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http://www.ncbi.nlm.nih.gov/pubmed/23001136 | 1. Pediatr Surg Int. 2012 Nov;28(11):1045-58. doi: 10.1007/s00383-012-3175-6.
Epub 2012 Sep 23.
Chromosomal and related Mendelian syndromes associated with Hirschsprung's
disease.
Moore SW(1).
Author information:
(1)Division of Pediatric Surgery, Department of Surgical Sciences, Faculty of
Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, South
Africa. swm@sun.ac.za
Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal
obstruction in children. It is characterized as a sex-linked heterogonous
disorder with variable severity and incomplete penetrance giving rise to a
variable pattern of inheritance. Although Hirschsprung's disease occurs as an
isolated phenotype in at least 70% of cases, it is not infrequently associated
with a number of congenital abnormalities and associated syndromes,
demonstrating a spectrum of congenital anomalies. Certain of these syndromic
phenotypes have been linked to distinct genetic sites, indicating underlying
genetic associations of the disease and probable gene-gene interaction, in its
pathogenesis. These associations with HSCR include Down's syndrome and other
chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural
deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other
brain-related syndromes, as well as the MEN2 and other tumour associations. A
number of other autosomal recessive syndromes include the Shah-Waardenburg, the
Bardet-Biedl and Cartilage-hair hypoplasia, Goldberg-Shprintzen syndromes and
other syndromes related to cholesterol and fat metabolism among others. The
genetics of Hirschsprung's disease are highly complex with the majority of known
genetic sites relating to the main susceptibility pathways (RET an EDNRB).
Non-syndromic non-familial, short-segment HSCR appears to represent a
non-Mendelian condition with variable expression and sex-dependent penetrance.
Syndromic and familial forms, on the other hand, have complex patterns of
inheritance and being reported as autosomal dominant, recessive and polygenic
patterns of inheritance. The phenotypic variability and incomplete penetrance
observed in Hirschsprung's disease could also be explained by the involvement of
modifier genes, especially in its syndromic forms. In this review, we look at
the chromosomal and Mendelian associations and their underlying signalling
pathways, to obtain a better understanding of the pathogenetic mechanisms
involved in developing aganglionosis of the distal bowel.
DOI: 10.1007/s00383-012-3175-6
PMID: 23001136 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8817329 | 1. Hum Mol Genet. 1996 Jul;5(7):953-8. doi: 10.1093/hmg/5.7.953.
cDNA characterization and chromosomal mapping of two human homologues of the
Drosophila dishevelled polarity gene.
Pizzuti A(1), Amati F, Calabrese G, Mari A, Colosimo A, Silani V, Giardino L,
Ratti A, Penso D, Calzà L, Palka G, Scarlato G, Novelli G, Dallapiccola B.
Author information:
(1)Istituto di Clinica Neurologica, Centro Dino Ferrari Università di Milano,
Italy.
The Drosophila dishevelled gene (dsh) encodes a secreted glycoprotein, which
regulates cell proliferation, acting as a transducer molecule for developmental
processes, including segmentation and neuroblast specification. We have isolated
and characterized cDNA clones from two different human dsh-homologous genes,
designated as DVL-1 and DVL-3. DVL-1 and DVL-3 putative protein products show
64% amino acid identity. The DVL-1 product is 50% identical to dsh and 92% to a
murine dsh homologue (Dvl-1). Both human DVL genes are widely expressed in fetal
and adult tissues, including brain, lung, kidney, skeletal muscle and heart.
DVL-1 locus maps to chromosome 1p36 and DVL-3 to chromosome 3q27. DVL-1 locus on
chromosome 1 corresponds to the murine syntenic region where Dvl-1 is located.
DVL-1 and DVL-3 are members of a human dsh-like gene family, which is probably
involved in human development. Although the precise role of these genes in
embryogenesis is only conjectural at present, the structural and evolutionary
characteristics suggest that mutations at their loci may be involved in neural
and heart developmental defects.
DOI: 10.1093/hmg/5.7.953
PMID: 8817329 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22247333 | 1. FASEB J. 2012 Apr;26(4):1704-16. doi: 10.1096/fj.11-197061. Epub 2012 Jan 12.
Histamine may induce airway remodeling through release of epidermal growth
factor receptor ligands from bronchial epithelial cells.
Hirota N(1), Risse PA, Novali M, McGovern T, Al-Alwan L, McCuaig S, Proud D,
Hayden P, Hamid Q, Martin JG.
Author information:
(1)Meakins-Christie Laboratories, Department of Medicine, McGill University,
3626 St-Urbain, Montréal, QC, H2X 2P2 Canada.
Erratum in
FASEB J. 2021 Nov;35(11):e22021. doi: 10.1096/fsb2.22021.
Asthma is a chronic inflammatory disease that is associated with airway
remodeling, including hyperplasia of airway epithelial cells and airway smooth
muscle cells, and goblet cell differentiation. We wished to address the
potential role of histamine, a key biogenic amine involved in allergic
reactions, in airway remodeling through the epidermal growth factor receptor
(EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands,
amphiregulin and heparin-binding epidermal growth factor-like growth factor
(HB-EGF), from airway epithelial cells. Amphiregulin and HB-EGF were expressed
in airway epithelium of patients with asthma. Histamine up-regulated their mRNA
expression (amphiregulin 3.2-fold, P<0.001; HB-EGF 2.3-fold, P<0.05) and
triggered their release (amphiregulin EC(50) 0.50 μM, 31.2 ± 2.7 pg/ml with 10
μM histamine, P<0.01; HB-EGF EC(50) 0.54 μM, 78.5 ± 1.8 pg/ml with 10 μM
histamine, P<0.001) compared to vehicle control (amphiregulin 19.3 ± 0.9 pg/ml;
HB-EGF 60.2 ± 1.0 pg/ml), in airway epithelial cells. Histamine increased EGFR
phosphorylation (2.1-fold by Western blot analysis) and induced goblet cell
differentiation (CLCA1 up-regulation by real-time qPCR) in normal human
bronchial epithelial (NHBE) cells. Moreover, amphiregulin and HB-EGF caused
proliferation and migration of both NHBE cells and human airway smooth muscle
cells. These results suggest that histamine may induce airway remodeling via the
epithelial-derived EGFR ligands amphiregulin and HB-EGF.
DOI: 10.1096/fj.11-197061
PMID: 22247333 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8896569 | 1. Nat Genet. 1996 Nov;14(3):345-7. doi: 10.1038/ng1196-345.
Germline mutations of the RET ligand GDNF are not sufficient to cause
Hirschsprung disease.
Salomon R(1), Attié T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O,
Ricour C, Nihoul-Fékété C, Munnich A, Lyonnet S.
Author information:
(1)Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393,
Hôpital des Enfants Malades, Institut Necker, Paris, France.
Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital
malformation leading to bowel obstruction, with an incidence of 1/5,000 live
births. It is characterized by the absence of intrinsic ganglion cells in the
myenteric and submucosal plexuses along variable lengths of the gastrointestinal
tract. As enteric neurons are derived from the vagal neural crest, HSCR is
regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1)
and a risk to relatives much higher than the incidence in the general
population, HSCR has long been regarded as a sex-modified multifactorial
disorder. Accordingly, segregation analysis suggested an incompletely penetrant
dominant inheritance in HSCR families with aganglionosis extending beyond the
sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome
10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene.
However, the lack of genotype-phenotype correlation, the low penetrance and the
sex-dependent effect of RET mutations supported the existence of one or more
modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only
accounted for 50% and 15-20% of familial and sporadic HSCR patients,
respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown.
Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been
identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice
display congenital intestinal aganglionosis and renal agenesis, a phenotype very
similar to the Ret-/- mouse. These data prompted us to hypothesize that
mutations of the gene encoding GDNF could either cause or modulate the HSCR
phenotype in some cases.
DOI: 10.1038/ng1196-345
PMID: 8896569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21618594 | 1. J Cell Biochem. 2011 Oct;112(10):2902-9. doi: 10.1002/jcb.23206.
Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts
and ovariectomized rats.
Mai QG(1), Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai
XC.
Author information:
(1)Department of Orthopedic, The Third Affiliated Hospital of Southern Medical
University, Guangzhou 510665, China.
Anti-diabetic drug metformin has been shown to enhance osteoblasts
differentiation and inhibit osteoclast differentiation in vitro and prevent bone
loss in ovariectomized (OVX) rats. But the mechanisms through which metformin
regulates osteoclastogensis are not known. Osteoprotegerin (OPG) and receptor
activator of nuclear factor κB ligand (RANKL) are cytokines predominantly
secreted by osteoblasts and play critical roles in the differentiation and
function of osteoclasts. In this study, we demonstrated that metformin
dose-dependently stimulated OPG and reduced RANKL mRNA and protein expression in
mouse calvarial osteoblasts and osteoblastic cell line MC3T3-E1. Inhibition of
AMP-activated protein kinase (AMPK) and CaM kinase kinase (CaMKK), two targets
of metformin, suppressed endogenous and metformin-induced OPG secretion in
osteoblasts. Moreover, supernatant of osteoblasts treated with metformin reduced
formation of tartrate resistant acid phosphatase (TRAP)-positive multi-nucleated
cells in Raw264.7 cells. Most importantly, metformin significantly increased
total body bone mineral density, prevented bone loss and decreased TRAP-positive
cells in OVX rats proximal tibiae, accompanied with an increase of OPG and
decrease of RANKL expression. These in vivo and in vitro studies suggest that
metformin reduces RANKL and stimulates OPG expression in osteoblasts, further
inhibits osteoclast differentiation and prevents bone loss in OVX rats.
Copyright © 2011 Wiley-Liss, Inc.
DOI: 10.1002/jcb.23206
PMID: 21618594 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3320045 | 1. J Biol Chem. 1987 Dec 25;262(36):17605-12.
Papilin: a Drosophila proteoglycan-like sulfated glycoprotein from basement
membranes.
Campbell AG(1), Fessler LI, Salo T, Fessler JH.
Author information:
(1)Molecular Biology Institute, University of California, Los Angeles 90024.
A sulfated glycoprotein was isolated from the culture media of Drosophila Kc
cells and named papilin. Affinity purified antibodies against this protein
localized it primarily to the basement membranes of embryos. The antibodies
cross-reacted with another material which was not sulfated and appeared to be
the core protein of papilin, which is proteoglycan-like. After reduction,
papilin electrophoresed in sodium dodecyl sulfate-polyacrylamide gel
electrophoresis as a broad band of about 900,000 apparent molecular weight and
the core protein as a narrow band of approximately 400,000. The core protein was
formed by some cell lines and by other cells on incubation with 1 mM
4-methylumbelliferyl xyloside, which inhibited formation of the
proteoglycan-like form. The buoyant density of papilin in CsCl/4 M guanidine
hydrochloride is 1.4 g/ml, that of the core protein is much less. Papilin forms
oligomers linked by disulfide bridges, as shown by sodium dodecyl
sulfate-agarose gel electrophoresis and electron microscopy. The protomer is a
225 +/- 15-nm thread which is disulfide-linked into a loop with fine, protruding
thread ends. Oligomers form clover-leaf-like structures. The protein contains
22% combined serine and threonine residues and 25% combined aspartic and
glutamic residues. 10 g of polypeptide has attached 6.4 g of glucosamine, 3.1 g
of galactosamine, 6.1 g of uronic acid, and 2.7 g of neutral sugars. There are
about 80 O-linked carbohydrate chains/core protein molecule. Sulfate is attached
to these chains. The O-linkage is through an unidentified neutral sugar. Papilin
is largely resistant to common glycosidases and several proteases. The degree of
sulfation varies with the sulfate concentration of the incubation medium. This
proteoglycan-like glycoprotein differs substantially from corresponding
proteoglycans found in vertebrate basement membranes, in contrast to Drosophila
basement membrane laminin and collagen IV which have been conserved
evolutionarily.
PMID: 3320045 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23652187 | 1. Gac Med Mex. 2013 Mar-Apr;149(2):204-11.
[Bone cancer pain: from preclinical pharmacology to clinical trials].
[Article in Spanish]
Montiel-Ruiz RM(1), Acosta-González RI, Jiménez Andrade JM.
Author information:
(1)Unidad Académica Multidisciplinaria Reynosa Aztlán, Universidad Autónoma de
Tamaulipas, Reynosa, Tamaulipas, México.
Worldwide over 12 million people were diagnosed with cancer (excluding
non-melanoma skin cancer) and 8 million individuals died from cancer in 2008.
Recent data indicate that 75-90% of patients with advanced stage diseases or
metastatic cancer will experience significant cancer pain. Bone cancer pain is
common in patients with advanced breast, prostate, and lung cancer as these
tumors have a marked affinity to metastasize to bone. Once tumors metastasize to
bone, they are a major cause of morbidity and mortality as the tumor induces
significant skeletal remodeling, fractures, pain and anemia; all of which reduce
the functional status, quality of life and survival of the patient. Currently,
the factors that drive cancer pain are poorly understood, however, several
recently introduced models of bone cancer pain that mirror the human condition,
are providing insight into the mechanisms that drive bone cancer pain and
guiding the development of novel therapies to treat the cancer pain. Several of
these therapies have recently been approved by the FDA to treat bone cancer pain
(bisphosphonates, denosumab) and others are currently being evaluated in human
clinical trials (tanezumab). These new mechanism-based therapies are enlarging
the repertoire of modalities available to treat bone cancer pain and improving
the quality of life and functional status of patients with bone cancer.
PMID: 23652187 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7515725 | 1. Dev Dyn. 1994 Feb;199(2):116-28. doi: 10.1002/aja.1001990205.
Differentiation, extracellular matrix synthesis, and integrin assembly by
Drosophila embryo cells cultured on vitronectin and laminin substrates.
Gullberg D(1), Fessler LI, Fessler JH.
Author information:
(1)Department of Biology, University of California, Los Angeles 90024-1606.
Two contrasting substrates, Drosophila laminin and human vitronectin, caused
determined primary Drosophila embryo cells to follow alternate intermediate
differentiation steps without affecting the final outcome of differentiation.
Integrin alpha PS2 beta PS3 was essential for the initial spreading of myocytes
on vitronectin: focal contacts rich in beta PS3 integrins formed and were
connected by actin- and myosin-containing stress fibers. While alpha PS2 beta
PS3 was unnecessary for myotube formation on laminin, it was required for the
subsequent change to a sarcomeric cytoarchitecture. The differentiating primary
cultures synthesized integrins and assembled them into detergent-insoluble,
cytoskeleton-associated complexes. Collagen IV, laminin, glutactin, papilin, and
other extracellular matrix proteins were made primarily by hemocytes and were
secreted into the medium. Further differentiation within the cultures was
influenced by secreted components and by later addition of vitronectin or bovine
serum. Comparison of the differentiation of various cell types on the two
substrates showed that vitronectin provided a selective advantage for the
differentiation of myocytes, with enrichment over epithelia, epidermal cells,
and neurites.
DOI: 10.1002/aja.1001990205
PMID: 7515725 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21113693 | 1. Curr Osteoporos Rep. 2011 Mar;9(1):31-5. doi: 10.1007/s11914-010-0039-7.
Osteoporosis in men: what has changed?
Adler RA(1).
Author information:
(1)Endocrinology and Metabolism, McGuire Veterans Affairs Medical Center, 1201
Broad Rock Boulevard, Richmond, VA 23249, USA. robert.adler@va.gov
Osteoporosis in men is finally receiving some attention; it has been realized
that men are more likely to die after hip fracture. Methods for screening men
for osteoporosis include dual energy x-ray absorptiometry and use of fracture
risk calculators such as FRAX (World Health Organization) and the Garvan
nomogram. Evaluation of men will often identify secondary causes of osteoporosis
as well as multiple risk factors. Alendronate, risedronate, zoledronic acid, and
teriparatide are US Food and Drug Administration (FDA)--approved therapy for
men. Men on androgen deprivation therapy (ADT) are at high risk for bone loss
and fracture, and all the bisphosphonates have been shown to increase bone
density. The new antiresorptive drug, denosumab, although FDA-approved only for
postmenopausal women, has been shown in a study of men on ADT to increase bone
density in spine, hip, and forearm and decrease vertebral fractures on x-ray.
Thus, there is great progress in osteoporosis in men, and recognition of its
importance is increasing.
DOI: 10.1007/s11914-010-0039-7
PMID: 21113693 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21942303 | 1. J Manag Care Pharm. 2011 Oct;17(8):621-43. doi: 10.18553/jmcp.2011.17.8.621.
Economic evaluation of denosumab compared with zoledronic acid in
hormone-refractory prostate cancer patients with bone metastases.
Xie J(1), Namjoshi M, Wu EQ, Parikh K, Diener M, Yu AP, Guo A, Culver KW.
Author information:
(1)Analysis Group, Inc., 10 Rockefeller Plaza, 15th Fl., New York, NY 10020,
USA. JXie@analysisgroup.com
Comment in
Eur Urol. 2012 Feb;61(2):427-8. doi: 10.1016/j.eururo.2011.11.027.
J Manag Care Pharm. 2012 Jan-Feb;18(1):74-5; author reply 75-6. doi:
10.18553/jmcp.2012.18.1.74.
BACKGROUND: Bone metastases are common in patients with hormone-refractory
prostate cancer. In a study of autopsies of patients with prostate cancer,
65%-75% had bone metastases. Bone metastases place a substantial economic burden
on payers with estimated total annual costs of $1.9 billion in the United
States. Skeletal-related events (SREs), including pathologic fractures, spinal
cord compression, surgery to bone, and radiation to bone, affect approximately
50% of patients with bone metastases. They are associated with a decreased
quality of life and increased health care costs. Zoledronic acid is an effective
treatment in preventing SREs in solid tumors and multiple myeloma. Recently,
denosumab was FDA-approved for prevention of SREs in patients with bone
metastases from solid tumors. A Phase 3 clinical trial (NCT00321620)
demonstrated that denosumab had superior efficacy in delaying first and
subsequent SREs compared with zoledronic acid. However, the economic value of
denosumab has not been assessed in patients with hormone-refractory prostate
cancer.
OBJECTIVE: To compare the cost-effectiveness of denosumab with zoledronic acid
in the treatment of bone metastases in men with hormone-refractory prostate
cancer.
METHODS: An Excel-based Markov model was developed to assess costs and
effectiveness associated with the 2 treatments over a 1- and 3-year time
horizon. Because the evaluation was conducted from the perspective of a U.S.
third-party payer, only direct costs were included. Consistent with the primary
outcome in the Phase 3 trial, effectiveness was assessed based on the number of
SREs. The model consisted of 9 health states defined by SRE occurrence, SRE
history, disease progression, and death. A hypothetical cohort of patients with
hormone-refractory prostate cancer received either denosumab 120 mg or
zoledronic acid 4 mg at the model entry and transitioned among the 9 health
states at the beginning of each 13-week cycle. Transition probabilities
associated with experiencing the first SRE, subsequent SREs, disease
progression, and death were primarily derived from the results of the Phase 3
clinical trial and were supplemented with published literature. The model
assumed that a maximum of 1 SRE could occur in each cycle. Drug costs included
wholesale acquisition cost, health care professional costs associated with drug
administration, and drug monitoring costs, if applicable. Nondrug costs included
incremental costs associated with disease progression, costs associated with
SREs, and terminal care costs, which were derived from the literature. Adverse
event (AE) costs were estimated based on the incidence rates reported in the
Phase 3 trial. Resource utilization associated with AEs was estimated based on
consultation with a senior medical director employed by the study sponsor. All
costs were presented in 2010 dollars. The base case estimated the incremental
total cost per SRE avoided over a 1-year time horizon. Results for a 3-year time
horizon were also estimated. One-way sensitivity analyses and probabilistic
sensitivity analyses (PSA) were performed to test the robustness of the model.
RESULTS: In the base case, the total per patient costs incurred over 1 year were
estimated at $35,341 ($19,230 drug costs and $16,111 nondrug costs) for
denosumab and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for
zoledronic acid, with an incremental total direct cost of $7,813 for denosumab.
The estimated numbers of SREs per patient during the 1-year period were 0.49 for
denosumab and 0.60 for zoledronic acid, resulting in an incremental number of
SREs of -0.11 in the denosumab arm. The estimated incremental total direct costs
per SRE avoided with the use of denosumab instead of zoledronic acid were
$71,027 for 1 year and $51,319 for 3 years. The 1-way sensitivity analysis
indicated that the results were sensitive to the drug costs, median time to
first SRE, and increased risk of SRE associated with disease progression.
Results of the PSA showed that based on willingness-to-pay thresholds of
$70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was
cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the
cases at 1 year, respectively, and 79.0%, 49.8%, and 4.1% of the cases at 3
years, respectively.
CONCLUSIONS: Although denosumab has demonstrated benefits over zoledronic acid
in preventing or delaying SREs in a Phase 3 trial, it may be a costly
alternative to zoledronic acid from a U.S. payer perspective.
DOI: 10.18553/jmcp.2011.17.8.621
PMCID: PMC10437654
PMID: 21942303 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7958461 | 1. Dev Biol. 1994 Nov;166(1):73-86. doi: 10.1006/dbio.1994.1297.
Isolation and characterization of a mouse homolog of the Drosophila segment
polarity gene dishevelled.
Sussman DJ(1), Klingensmith J, Salinas P, Adams PS, Nusse R, Perrimon N.
Author information:
(1)Department of Obstetrics and Gynecology, University of Maryland School of
Medicine, Baltimore 21201-1559.
In the Drosophila embryo dishevelled (dsh) function is required by target cells
in order to respond to wingless (wg, the homolog of Wnt-1), demonstrating a role
for dsh in Wnt signal transduction. We have isolated a mouse homolog of the
Drosophila dsh segment polarity gene. The 695-amino-acid protein encoded by the
mouse dishevelled gene (Dvl-1) shares 50% identity (65% similarity) with dsh.
Similarity searches of protein and DNA data bases revealed that Dvl-1 encodes an
otherwise novel polypeptide. While no functional motifs were identified, one
region of Dvl-1 was found to be similar to a domain of discs large-1 (dlg), a
Drosophila tumor suppressor gene. In the embryo, Dvl-1 is expressed in most
tissues, with uniformly high levels in the central nervous system. From 7.5 days
postcoitum Dvl-1 is expressed throughout the developing brain and spinal cord,
including those regions expressing Wnt-1 and En. Expression of Dvl-1 in adult
mice was found to be widespread, with brain and testis exhibiting the highest
levels. The majority of Dvl-1 expression in the adult cerebellum is in the
granular cell layer, similar to the pattern seen for engrailed-2 (En-2).
Throughout postnatal development of the brain Dvl-1 is highly expressed in areas
of high neuronal cell density.
DOI: 10.1006/dbio.1994.1297
PMID: 7958461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22867712 | 1. J Autoimmun. 2012 Dec;39(4):369-76. doi: 10.1016/j.jaut.2012.06.001. Epub 2012
Aug 3.
Rheumatoid and pyrophosphate arthritis synovial fibroblasts induce
osteoclastogenesis independently of RANKL, TNF and IL-6.
Dickerson TJ(1), Suzuki E, Stanecki C, Shin HS, Qui H, Adamopoulos IE.
Author information:
(1)University of California, Davis, Department of Internal Medicine, Division of
Rheumatology, Allergy and Clinical Immunology, Davis, CA, USA.
