions in photomorphogenesis and plant
development.
DOI: 10.1007/s11103-012-9873-6
PMID: 22278767 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24119542 | 1. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. doi:
10.1016/j.neurobiolaging.2013.09.009. Epub 2013 Oct 9.
Investigating the role of rare heterozygous TREM2 variants in Alzheimer's
disease and frontotemporal dementia.
Cuyvers E(1), Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der
Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G,
Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven
C, Cruts M, Sleegers K; BELNEU consortium.
Collaborators: De Bleecker J, Santens P, Sieben A, Dermaut B, Ivanoiu A, Deryck
O, Brugmans B, Versijpt J, Michotte A, Willems C, Salmon E.
Author information:
(1)Neurodegenerative Brain Diseases group, Department of Molecular Genetics,
VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp,
Belgium.
Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease,
can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant
(p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an
odds ratio as strong as that for APOEε4. We systematically screened the TREM2
coding region within a Belgian study on neurodegenerative brain diseases (1216
AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of
rare variants across TREM2 in both AD and FTD patients compared to controls,
most notably in the extracellular IgV-set domain (relative risk = 3.84 [95%
confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95%
confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare
variants individually reached significant association, but the frequency of
p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls,
in line with previous reports. Meta-analysis including 11 previously screened AD
cohorts confirmed the association of p.R47H with AD (p = 2.93×10(-17)). Our data
corroborate and extend previous findings to include an increased frequency of
rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants
may play a role in neurodegenerative diseases in general.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2013.09.009
PMID: 24119542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20981542 | 1. Pediatr Cardiol. 2011 Jan;32(1):102-4. doi: 10.1007/s00246-010-9821-7. Epub
2010 Oct 28.
Three generations of hereditary long-QT syndrome with complete penetrance caused
by the p.G316E KCNQ1 mutation.
Viadero MT(1), Rubín E, Amigo T, González-Lamuño D.
Author information:
(1)Cardiology Division, Pediatric Department, University Hospital Marqués de
Valdecilla, Cazoña s/n, 39008 Santander, Spain.
This report describes a three-generation family with a severe phenotype of
long-QT syndrome-1 (LQTS-1) caused by a single nucleotide mutation in the
KQT-like, voltage-gated potassium channel-1 gene (KCNQ1; MIM 607542). Two
members of the family died suddenly in their childhood, and all eight surviving
members with prolonged QT have a heterozygous missense mutation resulting in a
glycine-to-glutamate amino acid substitution at position 316 of the potassium
channel. In this family, the newly reported mutation, guanine-to-adenosine at
position 947 in the KCNQ1 gene, exhibits a dominant trait of LQTS with complete
penetrance, in contrast to the relatively reduced clinical penetrance found in
most LQTS cases.
DOI: 10.1007/s00246-010-9821-7
PMID: 20981542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19622120 | 1. Genes Cells. 2009 Aug;14(8):949-63. doi: 10.1111/j.1365-2443.2009.01322.x.
Epub 2009 Jul 19.
Replisome progression complex links DNA replication to sister chromatid cohesion
in Xenopus egg extracts.
Tanaka H(1), Kubota Y, Tsujimura T, Kumano M, Masai H, Takisawa H.
Author information:
(1)Department of Biological Sciences, Graduate School of Science, Osaka
University, Toyonaka, Osaka 560-0043, Japan.
Cohesin-mediated sister chromatid cohesion is established during the S-phase,
and recent studies demonstrate that a cohesin protein ring concatenates sister
DNA molecules. However, little is known about how DNA replication is linked to
the establishment of sister chromatid cohesion. Here, we used Xenopus egg
extracts to show that AND-1 and Tim1-Tipin, homologues of Saccharomyces
cerevisiae Ctf4 and Tof1-Csm3, respectively, are associated with the replisome
and are required for proper establishment of the cohesion observed in the
M-phase extracts. Immunodepletion of both AND-1 and Tim1-Tipin from the extracts
leads to aberrant sister chromatid cohesion, which is similarly induced by the
depletion of cohesin. These results demonstrate that AND-1 and Tim1-Tipin are
key factors linking DNA replication and establishment of sister chromatid
cohesion. On the basis of the physical interactions between AND-1 and DNA
polymerases, we discuss a model to describe how replisome progression complex
establishes sister chromatid cohesion.
DOI: 10.1111/j.1365-2443.2009.01322.x
PMID: 19622120 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21666370 | 1. Circ J. 2011;75(7):1539-47. doi: 10.1253/circj.cj-11-0304. Epub 2011 Jun 9.
Antithrombotic therapy in atrial fibrillation: evaluation and positioning of new
oral anticoagulant agents.
Ogawa S(1), Koretsune Y, Yasaka M, Aizawa Y, Atarashi H, Inoue H, Kamakura S,
Kumagai K, Mitamura H, Okumura K, Sugi K, Yamashita T.
Author information:
(1)Mita Hospital, International University of Health and Welfare, Tokyo, Japan.
[email protected]
Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major
risk factor for stroke. For more than 60 years, warfarin has been the only
approved anticoagulant for prevention of stroke in patients with AF. Although
highly effective, it has many limitations that make its use difficult.
Therefore, several novel anticoagulants are under development to overcome the
limitations of warfarin, and some of these have entered phase III clinical
trials. Dabigatran is an oral, reversible direct thrombin inhibitor approved in
Europe and in several other countries for the prevention of venous
thromboembolism after elective knee and hip replacement surgery. It has also
been approved in the United States and Japan for the prevention of stroke and
systemic embolism in patients with nonvalvular AF. In this review, the mechanism
of action and pharmacological properties of new anticoagulants are described in
detail, and the correct use of dabigatran in clinical practice is discussed.
DOI: 10.1253/circj.cj-11-0304
PMID: 21666370 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19387848 | 1. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub
2009 Apr 23.
Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors
to the lungs.
Kirson ED(1), Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS,
Wasserman Y, Ryffel B, Goldsher D, Palti Y.
