pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/22795129 | 1. Mol Cell. 2012 Aug 24;47(4):535-46. doi: 10.1016/j.molcel.2012.06.009. Epub
2012 Jul 12.
TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1.
Dibble CC(1), Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski
DJ, Murphy LO, Manning BD.
Author information:
(1)Department of Genetics and Complex Diseases, Harvard School of Public Health,
Boston, MA 02115, USA.
The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2
complex, which limits cell growth in response to poor growth conditions. Through
its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits
the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of
cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably
associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We
demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional
complex that senses specific cellular growth conditions and possesses Rheb-GAP
activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7
is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of
TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the
localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7
knockdown results in increased mTORC1 signaling, delayed induction of autophagy,
and enhanced cell growth under poor growth conditions.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2012.06.009
PMCID: PMC3693578
PMID: 22795129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9920104 | 1. J Clin Endocrinol Metab. 1999 Jan;84(1):336-41. doi: 10.1210/jcem.84.1.5398.
Phenocopies for deafness and goiter development in a large inbred Brazilian
kindred with Pendred's syndrome associated with a novel mutation in the PDS
gene.
Kopp P(1), Arseven OK, Sabacan L, Kotlar T, Dupuis J, Cavaliere H, Santos CL,
Jameson JL, Medeiros-Neto G.
Author information:
(1)Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern
University, Chicago, Illinois 60611, USA. [email protected]
Pendred's syndrome is an autosomal recessive disease characterized by goiter,
impaired iodide organification, and congenital sensorineural deafness. The gene
mutated in Pendred's syndrome, PDS (Pendred's syndrome gene), was cloned very
recently and encodes the putative sulfate transporter pendrin. Pendred's
syndrome may account for up to 10% of the cases with hereditary hearing loss,
and pendrin mutations have also been found in a kindred with non-syndromic
deafness. In this study, 41 individuals from a large, highly inbred pedigree
from Northeastern Brazil were examined for features of Pendred's syndrome.
Linkage studies and sequence analysis of the coding region of the PDS gene were
performed with DNA from 36 individuals. The index patient, with the classical
triad of deafness, positive perchlorate test, and goiter, was found to be
homozygous for a deletion of thymidine 279 in exon 3, resulting in a frameshift
and a premature stop codon at amino acid 96. This alteration resulted in
truncation of the protein in the first transmembrane domain. Two other patients
with deafness were found to be homozygous for this mutation; 19 were
heterozygous and 14 were homozygous for the wild type allele. Surprisingly, 6
deaf individuals in this kindred were not homozygous for the PDS gene mutation;
3 were heterozygous and 3 were homozygous for the wild type allele, suggesting a
probable distinct genetic cause for their deafness. All 3 homozygous individuals
for the PDS mutation had goiters. However, goiters were also found in 10
heterozygous individuals and in 6 individuals without the PDS mutation and are
most likely caused by iodine deficiency. In conclusion, we identified a novel
mutation in the PDS gene causing Pendred's syndrome. The comparison of phenotype
and genotype reveals, however, that phenocopies generated by distinct
environmental and/or genetic causes are present in this kindred and that the
diagnosis of Pendred's syndrome may be difficult without molecular analysis.
DOI: 10.1210/jcem.84.1.5398
PMID: 9920104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23117666 | 1. Ther Umsch. 2012 Nov;69(11):635-41. doi: 10.1024/0040-5930/a000341.
[New anticoagulants - direct factor Xa-inhibitors].
[Article in German]
Bächli E(1).
Author information:
(1)Medizinsche Klinik, Spital Uster. [email protected]
The direct oral factor Xa-inhibitors are at present in clinical use as
antithrombotics, after their efficiency and safety have been proved in clinical
studies. Three products are actually in the market, rivaroxaban (Xarelto®)
apixaban (Eliquis®) and edoxaban (Lixiana®). Efficacy and safety have been
tested for rivaroxaban and apixaban in large study programmes with more than
60'000 patients each. For edoxaban large phase III studies are under way. Based
on these data rivaroxaban was registered in the EU and CH for primary
prophylaxis against thrombosis after major orthopaedic surgery, such as hip- and
knee-joint protheses, for treatment and prophylaxis of deep vein thrombosis and
pulmonary embolism and for prophylaxis against thromboembolic stroke in patients
with atrial fibrillation. Apixaban is presently registered in the EU and CH for
prophylaxis against thrombosis after major orthopaedic surgery, Edoxaban is
registered only in Japan for the same indication. These products have been shown
to be non-inferior or superior compared with vitamin K antagonists or
low-molecular weight heparins, they are administered once or twice a day, they
do not need laboratory monitoring. But they have disadvantages also, they depend
on renal clearance, they can interact with other medicaments and they lack a
specific antidote. In total, though, they are considered as a progress for the
appropriate patients in terms of quality of treatment.
DOI: 10.1024/0040-5930/a000341
PMID: 23117666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22995770 | 1. Autophagy. 2012 Dec;8(12):1873-4. doi: 10.4161/auto.22185. Epub 2012 Sep 20.
The next generation proteasome inhibitors carfilzomib and oprozomib activate
prosurvival autophagy via induction of the unfolded protein response and ATF4.
Zang Y(1), Thomas SM, Chan ET, Kirk CJ, Freilino ML, DeLancey HM, Grandis JR, Li
C, Johnson DE.
Author information:
(1)Department of Medicine, University of Pittsburgh, University of Pittsburgh
Cancer Institute, Pittsburgh, PA, USA.
Comment on
Zang Y, Thomas SM, Chan ET, Kirk CJ, Freilino ML, Delancey HM, et al.
Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck
cancer and their activities are enhanced by suppression of Mcl-1 or autophagy.
Clin Cancer Res. 2012;18:5639–49. doi: 10.1158/1078-0432.CCR-12-1213.
The proteasome inhibitor bortezomib has shown remarkable clinical success in the
treatment of multiple myeloma. However, the efficacy and mechanism of action of
bortezomib in solid tumor malignancies is less well understood. In addition, the
use of this first-in-class proteasome inhibitor is limited by several factors,
including off-target effects that lead to adverse toxicities. We recently
reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class
proteasome inhibitors with higher specificities and reduced toxicities, against
head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib
potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both
compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which
serves to mediate and attenuate, respectively, the killing activities of these
proteasome inhibitors. Both compounds also induce complete autophagic flux that
is partially dependent on activation of the unfolded protein response (UPR) and
upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to
promote HNSCC cell survival. Our study indicates that the therapeutic benefit of
these promising proteasome inhibitors may be improved by inhibiting MCL1
expression or autophagy.
DOI: 10.4161/auto.22185
PMCID: PMC3541310
PMID: 22995770 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24661624 | 1. BMC Genomics. 2014 Mar 25;15:229. doi: 10.1186/1471-2164-15-229.
Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2
through an AtxA-dependent mechanism.
McKenzie AT, Pomerantsev AP(1), Sastalla I, Martens C, Ricklefs SM, Virtaneva K,
Anzick S, Porcella SF, Leppla SH.
Author information:
(1)Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
[email protected].
BACKGROUND: Upon infection of a mammalian host, Bacillus anthracis responds to
host cues, and particularly to elevated temperature (37°C) and bicarbonate/CO2
concentrations, with increased expression of virulence factors that include the
anthrax toxins and extracellular capsular layer. This response requires the
presence of the pXO1 virulence plasmid-encoded pleiotropic regulator AtxA. To
better understand the genetic basis of this response, we utilized a controlled
in vitro system and Next Generation sequencing to determine and compare RNA
expression profiles of the parental strain and an isogenic AtxA-deficient strain
in a 2 × 2 factorial design with growth environments containing or lacking
carbon dioxide.
RESULTS: We found 15 pXO1-encoded genes and 3 chromosomal genes that were
strongly regulated by the separate or synergistic actions of AtxA and carbon
dioxide. The majority of the regulated genes responded to both AtxA and carbon
dioxide rather than to just one of these factors. Interestingly, we identified
two previously unrecognized small RNAs that are highly expressed under
physiological carbon dioxide concentrations in an AtxA-dependent manner.
Expression levels of the two small RNAs were found to be higher than that of any
other gene differentially expressed in response to these conditions. Secondary
structure and small RNA-mRNA binding predictions for the two small RNAs suggest
that they may perform important functions in regulating B. anthracis virulence.
CONCLUSIONS: A majority of genes on the virulence plasmid pXO1 that are
regulated by the presence of either CO2 or AtxA separately are also regulated
synergistically in the presence of both. These results also elucidate novel
pXO1-encoded small RNAs that are associated with virulence conditions.
DOI: 10.1186/1471-2164-15-229
PMCID: PMC3987803
PMID: 24661624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9934984 | 1. Am J Med Genet. 1999 Jan 15;82(2):170-6. doi:
10.1002/(sici)1096-8628(19990115)82:2<170::aid-ajmg14>3.0.co;2-x.
TWIST gene mutation in a patient with radial aplasia and craniosynostosis:
further evidence for heterogeneity of Baller-Gerold syndrome.
Gripp KW(1), Stolle CA, Celle L, McDonald-McGinn DM, Whitaker LA, Zackai EH.
Author information:
(1)Division of Human Genetics and Molecular Biology, The Children's Hospital of
Philadelphia, Pennsylvania 19104, USA.
The term Baller-Gerold syndrome was coined by Cohen [1979: Birth Defects 15(5B):
13-63] to designate the phenotype of craniosynostosis and radial aplasia. It is
thought to be a rare autosomal recessive condition, which, in some patients,
presents with additional abnormalities, such as polymicrogyria, mental
retardation or anal atresia. A phenotypic overlap of Baller-Gerold and
Roberts-SC phocomelia syndrome was noted when a patient with bicoronal
synostosis and bilateral radial hypoplasia was found to have premature
centromere separation, a finding characteristic of Roberts syndrome [Huson et
al.,1990: J Med Genet 27:371-375]. Other cases of presumed Baller-Gerold
syndrome were rediagnosed as Fanconi pancytopenia, Rothmund-Thomson syndrome or
VACTERL association. These reports led to a narrowed redefinition of
Baller-Gerold syndrome based on the exclusion of cytogenetic and hematopoetic
abnormalities and the absence of additional malformations in patients with
craniosynostosis and preaxial upper limb abnormalities. Here we report on a
patient with unilateral radial aplasia and bicoronal synostosis without
additional malformations and without chromosome breakage, who fits this narrow
definition of Baller-Gerold syndrome. We identified a novel TWIST gene mutation
in this patient, a Glu181Stop mutation predicting a premature termination of the
protein carboxy-terminal to the helix 2 domain. This report provides further
evidence that Baller-Gerold is of heterogeneous cause, and a thorough evaluation
is indicated to identify a possibly more specific diagnosis, including
Saethre-Chotzen syndrome. This differential diagnosis is of particular
importance, as it is an autosomal dominant trait. Therefore, the recurrence risk
for parents of an affected child can be 50% if one parent carries the mutation,
as opposed to the 25% recurrence risk for autosomal recessive inheritance.
Offspring of the affected patient also have a 50% risk to inherit the mutation,
while the risk to bear an affected offspring for an autosomal recessive trait is
very low.
DOI: 10.1002/(sici)1096-8628(19990115)82:2<170::aid-ajmg14>3.0.co;2-x
PMID: 9934984 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7582897 | 1. Structure. 1995 Aug 15;3(8):805-14. doi: 10.1016/s0969-2126(01)00215-5.
Structure and function of a virally encoded fungal toxin from Ustilago maydis: a
fungal and mammalian Ca2+ channel inhibitor.
Gu F(1), Khimani A, Rane SG, Flurkey WH, Bozarth RF, Smith TJ.
Author information:
(1)Department of Biological Sciences, Purdue University, West Lafayette, IN
47907, USA.
BACKGROUND: The P4 strain of the corn smut fungus, Ustilago maydis, secretes a
fungal toxin, KP4, encoded by a fungal virus (UMV4) that persistently infects
its cells. UMV4, unlike most other (non-fungal) viruses, does not spread to
uninfected cells by release into the extracellular milieu during its normal life
cycle and is thus dependent upon host survival for replication. In symbiosis
with the host fungus, UMV4 encodes KP4 to kill other competitive strains of U.
maydis, thereby promoting both host and virus survival. KP4 belongs to a family
of fungal toxins and determining its structure should lead to a better
understanding of the function and evolutionary origins of these toxins.
Elucidation of the mechanism of toxin action could lead to new anti-fungal
agents against human pathogens.
RESULTS: We have determined the atomic structure of KP4 to 1.9 A resolution. KP4
belongs to the alpha/beta-sandwich family, and has a unique topology comprising
a five-stranded antiparallel beta-sheet with two antiparallel alpha-helices
lying at approximately 45 degrees to these strands. The structure has two
left-handed beta alpha beta cross-overs and a basic protuberance extending from
the beta-sheet. In vivo experiments demonstrated abrogation of toxin killing by
Ca2+ and, to a lesser extent, Mg2+. These results led to experiments
demonstrating that the toxin specifically inhibits voltage-gated Ca2+ channels
in mammalian cells.
CONCLUSIONS: Similarities, although somewhat limited, between KP4 and scorpion
toxins led us to investigate the possibility that the toxic effects of KP4 may
be mediated by inhibition of cation channels. Our results suggest that certain
properties of fungal Ca2+ channels are homologous to those in mammalian cells.
KP4 may, therefore, be a new tool for studying mammalian Ca2+ channels and
current mammalian Ca2+ channel inhibitors may be useful lead compounds for new
anti-fungal agents.
DOI: 10.1016/s0969-2126(01)00215-5
PMID: 7582897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24898252 | 1. J Biol Chem. 2014 Jul 18;289(29):20359-69. doi: 10.1074/jbc.M114.557249. Epub
2014 Jun 4.
Cocrystal structures of glycyl-tRNA synthetase in complex with tRNA suggest
multiple conformational states in glycylation.
Qin X(1), Hao Z(1), Tian Q(1), Zhang Z(1), Zhou C(2), Xie W(3).
Author information:
(1)From the Key Laboratory of Gene Engineering of the Ministry of Education,
State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen
University, Guangzhou 510275, China, Center for Cellular and Structural Biology,
The Sun Yat-Sen University, 132 E. Circle, University City, Guangzhou 510006,
China, and.
(2)Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York,
New York 10065.
(3)From the Key Laboratory of Gene Engineering of the Ministry of Education,
State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen
University, Guangzhou 510275, China, Center for Cellular and Structural Biology,
The Sun Yat-Sen University, 132 E. Circle, University City, Guangzhou 510006,
China, and [email protected].
Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically
charges tRNA molecules with cognate amino acids for protein synthesis.
Glycyl-tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA
synthetases due to its divergent quaternary structure and abnormal charging
properties. In the past decade, mutations of human GlyRS (hGlyRS) were also
found to be associated with Charcot-Marie-Tooth disease. However, the mechanisms
of traditional and alternative functions of hGlyRS are poorly understood due to
a lack of studies at the molecular basis. In this study we report crystal
structures of wild type and mutant hGlyRS in complex with tRNA and with small
substrates and describe the molecular details of enzymatic recognition of the
key tRNA identity elements in the acceptor stem and the anticodon loop. The
cocrystal structures suggest that insertions 1 and 3 work together with the
active site in a cooperative manner to facilitate efficient substrate binding.
Both the enzyme and tRNA molecules undergo significant conformational changes
during glycylation. A working model of multiple conformations for hGlyRS
catalysis is proposed based on the crystallographic and biochemical studies.
This study provides insights into the catalytic pathway of hGlyRS and may also
contribute to our understanding of Charcot-Marie-Tooth disease.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M114.557249
PMCID: PMC4106348
PMID: 24898252 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19409451 | 1. Neuroscience. 2009 Sep 15;162(4):1039-54. doi:
10.1016/j.neuroscience.2009.04.064. Epub 2009 May 3.
Pannexin1 in the outer retina of the zebrafish, Danio rerio.
Prochnow N(1), Hoffmann S, Vroman R, Klooster J, Bunse S, Kamermans M,
Dermietzel R, Zoidl G.
Author information:
(1)Department of Neuroanatomy and Molecular Brain Research, Ruhr University,
University Street 150, D-44780 Bochum, Germany.
In the retina, chemical and electrical synapses couple neurons into functional
networks. New candidates encoding for electrical synapse proteins have recently
emerged. In the present study, we determined the localization of the candidate
protein pannexin1 (zfPanx1) in the zebrafish retina and studied the functional
properties of zfPanx1 exogenously expressed in Neuroblastoma 2a (N2a) cells.
zfPanx1 was identified on the surface of horizontal cell dendrites invaginating
deeply into the cone pedicle near the glutamate release sites of the cones,
providing in vivo evidence for hemichannel formation at that location. This
strategic position of zfPanx1 in the photoreceptor synapse could potentially
allow modulation of cone output. Using whole cell voltage clamp and excised
patch recordings of transfected N2a cells, we demonstrated that zfPanx1 forms
voltage-activated hemichannels with a large unitary conductance in vitro. These
channels can open at physiological membrane potentials. Functional channels were
not formed following mutation of a single amino acid within a conserved protein
motif recently shown to be N-glycosylated in rodent Panx1. Together, these
findings indicate that zfPanx1 displays properties similar to its mammalian
homologues and can potentially play an important role in functions of the outer
retina.