Comment in
Nat Rev Rheumatol. 2012 Oct;8(10):563. doi: 10.1038/nrrheum.2012.141.
Bone destruction is a common feature of inflammatory arthritis and is mediated
by osteoclasts, the only specialized cells to carry out bone resorption.
Aberrant expression of receptor activator of nuclear factor kappa β ligand
(RANKL), an inducer of osteoclast differentiation has been linked with bone
pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this
manuscript, we challenge the current concept that an increase in RANKL
expression governs osteoclastogenesis and bone destruction in autoimmune
arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy
(PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression
profile and the capacity of their secreted factors to induce osteoclastogenesis.
We determined a 10-fold increase of RANKL mRNA and protein in fibroblasts
isolated from RA relative to PPA and OA patients. Peripheral blood mononuclear
cells (PBMC) from healthy volunteers were cultured in the presence of RA, PPA
and OA synovial fibroblast conditioned medium. Osteoclast differentiation was
assessed by expression of tartrate-resistant acid phosphatase (TRAP),
vitronectin receptor (VNR), F-actin ring formation and bone resorption assays.
The formation of TRAP(+), VNR(+) multinucleated cells, capable of F-actin ring
formation and lacunar resorption in synovial fibroblast conditioned medium
cultures occured in the presence of osteoprotegerin (OPG) a RANKL antagonist.
Osteoclasts did not form in these cultures in the absence of macrophage colony
stimulating factor (M-CSF). Our data suggest that the conditioned medium of pure
synovial fibroblast cultures contain inflammatory mediators that can induce
osteoclast formation in human PBMC independently of RANKL. Moreover inhibition
of the TNF or IL-6 pathway was not sufficient to abolish osteoclastogenic
signals derived from arthritic synovial fibroblasts. Collectively, our data
clearly show that alternate osteoclastogenic pathways exist in inflammatory
arthritis and place the synovial fibroblast as a key regulatory cell in bone and
joint destruction, which is a hallmark of autoimmune arthritis.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jaut.2012.06.001
PMCID: PMC3593104
PMID: 22867712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24040443 | 1. Int J Clin Exp Pathol. 2013 Aug 15;6(9):1791-8. eCollection 2013.
Expression of dishevelled gene in Hirschsprung's disease.
Chen D(1), Mi J, Wu M, Wang W, Gao H.
Author information:
(1)Department of Pediatric Surgery, Shengjing Hospital of China Medical
University Liaoning, China.
Hirschsprung's disease (HSCR) is a congenital disorder of the enteric nervous
system and is characterized by an absence of enteric ganglion cells in terminal
regions of the gut during development. Dishevelled (DVL) protein is a
cytoplasmic protein which plays pivotal roles in the embryonic development. In
this study, we explore the cause of HSCR by studying the expression of DVL-1 and
DVL-3 genes and their proteins in the aganglionic segment and the ganglionic
segment of colon in HSCR patients.
MATERIALS AND METHODS: Specimen of aganglionic segment and ganglionic segment of
colon in 50 cases of HSCR patients. Expression levels of mRNA and proteins of
DVL-1 and DVL-3 were confirmed by quantitative real-time PCR (qRT-PCR), western
blot and immunohistochemistry staining between the aganglionic segment and the
ganglionic segment of colon in HSCR patients.
RESULTS: The mRNA expression of DVL-1 and DVL-3 were 2.06 fold and 3.12 fold in
the aganglionic segment colon tissues compared to the ganglionic segment,
respectively. Similarly, the proteins expression of DVL-1 and DVL-3 were higher
(39.71 ± 4.53 vs and 53.90 ± 6.79 vs) in the aganglionic segment colon tissues
than in the ganglionic segment (15.01 ± 2.66 and 20.13 ± 3.63) by western blot.
Besides, immunohistochemical staining showed that DVL-1 and DVL-3 have a
significant increase in mucous and submucous layers from aganglionic colon
segments compared with ganglionic segments.
CONCLUSION: The study showed an association of DVL-1 and DVL-3 with HSCR, it may
play an important role in the pathogenesis of HSCR.
PMCID: PMC3759485
PMID: 24040443 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23821377 | 1. Target Oncol. 2014 Sep;9(3):205-14. doi: 10.1007/s11523-013-0284-7. Epub 2013
Jul 3.
EGFR ligands as pharmacodynamic biomarkers in metastatic colorectal cancer
patients treated with cetuximab and irinotecan.
Loupakis F(1), Cremolini C, Fioravanti A, Orlandi P, Salvatore L, Masi G,
Schirripa M, Di Desidero T, Antoniotti C, Canu B, Faviana P, Sensi E, Lupi C,
Fontanini G, Basolo F, Di Paolo A, Danesi R, Falcone A, Bocci G.
Author information:
(1)Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana,
Istituto Toscano Tumori, Via Roma 67, 56126, Pisa, Italy.
This study was conducted to describe the modulation of plasma epidermal growth
factor receptor (EGFR) ligands in EGFR-positive metastatic colorectal cancer
(mCRC) patients during treatment with cetuximab and irinotecan and to explore
the clinical implication of plasma levels' variations as potential biomarkers of
benefit. Plasma amphiregulin (AR), epidermal growth factor (EGF), transforming
growth factor-α, and heparin binding-EGF were assessed by ELISA in 45
chemorefractory mCRC patients, treated with cetuximab and irinotecan. Plasma
levels were measured before and 1 h after the first administration of cetuximab,
before and 1 h after the second administration, and before the third and the
fifth cycles. KRAS and BRAF mutational status were determined. EGFR ligands'
levels were differently modulated according to tumor KRAS and BRAF mutational
status. In KRAS wild-type patients (n = 34), AR and EGF early increased and
higher increases were significantly associated with worse clinical outcome. By
adopting a specific cut-off value, patients with higher levels of AR 1 h after
the first administration had significantly worse response rate, progression free
survival, and overall survival. This hypothesis-generating study shows that EGFR
ligands are significantly modulated by cetuximab plus irinotecan according to
KRAS and BRAF mutational status, and they warrant further investigation as
pharmacodynamic markers of resistance to anti-EGFRs.
DOI: 10.1007/s11523-013-0284-7
PMID: 23821377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23959273 | 1. Pharmacogenomics J. 2014 Jun;14(3):256-62. doi: 10.1038/tpj.2013.29. Epub 2013
Aug 20.
Intergenic polymorphisms in the amphiregulin gene region as biomarkers in
metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan.
Sebio A(1), Páez D(1), Salazar J(2), Berenguer-Llergo A(3), Paré-Brunet L(4),
Lasa A(4), Del Río E(4), Tobeña M(1), Martín-Richard M(1), Baiget M(2), Barnadas
A(1).
Author information:
(1)Department of Medical Oncology, Santa Creu i Sant Pau Hospital, Autònoma
University of Barcelona, Barcelona, Spain.
(2)1] Department of Genetics, Santa Creu i Sant Pau Hospital, Autònoma
University of Barcelona, Barcelona, Spain [2] U-705 CIBERER, Barcelona, Spain.
(3)IDIBELL, Catalan Institute of Oncology, Barcelona, Spain.
(4)Department of Genetics, Santa Creu i Sant Pau Hospital, Autònoma University
of Barcelona, Barcelona, Spain.
In the epidermal growth factor receptor (EGFR) pathway, polymorphisms in EGFR
and its ligand EGF have been studied as biomarkers for anti-EGFR treatment.
However, the potential pharmacogenetic role of other EGFR ligands such as
amphiregulin (AREG) and epiregulin (EREG) has not been elucidated. We studied 74
KRAS and BRAF wild-type metastatic colorectal cancer patients treated with
anti-EGFR plus irinotecan. Twenty-two genetic variants in EGFR, EGF, AREG and
EREG genes were selected using HapMap database and literature resources. Three
tagging single-nucleotide polymorphisms in the AREG gene region (rs11942466 C>A,
rs13104811 A>G, and rs9996584 C>T) predicted disease control in the multivariate
analyses. AREG rs11942466 C>A and rs9996584 C>T were also associated with
overall survival (OS). The functional polymorphism, EGFR rs712829 G>T, was
associated with progression-free and OS. Our findings support that intergenic
polymorphisms in the AREG gene region might help to identify colorectal cancer
patients that will benefit from irinotecan plus anti-EGFR therapy.
DOI: 10.1038/tpj.2013.29
PMID: 23959273 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23399900 | 1. J Neuropathol Exp Neurol. 2013 Mar;72(3):219-33. doi:
10.1097/NEN.0b013e3182859939.
Malignant peripheral nerve sheath tumor invasion requires aberrantly expressed
EGF receptors and is variably enhanced by multiple EGF family ligands.
Byer SJ(1), Brossier NM, Peavler LT, Eckert JM, Watkins S, Roth KA, Carroll SL.
Author information:
(1)Department of Pathology, The University of Alabama at Birmingham, Birmingham,
AL 35294, USA.
Aberrant epidermal growth factor receptor (EGFR) expression promotes the
pathogenesis of malignant peripheral nerve sheath tumors (MPNSTs), the most
common malignancy associated with neurofibromatosis type 1, but the mechanisms
by which EGFR expression promotes MPNST pathogenesis are poorly understood. We
hypothesized that inappropriately expressed EGFRs promote MPNST invasion and
found that these kinases are concentrated in MPNST invadopodia in vitro.
Epidermal growth factor receptor knockdown inhibited the migration of
unstimulated MPNST cells in vitro, and exogenous EGF further enhanced MPNST
migration in a substrate-specific manner, promoting migration on laminin and, to
a lesser extent, collagen. In this setting, EGF acts as a chemotactic factor. We
also found that the 7 known EGFR ligands (EGF, betacellulin, epiregulin,
heparin-binding EGF, transforming growth factor-α [TGF-α], amphiregulin, and
epigen) variably enhanced MPNST migration in a concentration-dependent manner,
with TGF-α being particularly potent. With the exception of epigen, these
factors similarly promoted the migration of nonneoplastic Schwann cells.
Although transcripts encoding all 7 EGFR ligands were detected in human MPNST
cells and tumor tissues, only TGF-α was consistently overexpressed and was found
to colocalize with EGFR in situ. These data indicate that constitutive EGFR
activation, potentially driven by autocrine or paracrine TGF-α signaling,
promotes the aggressive invasive behavior characteristic of MPNSTs.
DOI: 10.1097/NEN.0b013e3182859939
PMCID: PMC3579504
PMID: 23399900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22826702 | 1. Front Endocrinol (Lausanne). 2012 Jul 18;3:85. doi: 10.3389/fendo.2012.00085.
eCollection 2012.
A changing landscape in castration-resistant prostate cancer treatment.
Felici A(1), Pino MS, Carlini P.
Author information:
(1)Department of Medical Oncology, Regina Elena National Cancer Institute Rome,
Italy.
Prostate cancer (PC) is the leading cause of cancer and the second leading cause
of cancer-death among men in the Western world. About 10-20% of men with PC
present with metastatic disease at diagnosis, while 20-30% of patients diagnosed
with localized disease will eventually develop metastases. Although most respond
to initial androgen-deprivation therapy (ADT), progression to
castration-resistant PC (CRPC) is universal. In 2004 the docetaxel/prednisone
regimen was approved for the management of patients with metastatic CRPC,
becoming the standard first-line therapy. Recent advances have now led to an
unprecedented number of new drug approvals within the past years, providing many
new treatment options for patients with metastatic CRPC. Four new drugs have
received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011:
sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule
inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and
denosumab, a bone-targeting agent. The data supporting the approval of each of
these agents are described in this review, as are current approaches in the
treatment of metastatic CRPC and ongoing clinical trials of novel treatments and
strategies.
DOI: 10.3389/fendo.2012.00085
PMCID: PMC3399094
PMID: 22826702 |
http://www.ncbi.nlm.nih.gov/pubmed/16457155 | 1. Tumori. 2005 Nov-Dec;91(6):546-51. doi: 10.1177/030089160509100616.
Upregulation and overexpression of DVL1, the human counterpart of the Drosophila
dishevelled gene, in prostate cancer.
Mizutani K(1), Miyamoto S, Nagahata T, Konishi N, Emi M, Onda M.
Author information:
(1)Department of Molecular Biology, Institute of Gerontology, Nippon Medical
School, Kawasaki, Japan.
AIMS AND BACKGROUND: The Wnt/beta-catenin signaling pathway is one of the main
carcinogenic mechanisms in human malignancies including prostate cancer.
Recently, the DVL1 gene was identified as a middle molecule of the
Wnt/beta-catenin signaling pathway. In addition, alterations of the DVL1 gene
have been reported in breast and cervical cancer. The abnormality of
beta-catenin in prostate cancer has been well studied, so the examination of the
DVL1 gene in prostate cancer is appealing.
METHODS: We investigated DVL1 messenger RNA alterations by semiquantitative PCR
(SQ-PCR) in 20 primary prostate cancers and assessed the protein expression by
immunohistochemical analysis in the same samples. In addition, DVL1 and
beta-catenin protein expression was evaluated with a new validated set of 20
prostate cancers.
RESULTS: SQ-PCR revealed significant overexpression of DVL1 in prostate cancer
(65%). Upregulation of the DVL1 gene product in prostate cancer was confirmed by
immunostaining. With SQ-PCR and immunostaining, none of the cases showed
underexpression or downregulation of DVL1. In addition, the data showed
correlations between DVL1 mRNA and protein expression. Interestingly, the
expression level of DVL1 increased with worsening histological grade. In
addition, a correlation between DVL1 expression and beta-catenin expression was
confirmed.
CONCLUSIONS: DVL1 was overexpressed in prostate cancer and its overexpression
might be related to prostate cancer progression through the Wnt/beta-catenin
pathway.
DOI: 10.1177/030089160509100616
PMID: 16457155 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22074657 | 1. Urol Oncol. 2011 Nov-Dec;29(6 Suppl):S1-8. doi: 10.1016/j.urolonc.2011.08.013.
New and emerging agents for the treatment of castration-resistant prostate
cancer.
Higano CS(1), Crawford ED.
Author information:
(1)Department of Medicine, University of Washington School of Medicine, Clinical
Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109,
USA. thigano@u.washington.edu
Most men with recurrent prostate cancer (CaP) initially respond to androgen
deprivation therapy but eventually develop metastatic castration-resistant
prostate cancer (CRPC). Over the last decade, new therapeutic targets have been
identified in CRPC and several new drugs have reached advanced stages of
clinical development. In 2010, the Food and Drug Administration (FDA) approved
sipuleucel-T and cabazitaxel, and in 2011, abiraterone for patients with
metastatic CRPC based on phase 3 trials showing improved survival. Although not
yet available for clinical use, a press release in June 2011 announced that
radium 223 also demonstrated a survival advantage in men with metastatic CRPC.
Emerging therapies in advanced stages of clinical development in CRPC include
the hormonal therapies MDV3100 and TAK 700, and the immunotherapy ipilimumab.
Results are also pending on phase 3 studies comparing docetaxel plus prednisone
with docetaxel given with the novel agents aflibercept, dasatinib, lenalidomide,
and custirsen. In addition to these new and emerging therapeutic agents,
denosumab was approved for the prevention of skeletal complications in patients
with bone metastases due to solid tumor malignancies, providing an alternative
to zoledronic acid. While the addition of these new treatment options is a great
advance for men with metastatic CRPC, there are many new questions arising
regarding sequencing of these treatments with each other, with previously
existing therapies, and with the emerging agents now in clinical trials.
Furthermore, there are concerns that on-going phase 3 trials may be contaminated
if patients go off study treatment to start 1 of the newly approved agents or
take the agent subsequently. These realities make clinical trial design more
challenging than ever.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.urolonc.2011.08.013
PMID: 22074657 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24106460 | 1. Front Cell Neurosci. 2013 Oct 2;7:168. doi: 10.3389/fncel.2013.00168.
Identification and function of long non-coding RNA.
Ernst C(1), Morton CC.
Author information:
(1)Douglas Hospital Research Institute Montreal, QC, Canada ; Department of
Psychiatry, McGill University Montreal, QC, Canada.
Long non-coding (lnc) RNAs are defined as non-protein coding RNAs distinct from
housekeeping RNAs such as tRNAs, rRNAs, and snRNAs, and independent from small
RNAs with specific molecular processing machinery such as micro- or piwi-RNAs.
Recent studies of lncRNAs across different species have revealed a diverse
population of RNA molecules of differing size and function. RNA sequencing
studies suggest transcription throughout the genome, so there is a need to
understand how sequence relates to functional and structural relationships
amongst RNA molecules. Our synthesis of recent studies suggests that neither
size, presence of a poly-A tail, splicing, direction of transcription, nor
strand specificity are of importance to lncRNA function. Rather, relative
genomic position in relation to a target is fundamentally important. In this
review, we describe issues of key importance in functional assessment of lncRNA
and how this might apply to lncRNAs important in neurodevelopment.
DOI: 10.3389/fncel.2013.00168
PMCID: PMC3788346
PMID: 24106460 |
http://www.ncbi.nlm.nih.gov/pubmed/26191653 | 1. Thyroid. 2015 Oct;25(10):1080-4. doi: 10.1089/thy.2015.0211. Epub 2015 Aug 17.
Metformin Does Not Suppress Serum Thyrotropin by Increasing Levothyroxine
Absorption.
Al-Alusi MA(1), Du L(2), Li N(3), Yeh MW(4), He X(5), Braverman LE(5), Leung
AM(6)(7).
Author information:
(1)1 UCLA David Geffen School of Medicine, Los Angeles, California.
(2)2 Department of Biostatistics, UCLA Fielding School of Public Health , Los
Angeles, California.
(3)3 Department of Biomathematics, UCLA David Geffen School of Medicine , Los
Angeles, California.
(4)4 Section of Endocrine Surgery, UCLA David Geffen School of Medicine , Los
Angeles, California.
(5)5 Section of Endocrinology, Diabetes, and Nutrition, Boston University School
of Medicine , Boston, Massachusetts.
(6)6 Division of Endocrinology, VA Greater Los Angeles Healthcare System , Los
Angeles, California.
(7)7 Division of Endocrinology, UCLA David Geffen School of Medicine , Los
Angeles, California.
BACKGROUND: Levothyroxine (LT4) absorption is affected by concomitant ingestion
of certain minerals, medications, and foods. It has been hypothesized that
metformin may suppress serum thyrotropin (TSH) concentrations by enhancing LT4
absorption or by directly affecting the hypothalamic-pituitary axis. This study
examined the effect of metformin ingestion on LT4 absorption, as assessed by
serum total thyroxine (TT4) concentrations.
METHODS: A modified Food and Drug Administration LT4 bioequivalence protocol was
applied to healthy, metformin-naïve, euthyroid adult volunteers. Following an
overnight fast, 600 μg LT4 was administered orally. Serum TT4 concentrations
were measured at baseline and at 0.5, 1, 1.5, 2, 4, and 6 h following LT4
administration. Measurements were performed before and after one week of
metformin ingestion (850 mg three times daily). Peak serum TT4 concentrations,
time to peak TT4 concentrations, and area under the concentration-time curve
(AUC) were calculated.
RESULTS: Twenty-six subjects (54% men, 27% white, age 33 ± 10 years) were
studied. There were no significant differences in peak serum TT4 concentrations
(p = 0.13) and time to peak TT4 concentrations (p = 0.19) before and after one
week of metformin use. A trend toward reduced TT4 AUC was observed after
metformin ingestion (pre-metformin 3893 ± 568 μg/dL-min, post-metformin
3765 ± 588 μg/dL-min, p = 0.09).
CONCLUSIONS: LT4 absorption is unchanged by concomitant metformin ingestion.
Mechanisms other than increased LT4 absorption may be responsible for the
suppressed TSH concentrations observed in patients ingesting both drugs.
DOI: 10.1089/thy.2015.0211
PMCID: PMC4589100
PMID: 26191653 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17097409 | 1. J Am Acad Dermatol. 2006 Dec;55(6):1103-5. doi: 10.1016/j.jaad.2006.05.064.
Epub 2006 Aug 28.
Acrokeratosis paraneoplastica (Bazex's syndrome): association with liposarcoma.
Sator PG(1), Breier F, Gschnait F.
Author information:
(1)Department of Dermatology, Municipal Hospital Lainz, Vienna, Austria.
paul.sator@wienkav.at
Comment in
J Am Acad Dermatol. 2007 Jun;56(6):1065. doi: 10.1016/j.jaad.2006.12.039.
Acrokeratosis paraneoplastica (Bazex's syndrome) is a rare obligate
paraneoplastic dermatosis characterized by erythematosquamous lesions localized
symmetrically at the acral sites. The condition almost exclusively affects
Caucasian men older than 40 years. It is usually associated with primary
malignant neoplasms of the upper aerodigestive tract. In most cases, the skin
changes precede the clinical manifestation of the underlying neoplasm. The
dermatosis can be cured only by removal of the underlying carcinoma. We describe
a case of acrokeratosis paraneoplastica associated with a retroperitoneal
liposarcoma in a 71-year-old Caucasian man. The liposarcoma was surgically
removed but recurred several times, with acrokeratosis paraneoplastica showing a
parallel development. We, therefore, add liposarcoma to the growing list of
malignant neoplasms associated with acrokeratosis paraneoplastica.
DOI: 10.1016/j.jaad.2006.05.064
PMID: 17097409 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17374318 | 1. J Cutan Med Surg. 2007 Mar-Apr;11(2):78-83. doi: 10.2310/7750.2007.00015.
Acrokeratosis paraneoplastica (Bazex syndrome) presenting in a patient with
metastatic breast carcinoma: possible etiologic role of zinc.
Taher M(1), Grewal P, Gunn B, Tonkin K, Lauzon G.
Author information:
(1)Division of Dermatology, Department of Obstetrics and Gynecology, University
of Alberta, Edmonton, AB, Canada.
BACKGROUND: Bazex syndrome (acrokeratosis paraneoplastica) is a rare
paraneoplastic syndrome that usually occurs in males over 40 years old and is
particularly associated with squamous cell carcinoma of the upper aerodigestive
tract and adenopathy above the diaphragm.
OBJECTIVE: The objectives of our article are (1) to describe a unique case of
acrokeratosis paraneoplastica and (2) to review the current literature regarding
skin findings, commonly associated neoplasms, and treatment options relative to
this condition.
PATIENT: We describe a 68-year-old female with lobular breast carcinoma,
complicated by local and distant recurrences, who presented with a 1-year
history of prominent acral skin and nail changes.
RESULTS: Our patient's clinical skin findings improved significantly following
treatment and partial remission of her underlying malignancy.
CONCLUSIONS: Our patient represents one of few females described with this
syndrome, which is especially rare in association with lobular breast carcinoma.
Further, the patient's presentation is unique as she was discovered to
demonstrate laboratory findings consistent with coexistent porphyria cutanea
tarda and relative zinc deficiency.
DOI: 10.2310/7750.2007.00015
PMID: 17374318 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22470801 | 1. J Radiol Case Rep. 2011;5(7):1-6. doi: 10.3941/jrcr.v5i7.663. Epub 2011 Jul 1.
Acrokeratosis paraneoplastica (Bazex syndrome): report of a case associated with
small cell lung carcinoma and review of the literature.
Zarzour JG(1), Singh S, Andea A, Cafardi JA.