Author information:
(1)NovoCure Limited, Matam Advanced Technology Centre, 31905, Haifa, Israel.
[email protected]
Tumor treating fields (TTFields) are low intensity, intermediate frequency,
alternating electric fields used to treat cancerous tumors. This novel treatment
modality effectively inhibits the growth of solid tumors in vivo and has shown
promise in pilot clinical trials in patients with advanced stage solid tumors.
TTFields were tested for their potential to inhibit metastatic spread of solid
tumors to the lungs in two animal models: (1) Mice injected with malignant
melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits
implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were
treated using two-directional TTFields at 100-200 kHz. Animals were either
monitored for survival, or sacrificed for pathological and histological analysis
of the lungs. The total number of lung surface metastases and the absolute
weight of the lungs were both significantly lower in TTFields treated mice then
in sham control mice. TTFields treated rabbits survived longer than sham control
animals. This extension in survival was found to be due to an inhibition of
metastatic spread, seeding or growth in the lungs of TTFields treated rabbits
compared to controls. Histologically, extensive peri- and intra-tumoral immune
cell infiltration was seen in TTFields treated rabbits only. These results raise
the possibility that in addition to their proven inhibitory effect on the growth
of solid tumors, TTFields may also have clinical benefit in the prevention of
metastatic spread from primary tumors.
DOI: 10.1007/s10585-009-9262-y
PMCID: PMC2776150
PMID: 19387848 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12237298 | 1. J Biol Chem. 2002 Nov 22;277(47):44740-6. doi: 10.1074/jbc.M206171200. Epub
2002 Sep 16.
Sarcolipin overexpression in rat slow twitch muscle inhibits sarcoplasmic
reticulum Ca2+ uptake and impairs contractile function.
Tupling AR(1), Asahi M, MacLennan DH.
Author information:
(1)Banting and Best Department of Medical Research, University of Toronto,
Toronto, Ontario M5G 1L6, Canada.
Sarcolipin (SLN) is an inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPases
(SERCAs) in vitro, but its function in vivo has not been defined. NF-SLN cDNA
(SLN tagged N-terminally with a FLAG epitope) was introduced into rat soleus
muscle in one hindlimb by plasmid injection and electrotransfer. Western
blotting showed expression and co-immunoprecipitation showed physical
interaction between NF-SLN and SERCA2a. Contractile properties and SERCA2a
function were assessed and compared with vector-injected contralateral soleus
muscles. NF-SLN reduced both peak twitch force (P(t)) (123.9 +/- 12.5 versus
69.8 +/- 8.9 millinewtons) and tetanic force (P(o)) (562.3 +/- 51.0 versus 300.7
+/- 56.9 millinewtons) and reduced both twitch and tetanic rates of contraction
(+dF/dt) and relaxation (-dF/dt) significantly. Repetitive stimulation (750-ms
trains at 50 Hz once every 2 s for 3 min) showed that NF-SLN increased
susceptibility to fatigue. These changes in contractile function were observed
in the absence of endogenous phospholamban, and NF-SLN had no effect on either
SERCA2a or SERCA1a expression levels. NF-SLN also decreased maximal Ca(2+)
transport activity at pCa 5 by 31% with no significant change in apparent Ca(2+)
affinity (6.36 +/- 0.07 versus 6.39 +/- 0.08 pCa units). These results show that
NF-SLN expression impairs muscle contractile function by inhibiting SERCA
function and diminishing sarcoplasmic reticulum Ca(2+) stores.
DOI: 10.1074/jbc.M206171200
PMID: 12237298 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19482958 | 1. Oncologist. 2009 Jun;14(6):601-11. doi: 10.1634/theoncologist.2008-0153. Epub
2009 May 29.
Cetuximab and other anti-epidermal growth factor receptor monoclonal antibodies
in the treatment of non-small cell lung cancer.
Gridelli C(1), Maione P, Ferrara ML, Rossi A.
Author information:
(1)Division of Medical Oncology, SG Moscati Hospital, Contrada Amoretta, Città
Ospedaliera, 83100 Avellino, Italy. [email protected]
Non-small cell lung cancer (NSCLC) accounts for about 85% of all new diagnoses
of lung cancer. Unfortunately, few NSCLC patients are suitable for radical
treatment for curative intent. Because most patients with NSCLC have advanced
disease at diagnosis, chemotherapy represents the standard of care, although, to
date, a plateau has been reached with this approach. Improvements in the
knowledge of tumor biology and mechanisms of oncogenesis have identified the
epidermal growth factor receptor (EGFR), a member of the ErbB family, as a
molecular target for NSCLC treatment. EGFR is commonly overexpressed in NSCLC
and has been associated with impaired prognosis; therefore, its inhibition may
lead, through the suppression of tumor proliferation, to improvement in clinical
outcomes. Strategies to block EGFR include tyrosine kinase inhibitors,
monoclonal antibodies, ligand-linked toxins, and antisense approaches. This
article focuses on the treatment of NSCLC with the anti-EGFR monoclonal
antibodies, including cetuximab, for which the largest amount of data in the
literature exists. Recently, a phase III randomized trial performed in advanced
NSCLC patients yielded a statistically significant survival advantage for
patients treated with cetuximab plus chemotherapy versus chemotherapy alone.
Other anti-EGFR monoclonal antibodies, such as panitumumab, matuzumab,
nimotuzumab, and ch806, are in different stages of development for the treatment
of advanced NSCLC.
DOI: 10.1634/theoncologist.2008-0153
PMID: 19482958 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23978303 | 1. Cancer Cell Int. 2013 Aug 27;13(1):86. doi: 10.1186/1475-2867-13-86.
Candidate microRNA biomarkers in human epithelial ovarian cancer: systematic
review profiling studies and experimental validation.
Chen Y(#)(1)(2)(3), Zhang L(#)(1)(2)(3), Hao Q(1)(2)(3).
Author information:
(1)Department of Gynecologic Oncology, Tianjin Medical University Cancer
Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060, China.
(2)Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
(3)National Clinical Research Centre of Cancer, Tianjin, China.