DOI: 10.1016/j.neuroscience.2009.04.064
PMID: 19409451 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16937372 | 1. Dev Dyn. 2006 Nov;235(11):2961-8. doi: 10.1002/dvdy.20930.
Knockdown of the cAMP-dependent protein kinase (PKA) Type Ialpha regulatory
subunit in mouse oocytes disrupts meiotic arrest and results in meiotic spindle
defects.
Duncan FE(1), Moss SB, Williams CJ.
Author information:
(1)Center for Research on Reproduction and Women's Health, University of
Pennsylvania, Philadelphia, Pennsylvania, USA.
In mammalian oocytes, cyclic AMP-dependent protein kinase (PKA) is responsible
for maintaining meiotic arrest. We examined the role of the predominant
regulatory subunit, RIalpha in regulating PKA activity during mouse oocyte
maturation by knocking down the protein levels using an RNA interference
approach. In oocytes in which RIalpha protein was reduced to non-detectable
levels, compensatory decreases were also observed in the RIIalpha and catalytic
(Calpha) subunit levels. These oocytes resumed meiosis, despite culture under
conditions that maintain elevated intracellular cAMP levels, suggesting that the
remaining Calpha was not sufficient to maintain meiotic arrest. The resulting
eggs, however, displayed meiotic spindle abnormalities and abnormal cleavage
planes leading to extrusion of large polar bodies. These results demonstrate
that RIalpha is required for regulating PKA activity in maturing oocytes and
that compensatory upregulation of RII does not occur. Furthermore, we implicate
PKA as a modulator of spindle morphology and function during meiosis.
(c) 2006 Wiley-Liss, Inc.
DOI: 10.1002/dvdy.20930
PMID: 16937372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22096721 | 1. Int J Surg Case Rep. 2011;2(7):181-4. doi: 10.1016/j.ijscr.2011.06.001. Epub
2011 Jul 6.
Sigmoid endometriosis and a diagnostic dilemma - A case report and literature
review.
Nasim H(1), Sikafi D, Nasr A.
Author information:
(1)Department of Surgery, Our Lady of Lourdes Hospital, Drogheda, 1, Ard
Seascann Blackrock Road, Dundalk, Co. Louth, Ireland.
INTRODUCTION: Intestinal endometriosis is often an infrequently considered
diagnosis in female of childbearing age by general surgeon. There is a delay in
diagnosis because of constellation of symptoms and lack of specific diagnostic
modalities. Patients suffer from intestinal endometriosis for many years before
they are diagnosed. Often, such patients are labelled with irritable bowel
syndrome. Intestinal endometriosis has a diagnostic time delay of 8-11 years due
to its non-specific clinical features and multi-system involvement.
PRESENTATION OF CASE: Our patient was a 32 years old Caucasian female who was
referred to us with features of intestinal obstruction. Despite repeated
clinical assessments and use of different diagnostic modalities the diagnosis
was still inconclusive even after 21 days of her first presentation to primary
care physician. She had an exploratory laparotomy, sigmoid colectomy, and
Hartmann's procedure with a temporary colostomy with us. Histopathology
confirmed endometriosis and also showed melanosis coli. She was referred to the
gynaecological team for review and follow up.
DISCUSSION: Intestinal endometriosis should be considered as a differential
diagnosis in female patients of childbearing age group presenting with
non-specific gastrointestinal signs and symptoms. Our patient manifested
intestinal endometriosis and melanosis coli on histopathology suggesting
symptoms of long duration.
CONCLUSION: Bowel endometriosis is a less considered and often ignored
differential diagnosis in acute and chronic abdomen. This condition has
considerable effect on patient's health both physically and psychologically.
DOI: 10.1016/j.ijscr.2011.06.001
PMCID: PMC3199679
PMID: 22096721 |
http://www.ncbi.nlm.nih.gov/pubmed/1521479 | 1. Cutis. 1992 Apr;49(4):265-8.
Acrokeratosis paraneoplastica of Bazex: report of a case in a young black woman.
Baxter DL Jr(1), Kallgren DL, Leone KC.
Author information:
(1)Department of Dermatology, National Naval Medical Center, Bethesda, Maryland.
Acrokeratosis paraneoplastica of Bazex is a rare cutaneous syndrome associated
with malignant neoplasms of the pulmonary and upper gastrointestinal tract, or
cervical metastatic adenopathy, usually seen in middle-aged white men. We
present a unique case of Bazex syndrome in that the patient was young, black,
and a woman.
PMID: 1521479 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23827649 | 1. Cytokine Growth Factor Rev. 2013 Oct;24(5):401-9. doi:
10.1016/j.cytogfr.2013.06.001. Epub 2013 Jul 1.
Osteoprotegerin: multiple partners for multiple functions.
Baud'huin M(1), Duplomb L, Teletchea S, Lamoureux F, Ruiz-Velasco C, Maillasson
M, Redini F, Heymann MF, Heymann D.
Author information:
(1)INSERM, UMR957, Nantes F-44035, France; Université de Nantes, Nantes
atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse
et Thérapie des Tumeurs Osseuses Primitives, Nantes F-44035, France; CHU, Hôtel
Dieu, Nantes, France. Electronic address: [email protected].
Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to
its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB
ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation.
However, there are additional ligands of OPG that confer various biological
functions. OPG can promote cell survival, cell proliferation and facilitates
migration by binding TNF-related apoptosis inducing ligand (TRAIL),
glycosaminoglycans or proteoglycans. A large number of in vitro, pre-clinical
and clinical studies provide evidences of OPG involvement in vascular, bone,
immune and tumor biology. This review describes an overview of the different OPG
ligands regulating its biological functions.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cytogfr.2013.06.001
PMID: 23827649 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12239580 | 1. Int J Mol Med. 2002 Oct;10(4):367-70.
Hirschsprung, RET-SOX and beyond: the challenge of examining non-mendelian
traits (Review).
Pusch CM(1), Sasiadek MM, Blin N.
Author information:
(1)Division of Molecular Genetics, University of Tübingen, 72074 Tubingen,
Germany.
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a common
hereditary disorder causing intestinal obstruction, thereby showing considerable
phenotypic variation in conjunction with complex inheritance. Moreover,
phenotypic assessment of the disease has been complicated since a subset of the
observed mutations is also associated with several additional syndromic
anomalies. Coding sequence mutations in e.g. RET, GDNF, EDNRB, EDN3, and SOX10
lead to long-segment (L-HSCR) as well as syndromic HSCR but fail to explain the
transmission of the much more common short-segment form (S-HSCR). Furthermore,
mutations in the RET gene are responsible for approximately half of the familial
and some sporadic cases, strongly suggesting, on the one hand, the importance of
non-coding variations and, on the other hand, that additional genes involved in
the development of the enteric nervous system still await their discovery. For
almost all of the identified HSCR genes incomplete penetrance of the HSCR
phenotype has been reported, probably due to modifier loci. Therefore, HSCR has
become a model for a complex oligo-/polygenic disorder in which the relationship
between different genes creating a non-mendelian inheritance pattern still
remains to be elucidated.
PMID: 12239580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24548192 | 1. Pediatr Int. 2014 Feb;56(1):1-5. doi: 10.1111/ped.12274.
Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint
Committee of the Japanese Society of Nephrology and the Japan Pediatric Society.
Sawai T(1), Nangaku M, Ashida A, Fujimaru R, Hataya H, Hidaka Y, Kaname S, Okada
H, Sato W, Yasuda T, Yoshida Y, Fujimura Y, Hattori M, Kagami S.
Author information:
(1)Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of
microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.
Recently, abnormalities in the mechanisms underlying complement regulation have
been focused upon as causes of aHUS. The prognosis for patients who present with
aHUS is very poor, with the first aHUS attack being associated with a mortality
rate of approximately 25%, and with approximately 50% of cases resulting in
end-stage renal disease requiring dialysis. If treatment is delayed, there is a
high risk of this syndrome progressing to renal failure. Therefore, we have
developed diagnostic criteria for aHUS to enable its early diagnosis and to
facilitate the timely initiation of appropriate treatment. We hope these
diagnostic criteria will be disseminated to as many clinicians as possible and
that they will be used widely.
© 2014 Japan Pediatric Society and Japanese Society of Nephrology.
DOI: 10.1111/ped.12274
PMID: 24548192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20811384 | 1. Nat Rev Drug Discov. 2010 Oct;9(10):767-74. doi: 10.1038/nrd3229. Epub 2010
Sep 3.
Development trends for human monoclonal antibody therapeutics.
Nelson AL(1), Dhimolea E, Reichert JM.
Author information:
(1)Tufts University School of Medicine, Boston, Massachusetts 02118, USA.
Fully human monoclonal antibodies (mAbs) are a promising and rapidly growing
category of targeted therapeutic agents. The first such agents were developed
during the 1980s, but none achieved clinical or commercial success. Advances in
technology to generate the molecules for study - in particular, transgenic mice
and yeast or phage display - renewed interest in the development of human mAbs
during the 1990s. In 2002, adalimumab became the first human mAb to be approved
by the US Food and Drug Administration (FDA). Since then, an additional six
human mAbs have received FDA approval: panitumumab, golimumab, canakinumab,
ustekinumab, ofatumumab and denosumab. In addition, 3 candidates (raxibacumab,
belimumab and ipilimumab) are currently under review by the FDA, 7 are in Phase
III studies and 81 are in either Phase I or II studies. Here, we analyse data on
147 human mAbs that have entered clinical study to highlight trends in their
development and approval, which may help inform future studies of this class of
therapeutic agents.
DOI: 10.1038/nrd3229
PMID: 20811384 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22859826 | 1. J Infect Dis. 2012 Oct;206(8):1260-8. doi: 10.1093/infdis/jis488. Epub 2012
Aug 2.
A large, population-based study of 2009 pandemic Influenza A virus subtype H1N1
infection diagnosis during pregnancy and outcomes for mothers and neonates.
Hansen C(1), Desai S, Bredfeldt C, Cheetham C, Gallagher M, Li DK, Raebel MA,
Riedlinger K, Shay DK, Thompson M, Davis RL.
Author information:
(1)Center for Health Research, Kaiser Permanente Georgia, GA 30305, USA.
[email protected]
BACKGROUND: Pregnant women were at increased risk for serious outcomes of 2009
pandemic influenza A virus subtype H1N1 (influenza A[H1N1]pdm09) infection, but
little is known about the overall impact of the pandemic on neonatal and
maternal outcomes.
METHODS: We identified live births that occurred from 1 July 2008 through 31 May
2010 in 5 Kaiser Permanente regions. Pregnant women were considered to have
influenza if they had a positive result of a laboratory test for influenza virus
or if they received a diagnosis of influenza during a period in which seasonal
influenza virus or A(H1N1)pdm09 was the predominant circulating virus.
RESULTS: There were 111 158 births from 109 015 pregnancies involving 107 889
mothers; 368 pregnant women (0.3%) received a diagnosis of influenza due to
seasonal virus, and 959 (0.9%) received a diagnosis of influenza due to
A(H1N1)pdm09; 107 688 did not receive an influenza diagnosis. Pregnant women
with influenza due to A(H1N1)pdm09 were more likely than women with seasonal
influenza infection to be hospitalized within 30 days of the diagnosis (27% vs
12%; odds ratio [OR], 2.84 [95% confidence interval {CI}, 2.01-4.02]). Pregnant
women with A(H1N1)pdm09 who started antiviral treatment ≥2 days after the
diagnosis were significantly more likely to be hospitalized than those who
started antiviral treatment <2 days after diagnosis (OR, 3.43 [95% CI,
1.55-7.56]). Mothers with seasonal influenza virus infection had an increased
risk for having a small-for-gestational-age infant (OR, 1.59 [95% CI,
1.15-2.20]).
CONCLUSIONS: In this large, geographically diverse population, A(H1N1)pdm09
infection increased the risk for hospitalization during pregnancy. Late
initiation of antiviral treatment was also associated with an increased risk for
hospitalization.
DOI: 10.1093/infdis/jis488
PMID: 22859826 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20860806 | 1. BMC Med Genet. 2010 Sep 22;11:137. doi: 10.1186/1471-2350-11-137.
Novel association of severe neonatal encephalopathy and Hirschsprung disease in
a male with a duplication at the Xq28 region.
Fernández RM(1), Núñez-Torres R, González-Meneses A, Antiñolo G, Borrego S.
Author information:
(1)Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal,
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del
Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
BACKGROUND: Hirschsprung disease (HSCR) is a neurocristopathy characterized by
the absence of parasympathetic intrinsic ganglion cells in the submucosal and
myenteric plexuses along a variable portion of the intestinal tract. In
approximately 18% of the cases HSCR also presents with multiple congenital
anomalies including recognized syndromes.
METHODS: A combination of MLPA and microarray data analysis have been undertaken
to refine a duplication at the Xq28 region.
RESULTS: In this study we present a new clinical association of severe neonatal
encephalopathy (Lubs syndrome) and HSCR, in a male patient carrying a
duplication at the Xq28 region which encompasses the MECP2 and L1CAM genes.
CONCLUSIONS: While the encephalopathy has been traditionally attributed to the
MECP2 gene duplication in patients with Lubs syndrome, here we propose that the
enteric phenotype in our patient might be due to the dosage variation of the
L1CAM protein, together with additional molecular events not identified yet.
This would be in agreement with the hypothesis previously forwarded that
mutations in L1CAM may be involved in HSCR development in association with a
predisposing genetic background.
DOI: 10.1186/1471-2350-11-137
PMCID: PMC2955569
PMID: 20860806 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17211467 | 1. Br J Cancer. 2007 Jan 29;96(2):269-76. doi: 10.1038/sj.bjc.6603553. Epub 2007
Jan 9.
Potentiation of antitumour activity of docetaxel by combination with trastuzumab
in a human prostate cancer xenograft model and underlying mechanisms.
Legrier ME(1), Oudard S, Judde JG, Guyader C, de Pinieux G, Boyé K, de Cremoux
P, Dutrillaux B, Poupon MF.
Author information:
(1)Section Recherche, Institut Curie, U612 INSERM, 26 rue d'Ulm, Paris 75248,
France.
Antitumour activity of docetaxel (Taxotere) in hormone-dependent (HD) and
hormone-independent (HID) prostate cancer PAC120 xenograft model was previously
reported, and its level was associated with HER2 protein expression. In the
present study, we evaluate the antitumour effects of docetaxel combined with
trastuzumab (Herceptin), an anti-HER2 antibody. Although trastuzumab alone had
no effect on tumour growth, it potentiated the antitumour activity of docetaxel
in HD tumours and more strongly in HID variants. Using the HID28 variant, we
show that docetaxel treatment of tumour-bearing mice induces an increased HER2
mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel
treatment, while HER2 protein and p-AKT decreased. This was followed by an
increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a
strong HER2 release in the serum of treated mice; expression of phospho-ERK,
p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were
induced by docetaxel plus trastuzumab combination, except for that there was a
transient and complete disappearance of AR and HSP90 proteins 24 h after
treatment. We show that in addition to its known effects on tubulin and mitotic
spindles, docetaxel induces complex signalisation pathway mechanisms in
surviving cells, including HER2, which can be pharmacologically targeted. This
study suggests that the docetaxel/trastuzumab combination may prove an effective
therapeutic approach for HER2-expressing hormone-refractory prostate cancer.
DOI: 10.1038/sj.bjc.6603553
PMCID: PMC2359985
PMID: 17211467 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17955513 | 1. Am J Med Genet A. 2007 Dec 15;143A(24):2931-6. doi: 10.1002/ajmg.a.31946.
Craniosynostosis associated with distal 5q-trisomy: further evidence that extra
copy of MSX2 gene leads to craniosynostosis.
Wang JC(1), Steinraths M, Dang L, Lomax B, Eydoux P, Stockley T, Yong SL, Van
Allen MI.
Author information:
(1)Cytogenetics Laboratory, Hamilton Regional Laboratory Medicine Program,
Hamilton Health Sciences, Hamilton, Ontario, Canada. [email protected]
Distal 5q-trisomy has been reported in less than 30 patients, with
craniosynostosis present in five. We report two new patients with distal
5q-trisomy craniosynostosis. Patient 1 had mild Kleeblattschädel with synostosis
of multiple sutures together with wide and medially deviated thumbs and
halluces, indicative of Pfeiffer syndrome. Cytogenetic and CGH analyses showed a
karyotype of 46,XY,der(10)t(5;10)(q33;q26.3). Patient 2 had a prominent forehead
and ridging of the metopic suture. Craniosynostosis of the metopic suture was
shown by CT scan. Cytogenetic and CGH analyses disclosed a karyotype of
46,XX,der(17)t(5;17)(q35.1;p13.3). Of the 22 previously reported patients, all
had microcephaly and 14 had an abnormal skull shape. Our results support the
previous finding that distal 5q-trisomy together with an extra copy of the MSX2
gene leads to abnormal closure of sutures and craniosynostosis.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.31946
PMID: 17955513 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17689048 | 1. Genomics. 2007 Oct;90(4):530-41. doi: 10.1016/j.ygeno.2007.06.011. Epub 2007
Aug 3.
Plant cytosine-5 DNA methyltransferases: structure, function, and molecular
evolution.
Pavlopoulou A(1), Kossida S.