Author information:
(1)Department of Radiology, University of Alabama at Birmingham, Birmingham, AL
35294, USA. jgzarzour@uabmc.edu
Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive
paraneoplastic dermatosis characterized by erythematosquamous lesions located at
the acral sites and is most commonly associated with carcinomas of the upper
aerodigestive tract. We report a 58-year-old female with a history of a
pigmented rash on her extremities, thick keratotic plaques on her hands, and
brittle nails. Chest imaging revealed a right upper lobe mass that was proven to
be small cell lung carcinoma. While Bazex syndrome has been described in the
dermatology literature, it is also important for the radiologist to be aware of
this entity and its common presentations.
DOI: 10.3941/jrcr.v5i7.663
PMCID: PMC3303451
PMID: 22470801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8949310 | 1. J Laryngol Otol. 1996 Sep;110(9):899-900. doi: 10.1017/s0022215100135297.
Acrokeratosis paraneoplastica: Bazex syndrome.
Wareing MJ(1), Vaughan-Jones SA, McGibbon DH.
Author information:
(1)Department of Otolaryngology, Head and Neck Surgery, Guys' and St. Thomas'
Hospitals NHS Trust, London, UK.
Bazex syndrome, or acrokeratosis paraneoplastica, is a cutaneous paraneoplastic
syndrome characterized by psoriasiform lesions associated with, usually, a
squamous cell carcinoma of the upper aerodigestive tract. We present a case of
Bazex syndrome associated with metastatic cervical squamous cell carcinoma with
an unknown primary. The features of the condition are discussed in the light of
current knowledge.
DOI: 10.1017/s0022215100135297
PMID: 8949310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6650562 | 1. Am J Med Genet. 1983 Oct;16(2):163-7. doi: 10.1002/ajmg.1320160205.
Hirschsprung disease: etiologic implications of unsuccessful prenatal diagnosis.
Jarmas AL, Weaver DD, Padilla LM, Stecker E, Bender HA.
We describe an infant with Hirschsprung disease (congenital aganglionosis of the
intestine) involving the colon and terminal ileum. Midtrimester prenatal
diagnosis of this disorder in this infant was attempted utilizing amniotic fluid
disaccharidase analyses, ultrasound, and amniography. Decreased disaccharidase
activities in amniotic fluid have been reported previously in association with
other forms of intestinal obstruction. At 15 weeks' gestation, normal amniotic
fluid disaccharidase levels were obtained. Serial ultrasound evaluations did not
indicate any pathology, and the results from amniography were inconclusive. The
implication of the normal disaccharidase values is that Hirschsprung disease may
in some cases result from degeneration of intestinal ganglia after 16 weeks'
gestation rather than from faulty migration of neural crest cells. The
inheritance of Hirschsprung disease is generally consistent with sex-modified
multifactorial inheritance with a lower threshold of expression in males. The
case we report has a family history of three affected first- and second-degree
relatives. Autosomal dominance with variable expressivity is a possible
explanation in this family.
DOI: 10.1002/ajmg.1320160205
PMID: 6650562 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23888072 | 1. Clin Cancer Res. 2013 Sep 15;19(18):5027-38. doi:
10.1158/1078-0432.CCR-13-1275. Epub 2013 Jul 25.
Ligand-dependent activation of EGFR in follicular dendritic cells sarcoma is
sustained by local production of cognate ligands.
Vermi W(1), Giurisato E, Lonardi S, Balzarini P, Rossi E, Medicina D, Bosisio D,
Sozzani S, Pellegrini W, Doglioni C, Marchetti A, Rossi G, Pileri S, Facchetti
F.
Author information:
(1)Authors' Affiliations: Department of Molecular and Translational Medicine,
Section of Anatomic Pathology, Oncology and Experimental immunology, University
of Brescia, Brescia; Department of Physiopathology, Experimental Medicine and
Public Health, University of Siena, Siena; Department of Pathology, San Raffaele
Scientific Institute, Milan; Center of Predictive Molecular Medicine, Center of
Excellence on Aging University-Foundation, Chieti; Unita' Operativa di Anatomia
Patologica, Azienda Arcispedale S. Maria Nuova/IRCCS, Reggio Emilia;
Hematopathology Section, Policlinico S. Orsola, University of Bologna, Bologna;
Department of Pathology and Immunology, Washington University School of
Medicine, Saint Louis, Missouri; and Humanitas Clinical and Research Center.
PURPOSE: The aim of this study was to investigate the biological and clinical
significance of epidermal growth factor receptor (EGFR) signaling pathway in
follicular dendritic cell sarcoma (FDC-S).
EXPERIMENTAL DESIGN: Expression of EGFR and cognate ligands as well as
activation of EGFR signaling components was assessed in clinical samples and in
a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of
the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on
FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS,
BRAF, and PI3KCA was conducted on tumor DNA.
RESULTS: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On
FDC-AM09, we could show that engagement of surface EGFR by cognate ligands
drives the survival and proliferation of FDC-S cells, by signaling to the
nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding
EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor
microenvironment of FDC-S at RNA level. By extending this finding at protein
level we found that BTC is abundantly produced by FDC-S cells and surrounding
stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed
that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to
anti-EGFR MoAb in other cancer models, are not observed in FDC-S.
CONCLUSION: Activation of EGFR by cognate ligands produced in the tumor
microenvironment sustain viability and proliferation of FDC-S indicating that
the receptor blockade might be clinically relevant in this neoplasm.
©2013 AACR.
DOI: 10.1158/1078-0432.CCR-13-1275
PMID: 23888072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15617541 | 1. Clin Genet. 2005 Jan;67(1):6-14. doi: 10.1111/j.1399-0004.2004.00319.x.
Studying the genetics of Hirschsprung's disease: unraveling an oligogenic
disorder.
Brooks AS(1), Oostra BA, Hofstra RM.
Author information:
(1)Department of Clinical Genetics, Erasmus MC, Rotterdam.
Hirschsprung's disease is characterized by the absence of ganglion cells in the
myenteric and submucosal plexuses of the gastrointestinal tract. Genetic
dissection was successful as nine genes and four loci for Hirschsprung's disease
susceptibility were identified. Different approaches were used to find these
loci such as classical linkage in large families, identity by descent mapping in
an inbred kindred, candidate gene approaches based on naturally occurring mutant
mice models, and finally the use of model-free linkage and association analyzes.
In this study, we review the identification of genes and loci involved in the
non-syndromic common form and syndromic Mendelian forms of Hirschsprung's
disease. The majority of the identified genes are related to Mendelian syndromic
forms of Hirschsprung's disease. The non-Mendelian inheritance of sporadic
non-syndromic Hirschsprung's disease proved to be complex; involvement of
multiple loci was demonstrated in a multiplicative model. We discuss the
practical implications of the elucidation of genes associated with
Hirschsprung's disease susceptibility for genetic counseling. Finally, we
speculate on possible strategies to identify new genes for Hirschsprung's
disease.
DOI: 10.1111/j.1399-0004.2004.00319.x
PMID: 15617541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23757624 | 1. Endocr Pract. 2013 Sep-Oct;19(5):834-8. doi: 10.4158/EP13114.RA.
Osteoporosis in men.
Watts NB(1).
Author information:
(1)Mercy Health Osteoporosis and Bone Health Services, Cincinnati, Ohio.
OBJECTIVE: To review information pertinent to bone health and osteoporosis in
men.
METHODS: A review of pertinent literature was conducted.
RESULTS: Osteoporosis affects approximately 2 million men in the US and accounts
for an estimated 600,000 fractures each year. There are significant differences
in skeletal size and structure between men and women that account for
differences in fracture incidence, location, and outcomes. Bone density testing
is appropriate for men age 70 and older and younger men (50-69) who have risk
factors for osteoporosis. Lifestyle management, including adequate calcium and
vitamin D intake, appropriate physical activity, and avoidance of tobacco and
heavy alcohol use, is appropriate for all men. Pharmacologic therapy to reduce
fracture risk is advisable for men with a clinical diagnosis of osteoporosis (a
spine or hip fracture) or a T-score of -2.5 or below in the spine, femoral neck,
total hip or 1/3 radius; however, the majority of men at high risk will only be
identified using a fracture risk assessment tool, such as FRAX. Alendronate,
risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug
Administration (FDA)-approved therapeutic options.
CONCLUSIONS: Osteoporosis in men presents an important public health problem
with significant morbidity and mortality. There are recommended strategies for
identifying men at high risk of fracture, and effective agents are available for
treatment.
DOI: 10.4158/EP13114.RA
PMID: 23757624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20663605 | 1. Clin Neurol Neurosurg. 2010 Nov;112(9):781-4. doi:
10.1016/j.clineuro.2010.06.018. Epub 2010 Jul 21.
Benefits from sustained-release pyridostigmine bromide in myasthenia gravis:
results of a prospective multicenter open-label trial.
Sieb JP(1), Köhler W.
Author information:
(1)Department of Neurology, Geriatric Medicine and Palliative Care, General
Hospital, Grosse Parower St, 18435 Stralsund, Germany. j.sieb@klinikum-hst.de
INTRODUCTION: For more than 50 years the acetylcholinesterase inhibitor
pyridostigmine bromide has been the drug of choice in the symptomatic therapy
for myasthenia gravis. The sustained-release dosage form of pyridostigmine
(SR-Pyr) is only available in a limited number of countries (e.g. in the United
States and Germany). Astonishingly, the therapeutic usefulness of SR-Pyr has not
yet been evaluated.
METHODS: In this non-interventional prospective open-label trial, 72 patients
with stable myasthenia gravis were switched from instant-release dosage forms of
pyridostigmine bromide to SR-Pyr. The results from the 37 patients younger than
60 years were separately analyzed.
RESULTS: The initial daily dose of SR-Pyr was 288.1 ± 171.0mg. The drug switch
was unproblematic in all patients. The number of daily doses was significantly
reduced from 4.3 to 3.6 (p=0.011). The switch to SR-Pyr ameliorated the total
quantified myasthenia gravis (QMG) score from 0.9 ± 0.5 to 0.6 ± 0.4 (p<0.001)
in all patients and in the younger subgroup. This was accompanied by a
significant improvement in the quality of life parameters. The health status
valued by EuroQoL questionnaire improved from 0.626 ± 0.286 to 0.782 ± 0.186
(p<0.001). After switching to SR-Pyr, 28 adverse reactions disappeared and 24
adverse reactions occurred less frequent or weaker, however, 17 new adverse
reactions were documented.
CONCLUSIONS: Our results support the usefulness of SR-Pyr in an individualized
therapeutic regimen to improve quality of life regardless of the patient's age
in myasthenia gravis.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.clineuro.2010.06.018
PMID: 20663605 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23835909 | 1. Mol Med Rep. 2013 Sep;8(3):823-8. doi: 10.3892/mmr.2013.1572. Epub 2013 Jul 5.
Adipocytes regulate the bone marrow microenvironment in a mouse model of
obesity.
Xu F(1), Du Y, Hang S, Chen A, Guo F, Xu T.
Author information:
(1)Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Obesity is markedly associated with abnormal bone density indicating the
importance of adipocytes in bone metabolism. However, the specific function of
adipocytes remains unclear, with marked discrepancies in observations of
previous studies. In the present study, the effect of adipocytes on
osteoblasts/osteoclasts was analyzed. A mouse model of obesity was established
and an in vitro co-culture system was utilized containing adipocyte and
MC3T3/RAW 264.7 cells in a Transwell plate. Compared with control mice, obese
mice exhibited low body weight and bone mineral density of the tibia and fat
cells were observed to accumulate in bone marrow. MC3T3/RAW 264.7 cells were
co-cultured with adipocytes and the mRNA and protein expression of alkaline
phosphatase and osteocalcin was found to be decreased in MC3T3-E1 cells and mRNA
and protein expression of tartrate-resistant acid phosphatase and cathepsin K
was significantly increased in RAW 264.7 cells. In addition, the effect of
adipocytes on the osteoprotegerin (OPG)/receptor activator of nuclear factor κB
ligand (RANKL)/RANK system indicated that the RANKL/OPG ratio secreted by
osteoblasts increased and RANK expression by osteoclasts increased, leading to
increased osteoclastogenesis. These results indicate that bone metabolism is
impaired in obese mice leading to decreased osteoblastogenesis and marked
increases in osteoclastogenesis and low bone mass.
DOI: 10.3892/mmr.2013.1572
PMID: 23835909 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1433123 | 1. J R Soc Med. 1992 Sep;85(9):548-50. doi: 10.1177/014107689208500913.
Acrokeratosis paraneoplastica of Bazex.
Handfield-Jones SE(1), Matthews CN, Ellis JP, Das KB, McGibbon DH.
Author information:
(1)St John's Dermatology Centre, St Thomas Hospital, London.
Bazex disease is one of the rarer cutaneous paraneoplastic syndromes. It is
characterized by psoriasiform changes on the digits, and in some patients spread
to the ears, nose and in later stages to the limbs and trunk. The associated
malignancy is typically a squamous cell carcinoma of the upper aerodigestive
tract. We review the literature regarding acrokeratosis paraneoplastica of Bazex
and report three cases which illustrate both the typical and some of the less
common changes that are seen in the condition.
DOI: 10.1177/014107689208500913
PMCID: PMC1293643
PMID: 1433123 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23542579 | 1. Int J Gynecol Cancer. 2013 May;23(4):673-9. doi: 10.1097/IGC.0b013e31828c166d.
Detection of microRNA as novel biomarkers of epithelial ovarian cancer from the
serum of ovarian cancer patients.
Chung YW(1), Bae HS, Song JY, Lee JK, Lee NW, Kim T, Lee KW.
Author information:
(1)Department of Obstetrics and Gynecology, Korea University Medical Center,
Seoul, Korea.
OBJECTIVE: MicroRNA (miRNA) is an abundant class of small noncoding RNAs that
act as gene regulators. Recent studies have suggested that miRNA deregulation is
associated with the initiation and progression of human cancer. However,
information about cancer-related miRNA is mostly limited to tissue miRNA. The
aim of this study was to find specific profiles of serum-derived miRNAs of
ovarian cancer based on a comparative study using a miRNA microarray of serum,
tissue, and ascites.
METHODS: From 2 ovarian cancer patients and a healthy control, total RNA was
isolated from their serum, tissue, and ascites, respectively, and analyzed by a
microarray. Under the comparative study of each miRNA microarray, we sorted out
several miRNAs showing a consistent regulation tendency throughout all 3
specimens and the greatest range of alteration in serum as potential biomarkers.
The availability of biomarkers was confirmed by qRT-PCR of 18 patients and 12
controls.
RESULTS: Out of 2222 kinds of total miRNAs that were identified in the
microarray analysis, 95 miRNAs were down-regulated and 88 miRNAs were
up-regulated, in the serum, tissue, and ascites of cancer patients. Among the
miRNAs that showed a consistent regulation tendency through all specimens and
showed more than a 2-fold difference in serum, 5 miRNAs (miR-132, miR-26a,
let-7b, miR-145, and miR-143) were determined as the 5 most markedly
down-regulated miRNAs in the serum from ovarian cancer patients with respect to
those of controls. Four miRNAs (miR-132, miR-26a, let-7b, and miR-145) out of 5
selected miRNAs were significantly underexpressed in the serum of ovarian cancer
patients in qRT-PCR.
CONCLUSIONS: Serum miR-132, miR-26a, let-7b, and miR-145 could be considered as
potential candidates as novel biomarkers in serous ovarian cancer. Also, serum
miRNAs is a promising and useful tool for discriminating between controls and
patients with serous ovarian cancer.
DOI: 10.1097/IGC.0b013e31828c166d
PMID: 23542579 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15829955 | 1. Nature. 2005 Apr 14;434(7035):857-63. doi: 10.1038/nature03467.
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease
risk.
Emison ES(1), McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME,
Cutler DJ, Green ED, Chakravarti A.
Author information:
(1)McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205, USA.
The identification of common variants that contribute to the genesis of human
inherited disorders remains a significant challenge. Hirschsprung disease (HSCR)
is a multifactorial, non-mendelian disorder in which rare high-penetrance coding
sequence mutations in the receptor tyrosine kinase RET contribute to risk in
combination with mutations at other genes. We have used family-based association
studies to identify a disease interval, and integrated this with comparative and
functional genomic analysis to prioritize conserved and functional elements
within which mutations can be sought. We now show that a common non-coding RET
variant within a conserved enhancer-like sequence in intron 1 is significantly
associated with HSCR susceptibility and makes a 20-fold greater contribution to
risk than rare alleles do. This mutation reduces in vitro enhancer activity
markedly, has low penetrance, has different genetic effects in males and
females, and explains several features of the complex inheritance pattern of
HSCR. Thus, common low-penetrance variants, identified by association studies,
can underlie both common and rare diseases.
DOI: 10.1038/nature03467
PMID: 15829955 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21328290 | 1. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006986. doi:
10.1002/14651858.CD006986.pub2.
Acetylcholinesterase inhibitor treatment for myasthenia gravis.
Mehndiratta MM(1), Pandey S, Kuntzer T.
Author information:
(1)Department of Neurology, G.B. Pant Hospital, #502, Academic Block, New Delhi,
India, 110002.
Update in
Cochrane Database Syst Rev. 2014 Oct 13;(10):CD006986. doi:
10.1002/14651858.CD006986.pub3.
BACKGROUND: In myasthenia gravis, antibody-mediated blockade of acetylcholine
receptors at the neuromuscular junction abolishes the naturally occurring
'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors
provide temporary symptomatic treatment of muscle weakness, but there is
controversy about their long-term efficacy, dosage and side effects.
OBJECTIVES: To evaluate the efficacy of acetylcholinesterase inhibitors in all
forms of myasthenia gravis.
SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group
Specialized Register (5 October 2009), The Cochrane Central Register of
Controlled Trials CENTRAL) (The Cochrane Library Issue 3, 2009), MEDLINE
(January 1966 to September 2009), EMBASE (January 1980 to September 2009) for
randomised controlled trials and quasi-randomised controlled trials regarding
usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors
scanned the articles for any study eligible for inclusion. We also contacted the
authors and known experts in the field to identify additional published or
unpublished data.
SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials.
TYPES OF PARTICIPANTS: all myasthenia gravis patients diagnosed by an
internationally accepted definition.Types of interventions: treatment with any
form of acetylcholinesterase inhibitor.Types of outcome measuresPrimary outcome
measureImprovement in the presenting symptoms within 1 to 14 days of the start
of treatment.Secondary outcome measures(1) Improvement in the presenting
symptoms more than 14 days after the start of treatment.(2) Change in impairment
measured by a recognised and preferably validated scale, such as the
quantitative myasthenia gravis score within 1 to 14 days and more than 14 days
after the start of treatment.(3) Myasthenia Gravis Association of America
post-intervention status more than 14 days after start of treatment.(4) Adverse
events: muscarinic side effects.
DATA COLLECTION AND ANALYSIS: One author (MMM) extracted the data, which were
checked by a second author. We contacted study authors for extra information and
collected data on adverse effects from the trials.
MAIN RESULTS: We did not find any large randomised or quasi-randomised trials of
acetylcholinesterase inhibitors in generalised myasthenia gravis. One cross-over
randomised trial using intranasal neostigmine in a total of 10 subjects was only
available as an abstract.
AUTHORS' CONCLUSIONS: Except for one small and inconclusive trial of intranasal
neostigmine, no randomised controlled trial has been conducted on the use of
acetylcholinesterase inhibitors in myasthenia gravis. Response to
acetylcholinesterase inhibitors in observational studies is so clear that a
randomised controlled trial depriving participants in the placebo arm of
treatment would be difficult to justify.
DOI: 10.1002/14651858.CD006986.pub2
PMID: 21328290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10810787 | 1. Z Kardiol. 2000;89 Suppl 3:62-7.
[Current classification of anti-arrhythmia agents].
[Article in German]
Weirich J(1), Wenzel W.
Author information:
(1)Physiologisches Institut der Universität, Freiburg.
Antiarrhythmic drugs can be divided into four Vaughan Williams classes (I-IV)
according to defined electrophysiological effects on the myocardium. Thus, the
Vaughan Williams classification also coincides with the main myocardial targets
of the antiarrhythmics, i.e., myocardial sodium-, potassium-, and
calcium-channels or beta-adrenergic receptors. A more detailed characterization
which is also based on the myocardial targets of a drug is given by the
"Sicilian Gambit" approach of classification. Nevertheless, the appropriate drug
for the management of a given clinical arrhythmia has to be chosen according to
the electrophysiological effects of the respective drug. A main determinant of
the antiarrhythmic or proarrhythmic properties of a drug is the frequency
dependence of its electrophysiological effects. The sodium-channel blockade
induced by class-I substances is enhanced with increasing heart rates. Thus,
class-I antiarrhythmics can be subclassified as substances showing a more
exponential, an approximately linear, or rather saturated block-frequency
relation. Class-III antiarrhythmics (potassium-channel blockade) can be further
differentiated according to the component of the delayed rectifier potassium
current (IK) which is inhibited by a drug. Class-III drugs inhibiting
selectively the rapidly activating and deactivating IKr component exhibit a
marked reverse rate dependence, i.e., the drug induced prolongation of the
cardiac action potential is minimized at high rates. On the other hand, during
bradycardia the pronounced action potential prolongation may cause early
afterdepolarizations and triggered activity leading to torsades de pointes
arrhythmias (acquired QT syndrome). Class-III substances inhibiting the slowly
activating IKs component are currently under investigation and are expected to
show a direct rate dependence. Experimental data available so far point to an
action potential prolonging effect at least independent of rate. However, it is
uncertain whether proarrhythmic effects can be thus avoided, especially in light
of the fact that one form of congenital QT syndrome (LQT1) seems to be linked to
dysfunction of the IKs-channel.
PMID: 10810787 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23028706 | 1. PLoS One. 2012;7(9):e44964. doi: 10.1371/journal.pone.0044964. Epub 2012 Sep
18.
Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3.
Meng H(1), Zhang X, Yu G, Lee SJ, Chen YE, Prudovsky I, Wang MM.
Author information:
(1)Department of Neurology, University of Michigan, Ann Arbor, Michigan, United
States of America.
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy (CADASIL) is the best understood cause of dominantly
inherited stroke and results from NOTCH3 mutations that lead to NOTCH3 protein
accumulation and selective arterial smooth muscle degeneration. Previous studies
show that NOTCH3 protein forms multimers. Here, we investigate protein
interactions between NOTCH3 and other vascular Notch isoforms and characterize
the effects of elevated NOTCH3 on smooth muscle gene regulation. We demonstrate
that NOTCH3 forms heterodimers with NOTCH1, NOTCH3, and NOTCH4. R90C and C49Y
mutant NOTCH3 form complexes which are more resistant to detergents than wild
type NOTCH3 complexes. Using quantitative NOTCH3-luciferase clearance assays, we
found significant inhibition of mutant NOTCH3 clearance. In coculture assays of
NOTCH function, overexpressed wild type and mutant NOTCH3 significantly
repressed NOTCH-regulated smooth muscle transcripts and potently impaired the
activity of three independent smooth muscle promoters. Wildtype and R90C
recombinant NOTCH3 proteins applied to cell cultures also blocked canonical
Notch fuction. We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1,
3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant
NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle
cells.