(#)Contributed equally
Despite advances in detection and therapy, epithelial ovarian cancer (EOC) still
represents the most lethal gynecologic malignancy in women worldwide. The high
mortality of EOC is mainly due to late-stage diagnosis for more than 70% of
patients. There is an urgent need to search for specific and sensitive
biomarkers for early diagnosis of EOC. Recently, the cumulative data indicated
an essential role for microRNA (miRNA), a class of small non-coding RNAs
targeting multiple mRNAs and triggering translation repression and/or RNA
degradation, in ovarian caner carcinogenesis and progression. Here, we reviewed
the published miRNA expression profiling studies that compared the miRNA
expression profiles between EOC tissues or cell lines and normal ovarian tissues
or benign ovarian tumor or human primary cultured ovarian surface epithelial
cells. A miRNA ranking system that takes the number of comparisons in agreement
and direction of differential expression into the consideration was devised and
used. Finally, five promising differentially miRNAs (miR-200a, miR-100, miR-141,
miR-200b, and miR-200c) were reported with the consistent direction in four or
more studies. MiR-200a, miR-200b, miR-200c, and miR-141, all of them belong to
miR-200 family, were reported with consistently up-regulated in at least 4
studies, whereas miR-100 was reported with down-regulated in 4 studies.
Furthermore, we validated these miRNAs in a clinical setting using qRT-PCR and
their dysregulations in EOC tissues confirmed the findings. Conclusively, the
five most consistently expressed miRNAs might provide some clues of the
potential biomarkers in EOC. Further mechanistic and precise validation studies
are needed for their clinical significances and roles in the progression of EOC.
DOI: 10.1186/1475-2867-13-86
PMCID: PMC3765519
PMID: 23978303 |
http://www.ncbi.nlm.nih.gov/pubmed/23456457 | 1. Protoplasma. 2013 Oct;250(5):965-83. doi: 10.1007/s00709-013-0488-9. Epub 2013
Feb 28.
CEP proteins: the knights of centrosome dynasty.
Kumar A(1), Rajendran V, Sethumadhavan R, Purohit R.
Author information:
(1)Bioinformatics Division, School of Bio Sciences and Technology, Vellore
Institute of Technology University, Vellore, 632014, Tamil Nadu, India.
Centrosome forms the backbone of cell cycle progression mechanism. Recent
debates have occurred regarding the essentiality of centrosome in cell cycle
regulation. CEP family protein is the active component of centrosome and plays a
vital role in centriole biogenesis and cell cycle progression control. A total
of 31 proteins have been categorized into CEP family protein category and many
more are under candidate evaluation. Furthermore, by the recent advancements in
genomics and proteomics researches, several new CEP proteins have also been
characterized. Here we have summarized the importance of CEP family proteins and
their regulation mechanism involved in proper cell cycle progression. Further,
we have reviewed the detailed molecular mechanism behind the associated
pathological phenotypes and the possible therapeutic approaches. Proteins such
as CEP57, CEP63, CEP152, CEP164, and CEP215 have been extensively studied with a
detailed description of their molecular mechanisms, which are among the primary
targets for drug discovery. Moreover, CEP27, CEP55, CEP70, CEP110, CEP120,
CEP135, CEP192, CEP250, CEP290, and CEP350 also seem promising for future drug
discovery approaches. Since the overview implicates that the overall researches
on CEP proteins are not yet able to present significant details required for
effective therapeutics development, thus, it is timely to discuss the importance
of future investigations in this field.
DOI: 10.1007/s00709-013-0488-9
PMID: 23456457 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12203792 | 1. Genes Chromosomes Cancer. 2002 Sep;35(1):74-80. doi: 10.1002/gcc.10098.
Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer.
Frisk T(1), Foukakis T, Dwight T, Lundberg J, Höög A, Wallin G, Eng C, Zedenius
J, Larsson C.
Author information:
(1)Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Germline mutations in the tumor-suppressor gene PTEN (MMAC1, TEP1) are found in
Cowden syndrome, which predisposes to hamartomas, breast cancer, trichilemmomas,
and thyroid tumors of follicular epithelium. PTEN has also been found to be
somatically deleted, mutated, and/or silenced in various sporadically occurring
cancers such as glioblastoma, breast cancer, kidney cancer, malignant melanoma,
and endometrial cancer. Loss or reduction of PTEN protein expression as well as
inappropriate subcellular compartmentalization is seen in non-medullary thyroid
cancers. However, although allelic loss of the PTEN locus in 10q23.3 is
frequently seen, this is not coupled with mutations in the PTEN gene. To
approach further the frequency and mechanism behind PTEN silencing, we screened
a panel of 87 sporadic thyroid tumors for PTEN mRNA expression, including 14
anaplastic carcinomas, 37 follicular carcinomas, 21 atypical adenomas, and 15
ordinary adenomas. Complete loss of PTEN mRNA expression was evident in six of
the tumors, including four anaplastic carcinomas, one widely invasive carcinoma,
and one ordinary adenoma. The transcriptional silencing of PTEN was
significantly associated with the anaplastic subtype, suggesting that PTEN is
involved in the carcinogenesis of highly malignant or late-stage thyroid
cancers, whereas this particular mechanism appears to be of minor importance in
differentiated follicular thyroid tumors. No association was observed between
the expression, loss of heterozygosity, and mutation status in the 33 cases in
which these parameters were compared. This indicates that PTEN silencing is a
result of a wide variety of epigenetic and/or structural silencing mechanisms
rather than a consequence of structural biallelic inactivation of the classical
type. Furthermore, the high rate of alterations in the 10q23 region might
indicate the presence of an as-yet unknown tumor-suppressor gene with an
important role in the development of thyroid tumors.
Copyright 2002 Wiley-Liss, Inc.
DOI: 10.1002/gcc.10098
PMID: 12203792 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18846226 | 1. PLoS Genet. 2008 Oct;4(10):e1000217. doi: 10.1371/journal.pgen.1000217. Epub
2008 Oct 10.
Drosophila Kismet regulates histone H3 lysine 27 methylation and early
elongation by RNA polymerase II.