Author information:
(1)Biomedical Research Foundation of the Academy of Athens, Department of
Biotechnology, Bioinformatics & Medical Informatics Team, Soranou Efesiou 4,
11527 Athens, Greece.
A detailed analysis of the structure and function, along with evolutionary
aspects, of the main plant cytosine-5 DNA methyltransferases (C5-MTases) is
presented. The evolutionary relationships between the already known and four
candidate plant C5-MTases identified in this work were investigated using the
distance, maximum-parsimony, and maximum-likelihood approaches. The topologies
of the trees were overall congruent: four monophyletic groups corresponding to
the four plant C5-MTase families were clearly distinguished. In addition,
sequence analyses of the plant C5-MTase target recognition domain sequences were
performed and phylogenetic trees were reconstructed showing that there is good
conservation among but not within the plant C5-MTase families. Furthermore, a
conserved dipeptide that plays an important role in flipping the target base
into the catalytic site of the C5-MTases was identified in all plant C5-MTases
under study.
DOI: 10.1016/j.ygeno.2007.06.011
PMID: 17689048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24691094 | 1. J Am Coll Cardiol. 2014 Jun 17;63(23):2531-2540. doi:
10.1016/j.jacc.2014.03.018. Epub 2014 Mar 29.
Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized,
controlled phase III clinical trial of evolocumab.
Koren MJ(1), Lundqvist P(2), Bolognese M(3), Neutel JM(4), Monsalvo ML(5), Yang
J(5), Kim JB(5), Scott R(5), Wasserman SM(5), Bays H(6); MENDEL-2 Investigators.
Author information:
(1)Jacksonville Center for Clinical Research, Jacksonville, Florida. Electronic
address: [email protected].
(2)Center for Clinical and Basic Research, Ballerup, Denmark.
(3)Bethesda Health Research Center, Bethesda, Maryland.
(4)Orange County Research Center, Tustin, California.
(5)Amgen Inc., Thousand Oaks, California.
(6)L-MARC Research Center, Louisville, Kentucky.
OBJECTIVES: The aim of this study was to compare biweekly and monthly evolocumab
with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase
III trial.
BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein
convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase
II trials.
METHODS: Patients 18 to 80 years of age with fasting low-density lipoprotein
cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were
randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly;
oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly;
ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly;
or oral placebo and evolocumab 420 mg monthly.
RESULTS: A total of 614 patients were randomized and administered doses.
Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more
than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons).
Evolocumab treatment also favorably altered other lipoprotein levels.
Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory
abnormalities were comparable across treatment groups.
CONCLUSIONS: In the largest monotherapy trial using a PCSK9 inhibitor to date,
evolocumab yielded significant LDL-C reductions compared with placebo or
ezetimibe and was well tolerated in patients with hypercholesterolemia.
(Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects
Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2];
NCT01763827).
Copyright © 2014 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2014.03.018
PMID: 24691094 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11781102 | 1. Biochemistry. 2002 Jan 15;41(2):618-27. doi: 10.1021/bi0112309.
Structural features underlying the multisite phosphorylation of the A domain of
the NF-AT4 transcription factor by protein kinase CK1.
Marin O(1), Burzio V, Boschetti M, Meggio F, Allende CC, Allende JE, Pinna LA.
Author information:
(1)Dipartimento di Chimica Biologica and Centro di Studio delle Biomembrane del
CNR, Università di Padova, viale G. Colombo 3, 35121 Padova, Italy.
The phosphorylation and dephosphorylation of the NF-AT family of transcription
factors play a key role in the activation of T lymphocytes and in the control of
the immune response. The mechanistic aspects of NF-AT4 phosphorylation by
protein kinase CK1 have been studied in this work with the aid of a series of 27
peptides, reproducing with suitable modifications the regions of NF-AT4 that
have been reported to be phosphorylated by this protein kinase. The largest
parent peptide, representing the three regions A, Z, and L spanning amino acids
173-218, is readily phosphorylated by CK1 at seryl residues belonging to the A2
segment, none of which fulfill the canonical consensus sequence for CK1. An
acidic cluster of amino acids in the linker region between domains A and Z is
essential for high-efficiency phosphorylation of the A2 domain, as shown by the
increase in K(m) caused by a deletion of the linker region or a substitution of
the acidic residues with glycines. Individual substitutions with alanine of each
of the five serines in the A2 domain (S-177, S-180, S-181, S-184, and S-186)
reduce the phosphorylation rate, the most detrimental effect being caused by
Ser177 substitution which results in a 10-fold drop in V(max). On the contrary,
the replacement of Ser177 with phosphoserine triggers a hierarchical effect with
a dramatic improvement in phosphorylation efficiency, which no longer depends on
the linker region for optimal efficiency. These data are consistent with a
two-phase phosphorylation mechanism of NF-AT4 by CK1, initiated by the linker
region which provides a functional docking site for CK1 and allows the
unorthodox phosphorylation of Ser177; once achieved, this phosphoserine residue
primes the phosphorylation of other downstream seryl residues, according to a
hierarchical mechanism typically exploited by CK1.
DOI: 10.1021/bi0112309
PMID: 11781102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22851818 | 1. J Obstet Gynaecol India. 2011 Aug;61(4):386-93. doi:
10.1007/s13224-011-0055-2. Epub 2011 Sep 23.
Influenza A H1N1 2009 (Swine Flu) and Pregnancy.
Lim BH, Mahmood TA.
The Influenza A H1N1 pandemic (A H1N1) occurred between June 2009 and August
2010. Although the pandemic is now over, the virus has emerged as the
predominant strain in the current seasonal influenza phase in the northern
hemisphere. The A H1N1 influenza is a novel strain of the influenza A virus and
is widely known as swine flu. The virus contains a mixture of genetic material
from human, pig and bird flu virus. It is a new variety of flu which people have
not had much immunity to. Much has been learnt from the Pandemic of 2009/2010
but the messages about vaccination and treatment seem to be taken slowly by the
clinical profession. Most people affected by the virus, including pregnant
women, suffer a mild viral illness, and make a full recovery. The median
duration of illness is around seven days. This influenza typically affects the
younger age group i.e. from the ages of 5-65 years. Current experience shows
that the age group experiencing increased morbidity and mortality rates are in
those under 65 years of age. Pregnant women, because of their altered immunity
and physiological adaptations, are at higher risk of developing pulmonary
complications, especially in the second and third trimesters. In the United
Kingdom, twelve maternal deaths were reported to be associated with the H1N1
virus during the pandemic and clear avoidable factors were identified (Modder,
Review of Maternal Deaths in the UK related to A H1N1 2009 influenza (CMACE).
www.cmace.org.uk, 2010). The pregnancy outcomes were also poor for women who
were affected by the virus with a fivefold increase in the perinatal mortality
rate and threefold increase in the preterm delivery rate (Yates et al. Health
Technol Assess 14(34):109-182, 2010). There continues to be a low uptake of the
flu vaccine and commencement of antiviral treatment for pregnant women.
DOI: 10.1007/s13224-011-0055-2
PMCID: PMC3295877
PMID: 22851818 |
http://www.ncbi.nlm.nih.gov/pubmed/23382875 | 1. PLoS One. 2013;8(1):e54136. doi: 10.1371/journal.pone.0054136. Epub 2013 Jan
24.
Molecular determinants of epidermal growth factor binding: a molecular dynamics
study.
Sanders JM(1), Wampole ME, Thakur ML, Wickstrom E.
Author information:
(1)Department of Biochemistry and Molecular Biology, Thomas Jefferson
University, Philadelphia, Pennsylvania, United States of America.
The epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine
kinase family that plays a role in multiple cellular processes. Activation of
EGFR requires binding of a ligand on the extracellular domain to promote
conformational changes leading to dimerization and transphosphorylation of
intracellular kinase domains. Seven ligands are known to bind EGFR with
affinities ranging from sub-nanomolar to near micromolar dissociation constants.
In the case of EGFR, distinct conformational states assumed upon binding a
ligand is thought to be a determining factor in activation of a downstream
signaling network. Previous biochemical studies suggest the existence of both
low affinity and high affinity EGFR ligands. While these studies have identified
functional effects of ligand binding, high-resolution structural data are
lacking. To gain a better understanding of the molecular basis of EGFR binding
affinities, we docked each EGFR ligand to the putative active state
extracellular domain dimer and 25.0 ns molecular dynamics simulations were
performed. MM-PBSA/GBSA are efficient computational approaches to approximate
free energies of protein-protein interactions and decompose the free energy at
the amino acid level. We applied these methods to the last 6.0 ns of each
ligand-receptor simulation. MM-PBSA calculations were able to successfully rank
all seven of the EGFR ligands based on the two affinity classes:
EGF>HB-EGF>TGF-α>BTC>EPR>EPG>AR. Results from energy decomposition identified
several interactions that are common among binding ligands. These findings
reveal that while several residues are conserved among the EGFR ligand family,
no single set of residues determines the affinity class. Instead we found
heterogeneous sets of interactions that were driven primarily by electrostatic
and Van der Waals forces. These results not only illustrate the complexity of
EGFR dynamics but also pave the way for structure-based design of therapeutics
targeting EGF ligands or the receptor itself.
DOI: 10.1371/journal.pone.0054136
PMCID: PMC3554757
PMID: 23382875 [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/19618470 | 1. Dev Dyn. 2009 Aug;238(8):2044-57. doi: 10.1002/dvdy.22028.
Diversification of the expression patterns and developmental functions of the
dishevelled gene family during chordate evolution.
Gray RS(1), Bayly RD, Green SA, Agarwala S, Lowe CJ, Wallingford JB.
Author information:
(1)Section of Molecular Cell and Developmental Biology, University of Texas,
Austin, Texas 78712, USA.
Dishevelled (Dvl) proteins are key transducers of Wnt signaling encoded by
members of a multi-gene family in vertebrates. We report here the divergent,
tissue-specific expression patterns for all three Dvl genes in Xenopus embryos,
which contrast dramatically with their expression patterns in mice. Moreover, we
find that the expression patterns of Dvl genes in the chick diverge
significantly from those of Xenopus. In addition, in hemichordates, an outgroup
to chordates, we find that the one Dvl gene is dynamically expressed in a
tissue-specific manner. Using knockdowns, we find that Dvl1 and Dvl2 are
required for early neural crest specification and for somite segmentation in
Xenopus. Most strikingly, we report a novel role for Dvl3 in the maintenance of
gene expression in muscle and in the development of the Xenopus sclerotome.
These data demonstrate that the expression patterns and developmental functions
of specific Dvl genes have diverged significantly during chordate evolution.
Copyright (c) 2009 Wiley-Liss, Inc.
DOI: 10.1002/dvdy.22028
PMCID: PMC2782374
PMID: 19618470 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22246341 | 1. Oncol Rep. 2012 Apr;27(4):1238-44. doi: 10.3892/or.2012.1625. Epub 2012 Jan
11.
Prognostic implications of microRNA-100 and its functional roles in human
epithelial ovarian cancer.
Peng DX(1), Luo M, Qiu LW, He YL, Wang XF.
Author information:
(1)Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical
University, Guangzhou 510282, PR China. [email protected]
Dysregulation of microRNAs (miRNAs) has been found to be associated with a
variety of diseases, including epithelial ovarian cancer (EOC). Recently,
miR-100 was reported to be downregulated in human ovarian carcinoma, however,
the clinical significance and functional roles of miR-100 expression in human
EOC are unclear. TaqMan real-time quantitative RT-PCR assay was performed to
detect the expression of miR-100 in 98 EOC tissues and 15 adjacent normal
epithelial tissues. The relationship between miR-100 expression and
clinicopathological factors in 98 EOC patients was statistically analyzed. The
effect of miR-100 expression on patient survival was determined. Finally, the
role of miR-100 in EOC cell growth and its possible mechanisms were analyzed
with miR-100 precursor or inhibitor-transfected cells. We showed that the level
of miR-100 was significantly lower in EOC tissues compared to adjacent normal
tissues. Low miR-100 expression was found to be closely correlated with advanced
FIGO stage, higher serum CA125 expression level and lymph node involvement.
Also, low miR-100 expression was correlated with shorter overall survival of EOC
patients, and multivariate analysis showed that the status of miR-100 expression
was an independent predictor of overall survival in EOC. Additionally, miR-100
could affect the growth of EOC cells by post-transcriptionally regulating
polo-like kinase 1 (PLK1) expression. Together, these results suggest that low
miR-100 expression may be an independent poor prognostic factor and miR-100 can
function as a tumor suppressor by targeting PLK1 in human EOCs.
DOI: 10.3892/or.2012.1625
PMCID: PMC3583406
PMID: 22246341 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23212918 | 1. J Biol Chem. 2013 Jan 25;288(4):2365-75. doi: 10.1074/jbc.M112.429159. Epub
2012 Dec 4.
Prolidase directly binds and activates epidermal growth factor receptor and
stimulates downstream signaling.
Yang L(1), Li Y, Ding Y, Choi KS, Kazim AL, Zhang Y.
Author information:
(1)Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, New
York 14263, USA.
Prolidase, also known as Xaa-Pro dipeptidase or peptidase D (PEPD), is a
ubiquitously expressed cytosolic enzyme that hydrolyzes dipeptides with proline
or hydroxyproline at the carboxyl terminus. In this article, however, we
demonstrate that PEPD directly binds to and activates epidermal growth factor
receptor (EGFR), leading to stimulation of signaling proteins downstream of
EGFR, and that such activity is neither cell-specific nor dependent on the
enzymatic activity of PEPD. In line with the pro-survival and pro-proliferation
activities of EGFR, PEPD stimulates DNA synthesis. We further show that PEPD
activates EGFR only when it is present in the extracellular space, but that PEPD
is released from injured cells and tissues and that such release appears to
result in EGFR activation. PEPD differs from all known EGFR ligands in that it
does not possess an epidermal growth factor (EGF) motif and is not synthesized
as a transmembrane precursor, but PEPD binding to EGFR can be blocked by EGF. In
conclusion, PEPD is a ligand of EGFR and presents a novel mechanism of EGFR
activation.
DOI: 10.1074/jbc.M112.429159
PMCID: PMC3554907
PMID: 23212918 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22186629 | 1. Lung Cancer. 2012 Jun;76(3):324-31. doi: 10.1016/j.lungcan.2011.11.019. Epub
2011 Dec 18.
CHD5, a tumor suppressor that is epigenetically silenced in lung cancer.
Zhao R(1), Yan Q, Lv J, Huang H, Zheng W, Zhang B, Ma W.
Author information:
(1)Institute of Molecular Biology, Southern Medical University, Guangzhou
510515, PR China. [email protected]
Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor
that serves as a master regulator of a tumor-suppressive network. Examination of
the role played by CHD5 in a wide range of human cancers is warranted. In this
study, we focused on the epigenetic modification and tumor-suppressive role of
CHD5 in lung cancer. We measured CHD5 mRNA and protein expression in lung cancer
cells, lung cancer tissues, and their corresponding noncancerous lung tissues
using real-time PCR and Western blot analysis. We then determined the
methylation status of the CHD5 promoter in these samples using
methylation-specific sequencing and analyzed CHD5 re-expression in lung cancer
cells treated with or without 5-aza-2-deoxycytidine, an inhibitor of DNA
methylation. Next, the lung cancer cell clones stably expressing EGFP-CHD5
protein or EGFP protein, respectively, were obtained and the effects of restored
CHD5 expression on cell proliferation, colony formation, and tumorigenicity were
assessed. CHD5 expression ranged from low to absent in the lung cancer cell
lines and tissues examined; the CHD5 promoter was hyperethylated in these
samples. Treatment with 5-aza-dC resulted in a localized decrease in methylation
density and an increase in CHD5 expression. Clonogenicity and tumor growth were
abrogated in A549 and H1299 cells upon restoration of CHD5 expression. A
significant reduction in clonogenicity was observed; an average of 47.83 ± 4.6%
reduction for A549-EGFP-CHD5 was observed compared to A549-EGFP, and an average
of 56.39 ± 5.3% reduction for H1299-EGFP-CHD5 was observed compared to
H1299-EGFP. A549-EGFP exhibited an average tumor size of 452.3 ± 36.5 mm(3),
whereas A549-EGFP-CHD5 exhibited an average tumor size of only 57.7 ± 18.5
mm(3). Thus, our findings indicate that CHD5 is a potential tumor suppressor
gene that is inactivated via an epigenetic mechanism in lung cancer.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.lungcan.2011.11.019
PMID: 22186629 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11532143 | 1. Mol Microbiol. 2001 Aug;41(4):775-85. doi: 10.1046/j.1365-2958.2001.02554.x.
KP4 fungal toxin inhibits growth in Ustilago maydis by blocking calcium uptake.
Gage MJ(1), Bruenn J, Fischer M, Sanders D, Smith TJ.
Author information:
(1)Donald Danforth Plant Science Center, 7425 Forsyth Boulevard, Box 1098, St
Louis, MO 63105, USA.
KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of
Ustilago maydis. From our previous structural studies, it seemed unlikely that
KP4 acts by forming channels in the target cell membrane. Instead, KP4 was
proposed to act by blocking fungal calcium channels, as KP4 was shown to inhibit
voltage-gated calcium channels in rat neuronal cells, and its effects on fungal
cells were abrogated by exogenously added calcium. Here, we extend these studies
and demonstrate that KP4 acts in a reversible manner on the cell membrane and
does not kill the cells, but rather inhibits cell division. This action is
mimicked by EGTA and is abrogated specifically by low concentrations of calcium
or non-specifically by high ionic strength buffers. We also demonstrate that KP4
affects (45)Ca uptake in U. maydis. Finally, we show that cAMP and a cAMP
analogue, N 6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate, both abrogate
KP4 effects. These results suggest that KP4 may inhibit cell growth and division
by blocking calcium-regulated signal transduction pathways.