DOI: 10.1371/journal.pone.0044964
PMCID: PMC3445613
PMID: 23028706 [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/21639801 | 1. Pediatr Dev Pathol. 2011 Sep-Oct;14(5):378-83. doi: 10.2350/10-09-0900-OA.1.
Epub 2011 Jun 3.
Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical
study.
Litten JB(1), Chen TT, Schultz R, Herman K, Comstock J, Schiffman J, Tomlinson
GE, Rakheja D.
Author information:
(1)Department of Pediatrics, University of Texas Southwestern Medical Center,
Dallas, TX, USA.
Hepatoblastoma is a pediatric malignancy characterized by the uncontrolled
proliferation of immature hepatocytes (hepatoblasts). This disease is diagnosed
primarily in children younger than 5 years and is disproportionately observed in
former premature infants. Cytogenetically, hepatoblastoma is characterized by
numerical aberrations, as well as unbalanced translocations involving the
proximal region of chromosome 1q. The NOTCH2 gene has been mapped to this locus,
and it is well established that the NOTCH gene family is an important regulator
of several developmental pathways. Specifically, the NOTCH2 protein is known to
delay hepatoblast maturation during early hepatic organogenesis, and the
reduction of NOTCH2 expression correlates with the differentiation of
hepatoblasts into hepatocytes and biliary cells in the developing liver. We
hypothesized that NOTCH2 is involved in the pathogenesis of hepatoblastoma by
maintaining a population of undifferentiated hepatoblasts. We studied the
immunohistochemical expression of NOTCH2 and its isoforms NOTCH1, NOTCH3, and
NOTCH4 and the NOTCH2 primary ligand JAGGED1 in hepatoblastomas. Compared with
the normal liver, an increased level of NOTCH2 expression was seen in 22 of 24
(92%) hepatoblastomas. There was no significant staining for other NOTCH
isoforms and JAGGED1 in hepatoblastomas. Therefore, we suggest that NOTCH2
expression and activation, independent of JAGGED1 expression, may contribute to
the pathogenesis of hepatoblastoma. In the hepatoblastoma sinusoidal
vasculature, we saw NOTCH3 and NOTCH1 expression. These observations have
potential implications with regard to therapeutic targeting of the NOTCH
signaling pathway in hepatoblastomas.
DOI: 10.2350/10-09-0900-OA.1
PMID: 21639801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21356309 | 1. Mech Dev. 2011 May-Jun;128(5-6):247-57. doi: 10.1016/j.mod.2011.02.002. Epub
2011 Feb 26.
Numb regulates Notch1, but not Notch3, during myogenesis.
Beres BJ(1), George R, Lougher EJ, Barton M, Verrelli BC, McGlade CJ, Rawls JA,
Wilson-Rawls J.
Author information:
(1)Biology Graduate Program, School of Life Sciences, Arizona State University,
Tempe, USA.
In the vertebrate embryo, skeletal muscle is derived from the myotome of the
somites. Notch1-3 demonstrate overlapping and distinct expression patterns in
mouse somites. Notch1 and Notch2 have been shown to be inhibitors of skeletal
myogenesis. The current data demonstrate that Notch3 also is an effective
inhibitor of MyoD induced myogenesis. Numb, an adaptor protein that promotes
Notch degradation by recruiting the E3 ubiquitin ligase, Itch, is limited in
expression to dividing cells of the dorsal medial lip of the dermomyotome and
the myotome itself. Here the specificity of the four protein isoforms of Numb
for the Notch receptors was examined. In transcription and myogenic
differentiation assays, Notch1 was consistently negatively regulated by all four
Numb isoforms, and Notch3 was not a target for Numb. Notch2 however was variably
affected. Subsequent analyses showed that unlike Notch1, that Notch3 was not
polyubiquitinated, nor degraded when co-expressed in cells with Numb. These data
provide the first observations that Notch receptors are variably affected by
Numb and will be important for the interpretation of the function of Notch and
Numb interactions during the development of many different cells and tissues.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.mod.2011.02.002
PMID: 21356309 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6225397 | 1. Arch Dermatol. 1983 Oct;119(10):820-6. doi: 10.1001/archderm.119.10.820.
Acrokeratosis paraneoplastica (Bazex' syndrome). Report of a case and review of
the literature.
Pecora AL, Landsman L, Imgrund SP, Lambert WC.
Acrokeratosis paraneoplastica (Bazex' syndrome) is a rare but clinically
distinctive dermatosis that has been associated in all reported cases, to our
knowledge, with either a primary malignant neoplasm of the upper aerodigestive
tract or metastatic cancer to the lymph nodes of the neck. Acrokeratosis
paraneoplastica was found in a 53-year-old black man with squamous cell
carcinoma of the tonsil. A distinctive series of changes was found on
histopathologic examination of biopsy specimens taken from his skin lesions, and
direct immunofluorescence microscopy of both lesional and nonlesional skin
specimens showed immunoglobulin and complement deposition on the epidermal
basement membrane. The skin lesions largely resolved following radiation therapy
of the neoplasm and of the presumably involved lymph nodes.
DOI: 10.1001/archderm.119.10.820
PMID: 6225397 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22842086 | 1. Methods. 2012 Sep;58(1):69-78. doi: 10.1016/j.ymeth.2012.07.008. Epub 2012 Jul
27.
Generation of anti-Notch antibodies and their application in blocking Notch
signalling in neural stem cells.
Falk R(1), Falk A, Dyson MR, Melidoni AN, Parthiban K, Young JL, Roake W,
McCafferty J.
Author information:
(1)University of Cambridge, Department of Biochemistry, Tennis Court Road, CB2
1QW Cambridge, UK.
Notch signalling occurs via direct cell-cell interactions and plays an important
role in linking the fates of neighbouring cells. There are four different
mammalian Notch receptors that can be activated by five cell surface ligands.
The ability to inhibit specific Notch receptors would help identify the roles of
individual family members and potentially provide a means to study and control
cell differentiation. Anti-Notch antibodies in the form of single chain Fvs were
generated from an antibody phage display library by selection on either the
ligand binding domain or the negative regulatory region (NRR) of Notch1 and
Notch2. Six antibodies targeting the NRR of Notch1 and four antibodies
recognising the NRR of Notch2 were found to prevent receptor activation in
cell-based luciferase reporter assays. These antibodies were potent, highly
specific inhibitors of individual Notch receptors and interfered with endogenous
signalling in stem cell systems of both human and mouse origin.
Antibody-mediated inhibition of Notch efficiently down-regulated transcription
of the immediate Notch target gene hairy and enhancer of split 5 (Hes5) in both
mouse and human neural stem cells and revealed a redundant regulation of Hes5 in
these cells as complete down-regulation was seen only after simultaneous
blocking of Notch1 and Notch2. In addition, these antibodies promoted
differentiation of neural stem cells towards a neuronal fate. In contrast to the
widely used small molecule γ-secretase inhibitors, which block all 4 Notch
receptors (and a multitude of other signalling pathways), antibodies allow
blockade of individual Notch family members in a highly specific way. Specific
inhibition will allow examination of the effect of individual Notch receptors in
complex differentiation schemes regulated by the co-ordinated action of multiple
signalling pathways.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymeth.2012.07.008
PMCID: PMC3502869
PMID: 22842086 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11532344 | 1. Exp Hematol. 2001 Sep;29(9):1041-52. doi: 10.1016/s0301-472x(01)00676-2.
Notch receptors and hematopoiesis.
Kojika S(1), Griffin JD.
Author information:
(1)Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115,
USA.
Notch receptors are involved in a variety of cell-fate decisions that affect the
development and function of many organs, including hematopoiesis and the immune
system. There are four mammalian Notch receptors that have only partially
overlapping functions despite sharing similar structures and ligands. The
ligands for Notch are transmembrane proteins expressed on adjacent cells,
including Jagged and Delta, and it is quite possible that signaling is
bidirectional. A large Notch precursor protein is proteolytically cleaved to
form the mature cell-surface receptor. Ligand binding induces additional
proteolytic events followed by translocation of the intracellular domain to the
nucleus. There, Notch interacts with transcription factors such as RBPJ kappa,
activating transcription of basic helix-loop-helix genes such as HES1. These in
turn regulate expression of tissue-specific transcription factors that influence
lineage commitment and other events. In this review, the details of Notch
signaling will be discussed, with a focus on what is known about the role of
Notch in hematopoiesis.
DOI: 10.1016/s0301-472x(01)00676-2
PMID: 11532344 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23632157 | 1. Comp Biochem Physiol A Mol Integr Physiol. 2013 Sep;166(1):74-80. doi:
10.1016/j.cbpa.2013.04.023. Epub 2013 Apr 28.
Zebrafish scales respond differently to in vitro dynamic and static
acceleration: analysis of interaction between osteoblasts and osteoclasts.
Kitamura K(1), Takahira K, Inari M, Satoh Y, Hayakawa K, Tabuchi Y, Ogai K,
Nishiuchi T, Kondo T, Mikuni-Takagaki Y, Chen W, Hattori A, Suzuki N.
Author information:
(1)Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kanazawa, Ishikawa 920-0942, Japan.
kkitamur@staff.kanazawa-u.ac.jp
Zebrafish scales consist of bone-forming osteoblasts, bone-resorbing
osteoclasts, and calcified bone matrix. To elucidate the underlying molecular
mechanism of the effects induced by dynamic and static acceleration, we
investigated the scale osteoblast- and osteoclast-specific marker gene
expression involving osteoblast-osteoclast communication molecules. Osteoblasts
express RANKL, which binds to the osteoclast surface receptor, RANK, and
stimulates bone resorption. OPG, on the other hand, is secreted by osteoblast as
a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus
prevents bone resorption. Therefore, the RANK-RANKL-OPG pathway contributes to
the regulation of osteoclastogenesis by osteoblasts. Semaphorin 4D, in contrast,
is expressed on osteoclasts, and binding to its receptor Plexin-B1 on
osteoblasts results in suppression of bone formation. In the present study, we
found that both dynamic and static acceleration at 3.0×g decreased RANKL/OPG
ratio and increased osteoblast-specific functional mRNA such as alkaline
phosphatase, while static acceleration increased and dynamic acceleration
decreased osteoclast-specific mRNA such as cathepsin K. Static acceleration
increased semaphorin 4D mRNA expression, while dynamic acceleration had no
effect. The results of the present study indicated that osteoclasts have
predominant control over bone metabolism via semaphorin 4D expression induced by
static acceleration at 3.0×g.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cbpa.2013.04.023
PMID: 23632157 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23621186 | 1. Asian Pac J Cancer Prev. 2013;14(2):1057-60. doi:
10.7314/apjcp.2013.14.2.1057.
Identification of serum microRNA-21 as a biomarker for early detection and
prognosis in human epithelial ovarian cancer.
Xu YZ(1), Xi QH, Ge WL, Zhang XQ.
Author information:
(1)Department of Obstetrics and Gynecology, Affiliated Hospital of Nan Tong
University, Nan Tong, Jiangsu, China. manuxiqh@163.com
Recent investigations have confirmed up-regulation of serum miR-21 and its
diagnostic and prognostic value in several human malignancies. In this study, we
examined serum miR-21 levels in epithelial ovarian cancer (EOC) patients, and
explored its association with clinicopathological factors and prognosis. The
results showed significantly higher serum miR-21 levels in EOC patients than in
healthy controls. In addition, increased serum miR-21 expression was correlated
with advanced FIGO stage, high tumor grade, and shortened overall survival.
These findings indicate that serum miR-21 may serve as a novel diagnostic and
prognostic marker, and be used as a therapeutic target for the treatment of EOC.
DOI: 10.7314/apjcp.2013.14.2.1057
PMID: 23621186 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21326934 | 1. Bioeng Bugs. 2010 Mar-Apr;1(2):92-6. doi: 10.4161/bbug.1.2.11102. Epub 2010
Jan 4.
Bioengineered viral vectors for targeting and killing prostate cancer cells.
Zhang KX(1), Jia W, Rennie PS.
Author information:
(1)The Vancouver Prostate Centre, Vancouver, BC, Canada.
Enabling the transduction of therapeutic gene expression exclusively in diseased
sites is the key to developing more effective treatments for advanced prostate
cancer using viral-based therapy. While prostate cancers that express high
levels of HER-2 are resistant to the killing effects of trastuzumab, they can be
targeted for selective gene expression and destruction by lentiviruses with
envelope proteins engineered to bind to this therapeutic antibody. More
importantly, after intravenous injection, this trastuzumab-bound lentivirus is
able to target castration-resistant prostate tumor xenografts, albeit with low
efficiency. This proof of principle opens up multiple possibilities for the
prevention and treatment of prostate cancer using a viral-based therapy.
However, to be safe and more effective, the viral vectors must target prostate
cancer cells more selectively and efficiently. A higher degree of specificity
and efficiency of cancer cell targeting can be achieved by engineering viral
vectors to bind to a specific cell surface marker and by controlling the
expression of the therapeutic payload at transcriptional level, with a
tissue-specific promoter, and at the translational level, with a regulatory
sequences inserted into either the 5'UTR or 3'UTR regions of the therapeutic
gene(s). The latter would be designed to ensure that translation of this mRNA
occurs exclusively in malignant cells. Furthermore, in order to obtain a potent
anti-tumor effect, viral vectors would be engineered to express pro-apoptotic
genes, intra-cellar antibodies/nucleotide aptamers to block critical proteins,
or siRNAs to knockdown essential cellular mRNAs. Alternatively, controlled
expression of an essential viral gene would restore replication competence to
the virus and enable selective oncolysis of tumor cells. Successful delivery of
such bioengineered viruses may provide a more effective way to treat advanced
prostate cancer.
© 2010 Landes Bioscience
DOI: 10.4161/bbug.1.2.11102
PMCID: PMC3026449
PMID: 21326934 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15571968 | 1. Eur J Cancer. 2004 Dec;40(18):2837-44. doi: 10.1016/j.ejca.2004.07.033.
Dual HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and
trastuzumab.
Formento P(1), Hannoun-Levi JM, Fischel JL, Magné N, Etienne-Grimaldi MC, Milano
G.
Author information:
(1)Oncopharmacology Unit, Centre Antoine Lacassagne 33, Avenue de Valombrose,
06189 Nice 2, France.
Epidermal growth factor receptor (EGFR) and HER-2 are associated with a poor
prognosis in various cancers, including prostate cancer. Inhibition of these
receptors may provide a treatment for hormone-refractory prostate cancer. The
presence of HER-2 (Western blot) and EGFR (5830 fmol/mg protein, ligand-binding
assay) was assessed in the hormone-refractory human prostate cancer cell line,
DU-145. Cells were exposed to the selective EGFR-TKI (EGFR tyrosine kinase
inhibitor) gefitinib ('Iressa; ZD1839) and/or the HER-2-targeted monoclonal
antibody trastuzumab ('Herceptin'), for 96 h. Irradiation (RX) at 6 Gy the dose
causing 50% growth inhibition, was applied 48 h after the start of drug
treatment. There was a dose-related effect on cell survival for both ZD1839 and
trastuzumab treatments. Combining ZD1839 and trastuzumab led to less than
additive effects on cell survival. Chou and Talalay representations further
characterised this less than additive effect on cell survival. The application
of ZD1839 led to a marked elevation in the level of the negative regulator of
cell division, p27. The ZD1839-trastuzumab combination had less of an impact on
p27 expression compared with the effect of ZD1839 treatment alone. The lowest
expression of the apoptotic-related protein, Bax, was observed in the presence
of the drug combination. There was a significant interaction (synergism) between
RX and either ZD1839 or trastuzumab treatments. In contrast, the drug
combination with RX resulted in antagonistic cytotoxic effects. These results
indicate an antagonistic interaction between EGFR and HER-2 targeting and
provide molecular mechanisms supporting this observation. Data from DU-145 cells
suggest that dual targeting of EGFR and HER-2 may be inappropriate for the
treatment of hormone-refractory prostate cancer, especially in the context of
their combination with RX.
DOI: 10.1016/j.ejca.2004.07.033
PMID: 15571968 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21742803 | 1. Mol Cell Proteomics. 2011 Jul;10(7):M111.009993. doi: 10.1074/mcp.M111.009993.
The human proteome project: current state and future direction.
Legrain P(1), Aebersold R, Archakov A, Bairoch A, Bala K, Beretta L, Bergeron J,
Borchers CH, Corthals GL, Costello CE, Deutsch EW, Domon B, Hancock W, He F,
Hochstrasser D, Marko-Varga G, Salekdeh GH, Sechi S, Snyder M, Srivastava S,
Uhlén M, Wu CH, Yamamoto T, Paik YK, Omenn GS.
Author information:
(1)CEA, Life Sciences Division, Fontenay-aux-Roses, France.
pierre.legrain@cea.fr
After the successful completion of the Human Genome Project, the Human Proteome
Organization has recently officially launched a global Human Proteome Project
(HPP), which is designed to map the entire human protein set. Given the lack of
protein-level evidence for about 30% of the estimated 20,300 protein-coding
genes, a systematic global effort will be necessary to achieve this goal with
respect to protein abundance, distribution, subcellular localization,
interaction with other biomolecules, and functions at specific time points. As a
general experimental strategy, HPP research groups will use the three working
pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools
and knowledge bases. The HPP participants will take advantage of the output and
cross-analyses from the ongoing Human Proteome Organization initiatives and a
chromosome-centric protein mapping strategy, termed C-HPP, with which many
national teams are currently engaged. In addition, numerous biologically driven
and disease-oriented projects will be stimulated and facilitated by the HPP.
Timely planning with proper governance of HPP will deliver a protein parts list,
reagents, and tools for protein studies and analyses, and a stronger basis for
personalized medicine. The Human Proteome Organization urges each national
research funding agency and the scientific community at large to identify their
preferred pathways to participate in aspects of this highly promising project in
a HPP consortium of funders and investigators.
DOI: 10.1074/mcp.M111.009993
PMCID: PMC3134076
PMID: 21742803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20144262 | 1. Cell Transplant. 2010;19(5):525-36. doi: 10.3727/096368910X491374. Epub 2010
Feb 8.
The efficient generation of induced pluripotent stem (iPS) cells from adult
mouse adipose tissue-derived and neural stem cells.
Tat PA(1), Sumer H, Jones KL, Upton K, Verma PJ.
Author information:
(1)Centre for Reproduction and Development, Monash Institute of Medical
Research, Melbourne, Victoria, Australia.
Ectopic expression of key reprogramming transgenes in somatic cells enables them
to adopt the characteristics of pluripotency. Such cells have been termed
induced pluripotent stem (iPS) cells and have revolutionized the field of
somatic cell reprogramming, as the need for embryonic material is obviated. One
of the issues facing both the clinical translation of iPS cell technology and
the efficient derivation of iPS cell lines in the research laboratory is
choosing the most appropriate somatic cell type for induction. In this study, we
demonstrate the direct reprogramming of a defined population of neural stem
cells (NSCs) derived from the subventricular zone (SVZ) and adipose
tissue-derived cells (ADCs) from adult mice using retroviral transduction of the
Yamanaka factors Oct4, Sox2, Klf4, and c-Myc, and compared the results obtained
with a mouse embryonic fibroblast (mEF) control. We isolated mEFs, NSCs, and
ADCs from transgenic mice, which possess a GFP transgene under control of the
Oct4 promoter, and validated GFP expression as an indicator of reprogramming.
While transduction efficiencies were not significantly different among the
different cell types (mEFs 68.70 +/- 2.62%, ADCs 70.61 +/- 15.4%, NSCs, 68.72
+/- 3%, p = 0.97), the number of GFP-positive colonies and hence the number of
reprogramming events was significantly higher for both NSCs (13.50 +/- 4.10
colonies, 0.13 +/- 0.06%) and ADCs (118.20 +/- 38.28 colonies, 1.14 +/- 0.77%)
when compared with the mEF control (3.17 +/- 0.29 colonies, 0.03 +/- 0.005%).
ADCs were most amenable to reprogramming with an 8- and 38-fold greater
reprogramming efficiency than NSCs and mEFs, respectively. Both NSC iPS and ADC
iPS cells were demonstrated to express markers of pluripotency and could
differentiate to the three germ layers, both in vitro and in vivo, to cells
representative of the three germ lineages. Our findings confirm that ADCs are an
ideal candidate as a readily accessible somatic cell type for high efficiency
establishment of iPS cell lines.
DOI: 10.3727/096368910X491374
PMID: 20144262 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23312004 | 1. J Proteome Res. 2013 Jun 7;12(6):2414-21. doi: 10.1021/pr300825v. Epub 2013
Jan 11.
Identification of missing proteins in the neXtProt database and unregistered
phosphopeptides in the PhosphoSitePlus database as part of the
Chromosome-centric Human Proteome Project.
Shiromizu T(1), Adachi J, Watanabe S, Murakami T, Kuga T, Muraoka S, Tomonaga T.
Author information:
(1)Laboratory of Proteome Research, National Institute of Biomedical Innovation,
Ibaraki, Osaka, Japan.
The Chromosome-Centric Human Proteome Project (C-HPP) is an international effort
for creating an annotated proteomic catalog for each chromosome. The first step
of the C-HPP project is to find evidence of expression of all proteins encoded
on each chromosome. C-HPP also prioritizes particular protein subsets, such as
those with post-translational modifications (PTMs) and those found in low
abundance. As participants in C-HPP, we integrated proteomic and
phosphoproteomic analysis results from chromosome-independent biomarker
discovery research to create a chromosome-based list of proteins and
phosphorylation sites. Data were integrated from five independent colorectal
cancer (CRC) samples (three types of clinical tissue and two types of cell
lines) and lead to the identification of 11,278 proteins, including 8,305
phosphoproteins and 28,205 phosphorylation sites; all of these were categorized
on a chromosome-by-chromosome basis. In total, 3,033 "missing proteins", i.e.,
proteins that currently lack evidence by mass spectrometry, in the neXtProt
database and 12,852 unknown phosphorylation sites not registered in the
PhosphoSitePlus database were identified. Our in-depth phosphoproteomic study
represents a significant contribution to C-HPP. The mass spectrometry proteomics
data have been deposited to the ProteomeXchange Consortium with the data set
identifier PXD000089.
DOI: 10.1021/pr300825v
PMID: 23312004 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22449255 | 1. BMC Cell Biol. 2012 Mar 26;13:9. doi: 10.1186/1471-2121-13-9.
DNp73 improves generation efficiency of human induced pluripotent stem cells.
Lin Y(1), Cheng Z, Yang Z, Zheng J, Lin T.
Author information:
(1)Stem Cell Research Center, Fujian Agriculture and Forestry University,
Cangshan District, Fuzhou, Fujian, PR China.
BACKGROUND: Recent studies have found that p53 and its' associated cell cycle
pathways are major inhibitors of human induced pluripotent stem (iPS) cell
generation. In the same family as p53 is p73, which shares sequence similarities
with p53. However, p73 also has distinct properties of its own, such as two
alternative promoters to express transactivation of p73 (TAp73) and N terminal
deleted p73 (DNp73). Functionally, TAp73 acts similarly to p53 in tumor
suppression. However, DNp73, on the other hand acts as an oncogene to suppress
p53 and p73 induced apoptosis. Therefore, how can p73 have opposing roles in
human iPS cell generation?