Srinivasan S(1), Dorighi KM, Tamkun JW.
Author information:
(1)Department of Molecular, Cell, and Developmental Biology, University of
California Santa Cruz, Santa Cruz, CA, USA.
Polycomb and trithorax group proteins regulate cellular pluripotency and
differentiation by maintaining hereditable states of transcription. Many
Polycomb and trithorax group proteins have been implicated in the covalent
modification or remodeling of chromatin, but how they interact with each other
and the general transcription machinery to regulate transcription is not well
understood. The trithorax group protein Kismet-L (KIS-L) is a member of the CHD
subfamily of chromatin-remodeling factors that plays a global role in
transcription by RNA polymerase II (Pol II). Mutations in CHD7, the human
counterpart of kis, are associated with CHARGE syndrome, a developmental
disorder affecting multiple tissues and organs. To clarify how KIS-L activates
gene expression and counteracts Polycomb group silencing, we characterized
defects resulting from the loss of KIS-L function in Drosophila. These studies
revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate
elongation by Pol II. The presence of two chromodomains in KIS-L suggested that
its recruitment or function might be regulated by the methylation of histone H3
lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed
significant overlap between the distributions of KIS-L, ASH1, and TRX on
polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and
loss of TRX or ASH1 function did not alter the association of KIS-L with
chromatin. By contrast, loss of kis function led to a dramatic reduction in the
levels of TRX and ASH1 associated with chromatin and was accompanied by
increased histone H3 lysine 27 methylation-a modification required for Polycomb
group repression. A similar increase in H3 lysine 27 methylation was observed in
ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early
elongation and counteracts Polycomb group repression by recruiting the ASH1 and
TRX histone methyltransferases to chromatin.
DOI: 10.1371/journal.pgen.1000217
PMCID: PMC2563034
PMID: 18846226 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/17237066 | 1. Bioinformatics. 2007 Mar 1;23(5):538-44. doi: 10.1093/bioinformatics/btl677.
Epub 2007 Jan 19.
Improving the accuracy of transmembrane protein topology prediction using
evolutionary information.
Jones DT(1).
Author information:
(1)Department of Computer Science, University College London, Gower Street,
London WC1E 6BT, United Kingdom. [email protected]
MOTIVATION: Many important biological processes such as cell signaling,
transport of membrane-impermeable molecules, cell-cell communication, cell
recognition and cell adhesion are mediated by membrane proteins. Unfortunately,
as these proteins are not water soluble, it is extremely hard to experimentally
determine their structure. Therefore, improved methods for predicting the
structure of these proteins are vital in biological research. In order to
improve transmembrane topology prediction, we evaluate the combined use of both
integrated signal peptide prediction and evolutionary information in a single
algorithm.
RESULTS: A new method (MEMSAT3) for predicting transmembrane protein topology
from sequence profiles is described and benchmarked with full cross-validation
on a standard data set of 184 transmembrane proteins. The method is found to
predict both the correct topology and the locations of transmembrane segments
for 80% of the test set. This compares with accuracies of 62-72% for other
popular methods on the same benchmark. By using a second neural network
specifically to discriminate transmembrane from globular proteins, a very low
overall false positive rate (0.5%) can also be achieved in detecting
transmembrane proteins.
AVAILABILITY: An implementation of the described method is available both as a
web server (http://www.psipred.net) and as downloadable source code from
http://bioinf.cs.ucl.ac.uk/memsat. Both the server and source code files are
free to non-commercial users. Benchmark and training data are also available
from http://bioinf.cs.ucl.ac.uk/memsat.
DOI: 10.1093/bioinformatics/btl677
PMID: 17237066 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19570891 | 1. Am J Physiol Cell Physiol. 2009 Oct;297(4):C876-85. doi:
10.1152/ajpcell.00519.2008. Epub 2009 Jul 1.
Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are
revealed in human myotubes.
Sacconi S(1), Simkin D, Arrighi N, Chapon F, Larroque MM, Vicart S, Sternberg D,
Fontaine B, Barhanin J, Desnuelle C, Bendahhou S.
Author information:
(1)Centre Hospitalier Universitaire of Nice, Centre de Référence Maladies
Neuromusculaires et Sclérose Latérale Amyotrophique, Institut National de la
Santé et de la Recherche Médicale Unité 638, Institut Fédératif de Recherche 50,
Nice, France.
Andersen's syndrome is a rare disorder that has been defined with a triad:
periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle
weakness has been reported in two-thirds of the patients. KCNJ2 remains the only
gene linked to Andersen's syndrome; this gene encodes for the alpha-subunit of
the strong inward-rectifier K+ channel Kir2.1. Several studies have shown that
Andersen's syndrome mutations lead to a loss of function of the K+ channel
activity in vitro. However, ex vivo studies on isolated patient muscle tissue
have not been reported. We have performed muscle biopsies of controls and
patients presenting with clinically and genetically defined Andersen's syndrome
disorder. Myoblasts were cultured and characterized morphologically and
functionally using the whole cell patch-clamp technique. No morphological
difference was observed between Andersen's syndrome and control myoblasts at
each passage of the cell culture. Cellular proliferation and viability were
quantified in parallel with direct cell counts and showed no difference between
control and Andersen's syndrome patients. Moreover, our data show no significant
difference in myoblast fusion index among Andersen's syndrome and control
patients. Current recordings carried out on myotubes revealed the absence of an
inwardly rectifying Ba2+-sensitive current in affected patient cells. One
consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift
of the resting membrane potential toward depolarizing potentials. Our data
describe for the first time the functional consequences of Andersen's syndrome
mutations ex vivo and provide clues to the K+ channel pathophysiology in
skeletal muscle.
DOI: 10.1152/ajpcell.00519.2008
PMID: 19570891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24025022 | 1. Cardiovasc Hematol Agents Med Chem. 2013 Sep;11(3):203-6. doi:
10.2174/187152571103140120103032.