DOI: 10.1046/j.1365-2958.2001.02554.x
PMID: 11532143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24321385 | 1. Biochim Biophys Acta. 2014 Jan;1839(1):50-61. doi:
10.1016/j.bbagrm.2013.11.007. Epub 2013 Dec 7.
Cohesin and CTCF differentially regulate spatiotemporal runx1 expression during
zebrafish development.
Marsman J(1), O'Neill AC(1), Kao BR(1), Rhodes JM(1), Meier M(1), Antony J(1),
Mönnich M(1), Horsfield JA(2).
Author information:
(1)Department of Pathology, Dunedin School of Medicine, The University of Otago,
P.O. Box 913, Dunedin, New Zealand.
(2)Department of Pathology, Dunedin School of Medicine, The University of Otago,
P.O. Box 913, Dunedin, New Zealand. Electronic address:
[email protected].
Runx1 is a transcription factor essential for definitive hematopoiesis. In all
vertebrates, the Runx1 gene is transcribed from two promoters: a proximal
promoter (P2), and a distal promoter (P1). We previously found that runx1
expression in a specific hematopoietic cell population in zebrafish embryos
depends on cohesin. Here we show that zebrafish runx1 is directly bound by
cohesin and CCCTC binding factor (CTCF) at the P1 and P2 promoters, and within
the intron between P1 and P2. Cohesin initiates expression of runx1 in the
posterior lateral mesoderm and influences promoter use, while CTCF represses its
expression in the newly emerging cells of the tail bud. The intronic binding
sites for cohesin and CTCF coincide with histone modifications that confer
enhancer-like properties, and two of the cohesin/CTCF sites behaved as
insulators in an in vivo assay. The identified cohesin and CTCF binding sites
are likely to be cis-regulatory elements (CREs) for runx1 since they also
recruit RNA polymerase II (RNAPII). CTCF depletion excluded RNAPII from two
intronic CREs but not the promoters of runx1. We propose that cohesin and CTCF
have distinct functions in the regulation of runx1 during zebrafish
embryogenesis, and that these regulatory functions are likely to involve runx1
intronic CREs. Cohesin (but not CTCF) depletion enhanced RUNX1 expression in a
human leukemia cell line, suggesting conservation of RUNX1 regulation through
evolution.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2013.11.007
PMID: 24321385 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9743993 | 1. Mol Med Today. 1998 Jul;4(7):313-9. doi: 10.1016/s1357-4310(98)01245-3.
The genetic basis of tuberous sclerosis.
Young J, Povey S.
Tuberous sclerosis is a relatively common inherited disease that causes multiple
benign tumours in different organs, frequently leading to skin rashes, seizures
and mental handicap. The disease can be caused by mutations in either of two
genes, TSC2, identified in 1993, and TSC1, only recently identified. Here we
review the current state of knowledge of the molecular genetics of tuberous
sclerosis and the spectrum of mutations seen in and the implications of recent
findings for patients. Although both genes appear to function as tumour
suppressors, the function of their protein products is not understood. A
speculative model of how these proteins might function is briefly described.
DOI: 10.1016/s1357-4310(98)01245-3
PMID: 9743993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19254884 | 1. Clin Lymphoma Myeloma. 2008 Mar;8 Suppl 3:S75-81. doi: 10.3816/CLM.2008.s.002.
Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia
chromosome-positive chronic myeloid leukemia: focus on dosing schedules.
Jabbour E(1), Cortés JE, Kantarjian H.
Author information:
(1)Department of Leukemia, University of Texas M. D. Anderson Cancer Center,
Houston, TX 77030, USA. [email protected]
Chronic myeloid leukemia (CML) is characterized by the presence of the
Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which
plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl
was imatinib, which also targets KIT and platelet-derived growth factor receptor
kinase and has demonstrated improved outcomes when compared with interferon, the
previous standard of care. Imatinib resistance and intolerance have been an
issue for patients, and as a result, new therapeutic approaches have been
evaluated. Dose-escalated imatinib (800 mg daily) has shown some limited
activity in patients with imatinib-resistant CML, but the development of
second-generation tyrosine kinase inhibitors has broadened the treatment
options. Dasatinib is also an oral kinase inhibitor, but it has increased
potency for Brc-Abl compared with imatinib. Dasatinib has demonstrated activity
in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the
treatment of adults in this setting. Recent phase III data have demonstrated
that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally
effective, with improved tolerability, compared with the previously approved
70-mg twice-daily dose. Nilotinib, which has been recently approved, has
increased potency for Brc-Abl compared with imatinib and has demonstrated
activity in patients with imatinib-resistant and -intolerant chronic- and
accelerated-phase CML. As experience with these agents continues to mature, we
might optimize the treatment efficacy and safety profiles by altering dose
regimens.
DOI: 10.3816/CLM.2008.s.002
PMID: 19254884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24239210 | 1. Lancet Oncol. 2013 Dec;14(13):1317-25. doi: 10.1016/S1470-2045(13)70502-3.
Epub 2013 Nov 13.
Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel
plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus
trastuzumab as neoadjuvant treatment for patients with HER2-positive breast
cancer (Z1041): a randomised, controlled, phase 3 trial.
Buzdar AU(1), Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC,
Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons
Oncology Group investigators.
Author information:
(1)Office of Vice President for Clinical Research, University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
Comment in
Lancet Oncol. 2013 Dec;14(13):1250-1. doi: 10.1016/S1470-2045(13)70536-9.
Strahlenther Onkol. 2014 Apr;190(4):428-9. doi: 10.1007/s00066-014-0558-8.
BACKGROUND: Neoadjuvant chemotherapy with trastuzumab for patients with
HER2-positive breast cancer can produce a pathological complete response in the
breast in 30-65% of patients. We investigated the effect of the timing of
trastuzumab administration with anthracycline and taxane neoadjuvant
chemotherapy.
METHODS: This randomised trial was done at 36 centres in the USA and Puerto
Rico. Women with operable HER2-positive invasive breast cancer were randomly
assigned (1:1) with a biased coin minimisation algorithm, stratified for age,
tumour size, and hormone receptor status. Neither patients nor investigators
(except for a cardiac safety review panel) were masked to treatment assignment.
Patients randomly assigned to sequential treatment received fluorouracil 500
mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day
1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and
trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks,
while those randomly assigned to the concurrent treatment group received
paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of
FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same
doses as the sequential group. Surgery, including evaluation of the axilla, was
done within 6 weeks of completion of neoadjuvant treatment. The primary outcome
was the percentage of patients who had a pathological complete response in the
intention-to-treat population. The study is registered with ClinicalTrials.gov,
number NCT00513292.
FINDINGS: From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in
the sequential group, 142 in the concurrent group). Two patients in the
sequential group withdrew consent before starting treatment. 78 of 138 (56·5%,
95% CI 47·8-64·9) patients who received sequential treatment had a pathological
complete response in the breast versus 77 of 142 (54·2%, 95% CI 45·7-62·6) who
received concurrent treatment (difference 2·3%, 95% CI -9·3 to 13·9). No
treatment-related deaths occurred. The most common severe toxic effects were
neutropenia (35 [25·3%] of 138 patients in the sequential group vs 45 [31·7%] of
142 patients in the concurrent group) and fatigue (six [4·3%] vs 12 [8·5%]).
Left ventricular ejection fraction dropped below the institutional lower limit
of normal at week 12 in one (0·8%) of 130 patients who received sequential
treatment and four (2·9%) of 137 patients who received concurrent treatment; by
week 24, it had dropped below this limit in nine (7·1%) of 126 patients and in
six (4·6%) of 130 patients, respectively.
INTERPRETATION: Concurrent administration of trastuzumab with anthracyclines
offers no additional benefit and is not warranted.
FUNDING: US National Cancer Institute.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(13)70502-3
PMCID: PMC4176878
PMID: 24239210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22895079 | 1. Cancer Biol Ther. 2012 Nov;13(13):1244-54. doi: 10.4161/cbt.21460. Epub 2012
Aug 16.
Oridonin in combination with imatinib exerts synergetic anti-leukemia effect in
Ph+ acute lymphoblastic leukemia cells in vitro by inhibiting activation of
LYN/mTOR signaling pathway.
Guo Y(1), Shan Q, Gong Y, Lin J, Yang X, Zhou R.
Author information:
(1)Department of Hematology, State Key Laboratory of Biotherapy and Cancer
Center, West China Hospital of Sichuan University, Sichuan, China.
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is
triggered by constitutively activated BCR-ABL and SRC family tyrosine
kinases.They account for the activations of multiple growth-signaling pathways,
including Raf/MEK/ERK, Akt/mTOR and STAT5 pathways. The BCR-ABL tyrosine kinase
inhibitor imatinib is the standard treatment for Ph+ leukemia and plays
efficacious role in CML. However, imatinib has few inhibitory effects on SRC
tyrosine kinase with response rate of Ph+ ALL lower and relapse more frequent
and quicker compared with CML. Previous studies showed that oridonin inhibits
proliferation and induces apoptosis in many tumor cells. However, the anticancer
activity and mechanism of oridonin in Ph+ ALL is unknown. To investigate the
anticancer activity of oridonin, we examined its role in constitutively
activated Akt/mTOR, Raf/MEK/ERK, STAT5 and SRC pathway, mRNA level of bcr/abl
gene, cell viability and apoptosis in Ph+ ALL SUP-B15 cells. Furthermore, we
detected synergetic effect of oridonin plus imatinib. Our results showed that
oridonin inhibiting activations of LYN (one of SRC family kinases) and ABL and
their downstream Akt/mTOR, Raf/MEK/ERK and STAT5 pathways, downregulated Bcl-2
but upregulated Bax protein and then induced apoptosis in Ph+ ALL cells.
Oridonin plus imatinib exerted synergetic effects by overcoming imatinib defect
of upregulating Akt/mTOR and LYN signaling. Additionally, we examined the effect
of oridonin on the signaling pathways in the primary specimens from Ph+ ALL
patients. Our data showed that oridonin remarkably suppressed activations of
Akt/mTOR, Raf/MEK and STAT5 pathway in these primary specimens and oridonin with
imatinib exerted synergetic suppressive effects on mTOR, STAT5 and LYN signaling
in one imatinib resistant patient specimen. Additional evaluation of oridonin as
a potential therapeutic agent for Ph+ ALL seems warranted.
DOI: 10.4161/cbt.21460
PMCID: PMC3493431
PMID: 22895079 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17433624 | 1. Epilepsy Res. 2007 May;74(2-3):147-54. doi: 10.1016/j.eplepsyres.2007.03.004.
Epub 2007 Apr 12.
Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety
margin in rodent models for epilepsy.
Stöhr T(1), Kupferberg HJ, Stables JP, Choi D, Harris RH, Kohn H, Walton N,
White HS.
Author information:
(1)Schwarz BioSciences GmbH, Department Pharmacology/Toxicology, Alfred-Nobel
Str. 10, 40789 Monheim, Germany. [email protected]
<[email protected]>
This paper comprises a series of experiments in rodent models of partial and
generalized epilepsy which were designed to describe the anti-convulsant profile
of the functionalized amino acid lacosamide. Lacosamide was effective against
sound-induced seizures in the genetically susceptible Frings mouse, against
maximal electroshock test (MES)-induced seizures in rats and mice, in the rat
hippocampal kindling model of partial seizures, and in the 6Hz model of
psychomotor seizures in mice. The activity in the MES test in both mice
(4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously
reported for most clinically available anti-epileptic drugs. At both the median
effective dose for MES protection, as well as the median toxic dose for rotorod
impairment, lacosamide elevated the seizure threshold in the i.v.
pentylenetetrazol seizure test, suggesting that it is unlikely to be
pro-convulsant at high doses. Lacosamide was inactive against clonic seizures
induced by subcutaneous administration of the chemoconvulsants
pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced
seizures in mice and showed full efficacy in the homocysteine model of epilepsy.
In summary, the overall anti-convulsant profile of lacosamide appeared to be
unique, and the drug displayed a good margin of safety in those tests in which
it was effective. These results suggest that lacosamide may have the potential
to be clinically useful for at least the treatment of generalized tonic-clonic
and partial-onset epilepsies, and support ongoing clinical trials in these
indications.
DOI: 10.1016/j.eplepsyres.2007.03.004
PMID: 17433624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21479927 | 1. Breast Cancer Res Treat. 2012 Feb;131(3):871-80. doi:
10.1007/s10549-011-1470-x. Epub 2011 Apr 11.
A signature of immune function genes associated with recurrence-free survival in
breast cancer patients.
Ascierto ML(1), Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang
E, Ramakrishnan V, Wang XY, Bear HD, Marincola FM, Manjili MH.
Author information:
(1)Infectious Disease and Immunogenetics Section (IDIS), Department of
Transfusion Medicine and Center for Human Immunology, National Institutes of
Health, Bethesda, MD 20892, USA.
Comment in
Biomark Med. 2011 Oct;5(5):653-4.
The clinical significance of tumor-infiltrating immune cells has been reported
in a variety of human carcinomas including breast cancer. However, molecular
signature of tumor-infiltrating immune cells and their prognostic value in
breast cancer patients remain elusive. We hypothesized that a distinct network
of immune function genes at the tumor site can predict a low risk versus high
risk of distant relapse in breast cancer patients regardless of the status of
ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a
diverse cohort of breast cancer patients with a 1-5 year tumor relapse versus
those with up to 7 years relapse-free survival. The RNAs were extracted from the
frozen tumor specimens at the time of diagnosis and subjected to microarray
analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to
immunohistochemistry staining. We determined that a network of immune function
genes involved in B cell development, interferon signaling associated with
allograft rejection and autoimmune reaction, antigen presentation pathway, and
cross talk between adaptive and innate immune responses were exclusively
upregulated in patients with relapse-free survival. Among the 299 genes, five
genes which included B cell response genes were found to predict with >85%
accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic
signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint
panel and from the Oncotype DX recurrence score assay panel. These data suggest
that neoadjuvant immunotherapy in patients with high risk of relapse may reduce
tumor recurrence by inducing the immune function genes.
DOI: 10.1007/s10549-011-1470-x
PMCID: PMC3431022
PMID: 21479927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25247053 | 1. Oxid Med Cell Longev. 2014;2014:654198. doi: 10.1155/2014/654198. Epub 2014
Aug 27.
Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by
tafazzin gene knockdown in cardiac myocytes.
He Q(1), Harris N(1), Ren J(2), Han X(1).
Author information:
(1)Diabetes and Obesity Research Center, Sanford-Burnham Medical Research
Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
(2)Center for Cardiovascular Research and Alternative Medicine, University of
Wyoming, Laramie, WY 82071, USA.
Tafazzin, a mitochondrial acyltransferase, plays an important role in
cardiolipin side chain remodeling. Previous studies have shown that dysfunction
of tafazzin reduces cardiolipin content, impairs mitochondrial function, and
causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS)
have been implicated in the development of cardiomyopathy and are also the
obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown
increases ROS production from mitochondria, and a mitochondria-targeted
antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac
dysfunction. We employed cardiac myocytes transduced with an adenovirus
containing tafazzin shRNA as a model to investigate the effects of the
mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady
state levels of cardiolipin and increased mitochondrial ROS. Treatment of
cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced
mitochondrial ROS production and cellular ATP decline. Mito-Tempo also
significantly abrogated tafazzin knockdown induced cardiac hypertrophy,
contractile dysfunction, and cell death. We conclude that mitochondria-targeted
antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in
cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth
syndrome and other dilated cardiomyopathies resulting from mitochondrial
oxidative stress.
DOI: 10.1155/2014/654198
PMCID: PMC4160652
PMID: 25247053 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23890950 | 1. |
http://www.ncbi.nlm.nih.gov/pubmed/17929114 | 1. Int J Clin Oncol. 2007 Oct;12(5):327-40. doi: 10.1007/s10147-007-0699-1. Epub
2007 Oct 22.
The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against
Philadelphia chromosome-positive leukemias.
Maekawa T(1), Ashihara E, Kimura S.
Author information:
(1)Department of Transfusion Medicine and Cell Therapy, Kyoto University
Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku 606-8507, Japan.
[email protected]
Chronic myeloid leukemia (CML) was the first human malignant disease to be
linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl
kinase fusion protein and its pivotal role in the pathogenesis of CML provided
new opportunities to develop molecular-targeted therapies. Imatinib mesylate
(IM, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), which specifically
inhibits the autophosphorylation of the Abl TK, has improved the treatment of
CML. However, resistance is often reported in patients with advanced-stage
disease. Several novel TK inhibitors have been developed that override IM
resistance mechanisms caused by point mutations within the Abl kinase domain.