RESULTS: Transcription factors, Oct4, Sox2, Klf4 and cMyc (4TF, Yamanaka
factors) are used as basal conditions to generate iPS cells. In addition, the
factor of DNp73(actually alpha splicing DNp73, DNp73α) is used to generate iPS
cells. The experiment found that the addition of DNp73 gene increases human iPS
cell generation efficiency by 12.6 folds in comparison to human fibroblast cells
transduced with only the basal conditions. Also, iPS cells generated with DNp73
expression are more resistant to in vitro and in vivo differentiation.
CONCLUSIONS: This study found DNp73, a family member of p53, is also involved in
the human iPS cell generation. Specifically, that the involvement of DNp73
generates iPS cells that are more resistant to in vitro and in vivo
differentiation. Therefore, this data may prove to be useful in future
developmental studies and cancer researches.
DOI: 10.1186/1471-2121-13-9
PMCID: PMC3348002
PMID: 22449255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23205526 | 1. J Proteome Res. 2013 Jan 4;12(1):293-8. doi: 10.1021/pr300830v. Epub 2012 Dec
3.
neXtProt: organizing protein knowledge in the context of human proteome
projects.
Gaudet P(1), Argoud-Puy G, Cusin I, Duek P, Evalet O, Gateau A, Gleizes A,
Pereira M, Zahn-Zabal M, Zwahlen C, Bairoch A, Lane L.
Author information:
(1)CALIPHO Group, SIB-Swiss Institute of Bioinformatics, Faculty of Medicine,
University of Geneva, CMU-1, rue Michel Servet 1211 Geneva 4, Switzerland.
About 5000 (25%) of the ~20400 human protein-coding genes currently lack any
experimental evidence at the protein level. For many others, there is only
little information relative to their abundance, distribution, subcellular
localization, interactions, or cellular functions. The aim of the HUPO Human
Proteome Project (HPP, www.thehpp.org ) is to collect this information for every
human protein. HPP is based on three major pillars: mass spectrometry (MS),
antibody/affinity capture reagents (Ab), and bioinformatics-driven knowledge
base (KB). To meet this objective, the Chromosome-Centric Human Proteome Project
(C-HPP) proposes to build this catalog chromosome-by-chromosome ( www.c-hpp.org
) by focusing primarily on proteins that currently lack MS evidence or Ab
detection. These are termed "missing proteins" by the HPP consortium. The lack
of observation of a protein can be due to various factors including incorrect
and incomplete gene annotation, low or restricted expression, or instability.
neXtProt ( www.nextprot.org ) is a new web-based knowledge platform specific for
human proteins that aims to complement UniProtKB/Swiss-Prot ( www.uniprot.org )
with detailed information obtained from carefully selected high-throughput
experiments on genomic variation, post-translational modifications, as well as
protein expression in tissues and cells. This article describes how neXtProt
contributes to prioritize C-HPP efforts and integrates C-HPP results with other
research efforts to create a complete human proteome catalog.
DOI: 10.1021/pr300830v
PMID: 23205526 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21249204 | 1. PLoS One. 2011 Jan 13;6(1):e16182. doi: 10.1371/journal.pone.0016182.
Generation of human melanocytes from induced pluripotent stem cells.
Ohta S(1), Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, Amagai M,
Matsuzaki Y, Yamanaka S, Okano H, Kawakami Y.
Author information:
(1)Division of Cellular Signaling, Institute for Advanced Medical Research, Keio
University School of Medicine, Tokyo, Japan.
Epidermal melanocytes play an important role in protecting the skin from UV
rays, and their functional impairment results in pigment disorders.
Additionally, melanomas are considered to arise from mutations that accumulate
in melanocyte stem cells. The mechanisms underlying melanocyte differentiation
and the defining characteristics of melanocyte stem cells in humans are,
however, largely unknown. In the present study, we set out to generate
melanocytes from human iPS cells in vitro, leading to a preliminary
investigation of the mechanisms of human melanocyte differentiation. We
generated iPS cell lines from human dermal fibroblasts using the Yamanaka
factors (SOX2, OCT3/4, and KLF4, with or without c-MYC). These iPS cell lines
were subsequently used to form embryoid bodies (EBs) and then differentiated
into melanocytes via culture supplementation with Wnt3a, SCF, and ET-3. Seven
weeks after inducing differentiation, pigmented cells expressing melanocyte
markers such as MITF, tyrosinase, SILV, and TYRP1, were detected. Melanosomes
were identified in these pigmented cells by electron microscopy, and global gene
expression profiling of the pigmented cells showed a high similarity to that of
human primary foreskin-derived melanocytes, suggesting the successful generation
of melanocytes from iPS cells. This in vitro differentiation system should prove
useful for understanding human melanocyte biology and revealing the mechanism of
various pigment cell disorders, including melanoma.
DOI: 10.1371/journal.pone.0016182
PMCID: PMC3020956
PMID: 21249204 [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/23939864 | 1. Stem Cells. 2013 Nov;31(11):2364-73. doi: 10.1002/stem.1507.
Artd1/Parp1 regulates reprogramming by transcriptional regulation of Fgf4 via
Sox2 ADP-ribosylation.
Weber FA(1), Bartolomei G, Hottiger MO, Cinelli P.
Author information:
(1)Institute of Laboratory Animal Science, University of Zurich, Zurich,
Switzerland; Life Science Zurich Graduate School, University of Zurich, Zurich,
Switzerland.
The recently established reprogramming of somatic cells into induced pluripotent
stem cells (iPSCs) by Takahashi and Yamanaka represents a valuable tool for
future therapeutic applications. To date, the mechanisms underlying this process
are still largely unknown. In particular, the mechanisms how the Yamanaka
factors (Oct4, Sox2, Klf4, and c-Myc) directly drive reprogramming and which
additional components are involved are still not yet understood. In this study,
we aimed at analyzing the role of ADP-ribosyltransferase diphtheria toxin-like
one (Artd1; formerly called poly(ADP-ribose) polymerase 1 [Parp1]) during
reprogramming. We found that poly(ADP-ribosylation) (PARylation) of the
reprogramming factor Sox2 by Artd1 plays an important role during the first days
upon transduction with the reprogramming factors. A process that happens before
Artd1 in conjunction with 10-11 translocation-2 (Tet2) mediates the histone
modifications necessary for the establishment of an activated chromatin state at
pluripotency loci (e.g., Nanog and Essrb) [Nature 2012;488:652-655]. Wild-type
(WT) fibroblasts treated with an Artd1 inhibitor as well as fibroblasts
deficient for Artd1 (Artd1-/-) show strongly decreased reprogramming capacity.
Our data indicate that Artd1-mediated PARylation of Sox2 favors its binding to
the fibroblast growth factor 4 (Fgf4) enhancer, thereby activating Fgf4
expression. The importance of Fgf4 during the first 4 days upon initiation of
reprogramming was also highlighted by the observation that exogenous addition of
Fgf4 was sufficient to restore the reprogramming capacity of Artd1-/- fibroblast
to WT levels. In conclusion, our data clearly show that the interaction between
Artd1 and Sox2 is crucial for the first steps of the reprogramming process and
that early expression of Fgf4 (day 2 to day 4) is an essential component for the
successful generation of iPSCs.
Copyright © 2013 AlphaMed Press.
DOI: 10.1002/stem.1507
PMID: 23939864 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23276153 | 1. J Proteome Res. 2013 Jun 7;12(6):2439-48. doi: 10.1021/pr300924j. Epub 2012
Dec 31.
Contribution of antibody-based protein profiling to the human Chromosome-centric
Proteome Project (C-HPP).
Fagerberg L(1), Oksvold P, Skogs M, Algenäs C, Lundberg E, Pontén F, Sivertsson
A, Odeberg J, Klevebring D, Kampf C, Asplund A, Sjöstedt E, Al-Khalili Szigyarto
C, Edqvist PH, Olsson I, Rydberg U, Hudson P, Ottosson Takanen J, Berling H,
Björling L, Tegel H, Rockberg J, Nilsson P, Navani S, Jirström K, Mulder J,
Schwenk JM, Zwahlen M, Hober S, Forsberg M, von Feilitzen K, Uhlén M.
Author information:
(1)Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm,
Sweden.
A gene-centric Human Proteome Project has been proposed to characterize the
human protein-coding genes in a chromosome-centered manner to understand human
biology and disease. Here, we report on the protein evidence for all genes
predicted from the genome sequence based on manual annotation from literature
(UniProt), antibody-based profiling in cells, tissues and organs and analysis of
the transcript profiles using next generation sequencing in human cell lines of
different origins. We estimate that there is good evidence for protein existence
for 69% (n = 13985) of the human protein-coding genes, while 23% have only
evidence on the RNA level and 7% still lack experimental evidence. Analysis of
the expression patterns shows few tissue-specific proteins and approximately
half of the genes expressed in all the analyzed cells. The status for each gene
with regards to protein evidence is visualized in a chromosome-centric manner as
part of a new version of the Human Protein Atlas ( www.proteinatlas.org ).
DOI: 10.1021/pr300924j
PMID: 23276153 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17210707 | 1. Cancer Res. 2007 Jan 1;67(1):269-75. doi: 10.1158/0008-5472.CAN-06-2731.
Anti-HER2 cationic immunoemulsion as a potential targeted drug delivery system
for the treatment of prostate cancer.
Goldstein D(1), Gofrit O, Nyska A, Benita S.
Author information:
(1)Pharmaceutics Department, The School of Pharmacy, The Hebrew University of
Jerusalem, Jerusalem 91120, Israel.
Present management of metastatic prostate cancer, which includes hormonal
therapy, chemotherapy, and radiotherapy, are frequently palliative. Taxanes, and
specifically docetaxel, are being extensively investigated to improve the
survival of metastatic prostate cancer patients. Although paclitaxel exhibits a
wide spectrum of antitumor activity, its therapeutic application is limited, in
part, due to its low water solubility that necessitates the use of Cremophor EL,
which is known to induce hypersensitivity reactions. Therefore, the objective of
this present study was to assess the efficiency of paclitaxel palmitate-loaded
anti-HER2 immunoemulsions, a targeted drug delivery system based on cationic
emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a
well-established in vivo pharmacologic model of metastatic prostate cancer that
overexpresses the HER2 receptor. It was clearly noted that the cationic emulsion
and immunoemulsion did not activate the complement compared with the commercial
and paclitaxel palmitate hydroalcoholic formulations. In addition, 10 mg/kg of
paclitaxel palmitate-loaded immunoemulsion once weekly over 3 weeks inhibits the
tumor growth in severe combined immunodeficient mice much more than the cationic
emulsion (P < 0.05) and the paclitaxel palmitate formulation (P < 0.01). The
histopathologic analysis suggested a therapeutic improvement trend in favor of
the immunoemulsion. However, there was no significant difference in
antimetastatic activity between the emulsion and the immunoemulsion despite the
affinity of the immunoemulsion towards the HER2 receptor. Although the tumor
growth was not fully inhibited, the actual results are encouraging and may lead
to an improved therapeutic strategy of metastatic prostate cancer treatment.
DOI: 10.1158/0008-5472.CAN-06-2731
PMID: 17210707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21978946 | 1. Bioorg Med Chem. 2011 Nov 1;19(21):6383-99. doi: 10.1016/j.bmc.2011.08.066.
Epub 2011 Sep 1.
Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a
highly selective 17,20-lyase inhibitor with potential utility in the treatment
of prostate cancer.
Kaku T(1), Hitaka T, Ojida A, Matsunaga N, Adachi M, Tanaka T, Hara T, Yamaoka
M, Kusaka M, Okuda T, Asahi S, Furuya S, Tasaka A.
Author information:
(1)CNS Drug Discovery Unit, Takeda Pharmaceutical Company, Ltd., Shonan Research
Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan.
Kaku_Tomohiro@takeda.co.jp
A novel naphthylmethylimidazole derivative 1 and its related compounds were
identified as 17,20-lyase inhibitors. Based on the structure-activity
relationship around the naphthalene scaffold and the results of a docking study
of 1a in the homology model of 17,20-lyase, the
6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and
identified as a potent and highly selective 17,20-lyase inhibitor. Biological
evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked
reductions in both serum testosterone and dehydroepiandrosterone concentrations.
Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for
clinical evaluation and is currently in phase III clinical trials for the
treatment of castration-resistant prostate cancer.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.bmc.2011.08.066
PMID: 21978946 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8824885 | 1. Hum Mol Genet. 1996 Feb;5(2):283-92. doi: 10.1093/hmg/5.2.283.
Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase
activity induces features of cellular senescence and this effect is mediated by
hydrogen peroxide.
de Haan JB(1), Cristiano F, Iannello R, Bladier C, Kelner MJ, Kola I.
Author information:
(1)Institute of Reproduction and Development, Monash University, Clayton,
Victoria, Australia.
Although reactive oxygen species have been proposed to play a major role in the
aging process, the exact molecular mechanisms remain elusive. In this study we
investigate the effects of a perturbation in the ratio of Cu/Zn-superoxide
dismutase activity (Sod1 dismutases .O2-to H2O2) to glutathione peroxidase
activity (Gpx1 catalyses H2O2 conversion to H2O) on cell growth and development.
Our data demonstrate that Sod1 transfected cell lines that have an elevation in
the ratio of Sod1 activity to Gpx1 activity produce higher levels of H2O2 and
exhibit well characterised markers of cellular senescence viz. slower
proliferation and altered morphology. On the contrary, Sod1 transfected cell
lines that have an unaltered ratio in the activity of these two enzymes, have
unaltered levels of H2O2 and fail to show characteristics of senescence.
Furthermore, fibroblasts established from individuals with Down syndrome have an
increase in the ratio of Sod1 to Gpx1 activity compared with corresponding
controls and senesce earlier. Interestingly, cells treated with H2O2 also show
features of senescence and/or senesce earlier. We also show that Cip1 mRNA
levels are elevated in Down syndrome cells, Sod1 transfectants with an altered
Sod1 to Gpx1 activity ratio and those treated with H2O2, thus suggesting that
the slow proliferation may be mediated by Cip1. Furthermore, our data
demonstrate that Cip1 mRNA levels are induced by exposure of cells to H2O2.
These data give valuable insight into possible molecular mechanisms that
contribute tribute to cellular senescence and may be useful in the evolution of
therapeutic strategies for aging.
DOI: 10.1093/hmg/5.2.283
PMID: 8824885 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25624429 | 1. J Clin Oncol. 2015 Mar 1;33(7):723-31. doi: 10.1200/JCO.2014.56.5119. Epub
2015 Jan 26.
Phase III, randomized, double-blind, multicenter trial comparing orteronel
(TAK-700) plus prednisone with placebo plus prednisone in patients with
metastatic castration-resistant prostate cancer that has progressed during or
after docetaxel-based therapy: ELM-PC 5.
Fizazi K(1), Jones R(2), Oudard S(2), Efstathiou E(2), Saad F(2), de Wit R(2),
De Bono J(2), Cruz FM(2), Fountzilas G(2), Ulys A(2), Carcano F(2), Agarwal
N(2), Agus D(2), Bellmunt J(2), Petrylak DP(2), Lee SY(2), Webb IJ(2), Tejura
B(2), Borgstein N(2), Dreicer R(2).
Author information:
(1)Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif;
Stephane Oudard, Université Paris Descartes, Paris, France; Robert Jones,
Institute of Cancer Sciences, University of Glasgow, Glasgow; Johann De Bono,
The Institute of Cancer Research, London, United Kingdom; Eleni Efstathiou,
University of Athens Medical School, Athens; George Fountzilas, Aristotle
University of Thessaloniki School of Medicine, Thessaloniki, Greece; Fred Saad,
University of Montreal Hospital Center, Montreal, Canada; Ronald de Wit, Erasmus
University Medical Center, Rotterdam, the Netherlands; Felipe Melo Cruz, ABC
Foundation School of Medicine, Santo André; Flavio Carcano, Hospital de Cancer
de Barretos, Barretos, Brazil; Albertas Ulys, Institut of Oncology, Vilnius
University, Vilnius, Lithuania; Neeraj Agarwal, Huntsman Cancer Institute,
University of Utah, Salt Lake City, UT; David Agus, University of Southern
California, Los Angeles, CA; Daniel P. Petrylak, Yale University Cancer Center,
New Haven, CT; Shih-Yuan Lee, Bindu Tejura, Niels Borgstein, Takeda
Pharmaceuticals International; Iain J. Webb, Millennium: The Takeda Oncology
Company, Cambridge, MA; Robert Dreicer, Cleveland Clinic, Cleveland, OH; Joaquim
Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain.
karim.fizazi@gustaveroussy.fr.
(2)Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif;
Stephane Oudard, Université Paris Descartes, Paris, France; Robert Jones,
Institute of Cancer Sciences, University of Glasgow, Glasgow; Johann De Bono,
The Institute of Cancer Research, London, United Kingdom; Eleni Efstathiou,
University of Athens Medical School, Athens; George Fountzilas, Aristotle
University of Thessaloniki School of Medicine, Thessaloniki, Greece; Fred Saad,
University of Montreal Hospital Center, Montreal, Canada; Ronald de Wit, Erasmus
University Medical Center, Rotterdam, the Netherlands; Felipe Melo Cruz, ABC
Foundation School of Medicine, Santo André; Flavio Carcano, Hospital de Cancer
de Barretos, Barretos, Brazil; Albertas Ulys, Institut of Oncology, Vilnius
University, Vilnius, Lithuania; Neeraj Agarwal, Huntsman Cancer Institute,
University of Utah, Salt Lake City, UT; David Agus, University of Southern
California, Los Angeles, CA; Daniel P. Petrylak, Yale University Cancer Center,
New Haven, CT; Shih-Yuan Lee, Bindu Tejura, Niels Borgstein, Takeda
Pharmaceuticals International; Iain J. Webb, Millennium: The Takeda Oncology
Company, Cambridge, MA; Robert Dreicer, Cleveland Clinic, Cleveland, OH; Joaquim
Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain.
Comment in
J Clin Oncol. 2015 Mar 1;33(7):679-81. doi: 10.1200/JCO.2014.59.4309.
Nat Rev Urol. 2015 May;12(5):245-6. doi: 10.1038/nrurol.2015.66.
J Clin Oncol. 2015 Oct 1;33(28):3222-3. doi: 10.1200/JCO.2015.62.4692.
J Clin Oncol. 2015 Oct 1;33(28):3222. doi: 10.1200/JCO.2015.62.4684.
J Clin Oncol. 2015 Oct 1;33(28):3221. doi: 10.1200/JCO.2015.62.3165.
J Urol. 2015 Oct;194(4):990. doi: 10.1016/j.juro.2015.07.010.
PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible,
selective 17,20-lyase inhibitor. This study examined orteronel in patients with
metastatic castration-resistant prostate cancer that progressed after docetaxel
therapy.
PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1
schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo
plus prednisone 5 mg twice daily, stratified by region (Europe, North America
[NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score.
Primary end point was overall survival (OS). Key secondary end points
(radiographic progression-free survival [rPFS], ≥ 50% decrease of
prostate-specific antigen [PSA50], and pain response at 12 weeks) were to
undergo statistical testing only if the primary end point analysis was
significant.
RESULTS: The study was unblinded after crossing a prespecified OS futility
boundary. The median OS was 17.0 months versus 15.2 months with
orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95%
CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with
orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to
0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone
in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v
2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse
events (all grades) were generally more frequent with orteronel-prednisone,
including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and
increased amylase (14% v 2%).
CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and
a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.
© 2015 by American Society of Clinical Oncology.
DOI: 10.1200/JCO.2014.56.5119
PMCID: PMC4879718
PMID: 25624429 [Indexed for MEDLINE]
Conflict of interest statement: Authors' disclosures of potential conflicts of
interest are found in the article online at www.jco.org. Author contributions
are found at the end of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/21254978 | 1. Curr Med Chem. 2011;18(7):943-63. doi: 10.2174/092986711794940824.
Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors.
Cruz-López O(1), Conejo-García A, Núñez MC, Kimatrai M, García-Rubiño ME,
Morales F, Gómez-Pérez V, Campos JM.
Author information:
(1)Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/
Campus de Cartuja s/n, 18071 Granada, Spain. jmcampos@ugr.es
The type I receptor tyrosine kinases (RTKs) are involved in various aspects of
cell growth, survival, and differentiation. Among the known RTKs, the epidermal
growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins
that are prototypic members of the ErbB family which also includes ErbB-3
(Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been
associated with aggressive disease and poor patient prognosis in a range of
human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma
of head and neck). Disruption of signal transduction of these kinases has been
shown to have an antiproliferative effect. Various approaches have been
developed to target the ErbB signalling pathways including monoclonal antibodies
(trastuzumab/Herceptin™ and cetuximab/Erbitux™) directed against the receptor,
and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and
erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous
targeting of multiple ErbB receptors therefore becomes a promising approach to
cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was
approved for the treatment of ErbB-2-positive breast cancer. Despite years of
intensive research on EGFR inhibitors, there is a surprising dearth of
chemically distinct small inhibitors with a high degree of selectivity. There is
also a need for new scaffolds due to the recent finding of EGFR mutations which
render the kinase resistant to gefinitib and erlotinib. The structures under
study will be quinazolines with different substituents. The structure-activity
relationships and biological evaluation of compounds published during the last
four years will be reviewed herein.
DOI: 10.2174/092986711794940824
PMID: 21254978 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15036648 | 1. Cancer Lett. 2004 Mar 18;205(2):161-71. doi: 10.1016/j.canlet.2003.10.035.
Cytotoxicity of human prostate cancer cell lines in vitro and induction of
apoptosis using 213Bi-Herceptin alpha-conjugate.
Li Y(1), Cozzi PJ, Qu CF, Zhang DY, Abbas Rizvi SM, Raja C, Allen BJ.
Author information:
(1)Center for Experimental Radiation Oncology, Cancer Care Center, St George
Hospital, Gray St, Kogarah 2217, New South Wales, Australia.
HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and
is the target of a new treatment for metastatic breast cancer using the
humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a
novel alpha-particle emitting [213Bi]Herceptin construct, which targets the
HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We
used immunocytochemistry, flow cytometry and Western blot analysis to examine
the expression of HER-2 in a panel of established human CaP cell lines, used the
MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines
and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3
cells express high levels of HER-2 protein, in contrast, DU 145 cells express
low to medium levels, and PC-3 cells express an undetectable level of HER-2
protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a
concentration-dependent fashion, cause the cells to undergo apoptosis, whereas
DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity.
In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity.
The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by
incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin
alpha-conjugate might be a promising new agent for the treatment of
preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2
expression.
DOI: 10.1016/j.canlet.2003.10.035
PMID: 15036648 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23214983 | 1. J Proteome Res. 2013 Jan 4;12(1):308-15. doi: 10.1021/pr300996x. Epub 2012 Dec
13.
Tryptic peptide reference data sets for MALDI imaging mass spectrometry on
formalin-fixed ovarian cancer tissues.
Meding S(1), Martin K, Gustafsson OJ, Eddes JS, Hack S, Oehler MK, Hoffmann P.
Author information:
(1)Adelaide Proteomics Centre, School of Molecular and Biomedical Science, The
University of Adelaide, SA 5005, Adelaide, Australia.