Sodium glucose co-transporter 2 (SGLT2) inhibition with canagliflozin in type 2
diabetes mellitus.
Said S, Hernandez GT(1).
Author information:
(1)Division of Nephrology & Hypertension, Department of Internal Medicine, Paul
L. Foster School of Medicine, Texas Tech University Health Sciences Center at El
Paso, 4800 Alberta Avenue, El Paso, Texas, 79905, USA.
[email protected].
The sodium glucose cotransporter 2 (SGLT2) is expressed primarily in the kidneys
and is involved in the reabsorption of filtered glucose in the renal tubule.
Clinical trials of SGLT2 inhibitors in patients with type 2 diabetes mellitus
demonstrate a significant clinical effect in decreasing serum glucose,
hemoglobin A1C, body weight, systolic blood pressure, improving β-cell function,
and minimizing the risk of hypoglycemia. This report reviews the potentially
beneficial effects of SGLT2 inhibitors in type 2 diabetes mellitus, specifically
focusing on canagliflozin, the only SGLT2 inhibitor approved for use in the
United States.
DOI: 10.2174/187152571103140120103032
PMID: 24025022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24388463 | 1. Cardiovasc Pathol. 2014 Mar-Apr;23(2):101-6. doi:
10.1016/j.carpath.2013.11.002. Epub 2013 Nov 14.
Compromised mitochondrial remodeling in compensatory hypertrophied myocardium of
spontaneously hypertensive rat.
Tang Y(1), Mi C(2), Liu J(1), Gao F(3), Long J(4).
Author information:
(1)Center for Mitochondrial Biology and Medicine, The Key Laboratory of
Biomedical Information Engineering of Ministry of Education, School of Life
Science and Technology and Frontier Institute of Life Science, FIST, Xi'an
Jiaotong University, Xi'an 710049, China.
(2)School of Life Science and Technology, Shaanxi Normal University, Xi'an
710026, China; Sports Ministry, Xi'an University of Science and Technology,
Xi'an 710054, China.
(3)Department of Physiology, Fourth Military Medical University, Xi'an 710032,
China. Electronic address: [email protected].
(4)Center for Mitochondrial Biology and Medicine, The Key Laboratory of
Biomedical Information Engineering of Ministry of Education, School of Life
Science and Technology and Frontier Institute of Life Science, FIST, Xi'an
Jiaotong University, Xi'an 710049, China. Electronic address:
[email protected].
BACKGROUND: Hypertension leads to cardiac hypertrophy as an adaptive response to
increased workload. While initial development of hypertrophy is compensatory
when contractile function is maintained, persistent stress on heart leads to
deteriorated cardiac function and onset of heart failure. Mitochondrial
dysfunction develops in the failing heart; however, whether it presents in
compensatory cardiac hypertrophy is controversial.
METHODS: Spontaneously hypertensive rats (SHRs) and age-matched normotensive
Wistar Kyoto rats were used in the study. Mitochondrial function and
remodeling-related mechanisms in the left ventricles were measured by enzyme
activity tests, Western blots, and reverse transcriptase polymerase chain
reaction.
RESULTS: Compensatory cardiac hypertrophy in SHR was indicated by higher
heart/weigh ratio, left ventricular systolic pressure and ±dp/dt(max) (P<.001,
P<.05, and P<.01, respectively). Enzyme activities of mitochondrial complex I
and II were significantly reduced (P<.05 and P<.01) in SHR in concert with
decreased expression of complex subunits (P<.01 for NDUFS3, P=.068 for SDHB, and
P<.05 for ATP5A1). Mitochondrial fission protein Drp1 was decreased (P<.05),
while fusion protein OPA1 was increased (P<.01). Parkin and SirT1/AMPK-PGC-1α
signaling, responsible for mitochondrial elimination and biogenesis
respectively, were decreased in SHR (P<.01 for Parkin, P<.001 for SirT1 and
p-AMPK).
CONCLUSION: Our results implicated that mitochondrial function and remodeling,
indicated by mitochondrial enzyme activities and remodeling-related molecules,
were compromised in compensatory hypertrophied myocardium of the SHR
hypertensive model.
SUMMARY: Mitochondrial function in compensatory hypertrophied myocardium is
controversial. Our present study found mitochondrial dysfunction in the left
ventricle of spontaneously hypertensive rats, which was possibly a result of
compromised mitochondrial remodeling including mitochondrial dynamics,
elimination, and biogenesis.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.carpath.2013.11.002
PMID: 24388463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10560244 | 1. J Formos Med Assoc. 1999 Sep;98(9):649-52.
Romano-Ward long QT syndrome: identification of a HERG mutation in a Taiwanese
kindred.
Lee-Chen GJ(1), Tai DY, Chu CH, Teng YN.
Author information:
(1)Department of Biology, National Taiwan Normal University, Taipei, Taiwan.
Romano-Ward syndrome is an autosomal dominant long-QT syndrome (LQTS) that
predisposes affected individuals to sudden death from tachyarrhythmias. We
investigated the molecular basis of LQTS in a Taiwanese kindred. Clinical and
genetic analyses revealed that a mutation was linked to the human
ether-a-go-go-related gene (HERG). The coding sequences and exon-intron borders
of HERG were amplified by means of polymerase chain reaction and subjected to
single-strand conformation polymorphism (SSCP) analysis. An exon with an
aberrant SSCP pattern was cloned and sequenced to study the molecular lesion. A
C-->T transition in codon 614, leading to substitution of a valine for an
alanine residue in the pore region of the HERG protein, was identified. Analysis
with Bsp12861 endonuclease digestion showed the mutation to be present in all
affected family members. Given that an unaffected paternal uncle had inherited
the same allele from the grandfather as the proband's father, a de novo mutation
had apparently occurred in the father and was transmitted to his offspring. In
addition to offering presymptomatic genetic diagnosis, identification of the
disease-causing mutation may suggest new therapeutic approaches for treatment
and prevention of this cardiovascular disease.