Inhibitors of Abl TK are divided into two main groups, namely, ATP-competitive
and ATP noncompetitive inhibitors. The ATP-competitive inhibitors fall into two
subclasses, the Src/Abl inhibitors, and the 2-phenylaminopyrimidine-based
compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606, and PD166326 are
classified as Src/Abl inhibitors, while nilotinib (AMN107) and INNO-406 (NS-187)
belong to the latter subclass of inhibitors. Of these agents, dasatinib and
nilotinib underwent clinical trials earlier than the others and favorable
results are now accumulating. Clinical studies of the other compounds, including
SKI-606 and INNO-406, have been performed in rapid succession. Because of their
strong affinities for the ATP-binding site compared to IM, most ATP-competitive
inhibitors may be effective in IM-resistant patients. However, an
ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl
has not yet been developed. Instead, ATP noncompetitive inhibitors, such as
ON012380, Aurora kinase inhibitor MK0457 (VX-680), and p38 MAP kinase inhibitor
BIRB-796, have been developed to address this problem. This review provides an
update on the underlying pathophysiologies of disease progression and IM
resistance, and discusses the development of new targeted TK inhibitors for
managing CML and the importance of future strategies targeting CML stem cells.
DOI: 10.1007/s10147-007-0699-1
PMID: 17929114 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25287778 | 1. Cancer Immunol Immunother. 2015 Jan;64(1):61-73. doi:
10.1007/s00262-014-1610-3. Epub 2014 Oct 7.
Elotuzumab enhances natural killer cell activation and myeloma cell killing
through interleukin-2 and TNF-α pathways.
Balasa B(1), Yun R, Belmar NA, Fox M, Chao DT, Robbins MD, Starling GC, Rice AG.
Author information:
(1)Abbott Biotherapeutics Corp., Redwood City, CA, USA.
Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic
activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that
enhances natural killer (NK) cell-mediated antibody-dependent cellular
cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the
mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single
agent and in combination with lenalidomide, to support ongoing phase III trials
in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM).
An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was
developed to evaluate the combination of elotuzumab and lenalidomide. Expression
of activation markers and adhesion receptors was evaluated by flow cytometry,
cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma
cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in
PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide
demonstrated superior anti-myeloma activity on established MM xenografts in vivo
and in PBL/myeloma cell co-cultures in vitro than either agent alone. The
combination enhanced myeloma cell killing by modulating NK cell function that
coincided with the upregulation of adhesion and activation markers, including
interleukin (IL)-2Rα expression, IL-2 production by CD3(+)CD56(+) lymphocytes,
and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α
directly increased NK cell activation and myeloma cell death with elotuzumab or
elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell
activation and myeloma cell death with elotuzumab. These results demonstrate
that elotuzumab activates NK cells and induces myeloma cell death via NK
cell-mediated ADCC, which is further enhanced when combined with lenalidomide.
DOI: 10.1007/s00262-014-1610-3
PMCID: PMC4282702
PMID: 25287778 [Indexed for MEDLINE]
Conflict of interest statement: The investigational drug elotuzumab is being
developed in a partnership between AbbVie Biotherapeutics Inc. and Bristol-Myers
Squibb Co. Michael Robbins and Audie Rice are currently employees of
Bristol-Myers Squibb. All other authors are current or former employees of
AbbVie Biotherapeutics Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/7868070 | 1. Horm Res. 1994;42(4-5):176-81. doi: 10.1159/000184190.
Parental imprinting and the IGF2 gene.
Ekström TJ(1).
Author information:
(1)Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
The phenomenon of parental imprinting has become increasingly important in
disciplines such as evolution, genetics, molecular biology, embryology and
pathology. Principally, parental imprinting refers to a parent-of-origin
dependent expression of a subset of autosomal loci, independent of the sex of
the offspring. Today, at least seven such loci have been identified, including
the human IGF2 gene. It appears that the set of imprinted genes is not always
identical between the species, although the importance of maintaining this kind
of gene regulation is evolutionarily conserved. It is particularly interesting
from the clinical point of view that a number of human diseases, such as the
Beckwith-Wiedemann and Prader-Willi/Angelman syndromes, appear to involve
unbalanced parental contributions of imprinted loci. We show here that the four
different human IGF2 promoters are expressed mono- and/or biallelically in
complex patterns in postnatal liver specimens.
DOI: 10.1159/000184190
PMID: 7868070 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21248360 | 1. J Dent Res. 2011 May;90(5):665-71. doi: 10.1177/0022034510393516. Epub 2011
Jan 19.
Influence of experimental esophageal acidification on sleep bruxism: a
randomized trial.
Ohmure H(1), Oikawa K, Kanematsu K, Saito Y, Yamamoto T, Nagahama H, Tsubouchi
H, Miyawaki S.
Author information:
(1)Department of Orthodontics, Kagoshima University Graduate School of Medical
and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
Comment in
J Dent Res. 2011 Oct;90(10):1253; author reply 1254. doi:
10.1177/0022034511415276.
The aim of this cross-over, randomized, single-blinded trial was to examine
whether intra-esophageal acidification induces sleep bruxism (SB).
Polysomnography with electromyogram (EMG) of masseter muscle, audio-video
recording, and esophageal pH monitoring were performed in a sleep laboratory.
Twelve healthy adult males without SB participated. Intra-esophageal infusions
of 5-mL acidic solution (0.1 N HCl) or saline were administered. The frequencies
of EMG bursts, rhythmic masticatory muscle activity (RMMA) episodes, grinding
noise, and the RMMA/microarousal ratio were significantly higher in the
20-minute period after acidic infusion than after saline infusion. RMMA episodes
including SB were induced by esophageal acidification. This trial is registered
with the UMIN Clinical Trials Registry, UMIN000002923.
ABBREVIATIONS: ASDA, American Sleep Disorders Association; EMG, electromyogram;
GER, gastroesophageal reflux; LES, lower esophageal sphincter; NREM, non-rapid
eye movement; REM, rapid eye movement; RMMA, rhythmic masticatory muscle
activity; SB, sleep bruxism; SD, standard deviation; UES, upper esophageal
sphincter.
DOI: 10.1177/0022034510393516
PMID: 21248360 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14749092 | 1. Psychoneuroendocrinology. 2004 May;29(4):448-74. doi:
10.1016/s0306-4530(03)00054-4.
Mindfulness-based stress reduction in relation to quality of life, mood,
symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate
(DHEAS) and melatonin in breast and prostate cancer outpatients.
Carlson LE(1), Speca M, Patel KD, Goodey E.
Author information:
(1)Department of Psychosocial Resources, Tom Baker Cancer Centre, Alberta Cancer
Board, 1331 29 Street NW, Calgary, Alta, Canada T2N 4N2. [email protected]
OBJECTIVES: This study investigated the relationships between a
mindfulness-based stress reduction meditation program for early stage breast and
prostate cancer patients and quality of life, mood states, stress symptoms, and
levels of cortisol, dehydroepiandrosterone-sulfate (DHEAS) and melatonin.
METHODS: Fifty-nine patients with breast cancer and 10 with prostate cancer
enrolled in an eight-week Mindfulness-Based Stress Reduction (MBSR) program that
incorporated relaxation, meditation, gentle yoga, and daily home practice.
Demographic and health behavior variables, quality of life, mood, stress, and
the hormone measures of salivary cortisol (assessed three times/day), plasma
DHEAS, and salivary melatonin were assessed pre- and post-intervention.
RESULTS: Fifty-eight and 42 patients were assessed pre- and post-intervention,
respectively. Significant improvements were seen in overall quality of life,
symptoms of stress, and sleep quality, but these improvements were not
significantly correlated with the degree of program attendance or minutes of
home practice. No significant improvements were seen in mood disturbance.
Improvements in quality of life were associated with decreases in afternoon
cortisol levels, but not with morning or evening levels. Changes in stress
symptoms or mood were not related to changes in hormone levels. Approximately
40% of the sample demonstrated abnormal cortisol secretion patterns both pre-
and post-intervention, but within that group patterns shifted from
"inverted-V-shaped" patterns towards more "V-shaped" patterns of secretion. No
overall changes in DHEAS or melatonin were found, but nonsignificant shifts in
DHEAS patterns were consistent with healthier profiles for both men and women.
CONCLUSIONS: MBSR program enrollment was associated with enhanced quality of
life and decreased stress symptoms in breast and prostate cancer patients, and
resulted in possibly beneficial changes in hypothalamic-pituitary-adrenal (HPA)
axis functioning. These pilot data represent a preliminary investigation of the
relationships between MBSR program participation and hormone levels,
highlighting the need for better-controlled studies in this area.
DOI: 10.1016/s0306-4530(03)00054-4
PMID: 14749092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22981836 | 1. Med Hypotheses. 2012 Dec;79(6):731-4. doi: 10.1016/j.mehy.2012.08.012. Epub
2012 Sep 13.
Dissecting the different biological effects of oncogenic Ras isoforms in cancer
cell lines: could stimulation of oxidative stress be the one more weapon of
H-Ras? Regulation of oxidative stress and Ras biological effects.
Bellavia M(1), Gioviale MC, Damiano G, Palumbo VD, Spinelli G, Buscemi G, Lo
Monte AI.
Author information:
(1)Department of Surgical and Oncological Disciplines, University of Palermo,
Palermo, Italy. [email protected]
Ras proteins are small GTPase functioning as molecular switches that, in
response to particular extracellular signalling, as growth factors, activate a
diverse array of intracellular effector cascades regulating cell proliferation,
differentiation and apoptosis. Human tumours frequently express Ras proteins
(Ha-, Ki-, N-Ras) activated by point mutations which contribute to malignant
phenotype, including invasiveness and angiogenesis. Despite the common
signalling pathways leading to similar cellular responses, studies clearly
demonstrate unique roles of the Ras family members in normal and pathological
conditions and the lack of functional redundancy seems to be explainable, at
least in part, by the ability of Ras isoforms to localize in different
microdomains to plasma membrane and intracellular organelles. This different
intracellular compartmentalization could help Ras isoforms to contact different
downstream effectors finally leading to different biological outcomes.
Interestingly, it has also been shown that Ha- and Ki-Ras exert an opposite role
in regulating intracellular redox status. In this regard we suggest that H-Ras
specific induction of ROS (reactive oxygen species) production could be one of
the main determinants of the invasive phenotype which characterize cancer cells
harbouring H-Ras mutations. In our hypothesis then, while K-Ras (not able to
promote oxidative stress) could mainly contribute to cancer progression and
invasiveness through activation of MAPK and PI3K, H-Ras-mediated oxidative
stress could play a unique role in modulation of intercellular contacts leading
to a loss of cell adhesion and eventually also to a metastatic spread.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.mehy.2012.08.012
PMID: 22981836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17079093 | 1. Gene. 2007 Jan 15;386(1-2):131-8. doi: 10.1016/j.gene.2006.08.030. Epub 2006
Sep 20.
Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma.
Mandal D(1), Srivastava A, Mahlum E, Desai D, Maran A, Yaszemski M, Jalal SM,
Gitelis S, Bertoni F, Damron T, Irwin R, O'connor M, Schwartz H, Bolander ME,
Sarkar G.
Author information:
(1)Department of Orthopedic Research, Mayo Clinic and Foundation, 200 1st St.
SW, Rochester, MN 55905, USA.
Deciphering the molecular basis of cancer is critical for developing novel
diagnostic and therapeutic strategies. To better understand the early molecular
events involving osteogenic sarcoma (OGS), we have initiated a program to
identify potential tumor suppressor genes. Expression profiling of total RNA
from ten normal bone cell lines and eleven OGS-derived cell lines by microarray
showed 135-fold lower expression of FRZB/sFRP3 mRNA in OGS cells compared to
bone cells; this down-regulation of Frzb/sFRP3 mRNA expression was found to be
serum-independent. Subsequently, fourteen OGS biopsy specimens showed nine-fold
down-regulation of Frzb/sFRP3 mRNA expression compared to expression in eight
normal bone specimens as determined by microarray. FRZB /sFRP3 protein level was
also found to be at a very low level in 4/4 OGS cell lines examined.
Quantitation by RT-PCR indicated approximately 70% and approximately 90% loss of
Frzb/sFRP3 mRNA expression in OGS biopsy specimens and OGS-derived cell lines
respectively, compared to expression in bone (p<0.0001). Hybridization
experiments of a cDNA microarray containing paired normal and tumor specimens
from nineteen different organs did not show any significant difference in the
level of Frzb/sFRP3 mRNA expression between the normal and the corresponding
tumor tissues. Exogenous expression of FRZB/sFRP3 mRNA in two OGS-derived cell
lines lacking endogenous expression of the mRNA produced abundant mRNA from the
exogenous gene, eliminating degradation as a possibility for very low level of
FRZB/sFRP3 mRNA in OGS specimens. Results from PCR-based experiments suggest
that the FRZB/sFRP3 gene is not deleted in OGS cell lines, however, karyotyping
shows gross abnormalities involving chromosome 2 (location of the FRZB gene) in
five of twelve OGS-derived cell lines. Together, these data suggest a
tumor-suppressive potential for FRZB/sFRP3 in OGS.
DOI: 10.1016/j.gene.2006.08.030
PMID: 17079093 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17465245 | 1. Anticancer Res. 2007 Mar-Apr;27(2):1067-71.
Temozolomide and thalidomide in the treatment of glioblastoma multiforme.
Riva M(1), Imbesi F, Beghi E, Galli C, Citterio A, Trapani P, Sterzi R, Collice
M.
Author information:
(1)Department of Neurooncology, Niguarda Hospital, Milan, Italy.
[email protected]
OBJECTIVE: The aim of this study was to assess efficacy and toxicity of
temozolomide given alone or in combination with thalidomide, an
anti-angiogenetic drug, in patients with newly diagnosed glioblastoma multiforme
(GBM).
PATIENTS AND METHODS: 46 patients with histologically proven GBM were eligible
for inclusion. Twenty-three patients (15 males and 8 females) received
temozolomide on a conventional schedule; 23 patients (12 males and 11 females)
received temozolomide on the same schedule and thalidomide was dose-adjusted in
each individual patient based on their tolerance.
RESULTS: The median survival time was 12 months for temozolomide and 13 months
for temozolomide + thalidomide.
CONCLUSION: The administration of temozolomide in association with thalidomide
after radiotherapy (RT) does not offer an advantage over temozolomide alone in
adults with newly diagnosed GBM. The two therapeutic strategies produce similar
results for survival, but the latter regimen shows a moderate increase in
toxicity.
PMID: 17465245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23470527 | 1. Oncotarget. 2013 Feb;4(2):289-97. doi: 10.18632/oncotarget.833.
TAp73β-mediated suppression of cell migration requires p57Kip2 control of actin
cytoskeleton dynamics.
Rodhe J(1), Kavanagh E, Joseph B.
Author information:
(1)Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska
Institutet, 171 76 Stockholm, Sweden.
The TP73 gene, a member of the p53 family, due to the use of different promoters
and alternative splicing, is transcribed into different isoforms with
contrasting attributes and which contribute to its functional diversity.
Considerable efforts are made to identify the functional diversity of the p73
splicing variants during tumorigenesis. TAp73α and TAp73β isoforms have been
shown to differentially regulate cell cycle progression, differentiation and
apoptosis. Interestingly, a particular increase in expression of the TAp73
isoform, in favor of the α splicing variant, has been reported in multiple
tumour types. Here, we report a distinctive role for TAp73β isoform in the
control of cell migration and invasion. In fact, TAp73β- dependent induction of
p57(Kip2) expression accounted for inhibitory effects on the actin cytoskeleton
dynamics and thereby cancer cell motility. In contrast, TAp73α is not able to
induce p57(Kip2) expression, and exhibits a positive effect on actin
cytoskeleton dynamics as well as cell migration and invasion. In conclusion, the
inhibitory effect on cell migration and invasion of TAp73β would qualify this
distinct p73 isoform as tumor suppressor gene. In contrast, the promoting effect
of TAp73α on cell motility and invasion strengthens the potential oncogenic
activities of this p73 isoform.
DOI: 10.18632/oncotarget.833
PMCID: PMC3712574
PMID: 23470527 [Indexed for MEDLINE]
Conflict of interest statement: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/21209713 | 1. J Thyroid Res. 2010 Dec 14;2011:675703. doi: 10.4061/2011/675703.
Autoimmune thyroid diseases in children.
Cappa M(1), Bizzarri C, Crea F.
Author information:
(1)Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital,
University of Rome "Tor Vergata", Piazza S. Onofrio 4, 00165 Rome, Italy.
The two major autoimmune thyroid diseases (ATDs) include Graves' disease (GD)
and autoimmune thyroiditis (AT); both of which are characterized by infiltration
of the thyroid by T and B cells reactive to thyroid antigens, by the production
of thyroid autoantibodies and by abnormal thyroid function (hyperthyroidism in
GD and hypothyroidism in AT). While the exact etiology of thyroid autoimmunity
is not known, it is believed to develop when a combination of genetic
susceptibility and environmental encounters leads to breakdown of tolerance. It
is important to recognize thyroid dysfunction at an early stage by maintaining
an appropriate index of suspicion.
DOI: 10.4061/2011/675703
PMCID: PMC3010678
PMID: 21209713 |
http://www.ncbi.nlm.nih.gov/pubmed/17534191 | 1. Clin Orthop Relat Res. 2007 Sep;462:38-44. doi: 10.1097/BLO.0b013e3180d09dcc.
Genetic association of complex traits: using idiopathic scoliosis as an example.
Cheng JC(1), Tang NL, Yeung HY, Miller N.