MALDI imaging mass spectrometry is a powerful tool for morphology-based
proteomic tissue analysis. However, peptide identification is still a major
challenge due to low S/N ratios, low mass accuracy and difficulties in
correlating observed m/z species with peptide identities. To address this, we
have analyzed tryptic digests of formalin-fixed paraffin-embedded tissue
microarray cores, from 31 ovarian cancer patients, by LC-MS/MS. The sample
preparation closely resembled the MALDI imaging workflow in order to create
representative reference data sets containing peptides also observable in MALDI
imaging experiments. This resulted in 3844 distinct peptide sequences, at a
false discovery rate of 1%, for the entire cohort and an average of 982 distinct
peptide sequences per sample. From this, a total of 840 proteins and, on
average, 297 proteins per sample could be inferred. To support the efforts of
the Chromosome-centric Human Proteome Project Consortium, we have annotated
these proteins with their respective chromosome location. In the presented work,
the benefit of using a large cohort of data sets was exemplified by correct
identification of several m/z species observed in a MALDI imaging experiment.
The tryptic peptide data sets generated will facilitate peptide identification
in future MALDI imaging studies on ovarian cancer.
DOI: 10.1021/pr300996x
PMID: 23214983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23234512 | 1. J Proteome Res. 2013 Jan 4;12(1):112-22. doi: 10.1021/pr300898u. Epub 2012 Dec
12.
Spanish human proteome project: dissection of chromosome 16.
Segura V(1), Medina-Aunon JA, Guruceaga E, Gharbi SI, González-Tejedo C, Sánchez
del Pino MM, Canals F, Fuentes M, Casal JI, Martínez-Bartolomé S, Elortza F,
Mato JM, Arizmendi JM, Abian J, Oliveira E, Gil C, Vivanco F, Blanco F, Albar
JP, Corrales FJ.
Author information:
(1)ProteoRed-ISCIII, Center for Applied Medical Research, CIMA, University of
Navarra, Pamplona, Spain.
The Chromosome 16 Consortium forms part of the Human Proteome Project that aims
to develop an entire map of the proteins encoded by the human genome following a
chromosome-centric strategy (C-HPP) to make progress in the understanding of
human biology in health and disease (B/D-HPP). A Spanish consortium of 16
laboratories was organized into five working groups: Protein/Antibody
microarrays, protein expression and Peptide Standard, S/MRM, Protein Sequencing,
Bioinformatics and Clinical healthcare, and Biobanking. The project is conceived
on a multicenter configuration, assuming the standards and integration
procedures already available in ProteoRed-ISCIII, which is encompassed within
HUPO initiatives. The products of the 870 protein coding genes in chromosome 16
were analyzed in Jurkat T lymphocyte cells, MCF-7 epithelial cells, and the
CCD18 fibroblast cell line as it is theoretically expected that most chromosome
16 protein coding genes are expressed in at least one of these. The
transcriptome and proteome of these cell lines was studied using gene expression
microarray and shotgun proteomics approaches, indicating an ample coverage of
chromosome 16. With regard to the B/D section, the main research areas have been
adopted and a biobanking initiative has been designed to optimize methods for
sample collection, management, and storage under normalized conditions and to
define QC standards. The general strategy of the Chr-16 HPP and the current
state of the different initiatives are discussed.
DOI: 10.1021/pr300898u
PMID: 23234512 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14981003 | 1. Circulation. 2004 Apr 6;109(13):1674-9. doi:
10.1161/01.CIR.0000118464.48959.1C. Epub 2004 Feb 23.
Long-term heart rate reduction induced by the selective I(f) current inhibitor
ivabradine improves left ventricular function and intrinsic myocardial structure
in congestive heart failure.
Mulder P(1), Barbier S, Chagraoui A, Richard V, Henry JP, Lallemand F, Renet S,
Lerebours G, Mahlberg-Gaudin F, Thuillez C.
Author information:
(1)INSERM U644, UFR de Médecine et de Pharmacie, Rouen, France.
BACKGROUND: Heart rate reduction (HRR) improves left ventricular (LV) filling,
increases myocardial O2 supply, and reduces myocardial O2 consumption, which are
all beneficial in congestive heart failure (CHF). However, the long-term effects
of HRR on cardiac function and remodeling are unknown.
METHODS AND RESULTS: We assessed, in rats with CHF, the effects of long-term HRR
induced by the selective I(f) current inhibitor ivabradine (as food admix for 90
days starting 7 days after coronary artery ligation). To assess intrinsic
modifications of LV tissue induced by long-term HRR, all parameters were
reassessed 3 days after interruption of treatment. Ivabradine decreased heart
rate over the 90-day treatment period (-18% versus untreated at 10 mg x kg(-1) x
d(-1)), without modifying blood pressure, LV end-diastolic pressure, or
dP/dt(max/min). Ivabradine significantly reduced LV end-systolic but not
end-diastolic diameter, which resulted in preserved cardiac output due to
increased stroke volume. In the Langendorff preparation, ivabradine shifted LV
systolic but not end-diastolic pressure-volume relations to the left. Ivabradine
decreased LV collagen density and increased LV capillary density without
modifying LV weight. Three days after interruption of treatment, the effects of
ivabradine on LV geometry, shortening, and stroke volume persisted despite
normalization of heart rate.
CONCLUSIONS: In rats with CHF, long-term HRR induced by the selective I(f)
inhibitor ivabradine improves LV function and increases stroke volume,
preserving cardiac output despite the HRR. The improvement of cardiac function
is related not only to the HRR per se but also to modifications in the
extracellular matrix and/or function of myocytes as a consequence of long-term
HRR.
DOI: 10.1161/01.CIR.0000118464.48959.1C
PMID: 14981003 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19129742 | 1. J Cardiovasc Pharmacol. 2009 Jan;53(1):9-17. doi:
10.1097/FJC.0b013e318193dfce.
Effects of ivabradine and metoprolol on cardiac angiogenesis and endothelial
dysfunction in rats with heart failure.
Ulu N(1), Henning RH, Goris M, Schoemaker RG, van Gilst WH.
Author information:
(1)Departments of Clinical Pharmacology, University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands. n.ulu@med.umcg.nl
Myocardial infarction (MI)-induced remodeling is associated with disturbed
myocardial perfusion through vascular changes, such as reduced capillary density
and endothelial dysfunction. Heart rate reduction (HRR) initiated immediately
after MI stimulates angiogenesis and attenuates left ventricular dysfunction. We
aimed to investigate the effects of long-term HRR on cardiac angiogenesis and
endothelial function in a rat model of post-MI heart failure. Rats received
early or late ivabradine or metoprolol for 12 or 9 weeks, respectively, and
compared with untreated MI and sham animals 12 weeks after MI. Heart rate was
measured in the conscious rat. MI resulted in an increased heart weight to body
weight ratio, a decline in capillary density and a marked reduction in
acetylcholine-induced relaxation. Early and late HRR by either ivabradine or
metoprolol significantly increased capillary to myocyte ratio. Moreover, this
ratio was significantly correlated to heart rate (r = -0.324 and P = 0.036).
Neither early nor late chronic HRR prevented endothelial dysfunction, except a
moderate improvement in late MI ivabradine group. In MI rats, HRR either by
ivabradine or metoprolol treatment increases cardiac angiogenesis. Late HRR
strategy was comparable to early HRR, suggesting that the beneficial effects are
independent of the time of onset of therapy after MI.
DOI: 10.1097/FJC.0b013e318193dfce
PMID: 19129742 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22416440 | 1. Ter Arkh. 2011;83(12):19-26.
[Efficacy of ivabradin in combined treatment of patients with postinfarction
systolic chronic cardiac failure].
[Article in Russian]
Potapenko AV, Abdulazizov OSh, Diachuk LI, Kiiakbaev GK, Kobalava ZhD, Moiseev
VS.
AIM: To study effects of ivabradin on clinicohemodynamic and prognostic
parameters in patients after myocardial infarction (MI) with systolic chronic
cardiac failure (SCCF).
MATERIAL AND METHODS: A population-based randomized prospective trial enrolled
49 patients (40 males--81.6%, mean age 63.1 +/- 8.1 years) with sinus rhythm and
a longer than 3 month history of MI. The patients were randomized into 2 groups:
23 patients of group 1 received standard treatment plus ivabradin, 26 patients
of group 2 received standard treatment alone. Follow-up was 36.1 +/- 6.2 months.
We analysed the trend in heart rate (HR), blood pressure (BP), parameters of
echocardiography, ECG, levels of electrolytes, creatinin in blood plasma,
frequency of hospitalizations, recurrent non-fatal MI and lethality (combined
endpoint).
RESULTS: In the end of the trial ivabradin significantly decreased HR from 71 to
64 b/m. Frequency of combined end point of efficacy was 30.4 and 50% in group 1
and 2, respectively. In group 1 primary end point in high baseline HR occurred
more frequently than in HR < 70 b/m in 6 (50%) and 1 (9.1%) cases, respectively,
but these differences were not significant (p = 0.068). In group 2 the
differences were significant--9 (90%) and 4 (25%) cases, respectively (p =
0.004). By none of the parameters of ECG, plasma electrolytes, creatinine level
significant intergroup differences were found.
CONCLUSION: In the same trend in BP and ECG, group 1 patients showed significant
and more pronounced HR lowering than group 2 patients. Addition of ivabradin to
standard treatment of SCCF after MI promoted less frequency of hospitalizations,
recurrent non-fatal MI, fatal cardiovascular events. This effect was especially
strong in high baseline HR.
PMID: 22416440 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23294030 | 1. Int J Radiat Biol. 2013 May;89(5):346-55. doi: 10.3109/09553002.2013.762136.
Epub 2013 Feb 27.
Inhibitory effects of Rhenium-188-labeled Herceptin on prostate cancer cell
growth: a possible radioimmunotherapy to prostate carcinoma.
Wang HY(1), Lin WY, Chen MC, Lin T, Chao CH, Hsu FN, Lin E, Huang CY, Luo TY,
Lin H.
Author information:
(1)Department of Life Sciences, National Chung Hsing University, Taichung,
Taiwan.
PURPOSE: Herceptin is widely used in treating Her2-overexpressing breast cancer.
However, the application of Herceptin in prostate cancer is still controversial.
Our previous results have indicated the relevance of Her2 in the transition of
the androgen requirement in prostate cancer cells. In this study, the effects of
radioimmunotherapy against Her2 in prostate cancer were investigated.
MATERIALS AND METHODS: DU145, an androgen receptor-negative prostate cancer cell
line, was used in vitro and in vivo to evaluate the effects of Herceptin labeled
with a beta emitter, Rhenium-188 (Re-188). Its effects on cell growth, extent of
apoptosis, the bio-distribution of Re-188 labeled Herceptin (Re-H), and protein
levels were determined.
RESULTS: Treatments with Re-188 and Re-H reduced the proliferation of DU145
cells in dose- and time-dependent manners compared to the Herceptin-treated
group. Growth inhibition and apoptosis were induced after Re-H treatment; growth
inhibition was more distinct in cells with high Her2/p-Her2 levels. Our in vivo
xenograft studies revealed that Re-H treatment significantly retarded tumor
growth and altered the levels of apoptosis-related proteins. The
bio-distribution of Re-H in mice demonstrated a tissue-specific pattern.
Importantly, the levels of p35 protein, which is related to cancer cell survival
and invasion, dramatically decreased after Re-H treatment.
CONCLUSIONS: Our data demonstrate that Re-188-labeled Herceptin effectively
inhibited the growth of DU145 cells compared to the Herceptin- and
Re-188-treated cohorts. This implies that targeting Her2 by both radio- and
immuno- therapy might be a potential strategy for treating patients with
androgen-independent prostate cancer.
DOI: 10.3109/09553002.2013.762136
PMID: 23294030 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11685722 | 1. Semin Oncol. 2001 Aug;28(4 Suppl 15):3-7. doi: 10.1016/s0093-7754(01)90148-4.
Preclinical mechanisms of action of docetaxel and docetaxel combinations in
prostate cancer.
Pienta KJ(1).
Author information:
(1)Department of Internal Medicine, Division of Hematology/Oncology, University
of Michigan, Ann Arbor, MI 48109-0946, USA.
Docetaxel, a semisynthetic taxane, has exhibited significant single-agent
activity against prostatic tumors. In phase I/II studies, single-agent docetaxel
and the combination of docetaxel plus estramustine were effective in inducing
prostate-specific antigen reductions of > or =50% in men with
androgen-independent prostate cancer (AIPC). The underlying reason for
docetaxel's clinical activity against prostate cancer has been a focus of
ongoing research. Docetaxel is believed to have a twofold mechanism of
antineoplastic activity: (1) inhibition of microtubular depolymerization, and
(2) attenuation of the effects of bcl-2 and bcl-xL gene expression.
Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the
cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of
events that ultimately leads to apoptotic cell death. In preclinical studies,
docetaxel had a higher affinity for tubulin and was shown to be a more potent
inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also
supports the clinical evaluation of docetaxel-based combinations that include
agents such as trastuzumab and/or estramustine. The pathways for
docetaxel-induced apoptosis appear to differ in androgen-dependent and
androgen-independent prostate cancer cells. Further elucidation of these
differences will be instrumental in designing targeted regimens for the
treatment of localized and advanced prostate cancer.
Copyright 2001 by W.B. Saunders Company.
DOI: 10.1016/s0093-7754(01)90148-4
PMID: 11685722 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25007779 | 1. Fish Shellfish Immunol. 2014 Sep;40(1):164-73. doi: 10.1016/j.fsi.2014.06.034.
Epub 2014 Jul 5.
ATP release channel Pannexin1 is a novel immune response gene in Japanese
flounder Paralichthys olivaceus.
Li S(1), Li X(2), Chen X(2), Geng X(3), Sun J(4).
Author information:
(1)Tianjin Key Laboratory of Animal and Plant Resistance, College of Life
Sciences, Tianjin Normal University, 393 Binshuixidao, Xiqing District, Tianjin
300387, China. Electronic address: shuo1128@gmail.com.
(2)Tianjin Key Laboratory of Animal and Plant Resistance, College of Life
Sciences, Tianjin Normal University, 393 Binshuixidao, Xiqing District, Tianjin
300387, China.
(3)Tianjin Center for Control and Prevention of Aquatic Animal Infectious
Disease, 442 South Jiefang Road, Hexi District, Tianjin 300221, China.
(4)Tianjin Key Laboratory of Animal and Plant Resistance, College of Life
Sciences, Tianjin Normal University, 393 Binshuixidao, Xiqing District, Tianjin
300387, China. Electronic address: jssun1965@aliyun.com.
Extracellular ATP is an important damage-associated molecular pattern molecule
that plays key roles in innate immunity. In fish, however, the mechanism for
extracellular ATP release remains largely undefined. Pannexin1 (Panx1) is a
newly discovered extracellular ATP release channel with a wide tissue
distribution and diverse biological functions in mammals. In the present study,
we identified and characterized a Panx1 homolog cDNA, termed poPanx1, from
Japanese flounder Paralichthys olivaceus, which is one of the most important
economic mariculture fish species in China. PoPanx1 is a membrane protein that
is composed of 437 amino acids with an estimated molecular mass of 48.7 kDa and
an isoelectric point of 6.46. The poPanx1 mRNA ubiquitously expresses in all
examined tissues but with predominant expression in hepatopancreas in
unstimulated healthy adult Japanese flounder. In Japanese flounder head kidney
primary cells, poPanx1 gene expression could be significantly induced by
pathogen-associated molecular patterns (PAMPs; polyinosinic-polycytidylic acid
and bacterial endotoxin LPS) stimulations. In vivo experiments revealed that
poPanx1 mRNA expression was significantly up-regulated upon immune challenges
with Edwardsiella tarda and Vibrio anguillarum. Furthermore, we showed that
poPanx1 is an important channel protein for PAMP-induced extracellular ATP
release that is required for activation of purinergic signaling in fish innate
immunity. Taken together, our findings suggest that the ATP release channel,
poPanx1, is a novel immune response gene in purinergic signaling of Japanese
flounder P. olivaceus.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.fsi.2014.06.034
PMID: 25007779 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12825077 | 1. Eur J Hum Genet. 2003 Jul;11(7):547-9. doi: 10.1038/sj.ejhg.5201002.
Novel POLG mutations in progressive external ophthalmoplegia mimicking
mitochondrial neurogastrointestinal encephalomyopathy.
Van Goethem G(1), Schwartz M, Löfgren A, Dermaut B, Van Broeckhoven C, Vissing
J.
Author information:
(1)Neuromuscular Reference Center and Department of Neurology, University
Hospital of Antwerp (UZA), Antwerpen, Belgium. vgoethge@uia.ua.ac.be
Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical
disorder associated with multiple mitochondrial DNA deletions and can be caused
by missense mutations in POLG, the gene encoding the mitochondrial DNA
polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
is another autosomal recessive disorder associated with PEO and multiple
deletions of mitochondrial DNA in skeletal muscle. In several patients this
disorder is caused by loss of function mutations in the gene encoding thymidine
phosphorylase (TP). We report a recessive family with features of MNGIE but no
leukoencephalopathy in which two patients carry three missense mutations in
POLG, of which two are novel mutations (N846S and P587L). The third mutation was
previously reported as a recessive POLG mutation (T251I). This finding indicates
the need for POLG sequencing in patients with features of MNGIE without TP
mutations.
DOI: 10.1038/sj.ejhg.5201002
PMID: 12825077 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15351195 | 1. Lancet. 2004 Sep 4-10;364(9437):875-82. doi: 10.1016/S0140-6736(04)16983-3.
Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma
mutations: clinical and molecular genetic study.
Luoma P(1), Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors
A, Rautakorpi I, Peltonen L, Majamaa K, Somer H, Suomalainen A.
Author information:
(1)Department of Neurology and Programme of Neurosciences, Biomedicum-Helsinki,
Helsinki University, and Helsinki University Central Hospital, Helsinki,
Finland.
BACKGROUND: Mutations in the gene encoding mitochondrial DNA polymerase gamma
(POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been
associated with a mitochondrial disease-autosomal dominant or recessive
progressive external ophthalmoplegia-and multiple deletions of mtDNA.
Mitochondrial dysfunction is also suspected to participate in the pathogenesis
of Parkinson's disease. However, no primary gene defects affecting mitochondrial
proteins causing mendelian transmission of parkinsonism have been characterised.
We aimed to analyse the gene sequence of POLG in patients with progressive
external ophthalmoplegia and their healthy relatives.
METHODS: In seven families of various ethnic origins we assessed patients with
progressive external ophthalmoplegia and unaffected individuals by clinical,
biochemical, morphological, and molecular genetic characterisation and positron
emission tomography (PET).
FINDINGS: We recorded mutations in POLG in members of all seven families.
Clinical assessment showed significant cosegregation of parkinsonism with POLG
mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron
loss. Post-mortem examination in two individuals showed loss of pigmented
neurons and pigment phagocytosis in substantia nigra without Lewy bodies.
Furthermore, most women with progressive external ophthalmoplegia had early
menopause-before age 35 years. The POLG gene defect resulted in secondary
accumulation of mtDNA deletions in patients' tissues.
INTERPRETATION: Dysfunction of mitochondrial POLG causes a severe progressive
multisystem disorder including parkinsonism and premature menopause, which are
not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG
mutations in our families suggests that when defective, this gene can underlie
mendelian transmission of parkinsonism.
RELEVANCE TO PRACTICE: Awareness that mitochondrial POLG mutations can underlie
parkinsonism is important for clinicians working in diagnosis of movement
disorders, as well as for studies of the genetics of Parkinson's disease.
Further, progressive external ophthalmoplegia with muscle weakness and
neuropathy can mask symptoms of parkinsonism, and clinicians should pay special
attention to detect and treat parkinsonism in those individuals.
DOI: 10.1016/S0140-6736(04)16983-3
PMID: 15351195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15046685 | 1. Clin Prostate Cancer. 2003 Jun;2(1):50-7. doi: 10.3816/cgc.2003.n.013.
Involvement of growth factor receptors of the epidermal growth factor receptor
family in prostate cancer development and progression to androgen independence.
Lorenzo GD(1), Bianco R, Tortora G, Ciardiello F.
Author information:
(1)Department of Molecular and Clinical Endocrinology, Universita degli Studi di
Napoli Federico II, Naples, Italy.
The development of prostate cancer and the progression from a normal prostate
epithelium to androgen-dependent cancer and eventually to hormone-refractory
prostate cancer is a multistep process involving several changes in the function
of different growth-regulatory signals. In the past 10 years, conflicting
results on epidermal growth factor receptor (EGFR) family expression in prostate
cancer have been reported. These differences may result from technical
differences, lack of standardization of immunohistochemical assays, or different
scoring methodologies. Recently, 4 studies have shown experimental evidence of a
role of the EGFR family, particularly ErbB-2, in the development of prostate
cancer and, more specifically, in the progression to hormone-refractory clinical
behavior. These 4 studies were similar in some relevant aspects, such as the
patient population. In fact, the patients in each study were divided into 3
groups that represent the progression of prostate cancer. In 3 of 4 studies, a
statistically significant increase in ErbB-2 expression was detected by
immunohistochemistry in the progression from hormone-dependent to
hormone-independent disease. The expression of EGFR was also evaluated in 1 of
the 4 studies. In a recent report from our group, a significant increase in EGFR
expression was observed in patients treated with radical surgery, in patients
who received hormonal therapy as primary therapy before radical prostatectomy,
and, finally, in patients with metastatic and hormone-refractory disease. It has
been proposed that EGFR family receptors and androgen receptors function
synergistically in the absence of androgen suggesting cross-talk between the
ErbB-2 and androgen receptor pathways, and that mitogen-activated protein kinase
and phosphatidylinositol 3-kinase can be considered the transduction pathways.
Finally, clinical trials are currently in progress in patients with prostate
cancer testing novel agents that selectively interfere with these receptors,
such as trastuzumab, an anti- ErbB-2 monoclonal antibody, and gefitinib (ZD1839,
Iressa), a small-molecule selective EGFR tyrosine kinase inhibitor.
DOI: 10.3816/cgc.2003.n.013
PMID: 15046685 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19373278 | 1. Cancer Gene Ther. 2009 Nov;16(11):820-31. doi: 10.1038/cgt.2009.28. Epub 2009
Apr 17.
Lentiviruses with trastuzumab bound to their envelopes can target and kill
prostate cancer cells.
Zhang KX(1), Moussavi M, Kim C, Chow E, Chen IS, Fazli L, Jia W, Rennie PS.
Author information:
(1)Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia,
Canada V6H 3Z6.
In this study, we took advantage of the overexpression of human epidermal growth
factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with
modified envelope proteins that bind antibodies to specific cell-surface
antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses
were able to selectively infect androgen-sensitive LNCaP and
castration-resistant C4-2 human prostate cancer cell lines, both of which
express high levels of HER-2. To test for a therapeutic effect, we engineered
our antibody-binding lentiviruses to express thymidine kinase, which can convert
the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2
cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2
xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound
lentivirus expressed luciferase, although the latter route was less tumor
specific. When a prostate-specific promoter for governing luciferase expression
was combined with trastuzumab-mediated delivery, there was a further enrichment
in targeting viral gene expression in prostate tumors. In conclusion, we found
that although prostate cancers that express high levels of HER-2 are resistant
to the killing effects of trastuzumab, they can be targeted for selective gene
expression and destruction by viruses with envelope proteins engineered to bind
this antibody.