PMID: 10560244 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17095274 | 1. Mol Genet Metab. 2007 Jan;90(1):49-57. doi: 10.1016/j.ymgme.2006.09.010. Epub
2006 Nov 13.
Chemical chaperones improve transport and enhance stability of mutant
alpha-glucosidases in glycogen storage disease type II.
Okumiya T(1), Kroos MA, Vliet LV, Takeuchi H, Van der Ploeg AT, Reuser AJ.
Author information:
(1)Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam,
The Netherlands. [email protected]
Glycogen storage disease type II (GSDII; Pompe disease or acid maltase
deficiency) is an autosomal recessive disorder caused by lysosomal acid
alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal
muscle weakness. Defects in post-translational modification and transport of
mutant AalphaGlu species are frequently encountered and may potentially be
corrected with chaperone-mediated therapy. In the present study, we have tested
this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones
to correct the AalphaGlu deficiency in cultured fibroblasts from patients with
GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L,
525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L,
N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and
activity of AalphaGlu in a dose dependent manner, while it had no effect on the
reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the
endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of
mutant AalphaGlu species, Y455F and P545L, inside the lysosomes. In long-term
culture, the AalphaGlu activity in the fibroblasts from the patients with mutant
phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold,
respectively, in the presence of 10mumol/L NB-DNJ. However, the effect of NB-DNJ
on Y455F/Y455F subsided quickly after removal of the compound. We conclude that
NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms
of AalphaGlu that are trapped in the ER, poorly transported or labile in the
lysosomal environment. Chemical chaperone therapy could create new perspectives
for therapeutic intervention in GSDII.
DOI: 10.1016/j.ymgme.2006.09.010
PMID: 17095274 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18039954 | 1. Blood. 2008 Feb 15;111(4):1816-9. doi: 10.1182/blood-2007-03-080010. Epub 2007
Nov 26.
Valganciclovir prevents cytomegalovirus reactivation in patients receiving
alemtuzumab-based therapy.
O'Brien S(1), Ravandi F, Riehl T, Wierda W, Huang X, Tarrand J, O'Neal B,
Kantarjian H, Keating M.
Author information:
(1)Department of Leukemia, University of Texas M. D. Anderson Cancer Center,
Houston, TX 77030, USA. [email protected]
Comment in
Blood. 2008 Sep 1;112(5):2167. doi: 10.1182/blood-2008-05-155465.
Alemtuzumab is an immunosuppressive antibody that depletes normal T cells and B
cells. Prophylaxis for herpes virus and Pneumocystis carinii is standard with
this agent. Approximately 20% to 25% of patients will experience cytomegalovirus
(CMV) reactivation. We conducted a randomized trial wherein patients being
treated with an alemtuzumab-containing regimen received prophylaxis with either
valaciclovir 500 mg orally daily or valganciclovir 450 mg orally twice daily.
The study design planned to enroll 128 patients, but stopping rules for early
termination were met. Forty patients were evaluable. Median age was 58 years
(range, 25-83 years); median number of prior therapies was 2 (range, 0-10).
Diagnoses included chronic lymphocytic leukemia (29), T-cell prolymphocytic
leukemia (3), hairy cell leukemia (1), adult T-cell leukemia/lymphoma (ATLL)
(1), marginal zone leukemia (1), large granular lymphocyte leukemia (2), acute
lymphoblastic leukemia (1), and T-cell lymphoma (2). Patients received various
alemtuzumab-containing regimens, including single agent (5) or combined with:
rituximab (2), pentostatin (6), fludarabine, cyclophosphamide, and rituximab
(23), or fractionated cyclophosphamide, vincristine, adriamycin, and
dexamethasone (hyper-CVAD) (4). Seven of 20 patients enrolled on the
valaciclovir arm experienced CMV reactivation. None of the 20 patients
randomized to valganciclovir experienced CMV reactivation (P = .004). In
conclusion, this agent was highly effective for prophylaxis of CMV reactivation
in patients receiving alemtuzumab. This trial was registered at
www.ClinicalTrials.gov as #NCT00562770.
DOI: 10.1182/blood-2007-03-080010
PMID: 18039954 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15012892 | 1. Med Clin (Barc). 2004 Feb 21;122(6):223-6. doi: 10.1157/13058172.
[Miller-Fisher syndrome: clinical features, associated infections and clinical
course in 8 cases].
[Article in Spanish]
Rodríguez Uranga JJ(1), Delgado López F, Franco Macías E, Sánchez Arjona MB,
Martínez Quesada C, Palomino García A.
Author information:
(1)Servicio de Neurología, Hospitales Universitarios Virgen del Rocío, Sevilla,
España. [email protected]
BACKGROUND AND OBJECTIVE: Miller-Fisher syndrome (MFS) is considered the most
common variant of Guillain-Barré syndrome (GBS) and is characterized by the
clinical triad of ophthalmoplegia, ataxia and areflexia. Respiratory involvement
and relapses are unusual. Patients with MFS usually have a good recovery and no
residual deficits. We describe the clinical features, associated infections and
evolution in eight patients with MFS.
PATIENTS AND METHOD: Eight cases of MFS and sixty-one of GBS were studied
between 1994 and 2003. All cases showed the clinical triad of MFS without major
limb weakness or other signs suggestive of CNS involvement.
RESULTS: The proportion of MFS with respect to GBS during the same period was
13.1%. Four had a positive serology for Epstein-Barr virus, Salmonella
enteritidis, Chlamydia pneumoniae and Mycoplasma pneumoniae. Our cases showed
facial palsy (75%), dysphagia (75%), pupillary abnormalities (37.5%) and
ventilation support (37.5%). Antiganglioside antibodies, determined in three
cases (4 episodes), were positive [GQ1b (50%) and GD1b (50%)]. In all cases,
there was a markedly reduced amplitude of the distal sensory as well as frequent
axonal degeneration signs. The oldest three patients relapsed and required
ventilation support.
CONCLUSIONS: We report for the first time an association between S. enteritidis
and C. pneumoniae and MFS. Older patients in our series suffered a faster
disease progression with need of ventilation support. We conclude that an older
age correlates with poor prognosis and relapses.