Author information:
(1)Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health
Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
[email protected]
Although the exact etiology of adolescent idiopathic scoliosis is still
undefined, genetic factors play an important role. Some patients have familial
genetic disease that appears to have an autosomal dominant pattern. Linkage
studies of these families revealed multiple potential genetic loci that may
predispose individuals to the condition. Additional genetic analysis is required
to identify the disease-predisposition genes of the loci found in the linkage
studies. The initial localization of potential critical loci through large
family-based population studies now needs fine mapping by association studies
using high-density polymorphic markers (single nucleotide polymorphisms or
SNPs). These markers are now available as a result of the Human Genome Project,
International HapMap Project, and other genetic diversity projects. The
application of this emerging data in a large association study of affected
individuals and controls is integral for the identification of putative genes.
With these complementary approaches, we will be able to progress with mutational
analysis of hopefully a small set of candidate genes in the near future. In this
commentary, we illustrate what is possible in the genomic era, and indicate what
we should expect from genetic studies in adolescent idiopathic scoliosis, a
complex trait disease.
DOI: 10.1097/BLO.0b013e3180d09dcc
PMID: 17534191 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11403977 | 1. Psychoneuroendocrinology. 2001 Aug;26(6):551-64. doi:
10.1016/s0306-4530(01)00010-5.
Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid
diethylamide to 5-HT2A receptors in platelets from women with premenstrual
dysphoric disorder during gonadotropin releasing hormone treatment.
Bixo M(1), Allard P, Bäckström T, Mjörndal T, Nyberg S, Spigset O,
Sundström-Poromaa I.
Author information:
(1)Department of Clinical Sciences, Obstetrics and Gynecology, Umea University,
S-901 85, Umea, Sweden. [email protected]
Changes in serotonergic parameters have been reported in psychiatric conditions
such as depression but also in the premenstrual dysphoric disorder (PMDD). In
addition, hormonal effects on serotonergic activity have been established. In
the present study, binding of [3H]paroxetine to platelet serotonin uptake sites
and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin
(5-HT)2A receptors were studied in patients with PMDD treated with a low dose of
a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and
compared to controls. The PMDD patients were relieved of premenstrual symptoms
like depression and irritability during buserelin treatment. The number of
[3H]paroxetine binding sites (Bmax) were significantly higher in the follicular
phase in untreated PMDD patients compared to controls. When treated with
buserelin the difference disappeared. No differences in [3H]LSD binding between
the three groups were shown. The present study demonstrated altered platelet
[3H]paroxetine binding characteristics in women with PMDD compared to controls.
Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low
dose of buserelin. The results are consistent with the hypothesis that changes
in serotonergic transmission could be a trait in the premenstrual dysphoric
disorder.
DOI: 10.1016/s0306-4530(01)00010-5
PMID: 11403977 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24499550 | 1. Exp Hematol Oncol. 2013 Nov 8;2(1):30. doi: 10.1186/2162-3619-2-30.
Neoadjuvant treatment of melanoma: case reports and review.
Laks S, Brueske KA, Hsueh EC(1).
Author information:
(1)Department of Surgery, Saint Louis University, 3635 Vista at Grand Blvd,, St,
Louis, Missouri 63110, USA. [email protected].
Neoadjuvant therapy is an under-utilized regimen for the treatment of metastatic
melanoma. The use of this approach has been increasing in other tumor types.
Neoadjuvant therapy may reduce occult circulating tumor cell burden in the face
of bulky disease and afford a real time evaluation of treatment effectiveness.
Neoadjuvant approach can also provide preoperative histologic and molecular
analysis of treated tissue that may guide the postoperative treatment planning
in patients with resectable metastatic melanoma lesions. The putative benefits
of better margin control and clearance of occult systemic disease would
theoretically improve surgical outcome. With the advent of effective agents
against metastatic melanoma, this common approach to the treatment of rectal
cancer, metastatic colon cancer, and breast cancer should also be evaluated as a
viable treatment strategy for advanced stage melanoma.
DOI: 10.1186/2162-3619-2-30
PMCID: PMC3832230
PMID: 24499550 |
http://www.ncbi.nlm.nih.gov/pubmed/22486183 | 1. Transfusion. 2012 Dec;52(12):2585-9. doi: 10.1111/j.1537-2995.2012.03629.x.
Epub 2012 Apr 4.
A genetic risk factor for low serum ferritin levels in Danish blood donors.
Sørensen E(1), Grau K, Berg T, Simonsen AC, Magnussen K, Erikstrup C, Hansen MB,
Ullum H.
Author information:
(1)Department of Clinical Immunology, Capital Region, Copenhagen University
Hospital, Denmark. [email protected]
BACKGROUND: Iron deficiency is a frequent side effect of blood donation. In
recent years, several studies have described genetic variants associated with
iron concentrations. However, the impact of these variants on iron levels is
unknown in blood donors. Knowledge of genetic variants that predispose donors to
iron deficiency would allow bleeding frequency and iron supplementation to be
tailored to the individual donor.
STUDY DESIGN AND METHODS: The genotypes of five specific single-nucleotide
polymorphisms (SNPs) in three genes that have been previously associated with
iron status and/or restless leg syndrome (RLS) were investigated in two groups
of female blood donors. The first group had low iron stores (serum ferritin ≤
12 µg/L, n = 657), and the second group had normal to high iron stores (serum
ferritin > 30 µg/L, n = 645). Genotype distribution for each of the SNPs was
compared between the two groups.
RESULTS: Homozygosity for the T-allele of BTBD9 rs9296249 was associated with
lower serum ferritin. The odds ratio for low serum ferritin was 1.35 (95%
confidence interval, 1.02-1.77; p = 0.03) when comparing donors with the TT
genotype with donors with the CT genotype.
CONCLUSION: A frequent polymorphism in BTBD9 was significantly associated with
serum ferritin. This polymorphism has previously been associated with RLS, but
not low iron stores in blood donors.
© 2012 American Association of Blood Banks.
DOI: 10.1111/j.1537-2995.2012.03629.x
PMID: 22486183 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8243377 | 1. Epilepsia. 1993;34 Suppl 7:S7-17. doi: 10.1111/j.1528-1157.1993.tb04593.x.
The Lennox-Gastaut syndrome.
Dulac O(1), N'Guyen T.
Author information:
(1)Neuropediatric Department, Hôpital Saint-Vincent-de-Paul, Paris, France.
One of the most challenging areas in nosology is in the field of severe
generalized epilepsy of early childhood. This is certainly true in the case of
Lennox-Gastaut syndrome (LGS), an age-related epileptogenic encephalopathy which
comprises several types of generalized seizures including tonic seizures,
atypical absence seizures and frequent status epilepticus. EEG shows generalized
slow spike waves, and as the disease progresses, cognitive functions
deteriorate. LGS is listed in the 1989 classification of the International
League Against Epilepsy alongside epilepsy with myoclonic astatic seizures and
West's syndrome. A number of variants or atypical forms have been proposed. As a
result, differential diagnosis presents a major challenge and includes specific
generalized epilepsies, i.e., metabolic or inflammatory; secondarily generalized
epilepsies, i.e., those arising from the frontal lobe; and severe forms of
idiopathic generalized epilepsy, i.e., Doose syndrome. Antiepileptic drug (AED)
treatment of LGS has been disappointing. Results obtained from anterior
callosotomy have been promising, but only a small number of patients have been
evaluated. Although the syndrome is rare, the severe nature and intractability
of LGS emphasizes the need for the development of specific AEDs which would
completely modify the quality of life for these patients.
DOI: 10.1111/j.1528-1157.1993.tb04593.x
PMID: 8243377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22305802 | 1. Lancet Neurol. 2012 Mar;11(3):241-9. doi: 10.1016/S1474-4422(12)70015-7. Epub
2012 Feb 3.
Amyloid-related imaging abnormalities in patients with Alzheimer's disease
treated with bapineuzumab: a retrospective analysis.
Sperling R(1), Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M,
Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y,
Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M.
Author information:
(1)Center for Alzheimer Research and Treatment, Brigham and Women's Hospital,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
[email protected]
Comment in
Lancet Neurol. 2012 Mar;11(3):207-8. doi: 10.1016/S1474-4422(12)70021-2.
BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been reported in
patients with Alzheimer's disease treated with bapineuzumab, a humanised
monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities
suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and
microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate
the incidence of ARIA during treatment with bapineuzumab, and evaluate
associated risk factors.
METHODS: Two neuroradiologists independently reviewed 2572 fluid-attenuated
inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2
studies of bapineuzumab and an open-label extension study. Readers were masked
to the patient's treatment, APOE ɛ4 genotype, medical history, and demographics.
Patients were included in risk analyses if they had no evidence of ARIA-E in
their pre-treatment MRI, had received bapineuzumab, and had at least one MRI
scan after treatment. We used Kaplan-Meier survival analysis to examine the
distribution of incident ARIA-E from the start of bapineuzumab treatment and
proportional hazards regression models to assess risk factors associated with
ARIA.
FINDINGS: 210 patients were included in the risk analyses. 36 patients (17%)
developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases
(42%) had not been detected previously. 28 of these patients (78%) did not
report associated symptoms. Adverse events, reported in eight symptomatic
patients, included headache, confusion, and neuropsychiatric and
gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with
ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the
15 patients in whom ARIA were detected in our study received additional
treatment infusions while ARIA-E were present, without any associated symptoms.
Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24
per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE
ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001).
INTERPRETATION: ARIA consist of a spectrum of imaging findings with variable
clinical correlates, and some patients with ARIA-E remain asymptomatic even if
treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its
association with high bapineuzumab dose, and its timecourse in relation to
dosing suggest an association between ARIA and alterations in vascular amyloid
burden.
FUNDING: Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth
Pharmaceuticals, and Pfizer.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(12)70015-7
PMCID: PMC4063417
PMID: 22305802 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest RS has served as a study
investigator and a consultant for Janssen Alzheimer Immunotherapy Research &
Development, LLC, and for Pfizer Inc., and has received honoraria for
participation in symposiums. She has also served as a consultant and/or site
investigator for Bristol-Myers-Squibb, Roche, Elan, Biogen-IDEC, Avid, and
Bayer. SS has served as a consultant and study investigator for Janssen
Alzheimer Immunotherapy Research & Development, LLC., Pfizer Inc., and Elan
Corporation, plc. phase 2 and 3 studies of bapineuzumab. DB reports no conflicts
of interest. DT provides review of MRI images for Janssen Alzheimer
Immunotherapy Research & Development, LLC. JB serves as a neuroradiological
consultant to SYNARC Inc., an imaging contract research organization contracted
by both sponsor companies (Janssen Alzheimer Immunotherapy Research &
Development, LLC. and Pfizer Inc.); he also serves as a consultant to Janssen
Alzheimer Immunotherapy Research & Development, LLC. for non-clinical research
activities. NF has provided consulting and/or image analysis services to Elan
Corporation, plc., Janssen Alzheimer Immunotherapy Research & Development, LLC.,
Pfizer Inc., and Wyeth Pharmaceuticals as well as to AstraZeneca, Bristol-Myers
Squibb, Eli Lilly and Company, GE Healthcare, Lundbeck A/S, and IXICO. MR serves
as consultant to Janssen Alzheimer Immunotherapy Research & Development, LLC. MS
participates in a consulting/advisory capacity for Eli Lilly and Company,
Amerisciences, Takeda Pharmaceuticals Inc., Eisai Co., Ltd., Pfizer Inc., and
GlaxoSmithKline plc. and receives royalties from Wiley and AmeriSciences, LP. He
receives contracting fees/grants from Celgene Corporation, Ceregene, Inc., Bayer
AG, Baxter International Inc., Bristol-Myers Squibb, Eli Lilly and Company,
Pfizer Inc., Janssen Alzheimer Immunotherapy Research & Development, LLC., Avid
Radiopharmaceuticals, Inc., Genentech, Inc. and Eisai Co., Ltd. LH serves on the
study steering committee and has acted as a consultant for Janssen Alzheimer
Immunotherapy Research & Development, LLC., but receives less than $10,000
annually for such consulting activities. AP has received grant/research support
from Baxter International Inc., Bristol-Myers Squibb, Eisai Co., Ltd., Elan
Corporation, plc., Genentech, Inc./ Hoffmann-La Roche Inc., Janssen Alzheimer
Immunotherapy Research & Development, LLC., Medivation, Inc., Pfizer Inc., and
Toyama Chemical Co., Ltd. He has also served as a consultant/participated on
advisory boards for Elan Corporation, plc., Janssen Alzheimer Immunotherapy
Research & Development, LLC., Medivation, Inc., Pfizer Inc., Transition
Therapeutics Inc., and Toyama Chemical Co., Ltd.. He is also a member of the
speakers’ bureau for Forest Laboratories, Inc. IL is a stockholder in Elan
Corporation, plc. RB is an employee of and receives stock and stock options from
Pfizer Inc. MA, KM, YL, EL, KG, RHB, and GK are employees of Janssen Alzheimer
Immunotherapy Research & Development, LLC. MG is a consultant to Janssen
Alzheimer Immunotherapy Research & Development, LLC. and is a stockholder in
Elan Corporation, plc. |
http://www.ncbi.nlm.nih.gov/pubmed/19214742 | 1. Breast Cancer Res Treat. 2010 Feb;119(3):551-8. doi:
10.1007/s10549-009-0333-1. Epub 2009 Feb 13.
The 70-gene signature as a response predictor for neoadjuvant chemotherapy in
breast cancer.
Straver ME(1), Glas AM, Hannemann J, Wesseling J, van de Vijver MJ, Rutgers EJ,
Vrancken Peeters MJ, van Tinteren H, Van't Veer LJ, Rodenhuis S.
Author information:
(1)Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni
van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
[email protected]
The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant
treatment decisions. The aim of this study was to assess its value to predict
chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of
stage II-III patients prior to neoadjuvant chemotherapy and classified the
prognosis-signatures. Pathological complete remission (pCR) was used to measure
chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%)
a good prognosis-signature. None of the good prognosis-signature patients
achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor
prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38)
had a poor prognosis-signature. Within the non triple-negative subgroup, the
response of the primary tumor remained associated with the classification of the
prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that
have a good prognosis-signature. Tumors with a poor prognosis-signature are more
sensitive to chemotherapy.
DOI: 10.1007/s10549-009-0333-1
PMID: 19214742 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23055947 | 1. Core Evid. 2012;7:93-103. doi: 10.2147/CE.S29001. Epub 2012 Sep 14.
Rindopepimut: an evidence-based review of its therapeutic potential in the
treatment of EGFRvIII-positive glioblastoma.
Babu R(1), Adamson DC.
Author information:
(1)Division of Neurosurgery, Department of Surgery, Duke University Medical
Center, Durham, NC, USA.
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults
and is universally fatal. Despite surgical resection, radiotherapy, and systemic
chemotherapy, the median overall survival is less than 15 months. As current
therapies are not tumor-specific, treatment commonly results in toxicity. The
epidermal growth factor receptor variant III (EGFRvIII) is a naturally occurring
mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is
not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut
is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune
responses. Phase I and II clinical trials have demonstrated significantly higher
progression-free and overall survival times in vaccinated patients with
EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of
hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it
is a promising therapy for patients with GBM. Currently, rindopepimut is
undergoing clinical testing in an international Phase III trial for newly
diagnosed GBM and a Phase II trial for relapsed GBM.
DOI: 10.2147/CE.S29001
PMCID: PMC3459544
PMID: 23055947 |
http://www.ncbi.nlm.nih.gov/pubmed/24836310 | 1. N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub
2014 May 18.
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.
Richeldi L(1), du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V,
Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman
M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R,
Disse B, Collard HR; INPULSIS Trial Investigators.
Collaborators: Corte T, Davies H, Glaspole I, Mulder J, Veitch E, De Vuyst P,
Liistro G, Sibille Y, Vincken W, Wuyts W, Fell C, Hernandez P, Kolb M, Undurraga
A, Bai C, Chen P, Gao Z, Kang J, Li H, Li Z, Wan H, Wang H, Wen F, Xiao Q, Xu Z,
Zhang W, Zheng X, Zhu H, Pauk N, Reiterer P, Vasakova M, Hodgson U, Bourdin A,
Cadranel J, Camus P, Chanez P, Cottin V, Crestani B, Israel-Biet D, Jouneau S,
Lebargy F, Marquette C, Prévot G, Valeyre D, Wallaert B, Bonnet R, Costabel U,
Gläser S, Grohé C, Guenther A, Hammerl P, Höffken G, Karagiannidis C, Kirschner
J, Kirsten A, Korn S, Kreuter M, Müller-Quernheim J, Neurohr C, Pfeifer M,
Schönfeld N, Wiewrodt R, Antoniou K, Daniil Z, Diamantea F, Koulouris N,
Mathioudakis G, Ghosal A, Kadappa Shivappa S, Kawedia M, Khatavkar P, Kumar A,
Mehta P, Singh V, Srikanth K, Thakker H, Udwadia Z, Egan J, Fink G, Kramer M,
Yigla M, Agostini C, De Benedetto F, Harari S, Luppi F, Paggiaro P, Tavanti L,
Pesci A, Poletti V, Rottoli P, Saltini C, Sanduzzi Zamparelli A, Vancheri C,
Bando M, Hasegawa Y, Hashimoto K, Homma S, Inase N, Inoue Y, Arai T, Izumi S,
Kawamura T, Kishi K, Kondo Y, Kuwano K, Miura Y, Nishioka Y, Nishiyama O, Ogura
T, Ohkouchi S, Saito T, Setoguchi Y, Shindoh J, Taguchi Y, Tanakadate M, Tomii
K, Sugita Y, Yamaguchi T, Yoshimori K, Jeong S, Kim D, Kim Y, Park C, Song J, Uh
S, Selman M, Bresser P, Grutters J, Wijsenbeek M, Arrobas A, Cardoso J, Costa R,
Morais A, Neves S, Serrado M, Ilkovick M, Vizel A, Alfageme Michavila I,
Ancochea J, Castillo Villegas D, Molina-Molina M, Morell F, Xaubet A, Aktogu
Ozkan S, Kayacan O, Ongen G, Mogulkoc N, Tuncay E, Beirne P, Bettinson H, Burge
P, Dempsey O, Maher T, Millar A, Spencer L, Thickett D, Alvarez J, Andrews C,
Bajwa O, Baker A, Baughman R, Belperio J, Bradley J, Collard H, Cordova F,
Daniels C, de Andrade J, Dushay K, Enelow R, Ettinger N, Gibson K, Gotfried M,
Hajari Case A, Hotchkin D, Huggins J, Kaye M, Kershaw C, Kureishy S, Lancaster
L, Lederer D, Mageto Y, Masson J, Meyer K, Mohabir P, Morrison L, Nathan S, Noth
I, Oelberg D, Rahaghi F, Riley D, Rizzo A, Rossman M, Ruzi J, Sachs P,
Schaumberg T, Scholand M, Schroeder C, Seifer F, Shea J, Sinkowitz D, Tabak J,
Taylor J, Thompson J, Thurm C, Tita J, Wencel M, Westerman J, Lasky J, Demedts
M, Casteels M, Loddenkemper R, Michaelis J, Lasky J, Demedts M, Roman J, Tino G,
Luisetti M.