DOI: 10.1038/cgt.2009.28
PMID: 19373278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22505344 | 1. Oncol Rep. 2012 Jul;28(1):297-302. doi: 10.3892/or.2012.1760. Epub 2012 Apr
10.
Effects of a human compact anti-ErbB2 antibody on prostate cancer.
Malara AE(1), Fedele C, Aloj L, Arra C, Laccetti P, D'Alessio G, De Lorenzo C.
Author information:
(1)Department of Structural and Functional Biology, University of Naples
Federico II, I-80126 Naples, Italy.
Prostate cancer is the most commonly diagnosed malignancy in men in developed
countries. ErbB2, a tyrosine kinase receptor overexpressed in many human cancer
types, contributes to prostate cancer progression by activating the androgen
receptor in a steroid poor environment, thus promoting androgen-independent cell
growth. The consequent development of hormone refractory tumors is a major
obstacle in prostate cancer therapy. The inhibition of ErbB2 signal transduction
pathways by the use of human antibodies could be a valuable alternative strategy
for cancer therapy. We performed a comparative analysis in vitro and in vivo of
the antitumor effects of three different antibodies targeting different epitopes
of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human
anti-ErbB2-compact antibody), a novel fully human compact antibody produced in
our laboratory. Herein, we demonstrate that the growth of both
androgen-dependent and independent prostate cancer cells was efficiently
inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell
lines were more potent than those observed for either Herceptin or 2C4. Thus,
Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer
for which no obvious treatment has been reported so far.
DOI: 10.3892/or.2012.1760
PMID: 22505344 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20028694 | 1. Eur Heart J. 2010 Jun;31(12):1529-37. doi: 10.1093/eurheartj/ehp554. Epub 2009
Dec 21.
Chronic heart rate reduction with ivabradine improves systolic function of the
reperfused heart through a dual mechanism involving a direct mechanical effect
and a long-term increase in FKBP12/12.6 expression.
Couvreur N(1), Tissier R, Pons S, Chetboul V, Gouni V, Bruneval P, Mandet C,
Pouchelon JL, Berdeaux A, Ghaleh B.
Author information:
(1)INSERM U955 Equipe 03, 8, rue du Général Sarrail, Créteil F-94010, France.
AIMS: To investigate the adaptations of left ventricular function and calcium
handling to chronic heart rate reduction with ivabradine in the reperfused
heart.
METHODS AND RESULTS: Rabbits underwent 20 min coronary artery occlusion followed
by 3 weeks of reperfusion. Throughout reperfusion, rabbits received ivabradine
(10 mg/kg/day) or vehicle (control). Ivabradine reduced heart rate by about 20%
and improved both ejection fraction (+35%) and systolic displacement (+26%)
after 3 weeks of treatment. Interestingly, this was associated with a two-fold
increase expression of FKBP12/12.6. There was no difference in the expressions
of phospholamban, SERCA2a, calsequestrin, ryanodine, phospho-ryanodine, and
Na(2+)/Ca(2+) exchanger in the two groups. Infarct scar and vascular density
were similar in both groups. Administration of a single intravenous bolus of
ivabradine (1 mg/kg) in control rabbits at 3 weeks of reperfusion also
significantly improved acutely ejection fraction and systolic displacement.
CONCLUSION: Chronic heart rate reduction protects the myocardium against
ventricular dysfunction induced by myocardial ischaemia followed by 3 weeks of
reperfusion. Beyond pure heart rate reduction, ivabradine improves global and
regional systolic function of the reperfused heart through a dual mechanism
involving a direct mechanical effect and a long-term adaptation in calcium
handling, as supported by the increase in FKBP12/12.6 expression.
DOI: 10.1093/eurheartj/ehp554
PMCID: PMC3064678
PMID: 20028694 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST Alain Berdeaux has received
honoraria for lectures and has served as consultant to Servier. The other
authors have no conflict of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/23536611 | 1. Eur Heart J. 2013 Aug;34(29):2263-70. doi: 10.1093/eurheartj/eht101. Epub 2013
Mar 26.
Effect of ivabradine in patients with left-ventricular systolic dysfunction: a
pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials.
Fox K(1), Komajda M, Ford I, Robertson M, Böhm M, Borer JS, Steg PG, Tavazzi L,
Tendera M, Ferrari R, Swedberg K.
Author information:
(1)NHLI Imperial College and ICMS, Royal Brompton Hospital, Sydney Street,
London SW3 6NP, UK. k.fox@rbht.nhs.uk
AIMS: To test the effect of ivabradine on the outcomes in a broad population
with left-ventricular (LV) systolic dysfunction with coronary artery disease
(CAD) and/or heart failure (HF).
METHODS AND RESULTS: Individual trial data from BEAUTIFUL and SHIFT were pooled
to evaluate the effect of ivabradine on the outcomes in patients with LV
dysfunction and heart rate ≥ 70 b.p.m. The pooled population (n = 11 897;
baseline age 62.3 ± 10.4 years, heart rate 79.6 ± 9.2 b.p.m., and LV ejection
fraction 30.3 ± 5.6%) was well treated according to current recommendations (87%
beta-blockers, 90% renin-angiotensin system inhibitors). Median follow-up was 21
months. Treatment with ivabradine was associated with a 13% relative risk
reduction for the composite of cardiovascular mortality or HF hospitalization (P
< 0.001 vs. placebo); this was driven by HF hospitalizations (19%, P < 0.001).
There were also significant relative risk reductions for the composite of
cardiovascular mortality, HF hospitalizations, or myocardial infarction (MI)
hospitalization (15%, P < 0.001); cardiovascular mortality and non-fatal MI
(10%, P = 0.023); and MI hospitalization (23%, P = 0.009). Similar results were
found in patients with differing clinical profiles. Ivabradine was well
tolerated.
CONCLUSION: Ivabradine may be important for the improvement of clinical outcomes
in patients with LV systolic dysfunction and heart rate ≥ 70 b.p.m., whatever
the primary clinical presentation (CAD or HF) or clinical status (NYHA class).
DOI: 10.1093/eurheartj/eht101
PMID: 23536611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1940586 | 1. J Lab Clin Med. 1991 Nov;118(5):458-65.
Diagnosis and characterization of presymptomatic patients with Wilson's disease
and the use of molecular genetics to aid in the diagnosis.
Yuzbasiyan-Gurkan V(1), Johnson V, Brewer GJ.
Author information:
(1)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor.
Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation
leading to liver and/or brain damage. Although fatal if untreated, the condition
can be treated effectively. Autosomal recessive inheritance indicates that
siblings of affected patients are at 25% risk of having the disease. If they are
diagnosed prior to becoming symptomatic, affected siblings can be kept free of
symptoms by prophylactic therapy. In this paper we have examined the utility of
copper-related variables, along with other clinical and molecular findings, in
identifying those siblings of affected patients who should be further evaluated
with a liver biopsy. Data are presented on a series of 13 presymptomatic
patients in whom we have made the diagnosis of WD based on liver biopsy
findings. Signs of liver disease were present in 12 out of 13 cases. The
classic, noninvasive, screening approaches that we evaluated were not adequate
to identify all cases of WD in this group of patients. These included positive
Kayser-Fleischer (KF) rings, elevated liver serum alanine transferase, elevated
urine copper, or elevated plasma nonceruloplasmin copper. We have introduced the
use of molecular genetics for screening siblings of affected patients for WD. We
show that a probe from the linked retinoblastoma (RB) gene can be very helpful
in problem cases. However, at this time, the quantitative determination of liver
copper concentration remains as the definitive diagnostic criterion.
PMID: 1940586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/759736 | 1. Mayo Clin Proc. 1979 Jan;54(1):35-42.
Clinical spectrum of Wilson's disease (hepatolenticular degeneration).
Dobyns WB, Goldstein NP, Gordon H.
Fifty-eight patients with Wilson's disease are reviewed, of whom 25 symptomatic
patients experienced liver disease first and 28, brain disease. Ten of these
patients presented with liver disease alone, 19 with brain disease alone, and 24
with evidence of both liver and brain disease. The remaining five were
discovered as asymptomatic siblings of known patients. Three of the patients
with hepatic presentation and one with neurologic presentation later experienced
the other type of symptomatology, bringing the total number of patients with
mixed disease to 28. Of the 44 patients with brain disease, 12 presented
primarily with extrapyramidal findings, 6 with cerebellar findings, and 17 with
both; pseudobulbar findings were noted in 9 patients, all of whom had other
symptoms of severe nervous system disease. In addition to these presentations,
in an appreciable number of patients the first symptoms were of a mental or
emotional disorder. Disease of other organ systems, such as the joints and
kidneys, also occurred but infrequently. Where adequate family information was
available, 13 of 65 siblings (20%) were known to have had or were suspected of
having had Wilson's disease. This is consistent with the autosomal-recessive
pattern of inheritance.
PMID: 759736 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6620327 | 1. J Med Genet. 1983 Aug;20(4):271-5. doi: 10.1136/jmg.20.4.271.
Evaluation of segregation ratio in Wilson's disease.
Saito T.
Two problems relating to segregation analysis for Wilson's disease are discussed
and a practical solution is presented. A problem in the ascertainment of
families with Wilson's disease is illustrated by comparing segregation ratios
calculated by the single selection, complete truncate, and multiple incomplete
selection methods. The effect on the segregation ratio of exclusion from the
analysis of those sibs who had died of other diseases at a young age is also
discussed and a method of adjustment of the number of the affected using the
data on age at onset is proposed. The segregation ratio by multiple incomplete
selection (Weinberg proband method) after adjustment for those sibs who had died
of other diseases was 0.243, consistent with the theoretical value for autosomal
recessive inheritance. The segregation ratio calculated by the single selection
method tended to give a lower value, while that calculated by the complete
truncate method was greater than the theoretical value. Recessive inheritance
is, however, supported. The actual effect of exclusion of those sibs who had
died of other diseases on gene frequency estimation is shown to be very small.
DOI: 10.1136/jmg.20.4.271
PMCID: PMC1049118
PMID: 6620327 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23074139 | 1. Wiley Interdiscip Rev RNA. 2013 Jan-Feb;4(1):77-91. doi: 10.1002/wrna.1142.
Epub 2012 Oct 16.
Connections between chromatin signatures and splicing.
Gómez Acuña LI(1), Fiszbein A, Alló M, Schor IE, Kornblihtt AR.
Author information:
(1)Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología,
Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y
Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires,
Argentina.
Splicing and alternative splicing are involved in the expression of most human
genes, playing key roles in differentiation, cell cycle progression, and
development. Misregulation of splicing is frequently associated to disease,
which imposes a better understanding of the mechanisms underlying splicing
regulation. Accumulated evidence suggests that multiple trans-acting factors and
cis-regulatory elements act together to determine tissue-specific splicing
patterns. Besides, as splicing is often cotranscriptional, a complex picture
emerges in which splicing regulation not only depends on the balance of splicing
factor binding to their pre-mRNA target sites but also on
transcription-associated features such as protein recruitment to the
transcribing machinery and elongation kinetics. Adding more complexity to the
splicing regulation network, recent evidence shows that chromatin structure is
another layer of regulation that may act through various mechanisms. These span
from regulation of RNA polymerase II elongation, which ultimately determines
splicing decisions, to splicing factor recruitment by specific histone marks.
Chromatin may not only be involved in alternative splicing regulation but in
constitutive exon recognition as well. Moreover, splicing was found to be
necessary for the proper 'writing' of particular chromatin signatures, giving
further mechanistic support to functional interconnections between splicing,
transcription and chromatin structure. These links between chromatin
configuration and splicing raise the intriguing possibility of the existence of
a memory for splicing patterns to be inherited through epigenetic modifications.
Copyright © 2012 John Wiley & Sons, Ltd.
DOI: 10.1002/wrna.1142
PMID: 23074139 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20808788 | 1. PLoS One. 2010 Aug 23;5(8):e12339. doi: 10.1371/journal.pone.0012339.
Complex exon-intron marking by histone modifications is not determined solely by
nucleosome distribution.
Dhami P(1), Saffrey P, Bruce AW, Dillon SC, Chiang K, Bonhoure N, Koch CM, Bye
J, James K, Foad NS, Ellis P, Watkins NA, Ouwehand WH, Langford C, Andrews RM,
Dunham I, Vetrie D.
Author information:
(1)The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton,
United Kingdom.
It has recently been shown that nucleosome distribution, histone modifications
and RNA polymerase II (Pol II) occupancy show preferential association with
exons ("exon-intron marking"), linking chromatin structure and function to
co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing
studies suggested that these marking patterns reflect the nucleosomal landscape.
By analyzing ChIP-chip datasets across the human genome in three cell types, we
have found that this marking system is far more complex than previously
observed. We show here that a range of histone modifications and Pol II are
preferentially associated with exons. However, there is noticeable cell-type
specificity in the degree of exon marking by histone modifications and,
surprisingly, this is also reflected in some histone modifications patterns
showing biases towards introns. Exon-intron marking is laid down in the absence
of transcription on silent genes, with some marking biases changing or becoming
reversed for genes expressed at different levels. Furthermore, the relationship
of this marking system with splicing is not simple, with only some histone
modifications reflecting exon usage/inclusion, while others mirror patterns of
exon exclusion. By examining nucleosomal distributions in all three cell types,
we demonstrate that these histone modification patterns cannot solely be
accounted for by differences in nucleosome levels between exons and introns. In
addition, because of inherent differences between ChIP-chip array and
ChIP-sequencing approaches, these platforms report different nucleosome
distribution patterns across the human genome. Our findings confound existing
views and point to active cellular mechanisms which dynamically regulate histone
modification levels and account for exon-intron marking. We believe that these
histone modification patterns provide links between chromatin accessibility, Pol
II movement and co-transcriptional splicing.
DOI: 10.1371/journal.pone.0012339
PMCID: PMC2925886
PMID: 20808788 [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/12152840 | 1. J Assoc Physicians India. 1998 Jul;46(7):602-5.
Wilson's disease: clinical and radiological features.
Jha SK(1), Behari M, Ahuja GK.
Author information:
(1)Neurology Department, All India Institute of Medical Sciences, New Delhi.
BACKGROUND: Wilson's disease is a treatable movement disorder with autosomal
recessive inheritance which is associated with severe morbidity and mortality if
not treated early.
MATERIAL AND METHODS: The clinical and radiological features of 22 cases of
Wilson's disease seen during January 1984 to December 1993 were analysed for
clinical presentation and common radiological features.
RESULTS: Among all the patients extrapyramidal features were the commonest
(19/22 patients), followed closely by impaired higher mental functions (17/22
patients) and cerebellar signs (11/22 patients). In patients with onset of
symptoms before 20 years, the common presentations were impaired higher mental
functions, speech disturbance, dystonia and choreo-athetosis; whereas in
patients with onset after 20 years cerebellar signs were commonest. The
commonest CT head abnormality was basal ganglion hypodensity (10 patients)
followed by brain stem hypodensity (6 patients).
CONCLUSIONS: The clinical and CT scan features are evaluated and compared with
reported series. Hypodensities of brain stem earlier reported a rarity, was seen
in 6 out of 22 cases.
PMID: 12152840 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15383674 | 1. RNA. 2004 Oct;10(10):1489-98. doi: 10.1261/rna.7100104.
Multiple links between transcription and splicing.
Kornblihtt AR(1), de la Mata M, Fededa JP, Munoz MJ, Nogues G.
Author information:
(1)Departamento de Fisiología, Biología Molecular y Celular, Facultad de
Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFIByNE-CONICET,
Ciudad Universitaria, Pabellón II (C1428EHA) Buenos Aires, Argentina.
ark@fbmc.fcen.uba.ar
Transcription and pre-mRNA splicing are extremely complex multimolecular
processes that involve protein-DNA, protein-RNA, and protein-protein
interactions. Splicing occurs in the close vicinity of genes and is frequently
cotranscriptional. This is consistent with evidence that both processes are
coordinated and, in some cases, functionally coupled. This review focuses on the
roles of cis- and trans-acting factors that regulate transcription, on
constitutive and alternative splicing. We also discuss possible functions in
splicing of the C-terminal domain (CTD) of the RNA polymerase II (pol II)
largest subunit, whose participation in other key pre-mRNA processing reactions
(capping and cleavage/polyadenylation) is well documented. Recent evidence
indicates that transcriptional elongation and splicing can be influenced
reciprocally: Elongation rates control alternative splicing and splicing factors
can, in turn, modulate pol II elongation. The presence of transcription factors
in the spliceosome and the existence of proteins, such as the coactivator PGC-1,
with dual activities in splicing and transcription can explain the links between
both processes and add a new level of complexity to the regulation of gene
expression in eukaryotes.
Copyright 2004 RNA Society
DOI: 10.1261/rna.7100104
PMCID: PMC1370635
PMID: 15383674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14580665 | 1. Pediatr Neurol. 2003 Aug;29(2):170-2. doi: 10.1016/s0887-8994(03)00231-5.
Familial pediatric rapidly progressive extrapyramidal syndrome: is it
Hallervorden-Spatz disease?
Chakravarty A(1), Mukherjee A, Sen A.
Author information:
(1)Department of Neurology, Vivekananda Institute of Medical Sciences, Calcutta,
India.
The clinical features of two children of a family with rapidly progressive
extrapyramidal-pyramidal-dementia complex have been described. Inheritance seems
most likely to be autosomal recessive. Magnetic resonance imaging results of
brain were negative. Even so, the authors argued in favor of a diagnosis of
Hallervorden-Spatz disease because the cases fulfilled the clinical criteria for
diagnosis of this disease. Apart from the negative magnetic resonance findings,
the other unusual feature was the early development of levodopa-induced
dyskinesia. Few conditions need to be considered in the differential diagnosis
of a childhood-onset rapidly progressive extrapyramidal syndrome. Such
conditions include Wilson's disease, Hallervorden-Spatz disease (HSD), juvenile
form of Huntington's disease, juvenile neuronal ceroid lipofuscinosis,
early-onset Machado-Joseph disease neuroacanthocytosis, storage disorders, and
variant form of dopa-response dystonias (DRD). Rarer conditions are Leigh's
disease, Lafora body disease, and dentato-rubro-pallido-luysian atrophy. HSD is
a rare disorder characterized by progressive extrapyramidal dysfunction and
dementia. Onset is most commonly in late childhood or early adolescence. The
disease can be familial or sporadic. When familial, it is inherited recessively
and has been linked to chromosome 20. Recently, a mutation in the pantothenate
kinase (PANK2) gene on band 20pl3 has been described in patients with typical
HSD. HSD produces typical magnetic resonance imaging (MRI) changes in brain,
aiding in antemortem diagnosis. The typical finding is of bilaterally
symmetrical hyperintense signal changes in the external segment of globus
pallidus, with surrounding hypointensity on T(2)-weighted image. These imaging
features are fairly diagnostic and have been termed the "eye-of-the tiger sign".
The hyperintensity represents pathologic changes, including gliosis,
demyelination, neuronal loss, and axonal swelling, and the surrounding
hypointensity is caused by loss of signal secondary to iron deposition.
Described herein are the clinical aspects of a family with autosomal recessive
inheritance with rapidly progressive extrapyramidal-pyramidal-dementia complex
but with negative brain MRI results. The diagnosis should be considered a
variant form of HSD.
DOI: 10.1016/s0887-8994(03)00231-5
PMID: 14580665 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20000882 | 1. Am J Cardiovasc Drugs. 2009;9 Suppl 1:9-12. doi:
10.2165/1153162-S0-000000000-00000.
Role of heart rate in cardiovascular diseases: how the results of the BEAUTIFUL
study change clinical practice.
Bruguera Cortada J(1), Varela A.
Author information:
(1)Cardiology Department, Hospital del Mar, Barcelona, Spain.
jbruguera@imas.imim.es
The BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in
patients with coronary artery disease and left ventricULar systolic dysfunction)
study assessed the morbidity and mortality benefits of the HR-lowering agent
ivabradine. The placebo arm of the BEAUTIFUL trial was a large cohort of
patients with stable coronary artery disease (CAD) and left ventricular systolic
dysfunction. A subanalysis in the placebo group tested the hypothesis that
elevated resting HR at baseline was a marker for subsequent cardiovascular death
and morbidity. The primary aim of the study was to test whether lowering the HR
with ivabradine reduced cardiovascular death and morbidity in patients with CAD
and left ventricular systolic dysfunction. In the overall analysis, reduction in
HR with ivabradine did not improve cardiac outcomes compared with placebo. The
most important finding of the study was that patients with high baseline HR had
an increase in serious cardiovascular events including death (34%), hospital
admission secondary to congestive heart failure (53%), acute myocardial
infarction (46%), or revascularization procedure (38%). In addition, in the
subset analysis focusing on patients with baseline HR > or =70 bpm and left
ventricular ejection fraction <40% the agent resulted in a 36% decrease in
hospital admissions secondary to fatal and nonfatal myocardial infarction and a
30% decrease in coronary revascularization. The first practical implication from
the study includes that baseline HR should be recorded in addition to other risk
factors such as BP and lipid profile, in the follow-up of patients with CAD.
Attempts should be made to achieve HR <70 bpm by cardiac rehabilitation and
routine use of appropriately dosed beta-blockers. Despite the neutral results
obtained in the BEAUTIFUL study, ivabradine could be administered to the
subgroup of patients in whom HR <70 bpm is not achieved despite proper dosing of
beta-blockers and in those in whom beta-blockers are contraindicated.
Furthermore, in clinical practice, ivabradine may be helpful for patients with
stable CAD who have a high HR while receiving beta-blockers. Future studies are
needed to confirm the hypothesis that single reduction of HR can improve
cardiovascular prognosis.
DOI: 10.2165/1153162-S0-000000000-00000
PMID: 20000882 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21095588 | 1. Mol Cell. 2010 Nov 24;40(4):582-93. doi: 10.1016/j.molcel.2010.11.005.
Splicing-dependent RNA polymerase pausing in yeast.
Alexander RD(1), Innocente SA, Barrass JD, Beggs JD.
Author information:
(1)Wellcome Trust Centre for Cell Biology, University of Edinburgh, King's
Buildings, Edinburgh EH9 3JR, UK.
Comment in
Mol Cell. 2010 Nov 24;40(4):503-5. doi: 10.1016/j.molcel.2010.11.019.
In eukaryotic cells, there is evidence for functional coupling between
transcription and processing of pre-mRNAs. To better understand this coupling,
we performed a high-resolution kinetic analysis of transcription and splicing in
budding yeast. This revealed that shortly after induction of transcription, RNA
polymerase accumulates transiently around the 3' end of the intron on two
reporter genes. This apparent transcriptional pause coincides with splicing
factor recruitment and with the first detection of spliced mRNA and is repeated
periodically thereafter. Pausing requires productive splicing, as it is lost
upon mutation of the intron and restored by suppressing the splicing defect. The
carboxy-terminal domain of the paused polymerase large subunit is
hyperphosphorylated on serine 5, and phosphorylation of serine 2 is first
detected here. Phosphorylated polymerase also accumulates around the 3' splice
sites of constitutively expressed, endogenous yeast genes. We propose that
transcriptional pausing is imposed by a checkpoint associated with
cotranscriptional splicing.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2010.11.005
PMCID: PMC3000496
PMID: 21095588 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22156210 | 1. Genes Dev. 2011 Dec 1;25(23):2502-12. doi: 10.1101/gad.178962.111.
Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in
Drosophila.
Khodor YL(1), Rodriguez J, Abruzzi KC, Tang CH, Marr MT 2nd, Rosbash M.
Author information:
(1)Howard Hughes Medical Institute, National Center for Behavioral Genomics,
Brandeis University, Waltham, Massachusetts 02454, USA.
To determine the prevalence of cotranscriptional splicing in Drosophila, we
sequenced nascent RNA transcripts from Drosophila S2 cells as well as from
Drosophila heads. Eighty-seven percent of the introns assayed manifest >50%
cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced
poorly or slowly, with ∼3% being almost completely retained in nascent pre-mRNA.
Although individual introns showed slight but statistically significant
differences in splicing efficiency, similar global levels of splicing were seen
from both sources. Importantly, introns with low cotranscriptional splicing
efficiencies are present in the same primary transcript with efficiently spliced
introns, indicating that splicing is intron-specific. The analysis also
indicates that cotranscriptional splicing is less efficient for first introns,
longer introns, and introns annotated as alternative. Finally, S2 cells
expressing the slow RpII215(C4) mutant show substantially less intron retention
than wild-type S2 cells.
DOI: 10.1101/gad.178962.111
PMCID: PMC3243060
PMID: 22156210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23209445 | 1. PLoS Genet. 2012;8(11):e1003101. doi: 10.1371/journal.pgen.1003101. Epub 2012
Nov 29.
The yeast SR-like protein Npl3 links chromatin modification to mRNA processing.
Moehle EA(1), Ryan CJ, Krogan NJ, Kress TL, Guthrie C.
Author information:
(1)Department of Biochemistry and Biophysics, University of California San
Francisco, San Francisco, California, United States of America.
Eukaryotic gene expression involves tight coordination between transcription and
pre-mRNA splicing; however, factors responsible for this coordination remain
incompletely defined. Here, we explored the genetic, functional, and biochemical
interactions of a likely coordinator, Npl3, an SR-like protein in Saccharomyces
cerevisiae that we recently showed is required for efficient co-transcriptional
recruitment of the splicing machinery. We surveyed the NPL3 genetic interaction
space and observed a significant enrichment for genes involved in histone
modification and chromatin remodeling. Specifically, we found that Npl3
genetically interacts with both Bre1, which mono-ubiquitinates histone H2B as
part of the RAD6 Complex, and Ubp8, the de-ubiquitinase of the SAGA Complex. In
support of these genetic data, we show that Bre1 physically interacts with Npl3
in an RNA-independent manner. Furthermore, using a genome-wide splicing
microarray, we found that the known splicing defect of a strain lacking Npl3 is
exacerbated by deletion of BRE1 or UBP8, a phenomenon phenocopied by a point
mutation in H2B that abrogates ubiquitination. Intriguingly, even in the
presence of wild-type NPL3, deletion of BRE1 exhibits a mild splicing defect and
elicits a growth defect in combination with deletions of early and late splicing
factors. Taken together, our data reveal a connection between Npl3 and an
extensive array of chromatin factors and describe an unanticipated functional
link between histone H2B ubiquitination and pre-mRNA splicing.
DOI: 10.1371/journal.pgen.1003101
PMCID: PMC3510044
PMID: 23209445 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/16769980 | 1. Genome Res. 2006 Jul;16(7):912-21. doi: 10.1101/gr.5211806. Epub 2006 Jun 12.
Genomic localization of RNA binding proteins reveals links between pre-mRNA
processing and transcription.
Swinburne IA(1), Meyer CA, Liu XS, Silver PA, Brodsky AS.
Author information:
(1)Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
02115, USA.
Pre-mRNA processing often occurs in coordination with transcription thereby
coupling these two key regulatory events. As such, many proteins involved in
mRNA processing associate with the transcriptional machinery and are in
proximity to DNA. This proximity allows for the mapping of the genomic
associations of RNA binding proteins by chromatin immunoprecipitation (ChIP) as
a way of determining their sites of action on the encoded mRNA. Here, we used
ChIP combined with high-density microarrays to localize on the human genome
three functionally distinct RNA binding proteins: the splicing factor
polypyrimidine tract binding protein (PTBP1/hnRNP I), the mRNA export factor THO
complex subunit 4 (ALY/THOC4), and the 3' end cleavage stimulation factor 64 kDa
(CSTF2). We observed interactions at promoters, internal exons, and 3' ends of
active genes. PTBP1 had biases toward promoters and often coincided with RNA
polymerase II (RNA Pol II). The 3' processing factor, CSTF2, had biases toward
3' ends but was also observed at promoters. The mRNA processing and export
factor, ALY, mapped to some exons but predominantly localized to introns and did
not coincide with RNA Pol II. Because the RNA binding proteins did not
consistently coincide with RNA Pol II, the data support a processing mechanism
driven by reorganization of transcription complexes as opposed to a scanning
mechanism. In sum, we present the mapping in mammalian cells of RNA binding
proteins across a portion of the genome that provides insight into the
transcriptional assembly of RNA-protein complexes.
DOI: 10.1101/gr.5211806
PMCID: PMC1484458
PMID: 16769980 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15307599 | 1. Neurol Neurochir Pol. 2004 Mar-Apr;38(2):83-8.
[Genetic investigations in facioscapulohumeral muscular dystrophy: a preliminary
report].
[Article in Polish]
Dorobek M(1), Kabzińska D, Ryniewicz B, Fidziańska-Dolot A,
Hausmanowa-Petrusewicz I.
Author information:
(1)Zespół Badawczo-Leczniczy Chorób Nerwowo-Mieśniowych, Instytut Medycyny
Doświadczalnej i Klinicznej im.. M. Mossakowskiego, PAN w Warszawie.
maldor@cmdik.pan.pl
Facioscapulohumeral muscular dystrophy (FSHD) is a primary muscle disorder with
autosomal dominant inheritance. FSHD was mapped to chromosome 4 locus q35, but
the gene is not yet known. It is characterised by progressive, often asymmetric,
selective muscular weakness and great clinical variability. The aim of the study
was to analyze 62 FSHD cases from 44 Polish families in which the diagnosis was
confirmed by DNA analyses. FSHD diagnosis was based on the clinical findings and
standardized investigations confirming primary muscular involvement (EMG, muscle
biopsy). DNA analysis was based on EcoRI/BlnI restriction enzyme digestion
followed by hybridization with P13E-11 molecular probe. In our material, we have
found a relatively large percentage (41%) of big deletions (EcoRI/BlnI fragment
of 10-15 kb [kilo bases]), which in the majority of cases (67%) was present in
isolated cases. In 10 families (23%) the phenotype was assessed as severe. These
are cases with the onset before the age of 10 and fast progression. "Middle
sized" deletions (EcoRI/BlnI fragment of 16-29 kb) were prevalent in familial
cases and present in 57% of families. "Small" deletion was found in one family
(EcoRI/BlnI fragment of 30 kb). Somatic mosaicism was confirmed in one case. De
novo mutations were shown in 11% of the examined families. The results of this
study indicate that the bigger the deletion, the more severe the FSHD course,
however there are some exceptions. A similar relationship has been shown by
previous research. Molecular analyses are particularly important in atypical and
sporadic cases. It is the first genetic presentation of a group of patients'
with this kind of dystrophy in the Polish population.
PMID: 15307599 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10864616 | 1. J Neurol Neurosurg Psychiatry. 2000 Jul;69(1):114-6. doi:
10.1136/jnnp.69.1.114.
Extension of the clinical range of facioscapulohumeral dystrophy: report of six
cases.
van der Kooi AJ(1), Visser MC, Rosenberg N, van den Berg-Vos R, Wokke JH, Bakker
E, de Visser M.
Author information:
(1)Department of Neurology, Academic Medical Center, University of Amsterdam,
The Netherlands. a.j.kooi@amc.uva.nl
Consensual diagnostic criteria for facioscapulohumeral dystrophy (FSHD) include
onset of the disease in facial or shoulder girdle muscles, facial weakness in
more than 50% of affected family members, autosomal dominant inheritance in
familial cases, and evidence of myopathic disease in at least one affected
member without biopsy features specific to alternative diagnoses. Six patients
did not meet most of these criteria but were diagnosed as FSHD by DNA testing,
which showed small EcoRI fragments on chromosome 4q. Their clinical signs and
symptoms and results of auxiliary investigations are reported. The patients
presented with foot extensor, thigh, or calf muscle weakness. None of them had
apparent facial weakness, only one complained of weakness in the shoulders, none
had a positive family history. Expert physical examination, however, showed a
typical facial expression, an abnormal shoulder configuration on lifting the
arms, or scapular winging. This raised the suspicion of FSHD, whereupon DNA
analysis was done. In conclusion, the clinical expression of FSHD is much
broader than indicated by the nomenclature. The possibility to perform DNA tests
is likely to greatly expand the clinical range of FSHD.
DOI: 10.1136/jnnp.69.1.114
PMCID: PMC1737027
PMID: 10864616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10969520 | 1. Kaohsiung J Med Sci. 2000 May;16(5):248-54.
The strength and functional performance in patients with facioscapulohumeral
muscular dystrophy.
Lue YJ(1), Chen SS.
Author information:
(1)School of Rehabilitation Medicine, Kaohsiung Medical University, Taiwan.
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive myopathy
with autosomal dominant inheritance remarkable for its early involvement of
facial musculature. The purpose of our study was to assess the rate of strength
deterioration, functional condition and performance of activity of daily living
of patients with FSHD in Taiwan. Twenty patients diagnosed with FSHD were
included in this study. Manual muscle testing (MMT) was used to evaluate muscle
strength. The Brooke and Vignos scales were used to assess upper and lower
extremity function respectively, and the capability of the activity of daily
living was measured by Barthel index. The result of the strength testing was
characterized by the presence of a progressive asymmetrical muscular weakness in
patients with FSHD. The mean muscular strength of the right extremity was weaker
than its left counterparts (p < 0.05) and the shoulder muscle group was the
weakest. According to the Brooke functional scale, 20% of our patients were
graded as 1, 30% as grade 2, and 50% as grade 3. On the Vignos functional scale,
50% of patients fell into grade 1, 10% in grade 2, and 40% in grades 3-5. Vignos
scale was significantly correlated with mean muscle strength (p < 0.05). The
average value of Barthel index was 97.8 +/- 4.7. The muscle strength decline in
this Taiwanese of FSHD population was more severe in shoulder girdle area. The
mean muscle strength of the right extremity was weaker than the left. Most of
our patients suffered from mild or moderate physical disability. Finding of
these Taiwanese FSHD population is similar to those reported elsewhere in the
world.
PMID: 10969520 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10487912 | 1. Muscle Nerve. 1999 Oct;22(10):1437-41. doi:
10.1002/(sici)1097-4598(199910)22:10<1437::aid-mus15>3.0.co;2-7.
Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral
muscular dystrophy.
Vitelli F(1), Villanova M, Malandrini A, Bruttini M, Piccini M, Merlini L,
Guazzi G, Renieri A.
Author information:
(1)Medical Genetics Unit, Department of Molecular Biology, Policlinico "Le
Scotte," viale Bracci 2, 53100 Siena, Italy.
Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant muscular disorder
associated with a short (<35 kb) EcoRI/BlnI fragment resulting from deletion of
an integral number of units of a 3.3-kb repeat located at 4q35. In this study,
we determined fragment sizes separated by pulsed-field gel electrophoresis in a
patient with an apparently sporadic case of FSHD and in his healthy family
members. A 38-kb fragment was detected in the proband, in his older brother, and
in their father. This finding prompted a clinical reevaluation of the father and
brother. A subclinical phenotype restricted to abdominal muscle weakness was
detected, and serum creatine kinase values were found to be elevated in both.
The proband's brother also showed evidence of an independently occurring
subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the
population. The identification of a "borderline" 38-kb EcoRI/BlnI fragment in an
affected subject and his very mildly affected relatives extends the size range
of disease alleles and expands existing data on the variable intrafamilial
expressivity of FSHD. This study highlights the importance of a careful
molecular and clinical analysis extended to family members of apparently
sporadic cases with larger EcoRI/BlnI fragments for accurate diagnosis and
appropriate genetic counseling in FSHD.
Copyright 1999 John Wiley & Sons, Inc.
DOI: 10.1002/(sici)1097-4598(199910)22:10<1437::aid-mus15>3.0.co;2-7
PMID: 10487912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22525183 | 1. J AAPOS. 2012 Apr;16(2):204-6. doi: 10.1016/j.jaapos.2011.11.005.
Coats-like retinopathy in an infant with preclinical facioscapulohumeral
dystrophy.
Ganesh A(1), Kaliki S, Shields CL.
Author information:
(1)Pediatric Ophthalmology and Ocular Genetics Services, Wills Eye Institute,
Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant disorder
characterized by weakness of the face, upper arm, shoulder, and lower limb
musculature, with an onset between the first and third decades. Coats disease is
a congenital disorder of retinal vascular development characterized by
unilateral peripheral retinal telangiectasia and progressive subretinal and
intraretinal exudation. This condition has a predilection for children and is
usually isolated. Retinal vascular changes similar to those seen in Coats
disease have been demonstrated by fluorescein angiography in 40% to 75% of
patients with FSHD. Most patients have asymptomatic retinal telangiectasia found
at ocular screening in adulthood after diagnosis of FSHD. We report a
7-month-old infant with bilateral Coats-like retinopathy in which the eye
disease was discovered before findings of FSHD were clinically evident. To our
knowledge, this patient represents the youngest reported case of preclinical
FSHD with ocular disease.
Copyright © 2012 American Association for Pediatric Ophthalmology and
Strabismus. Published by Mosby, Inc. All rights reserved.
DOI: 10.1016/j.jaapos.2011.11.005
PMID: 22525183 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21795275 | 1. Age Ageing. 2012 Mar;41(2):273-4. doi: 10.1093/ageing/afr095. Epub 2011 Jul
27.
A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's
muscular dystrophy for 20 years.
Ramos VF(1), Thaisetthawatkul P.
Author information:
(1)Neurological Sciences, University of Nebraska Medical Center, 982045 Nebraska
Medical Center, Omaha, NE 68198-2045, USA. vesper.ramos@yahoo.com
A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years
ago by another physician presented with gradually progressive proximal muscle
weakness since teenage years. Family history revealed a strong paternal familial
inheritance pattern of similar distribution of weakness-face, forearm flexion,
knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and
allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing.
FSHD is the third most common muscular dystrophy. Clinical diagnosis is made
from the distinctive pattern of weakness, autosomal-dominant inheritance, and
confirmed by genetic testing. This case strongly demonstrates the importance of
a thorough and careful clinical evaluation even in a case with a long standing
diagnosis.
DOI: 10.1093/ageing/afr095
PMID: 21795275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23573591 | 1. Muscle Nerve Suppl. 1995;(2):S81-4.
Facioscapulohumeral muscular dystrophy in the Dutch population.
Padberg GW(1), Frants RR, Brouwer OF, Wijmenga C, Bakker E, Sandkuijl LA.
Author information:
(1)From the Department of Neurology, University Hospital, Nijmegen, The
Netherlands.
Extrapolating the figures from a previous study on FSHD in a province of The
Netherlands to the entire Dutch population suggests that at present a nearly
complete overview is obtained of all symptomatic kindred. In 139 families,
dominant inheritance was observed in 97, a pattern compatible with germline
mosaicism in 6, while sporadic cases were found in 36 families. A mutation
frequency of 9.6% was calculated. Mental retardation and severe retinal
vasculopathy were reported in low frequencies (1%). Early onset was seen more
frequently in sporadic cases. Chromosome 4 linkage appeared excluded in 3 of 22
autosomal-dominant families. The clinical pictures in the linked and nonlinked
families were identical.
PMID: 23573591 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8186659 | 1. Clin Investig. 1994 Jan;72(2):134-6. doi: 10.1007/BF00184590.
Excessive iron storage in a patient with Wilson's disease.
Hafkemeyer P(1), Schupp M, Storch M, Gerok W, Häussinger D.
Author information:
(1)Medizinische Universitätsklinik, Freiburg, Germany.
We report on an otherwise healthy female, mother of two children, with severe
decompensated liver cirrhosis due to an iron overload and Wilson's disease. The
patient was considered heterozygote for hemochromatosis on the basis of the
autosomal recessive inheritance for hemochromatosis, the frequency of the
hemochromatosis gene, and the laboratory parameters defining her iron overload.
The case is interesting because of the coincidence of Wilson's disease and
excessive iron storage.
DOI: 10.1007/BF00184590
PMID: 8186659 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23097425 | 1. RNA. 2012 Dec;18(12):2174-86. doi: 10.1261/rna.034090.112. Epub 2012 Oct 24.
Cotranscriptional splicing efficiency differs dramatically between Drosophila
and mouse.
Khodor YL(1), Menet JS, Tolan M, Rosbash M.
Author information:
(1)Howard Hughes Medical Institute and National Center for Behavioral Genomics,
Department of Biology, Brandeis University, Waltham, Massachusetts 02454, USA.
Spliceosome assembly and/or splicing of a nascent transcript may be crucial for
proper isoform expression and gene regulation in higher eukaryotes. We recently
showed that cotranscriptional splicing occurs efficiently in Drosophila, but
there are not comparable genome-wide nascent splicing data from mammals. To
provide this comparison, we analyze a recently generated, high-throughput
sequencing data set of mouse liver nascent RNA, originally studied for circadian
transcriptional regulation. Cotranscriptional splicing is approximately twofold
less efficient in mouse liver than in Drosophila, i.e., nascent intron levels
relative to exon levels are ∼0.55 in mouse versus 0.25 in the fly. An additional
difference between species is that only mouse cotranscriptional splicing is
optimal when 5'-exon length is between 50 and 500 bp, and intron length does not
correlate with splicing efficiency, consistent with exon definition. A similar
analysis of intron and exon length dependence in the fly is more consistent with
intron definition. Contrasted with these differences are many similarities
between the two systems: Alternatively annotated introns are less efficiently
spliced cotranscriptionally than constitutive introns, and introns of
single-intron genes are less efficiently spliced than introns from multi-intron
genes. The most striking common feature is intron position: Cotranscriptional
splicing is much more efficient when introns are far from the 3' ends of their
genes. Additionally, absolute gene length correlates positively with
cotranscriptional splicing efficiency independently of intron location and
position, in flies as well as in mice. The gene length and distance effects
indicate that more "nascent time" gives rise to greater cotranscriptional
splicing efficiency in both systems.
DOI: 10.1261/rna.034090.112
PMCID: PMC3504670
PMID: 23097425 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21964334 | 1. Nature. 2011 Nov 3;479(7371):74-9. doi: 10.1038/nature10442.
CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.
Shukla S(1), Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M,
Oberdoerffer P, Sandberg R, Oberdoerffer S.
Author information:
(1)Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer
Institute at Frederick, Frederick, Maryland 21702, USA.
Alternative splicing of pre-messenger RNA is a key feature of transcriptome
expansion in eukaryotic cells, yet its regulation is poorly understood.
Spliceosome assembly occurs co-transcriptionally, raising the possibility that
DNA structure may directly influence alternative splicing. Supporting such an
association, recent reports have identified distinct histone methylation
patterns, elevated nucleosome occupancy and enriched DNA methylation at exons
relative to introns. Moreover, the rate of transcription elongation has been
linked to alternative splicing. Here we provide the first evidence that a
DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak
upstream exons by mediating local RNA polymerase II pausing both in a mammalian
model system for alternative splicing, CD45, and genome-wide. We further show
that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to
reciprocal effects on exon 5 inclusion. These findings provide a mechanistic
basis for developmental regulation of splicing outcome through heritable
epigenetic marks.
DOI: 10.1038/nature10442
PMCID: PMC7398428
PMID: 21964334 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17189193 | 1. Mol Cell. 2006 Dec 28;24(6):917-29. doi: 10.1016/j.molcel.2006.12.002.
A genome-wide analysis indicates that yeast pre-mRNA splicing is predominantly
posttranscriptional.
Tardiff DF(1), Lacadie SA, Rosbash M.
Author information:
(1)Biology Department MS008, Howard Hughes Medical Institute, Brandeis
University, 415 South Street, Waltham, Massachusetts 02454, USA.
Recent ChIP experiments indicate that spliceosome assembly and splicing can
occur cotranscriptionally in S. cerevisiae. However, only a few genes have been
examined, and all have long second exons. To extend these studies, we analyzed
intron-containing genes with different second exon lengths by using ChIP as well
as whole-genome tiling arrays (ChIP-CHIP). The data indicate that U1 snRNP
recruitment is independent of exon length. Recursive splicing constructs, which
uncouple U1 recruitment from transcription, suggest that cotranscriptional U1
recruitment contributes to optimal splicing efficiency. In contrast, U2 snRNP
recruitment, as well as cotranscriptional splicing, is deficient on short second
exon genes. We estimate that > or =90% of endogenous yeast splicing is
posttranscriptional, consistent with an analysis of posttranscriptional
snRNP-associated pre-mRNA.
DOI: 10.1016/j.molcel.2006.12.002
PMCID: PMC1828117
PMID: 17189193 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20682973 | 1. Anticancer Res. 2010 Jul;30(7):2489-96.
Aberrant promoter hypermethylation and genomic hypomethylation in tumor,
adjacent normal tissues and blood from breast cancer patients.
Cho YH(1), Yazici H, Wu HC, Terry MB, Gonzalez K, Qu M, Dalay N, Santella RM.
Author information:
(1)Department of Environmental Health Sciences, Mailman School of Public Health,
Columbia University, 630 West 168 St. New York, NY 10032, USA.
BACKGROUND: Promoter hypermethylation and global hypomethylation in the human
genome are hallmarks of most cancers. Detection of aberrant methylation in white
blood cells (WBC) has been suggested as a marker for cancer development, but has
not been extensively investigated. This study was carried out to determine
whether aberrant methylation in WBC DNA can be used as a surrogate biomarker for
breast cancer risk.
PATIENTS AND METHODS: Promoter hypermethylation of 8 tumor suppressor genes
(RASSF1A, APC, HIN1, BRCA1, CYCLIND2, RARbeta, CDH1 and TWIST1) and DNA
methylation for three repetitive elements (LINE1, Sat2 and Alu) were analyzed in
invasive ductal carcinoma of the breast, paired adjacent normal tissue and WBC
from 40 breast cancer patients by the MethyLight assay. Methylation in WBC from
40 controls was also analyzed.
RESULTS: Tumor and adjacent tissues showed frequent hypermethylation for all
genes tested, while WBC DNA was rarely hypermethylated. For HIN1, RASSF1A, APC
and TWIST1, there was agreement between hypermethylation in tumor and adjacent
tissues (p=0.04, p=0.02, p=0.005 and p<0.0001, respectively). DNA methylation
for the three repetitive elements was lower in tumor compared to adjacent tissue
and WBC DNA. Significant correlations in the methylation of Sat2M1 between tumor
and adjacent tissues and WBC DNA were found (p<0.0001 and p=0.046,
respectively). There was also a significant difference in methylation of Sat2M1
between cases and controls (p=0.01).
CONCLUSION: These results suggest that further studies of WBC methylation,
including prospective studies, may provide biomarkers of breast cancer risk.
PMCID: PMC3568974
PMID: 20682973 [Indexed for MEDLINE] |