DOI: 10.1157/13058172
PMID: 15012892 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10570983 | 1. Gene. 1999 Sep 30;238(1):53-8. doi: 10.1016/s0378-1119(99)00320-0.
Translation-coupled violation of Parity Rule 2 in human genes is not the cause
of heterogeneity of the DNA G+C content of third codon position.
Sueoka N(1).
Author information:
(1)University of Colorado, Department of Molecular, Cellular, and Developmental
Biology, Boulder 80309-0347, USA. [email protected]
The genome of higher eukaryotes consists of genes having a widely heterogeneous
base composition at the third codon position. Ubiquitous variability of the DNA
base composition has the following two aspects: intragenomic heterogeneity of
the G+C content and the amino-acid-specific translation-coupled biases from the
Parity Rule 2 (PR2). PR2 is an intrastrand rule where A = T and G = C are
expected if there is no bias in mutation and selection between the two
complementary strands of DNA. To examine whether or not the biases from PR2 are
responsible for the wide heterogeneity of the DNA G+C content in human, the
third codon position of 846 human genes was analyzed. Genes were separated into
six groups according to their G+C content of the third codon position, and each
group was examined for the translation-coupled PR2 biases in the nucleotide
composition of the third codon position for two- and four-codon amino acids. The
results show that genes in the different G+C content groups have similar PR2
biases, indicating that the intragenomic heterogeneity of the G+C content is not
correlated with translation-coupled biases from the PR2. Therefore, the
heterogeneity of the G+C content is likely to be determined by some other
mechanism (e.g. locally variable directional mutation pressures) than
amino-acid-specific selections for the codon preference.
DOI: 10.1016/s0378-1119(99)00320-0
PMID: 10570983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19846786 | 1. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18763-8. doi:
10.1073/pnas.0900705106. Epub 2009 Oct 21.
T-tubule disorganization and defective excitation-contraction coupling in muscle
fibers lacking myotubularin lipid phosphatase.
Al-Qusairi L(1), Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C, Sanoudou
D, Beggs AH, Allard B, Mandel JL, Laporte J, Jacquemond V, Buj-Bello A.
Author information:
(1)Department of Neurobiology and Genetics, and Imaging Center-Electron
Microscopy, Institut de Génétique et de Biologie Moléculaire et Cellulaire,
Institut National de la Santé et de la Recherche Médicale U964, Centre National
de la Recherche Scientifique, Unite Mixte de Recherche 7104, Université Louis
Pasteur, Collège de France, 67404 Illkirch, France.
Skeletal muscle contraction is triggered by the excitation-contraction (E-C)
coupling machinery residing at the triad, a membrane structure formed by the
juxtaposition of T-tubules and sarcoplasmic reticulum (SR) cisternae. The
formation and maintenance of this structure is key for muscle function but is
not well characterized. We have investigated the mechanisms leading to X-linked
myotubular myopathy (XLMTM), a severe congenital disorder due to loss of
function mutations in the MTM1 gene, encoding myotubularin, a phosphoinositide
phosphatase thought to have a role in plasma membrane homeostasis and
endocytosis. Using a mouse model of the disease, we report that Mtm1-deficient
muscle fibers have a decreased number of triads and abnormal longitudinally
oriented T-tubules. In addition, SR Ca(2+) release elicited by voltage-clamp
depolarizations is strongly depressed in myotubularin-deficient muscle fibers,
with myoplasmic Ca(2+) removal and SR Ca(2+) content essentially unaffected. At
the molecular level, Mtm1-deficient myofibers exhibit a 3-fold reduction in type
1 ryanodine receptor (RyR1) protein level. These data reveal a critical role of
myotubularin in the proper organization and function of the E-C coupling
machinery and strongly suggest that defective RyR1-mediated SR Ca(2+) release is
responsible for the failure of muscle function in myotubular myopathy.
DOI: 10.1073/pnas.0900705106
PMCID: PMC2773964
PMID: 19846786 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/17261956 | 1. J Cardiovasc Pharmacol. 2007 Jan;49(1):1-5. doi: 10.1097/FJC.0b013e31802b3184.
Rapid switch from intravenous epoprostenol to intravenous treprostinil in
patients with pulmonary arterial hypertension.
Sitbon O(1), Manes A, Jais X, Pallazini M, Humbert M, Presotto L, Paillette Ld,
Zaccardelli D, Davis G, Jeffs R, Simonneau G, Galie N.
Author information:
(1)Service de Pneumologie, Hôpital Antoine Béclère, Université Paris-Sud,
Clamart, France. [email protected]
Intravenous epoprostenol improves exercise capacity and survival in patients
with pulmonary arterial hypertension (PAH); however, chemical instability and a
short half-life have caused limitations in its use. The chemically stable
prostacyclin analogue treprostinil has a longer half-life, and improves
hemodynamics and signs/symptoms of PAH. This study investigated the feasibility
of transitioning patients with PAH from intravenous epoprostenol to intravenous
treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in
a 12 week prospective open label study. Patients were switched from intravenous
epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of
the medication reservoir from epoprostenol to treprostinil. The dose of
treprostinil was adjusted throughout the study to achieve a 2-fold increase of
treprostinil compared with the baseline epoprostenol dose. Rapid transition to
treprostinil was achieved without serious adverse events and, baseline clinical
status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28
+/- 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 +/- 30
ng/kg/min. All patients reported less prostacyclin-related side effects with
treprostinil and remained on treprostinil after study completion. Selected
patients with PAH can be safely transitioned from intravenous epoprostenol to
intravenous treprostinil using a rapid switch protocol.
DOI: 10.1097/FJC.0b013e31802b3184
PMID: 17261956 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22427521 | 1. Am J Physiol Heart Circ Physiol. 2012 May 15;302(10):H2008-17. doi:
10.1152/ajpheart.00457.2011. Epub 2012 Mar 16.
Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in
ventricular myocytes.