Author information:
(1)The authors' affiliations are listed in the Appendix.
Erratum in
N Engl J Med. 2015 Aug 20;373(8):782. doi: 10.1056/NEJMx150012.
Comment in
N Engl J Med. 2014 May 29;370(22):2142-3. doi: 10.1056/NEJMe1403448.
N Engl J Med. 2014 Aug 21;371(8):783. doi: 10.1056/NEJMc1407776.
N Engl J Med. 2014 Aug 21;371(8):781. doi: 10.1056/NEJMc1407776.
N Engl J Med. 2014 Aug 21;371(8):781-2. doi: 10.1056/NEJMc1407776.
Ann Intern Med. 2014 Oct 21;161(8):JC5. doi:
10.7326/0003-4819-161-8-201410210-02005.
Perspect Infirm. 2015 Jan-Feb;12(1):62.
Am J Respir Crit Care Med. 2015 Jul 15;192(2):249-51. doi:
10.1164/rccm.201503-0554RR.
Am J Respir Crit Care Med. 2015 Oct 15;192(8):1020. doi:
10.1164/rccm.201505-0937LE.
Am J Respir Crit Care Med. 2015 Oct 15;192(8):1020-1. doi:
10.1164/rccm.201507-1354LE.
BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular
inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that
treatment with 150 mg of nintedanib twice daily reduced lung-function decline
and acute exacerbations in patients with idiopathic pulmonary fibrosis.
METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3
trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg
of nintedanib twice daily as compared with placebo in patients with idiopathic
pulmonary fibrosis. The primary end point was the annual rate of decline in
forced vital capacity (FVC). Key secondary end points were the time to the first
acute exacerbation and the change from baseline in the total score on the St.
George's Respiratory Questionnaire, both assessed over a 52-week period.
RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to
receive nintedanib or placebo. The adjusted annual rate of change in FVC was
-114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml;
95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6
ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI,
44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant
difference between the nintedanib and placebo groups in the time to the first
acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42;
P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus
placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent
adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and
18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and
63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced
the decline in FVC, which is consistent with a slowing of disease progression;
nintedanib was frequently associated with diarrhea, which led to discontinuation
of the study medication in less than 5% of patients. (Funded by Boehringer
Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and
NCT01335477.).
DOI: 10.1056/NEJMoa1402584
PMID: 24836310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22926262 | 1. Methods. 2012 Nov;58(3):289-99. doi: 10.1016/j.ymeth.2012.08.009. Epub 2012
Aug 25.
ChIA-PET analysis of transcriptional chromatin interactions.
Zhang J(1), Poh HM, Peh SQ, Sia YY, Li G, Mulawadi FH, Goh Y, Fullwood MJ, Sung
WK, Ruan X, Ruan Y.
Author information:
(1)Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672,
Singapore.
Long-range chromatin contacts between specific DNA regulatory elements play a
pivotal role in gene expression regulation, and a global characterization of
these interactions in the 3-dimensional (3D) chromatin structure is imperative
in understanding signaling networks and cell states. Chromatin Interaction
Analysis using Paired-End Tag sequencing (ChIA-PET) is a method which converts
functional chromatin structure into millions of short tag sequences. Combining
Chromatin Immunoprecipitation (ChIP), proximity ligation and high-throughput
sequencing, ChIA-PET provides a global and unbiased interrogation of
higher-order chromatin structures associated with specific protein factors.
Here, we describe the detailed procedures of the ChIA-PET methodology,
unraveling transcription-associated chromatin contacts in a model human cell
line.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymeth.2012.08.009
PMID: 22926262 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8180508 | 1. Tex Heart Inst J. 1994;21(1):22-9.
Identification of defects in the fibrillin gene and protein in individuals with
the Marfan syndrome and related disorders.
Milewicz DM(1).
Author information:
(1)Department of Internal Medicine, University of Texas Medical School, Houston
77030.
The Marfan syndrome is an autosomal dominant disorder with pleiotropic
manifestations that involve the cardiovascular, ocular, and skeletal systems.
Through a number of investigational approaches, the gene encoding for fibrillin,
the FBN1 gene on chromosome 15, has been identified as the defective gene
causing the Marfan syndrome. Fibrillin is the large glycoprotein with a
repetitive domain structure and is a major protein component of microfibrils, a
fibrillar system closely associated with elastin in connective tissue.
Mutational analysis of defects in the FBN1 gene in patients with the Marfan
syndrome has revealed that most mutations are private or unique in an affected
individual or family. Analysis of fibrillin protein or gene defects in
individuals with related phenotypes has revealed that a perinatal lethal
syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations. In
addition, fibroblast cell strains from a subset of patients with idiopathic
scoliosis have fibrillin protein defects. Last, fibroblasts from calves affected
with bovine Marfan syndrome display defects in the fibrillin protein. These
studies have wide-ranging implications in the diagnosis, treatment, and
prevention of Marfan syndrome and related disorders.
PMCID: PMC325128
PMID: 8180508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23734615 | 1. Am J Intellect Dev Disabil. 2013 May;118(3):201-10. doi:
10.1352/1944-7558-118.3.201.
Diurnal cortisol profile in Williams syndrome in novel and familiar settings.
Lense MD(1), Tomarken AJ, Dykens EM.
Author information:
(1)Vanderbilt University, Nashville, TN, USA. [email protected]
Williams syndrome (WS) is a neurodevelopmental genetic disorder associated with
high rates of anxiety and social issues. We examined diurnal cortisol, a
biomarker of the stress response, in adults with WS in novel and familiar
settings, and compared these profiles to typically developing (TD) adults. WS
and TD participants had similar profiles in a familiar setting, while
participants with WS had elevated cortisol late in the day in the novel setting
when social demands were higher. The cortisol awakening response in WS was
associated with parent-reported levels of somatic complaints and social
difficulties. Results suggest that adults with WS have a typical diurnal
cortisol profile that may be sensitive to social and activity transitions
throughout the day.
DOI: 10.1352/1944-7558-118.3.201
PMID: 23734615 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21113021 | 1. Nucleic Acids Res. 2011 Jan;39(Database issue):D926-32. doi:
10.1093/nar/gkq1236. Epub 2010 Nov 27.
FINDbase: a worldwide database for genetic variation allele frequencies updated.
Georgitsi M(1), Viennas E, Antoniou DI, Gkantouna V, van Baal S, Petricoin EF
3rd, Poulas K, Tzimas G, Patrinos GP.
Author information:
(1)Department of Pharmacy, School of Health Sciences, Faculty of Engineering,
University of Patras, Patras, Greece.
Frequency of INherited Disorders database (FIND base; http://www.findbase.org)
records frequencies of causative genetic variations worldwide. Database records
include the population and ethnic group or geographical region, the disorder
name and the related gene, accompanied by links to any related external
resources and the genetic variation together with its frequency in that
population. In addition to the regular data content updates, we report the
following significant advances: (i) the systematic collection and thorough
documentation of population/ethnic group-specific pharmacogenomic markers allele
frequencies for 144 markers in 14 genes of pharmacogenomic interest from
different classes of drug-metabolizing enzymes and transporters, representing
150 populations and ethnic groups worldwide; (ii) the development of new data
querying and visualization tools in the expanded FINDbase data collection, built
around Microsoft's PivotViewer software (http://www.getpivot.com), based on
Microsoft Silverlight technology (http://www.silverlight.net) that facilitates
querying of large data sets and visualizing the results; and (iii) the
establishment of the first database journal, by affiliating FINDbase with Human
Genomics and Proteomics, a new open-access scientific journal, which would serve
as a prime example of a non-profit model for sustainable database funding.
DOI: 10.1093/nar/gkq1236
PMCID: PMC3013745
PMID: 21113021 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21727247 | 1. Arch Gen Psychiatry. 2011 Nov;68(11):1104-12. doi:
10.1001/archgenpsychiatry.2011.73. Epub 2011 Jul 4.
Antidepressant use during pregnancy and childhood autism spectrum disorders.
Croen LA(1), Grether JK, Yoshida CK, Odouli R, Hendrick V.
Author information:
(1)Division of Research, Kaiser Permanente Northern California, Oakland, CA
94612, USA. [email protected]
CONTEXT: The prevalence of autism spectrum disorders (ASDs) has increased over
recent years. Use of antidepressant medications during pregnancy also shows a
secular increase in recent decades, prompting concerns that prenatal exposure
may contribute to increased risk of ASD.
OBJECTIVE: To systematically evaluate whether prenatal exposure to
antidepressant medications is associated with increased risk of ASD.
DESIGN: Population-based case-control study. Medical records were used to
ascertain case children and control children and to derive prospectively
recorded information on mothers' use of antidepressant medications, mental
health history of mothers, and demographic and medical covariates.
SETTING: The Kaiser Permanente Medical Care Program in Northern California.
PARTICIPANTS: A total of 298 case children with ASD (and their mothers) and 1507
randomly selected control children (and their mothers) drawn from the membership
of the Kaiser Permanente Medical Care Program in Northern California.
MAIN OUTCOME MEASURES: ASDs.
RESULTS: Prenatal exposure to antidepressant medications was reported for 20
case children (6.7%) and 50 control children (3.3%). In adjusted logistic
regression models, we found a 2-fold increased risk of ASD associated with
treatment with selective serotonin reuptake inhibitors by the mother during the
year before delivery (adjusted odds ratio, 2.2 [95% confidence interval,
1.2-4.3]), with the strongest effect associated with treatment during the first
trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No
increase in risk was found for mothers with a history of mental health treatment
in the absence of prenatal exposure to selective serotonin reuptake inhibitors.
CONCLUSION: Although the number of children exposed prenatally to selective
serotonin reuptake inhibitors in this population was low, results suggest that
exposure, especially during the first trimester, may modestly increase the risk
of ASD. The potential risk associated with exposure must be balanced with the
risk to the mother or fetus of untreated mental health disorders. Further
studies are needed to replicate and extend these findings.
DOI: 10.1001/archgenpsychiatry.2011.73
PMID: 21727247 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14519394 | 1. Curr Opin Cell Biol. 2003 Oct;15(5):590-7. doi: 10.1016/s0955-0674(03)00097-8.
Roles of Rho-family GTPases in cell polarisation and directional migration.
Fukata M(1), Nakagawa M, Kaibuchi K.
Author information:
(1)Department of Cell Pharmacology, Nagoya University, Graduate School of
Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan.
Polarised cell migration is a tightly regulated process that occurs in tissue
development, chemotaxis and wound healing. Rho-family GTPases, including Cdc42,
Rac1 and RhoA, play a central role in establishing cell polarisation, which
requires asymmetric and ordered distribution of the signalling molecules and the
cytoskeleton. Recent advances reveal that Rho GTPases, together with
phosphatidylinositol 3-kinase, contribute to asymmetric phosphatidylinositol
3,4,5-trisphosphate distribution via a positive-feedback loop.
Phosphatidylinositol 3,4,5-trisphosphate thereby activates the signalling
cascades to the cytoskeleton as a second messenger. Rho GTPases also capture and
stabilise microtubules through their effectors (e.g. IQGAP1, mDia and Par6) near
the cell cortex, leading to polarised cell morphology and directional cell
migration. Thus, elucidation of the signal transduction cascades from receptors
to Rho GTPases and, subsequently, from Rho GTPases to microtubules has begun.
DOI: 10.1016/s0955-0674(03)00097-8
PMID: 14519394 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20627007 | 1. Zhonghua Wai Ke Za Zhi. 2010 Mar 15;48(6):435-8.
[Comparative analysis of sequence alignment of SH3GL1 gene as a disease
candidate gene of adolescent idiopathic scoliosis].
[Article in Chinese]
Yang T(1), Xu JZ, Jia QZ, Guo H, Luo F, Ye Q, Bai Y.
Author information:
(1)Department of Orthopaedics Surgery, Southwest Hospital, Third Military
University, Chongqing 400038, China.
OBJECTIVE: To identify whether SH3GL1 gene serves as a disease associated gene
of adolescent idiopathic scoliosis (AIS).
METHODS: Positioning candidate cloning: "case-sibling or case-family control
design" research scheme based on family constellation was designed. Fifty-six
AIS patients (15 male and 41 female, mean age 15 years old, ranged from 8 to 22
years old, Cobb angle from 25 degrees to 110 degrees , average Cobb angle of
67.5 degrees ) from November 2007 to December 2008 were recruited. In all
patients, blood preparation was collected, and genome DNA was extracted.
According to nucleotide sequence of gene SH3GL1, primer pair for PCR
amplification, cloning, and sequencing with 10 exons as emphasis was designed.
Sequence comparative analysis for exon sequencing result between sib pairs or
family pairs, and that between sib pair or family pairs and NCBI (National
Center for Biotechnology Information) were conducted through Vector NTI Advance
10.3 software to judge whether basic group mutation occurred or not. Amino acid
sequence comparative analysis for prediction was made.
RESULTS: Ten exons of the candidate gene SH3GL1 were successfully amplified and
cloned in genome DNA of an AIS sib pair and family pairs, and the sequencing
obtained positive results. Twelve basic group mutations were found in 10 exons
of the candidate gene SH3GL1 of patients with AIS. These mutations were located
in the second exon (3 mutations), the fourth exon (1 mutations), the fifth exon
(4 mutations), the sixth exon (1 mutations), the eighth exon (1 mutations), and
the tenth exon (2 mutations, noncoding region). If basic group in 515 of mRNA
was mutated to T, termination codon(TAG) came into being and open reading frame
was altered. The sequence of protein showed brachytmema protein was encoded,
which could cause changes of primary structure.
CONCLUSION: SH3GL1 is possibly one of the disease associated genes of AIS.
PMID: 20627007 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23412389 | 1. Cell Death Dis. 2013 Feb 14;4(2):e496. doi: 10.1038/cddis.2013.16.
Rasosomes originate from the Golgi to dispense Ras signals.
Grunwald A(1), Gottfried I, Cox AD, Haklai R, Kloog Y, Ashery U.
Author information:
(1)Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University,
Ramat-Aviv 69978, Israel.
Ras proteins undergo an incompletely understood trafficking process in the cell.
Rasosomes are protein nanoparticles of 80-100 nm diameter that carry lipidated
Ras isoforms (H-Ras and N-Ras) as well as their effectors through the cytoplasm
and near the plasma membrane (PM). In this study, we identified the subcellular
origin of rasosomes and how they spread Ras proteins through the cell. We found
no dependency of rasosome formation on galectins, or on the GDP-/GTP-bound state
of Ras. We found that significantly more rasosomes are associated with forms of
Ras that are localized to the Golgi, namely N-Ras or the singly palmitoylated
H-Ras mutant (C181S). To explore the possibility that rasosome originate from
the Golgi, we used photoactivatable (PA)-GFP-H-Ras mutants and showed that
rasosomes bud from the Golgi in a two-step mechanism. Newly released rasosomes
first move in an energy-dependent directed fashion and then convert to randomly
diffusing rasosomes. Dual fluorescence time-lapse imaging revealed the
appearance of dually labeled rasosomes, indicating a dynamic exchange of
cytoplasmic and PM-associated Ras with rasosome-associated Ras. Finally, higher
levels of rasosomes correlate with higher levels of ERK phosphorylation, a key
marker of Ras downstream signaling. We suggest that H-Ras and N-Ras proteins
exchange with rasosomes that can function as carriers of palmitoylated Ras and
its signals.
DOI: 10.1038/cddis.2013.16
PMCID: PMC3734827
PMID: 23412389 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23590413 | 1. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):763-75. doi:
10.1517/17425255.2013.791282. Epub 2013 Apr 17.
Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the
treatment of type 2 diabetes mellitus.
Lamos EM(1), Younk LM, Davis SN.
Author information:
(1)University of Maryland School of Medicine, Department of Medicine, Baltimore,
MD 21201, USA.
INTRODUCTION: Canagliflozin is an orally administered sodium glucose
cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes.