Kučerová D(1), Baba HA, Bokník P, Fabritz L, Heinick A, Mát'uš M, Müller FU,
Neumann J, Schmitz W, Kirchhefer U.
Author information:
(1)Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster,
Münster, Germany. [email protected]
Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin
(TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular
tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic
reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice
(TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release,
and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we
tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could
be beneficial for impaired intracellular Ca(2+) signaling and contractile
function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i))
peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT)
myocytes. This effect was associated with changes in the expression of cardiac
Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+)
channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic
reticulum Ca(2+)-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared
with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in
both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these
expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ)
myocytes. In contrast to the improved cellular Ca(2+), transient
co-overexpression of CSQ and TRN resulted in a reduced survival rate, an
increased cardiac fibrosis, and a decreased basal contractility in catheterized
mice, working heart preparations, and isolated myocytes. Echocardiographic and
hemodynamic measurements revealed a depressed cardiac performance after
isoproterenol application in TG(CxT) compared with TG(CSQ). Our results suggest
that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+)
release compared with TG(CSQ) mice but a depressed contractile function and
survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and
a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a
critical modulator of the SR Ca(2+) signaling.
DOI: 10.1152/ajpheart.00457.2011
PMID: 22427521 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20865638 | 1. Semin Thromb Hemost. 2010 Sep;36(6):620-4. doi: 10.1055/s-0030-1262883. Epub
2010 Sep 23.
Complement in typical hemolytic uremic syndrome.
Orth D(1), Würzner R.
Author information:
(1)Division of Hygiene and Medical Microbiology, Innsbruck Medical University,
Innsbruck, Austria.
Hemolytic uremic syndrome (HUS) is a severe disease characterized by the
clinical triad of hemolytic anemia, thrombocytopenia, and acute renal failure.
HUS exists in two forms: the atypical diarrhea-negative HUS, which is often
associated with complement disorders, and the more frequent diarrheal-associated
typical HUS, which is caused by infections with enterohemorrhagic ESCHERICHIA
COLI. The virulence factors of the latter have been studied well, and Shiga
toxin (Stx)2 is reported to represent the most important one. In contrast, risk
factors on the host side have not been intensively studied until recently:
Complement activation products have been detected in the serum and plasma of HUS
patients, and an in vitro study could show that Stx2 not only damages the kidney
directly but also indirectly via complement, in two ways. First, it activates
complement, and second, it delays the functions of its control protein factor H
on the cell surface, both known to damage the kidney.
© Thieme Medical Publishers.
DOI: 10.1055/s-0030-1262883
PMID: 20865638 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12020825 | 1. Biochim Biophys Acta. 2002 May 3;1575(1-3):108-16. doi:
10.1016/s0167-4781(02)00235-x.
Cloning and functional characterisation of the interleukin-1 beta 1 promoter of
rainbow trout (Oncorhynchus mykiss).
Wang T(1), Zou J, Cunningham C, Secombes CJ.
Author information:
(1)Department of Zoology, University of Aberdeen, Tillydrone Avenue, Aberdeen
AB24 2TZ, UK.
The upstream flanking region of the rainbow trout (Oncorhynchus mykiss) IL-1
beta 1 gene has been cloned and characterised functionally using
luciferase-based reporter gene constructs, and the transcription start site
(TSS) confirmed by RLM-RACE. A TATA box was present 27 bp upstream of the TSS,
with an NF-kB site 19 bp upstream of the TATA box. Within 1217 bp of upstream
sequence, 3 sites for NF-kB, 10 sites for NF-IL6, 15 sites for AP1, 6 sites for
AP4, 2 sites for CHOP/CEBP alpha and 1 site for SP1 and PU.1 were identified.
Seven potential sites for the transcription repressor Gfi-1 were also
identified. Analysis of eight IL-1 beta 1s promoter luciferase constructs
transfected into a trout fibroblast (RTG-2) cell line known to constitutively
express IL-1 beta revealed that in the absence of intron 1, very low luciferase
activity was detectable. All of the constructs containing intron 1 gave clear
luciferase activity, with the highest luciferase activity detected with
construct P2-4 containing 617 bp of upstream sequence. As little as 82 bp of
upstream sequence gave relatively strong luciferase activity, a region
containing both a PU.1 and NF-kB site. That NF-kB is a transcription factor
required for expression of the trout IL-1 beta 1 gene was confirmed using
inhibitor studies with lipopolysaccharide (LPS)-stimulated macrophages. Both
trout recombinant IL-1 beta and LPS were able to increase luciferase activity in
the reporter constructs, especially in those containing the most upstream
sequence with the lowest constitutive expression. The possibility that an
upstream repressor is functioning to inhibit constitutive expression of IL-1
beta in this species is discussed.
DOI: 10.1016/s0167-4781(02)00235-x
PMID: 12020825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15457701 | 1. Stud Health Technol Inform. 2002;91:90-6.
Prediction of curve progression in idiopathic scoliosis from gene polymorphic
analysis.
Inoue M(1), Minami S, Nakata Y, Takaso M, Otsuka Y, Kitahara H, Isobe K, Kotani
T, Maruta T, Moriya H.
Author information:
(1)Department of Orthopedic Surgery, School of Medicine, Chiba University, 1-8-]
Inohana, Chuo-ku, Chiba, Japan.
Three hundred and four girls with adolescent idiopathic scoliosis were
investigated to determine if DNA polymorphisms in the vitamin D receptor (VDR),
estrogen receptor (BR), and CYP17 gene were related to curve progression of
idiopathic scoliosis. The results suggested that XbaJ site polymorphism in the
ER gene was associated with curve progression. The Cobb's curve angle with
genotype XX and Xx was statistically greater than that with genotype xx. The
curve progression risk (approximately 5 degrees) was higher for genotype XX and
Xx than for genotype xx. Furthermore, patients with genotype XX and Xx had a
higher risk of receiving operative treatment than those with genotype xx. In
conclusion, DNA analysis may predict curve progression, although other
polymorphisms were not associated with curve severity.
PMID: 15457701 [Indexed for MEDLINE] |