Canagliflozin improves glycemic control in an insulin-independent fashion
through inhibition of glucose reuptake in the kidney.
AREAS COVERED: This article reviews the available data on the pharmacodynamics,
the pharmacokinetics and metabolism, and the efficacy and safety of
canagliflozin. Relevant articles were identified via PubMed using the search
term canagliflozin with no date restriction. The authors also discuss the
abstracts from canagliflozin studies presented at large diabetes conferences.
EXPERT OPINION: Canagliflozin offers a relatively modest reduction in HbA1c,
FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body
weight. Dose adjustment may be recommended in the elderly, those on loop
diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60
ml/min/1.73 m(2) if there are concerns or symptoms of volume-related side
effects. Issues remain with observed increases in low-density lipoprotein
cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin
offers a novel mechanism of action, a modest glycemic control, and a favorable
side-effect profile. It was approved by the US Food and Drug Administration in
April 2013 and is undergoing evaluation by the European Medicines Agency.
DOI: 10.1517/17425255.2013.791282
PMID: 23590413 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23568994 | 1. Brain Nerve. 2013 Apr;65(4):461-8.
[Aβ immunotherapy for Alzheimer's disease].
[Article in Japanese]
Sakai K(1), Yamada M.
Author information:
(1)Department of Neurology and Neurobiology of Aging, Kanazawa University
Graduate School of Medical Sciences, Japan.
Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized
by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain
parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the
neurons. Although details of the disease pathomechanisms remain unclear, Aβ
likely acts as a key protein for AD initiation and progression, followed by
abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis).
According to this hypothesis, Aβ immunization therapies are created to eliminate
Aβ from the brain, and to prevent the neurons from damage by these pathogenic
proteins. There are two methods for Aβ immunotherapies: active and passive
immunization. Previous studies have shown Aβ removal and improved cognitive
function in animal models of AD. Clinical trials on various drugs, including
AN1792, bapineuzumab, and solanezumab, have been carried out; however, all
trials have failed to demonstrate apparent clinical benefits. On the contrary,
side effects emerged, such as meningoencephalitis, vasogenic edema, which are
currently called amyloid related imaging abnormalities (ARIA)-E and
microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, Aβ
was removed from the brain parenchyma and phosphorylated-tau was reduced in the
neuronal processes. Moreover, deterioration of the cerebral amyloid angiopathy
(CAA) and an increase of microhemorrhages and microinfarcts were described. Aβ
is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could
stem from severe CAA due to dysfunction of the drainage pathway after
immunotherapy. Aβ immunization has a potential of cure for AD patients, although
the above-described problems must be overcome before applying this therapy in
clinical treatment.
PMID: 23568994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16254107 | 1. J Clin Pathol. 2005 Nov;58(11):1175-9. doi: 10.1136/jcp.2005.026955.
Aberrant expression of DeltaNp73 in benign and malignant tumours of the
prostate: correlation with Gleason score.
Guan M(1), Chen Y.
Author information:
(1)Centre of Laboratory Medicine, Hua Shan Hospital, Fudan University, Shanghai,
200040, PR China. [email protected]
BACKGROUND: The p73 gene is a p53 homologue that induces apoptosis and inhibits
cell proliferation. N-terminal truncated isoforms of p73 (DeltaNp73) act as
dominant-negative inhibitors of wild-type p53 and TAp73 and result in tumour
growth in nude mice.
AIMS: To detect DeltaNp73 expression in 24 benign prostatic hyperplasia samples,
33 prostate carcinomas, and five normal samples and to evaluate the relation
between DeltaNp73, TAp73 concentrations, and the clinicopathological
characteristics of patients with prostate cancer.
METHODS: TAp73 was determined by real time polymerase chain reaction (PCR);
DeltaNp73 and DeltaN'p73 were assessed using reverse transcription PCR. western
blotting was used to analyse protein expression. p53 mutation was determined by
immunohistochemistry.
RESULTS: A significant increase of DeltaNp73 was seen in 20 of 33 carcinomas and
17 of 24 benign prostate hyperplasia tissues, but in none of the normal samples.
None of the specimens expressed DeltaN'p73. No significant relation was found
between TAp73 expression and clinical parameters. The incidence of positive
expression of DeltaNp73 correlated with the Gleason score in prostate
carcinomas. Cancer samples with wild-type p53 had significantly higher
expression of DeltaNp73 than p53 mutant cancers.
CONCLUSION: These data suggest a potential role for DeltaNp73 in prostate cancer
progression.
DOI: 10.1136/jcp.2005.026955
PMCID: PMC1770779
PMID: 16254107 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21790283 | 1. Expert Rev Clin Immunol. 2011 Jul;7(4):411-7. doi: 10.1586/eci.11.27.
Mepolizumab in eosinophilic disorders.
Abonia JP(1), Putnam PE.
Author information:
(1)Division of Allergy and Immunology, Cincinnati Children's Hospital Medical
Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue,
ML2010, Cincinnati, OH 45229-3039, USA.
Mepolizumab (Bosatria(®), GlaxoSmithKline) is a biologic agent developed to
treat asthma. It represents a humanized monoclonal antibody of IgG1 κ type,
which targets human IL-5 and thus prevents its interaction with the α-chain of
the IL-5 receptor. To date, it has not been approved for use in any
eosinophil-related disorder; however, several studies have suggested some
therapeutic benefit across a spectrum of eosinophil-related disorders. This
article evaluates the currently available preclinical and clinical studies, and
the impact of mepolizumab against a variety of eosinophilic disorders.
DOI: 10.1586/eci.11.27
PMCID: PMC3201786
PMID: 21790283 [Indexed for MEDLINE]
Conflict of interest statement: Financial & competing interests disclosure The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this
manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/17420170 | 1. Carcinogenesis. 2007 Sep;28(9):1914-7. doi: 10.1093/carcin/bgm077. Epub 2007
Apr 9.
The functional genetic variant Arg324Gly of frizzled-related protein is
associated with colorectal cancer risk.
Shanmugam KS(1), Brenner H, Hoffmeister M, Chang-Claude J, Burwinkel B.
Author information:
(1)Helmholtz-University Group Molecular Epidemiology, Heidelberg, Germany.
[email protected]
The Wnt-beta-catenin pathway plays a central role in colorectal tumorigenesis.
Frizzled-related protein (FRZB, also termed secreted frizzled-related protein 3,
sFRP3) antagonizes the signaling of wingless (Wnt) ligands through the frizzled
membrane-bound receptors, resulting in beta-catenin destabilization thereby
suppressing the expression of target genes. Recently, the FRZB Gly324 variant
has been shown to have an attenuated ability to antagonize Wnt signaling and to
be associated with an increased osteoarthritis risk. Here, we investigated, for
the first time, the role of Arg324Gly (970C>G) along with Arg200Trp (598C>T) on
colorectal cancer (CRC) risk by analyzing 659 patients and 607 control
individuals drawn from the German DACHS (Darmkrebs: Chancen der Verhütung durch
Screening) study. Although Arg200Trp showed no effect on CRC risk, we found
homozygous carriers of Gly324 more frequent in cases than in controls, leading
to a significantly increased risk for CRC [odds ratio (OR) = 5.1, 95% confidence
interval (95% CI) = 1.74-14.71, P < 0.001]. The association was stronger in
rectal cancer (OR = 7.52, 95% CI = 2.40-23.25, P < 0.0001) than in colon cancer
(OR = 3.66, 95% CI = 1.14-11.76, P < 0.05). Since modified Wnt signaling and
down-regulation of frizzled-related proteins have been observed in many human
cancers, this variant may also affect the susceptibility to other cancers.
DOI: 10.1093/carcin/bgm077
PMID: 17420170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15814030 | 1. Ann Trop Med Parasitol. 2005 Mar;99(2):119-24. doi: 10.1179/136485905X19946.
ABO-blood-group types and protection against severe, Plasmodium falciparum
malaria.
Pathirana SL(1), Alles HK, Bandara S, Phone-Kyaw M, Perera MK, Wickremasinghe
AR, Mendis KN, Handunnetti SM.
Author information:
(1)Malaria Research Unit, Department of Parasitology, Faculty of Medicine,
University of Colombo, P.O. Box 271, Colombo, Sri Lanka. [email protected]
Although the ABO blood group of the human host has been reported to influence
malarial infection, there have been few clinical observations on this effect. A
hospital-based, comparative study was therefore performed to investigate the
relationship between blood-group type and severe disease i nPlasmodium
falciparum malaria. Overall, 243 cases of malaria (163 uncomplicated and 80
severe) and 65 patients with severe, non-malarial infections were studied. In
terms of ABO-blood-group composition, the patients with severe malaria were
significantly different from the patients with the uncomplicated disease
(P<0.001) and also from a population control described previously (P<0.0001).
The patients with uncomplicated malaria or severe but non-malarial disease were,
however, similar to the population control. The cases of severe malaria were
significantly less likely to be of blood group O (P=0.0003), and significantly
more likely to be of group AB (P<0.0001), than the patients with nonsevere
malaria. It appears that individuals who are of blood-group O are relatively
resistant to the severe disease caused by P. falciparum infection.
DOI: 10.1179/136485905X19946
PMID: 15814030 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23355615 | 1. Nucleic Acids Res. 2013 Mar 1;41(5):3314-26. doi: 10.1093/nar/gkt019. Epub
2013 Jan 25.
MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA
binding and degradation.
Lin RJ(1), Chien HL, Lin SY, Chang BL, Yu HP, Tang WC, Lin YL.
Author information:
(1)Department of General Medicine, School of Medicine, College of Medicine,
Taipei Medical University, Taipei 110, Taiwan. [email protected]
Erratum in
Nucleic Acids Res. 2024 Jul 8;52(12):7398. doi: 10.1093/nar/gkae488.
Expression of concern in
Nucleic Acids Res. 2024 Jun 10;52(10):6097. doi: 10.1093/nar/gkae342.
Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), belonging to the
MCPIP family with highly conserved CCCH-type zinc finger and Nedd4-BP1, YacP
Nuclease domains, has been implicated in negative regulation of the cellular
inflammatory responses. In this report, we demonstrate for the first time that
this RNA-binding nuclease also targets viral RNA and possesses potent antiviral
activities. Overexpression of the human MCPIP1, but not MCPIP2, MCPIP3 or
MCPIP4, inhibited Japanese encephalitis virus (JEV) and dengue virus (DEN)
replication. The functional analysis of MCPIP1 revealed that the activities of
RNase, RNA binding and oligomerization, but not deubiqutinase, are required for
its antiviral potential. Furthermore, infection of other positive-sense RNA
viruses, such as sindbis virus and encephalomyocarditis virus, and
negative-sense RNA virus, such as influenza virus, as well as DNA virus, such as
adenovirus, can also be blocked by MCPIP1. Moreover, the endogenous MCPIP1 gene
expression was induced by JEV and DEN infection, and knockdown of MCPIP1
expression enhanced the replication of JEV and DEN in human cells. Thus, MCPIP1
can act as a host innate defense via RNase activity for targeting and degrading
viral RNA.
DOI: 10.1093/nar/gkt019
PMCID: PMC3597685
PMID: 23355615 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22362925 | 1. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. doi: 10.1093/hmg/dds045. Epub 2012
Feb 23.
An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing
defects.
Fernandez Alanis E(1), Pinotti M, Dal Mas A, Balestra D, Cavallari N, Rogalska
ME, Bernardi F, Pagani F.
Author information:
(1)Human Molecular Genetics, International Centre for Genetic Engineering and
Biotechnology, Trieste, Italy.
A significant proportion of disease-causing mutations affect precursor-mRNA
splicing, inducing skipping of the exon from the mature transcript. Using F9
exon 5, CFTR exon 12 and SMN2 exon 7 models, we characterized natural mutations
associated to exon skipping in Haemophilia B, cystic fibrosis and spinal
muscular atrophy (SMA), respectively, and the therapeutic splicing rescue by
using U1 small nuclear RNA (snRNA). In minigene expression systems, loading of
U1 snRNA by complementarity to the normal or mutated donor splice sites (5'ss)
corrected the exon skipping caused by mutations at the polypyrimidine tract of
the acceptor splice site, at the consensus 5'ss or at exonic regulatory
elements. To improve specificity and reduce potential off-target effects, we
developed U1 snRNA variants targeting non-conserved intronic sequences
downstream of the 5'ss. For each gene system, we identified an exon-specific U1
snRNA (ExSpeU1) able to rescue splicing impaired by the different types of
mutations. Through splicing-competent cDNA constructs, we demonstrated that the
ExSpeU1-mediated splicing correction of several F9 mutations results in complete
restoration of secreted functional factor IX levels. Furthermore, two ExSpeU1s
for SMA improved SMN exon 7 splicing in the chromosomal context of normal cells.
We propose ExSpeU1s as a novel therapeutic strategy to correct, in several human
disorders, different types of splicing mutations associated with defective exon
definition.
DOI: 10.1093/hmg/dds045
PMCID: PMC3349419
PMID: 22362925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25093016 | 1. Core Evid. 2014 Jul 21;9:89-97. doi: 10.2147/CE.S33940. eCollection 2014.
Brodalumab: an evidence-based review of its potential in the treatment of
moderate-to-severe psoriasis.
Coimbra S(1), Figueiredo A(2), Santos-Silva A(3).
Author information:
(1)CESPU (Advanced Polytechnic and University Cooperative), Institute of
Research and Advanced Training in Health Sciences and Technologies, Gandra-PRD,
Portugal ; IBMC, Institute for Molecular and Cell Biology, University of Porto,
Porto, Portugal.
(2)Service of Dermatology, Hospital and University Centre of Coimbra (CHUC),
University of Coimbra, Coimbra, Portugal.
(3)IBMC, Institute for Molecular and Cell Biology, University of Porto, Porto,
Portugal ; Biochemistry Laboratory, Biological Sciences Department, Faculty of
Pharmacy (FFUP), University of Porto, Porto, Portugal.
Advances in knowledge regarding the pathogenesis of psoriasis have allowed the
development of a new class of agents known as biologic drugs. Data confirm that
T helper (Th)17 and interleukin (IL)-17 signaling has a crucial role in the
pathogenesis of the disease. High levels of IL-17 and Th17-related cytokines
have been reported in psoriasis, leading to the suggestion of agents targeting
IL-17 as a potential therapeutic strategy in psoriasis. Brodalumab is a human
monoclonal antibody that targets IL-17 receptor A, blocking the effects of
IL-17A, IL-17F, and IL-17E. Data from Phase I and Phase II clinical trials
indicate that brodalumab has a favorable safety and tolerability profile, with
strong clinical activity, suggesting that it is a potential tool for use in the
treatment of moderate-to-severe psoriasis.
DOI: 10.2147/CE.S33940
PMCID: PMC4112723
PMID: 25093016 |
http://www.ncbi.nlm.nih.gov/pubmed/16618617 | 1. J Formos Med Assoc. 2006 Apr;105(4):349-54. doi:
10.1016/S0929-6646(09)60128-5.
A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung
disease.
Chen WC(1), Chang SS, Sy ED, Tsai MC.
Author information:
(1)Department of Emergency Medicine, National Cheng Kung University Medical
College and Hospital, Tainan, Taiwan.
Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence
of ganglion cells in the nerve plexuses of the lower digestive tract. Although
mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN,
SIP1) have been identified in affected individuals, it is now clear that RET and
EDNRB are the primary genes implicated in the etiology of HSCR. All eight genes
are involved in the early development of the enteric nervous system, and most
act through two distinct biochemical pathways mediated by RET and EDNRB.
Mutations in RET and EDNRB account for up to 50% and 5% of HSCR cases in the
general population, respectively. Interaction between these two signaling
pathways could modify RET expression and, therefore, HSCR phenotype. Here, we
report the case of a 1-year-old Taiwanese boy who presented with abdominal
distension since birth and bilious vomiting after feeding. HSCR (short-segment
type) was diagnosed based on X-ray, lower gastrointestinal series and biopsy
findings. Mutation analysis revealed a heterozygous T>C missense mutation in
exon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90
residue in the extracellular domain of the G protein-coupled receptor with an
arginine residue (C90R). No RET gene mutation was detected in this patient.
DOI: 10.1016/S0929-6646(09)60128-5
PMID: 16618617 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23538392 | 1. J Med Internet Res. 2013 Mar 28;15(3):e72. doi: 10.2196/jmir.2442.
A smartphone-based intervention with diaries and therapist feedback to reduce
catastrophizing and increase functioning in women with chronic widespread pain.
part 2: 11-month follow-up results of a randomized trial.
Kristjánsdóttir ÓB(1), Fors EA, Eide E, Finset A, Stensrud TL, van Dulmen S,
Wigers SH, Eide H.
Author information:
(1)Department of Behavioral Sciences in Medicine, Faculty of Medicine,
University of Oslo, Oslo, Norway. [email protected]
BACKGROUND: Internet-based interventions are increasingly used to support
self-management of individuals with chronic illnesses. Web-based interventions
may also be effective in enhancing self-management for individuals with chronic
pain, but little is known about long-term effects. Research on Web-based
interventions to support self-management following participation in pain
management programs is limited.
OBJECTIVE: The aim is to examine the long-term effects of a 4-week
smartphone-intervention with diaries and therapist-written feedback following an
inpatient chronic pain rehabilitation program, previously found to be effective
at short-term and 5-month follow-ups.
METHODS: 140 women with chronic widespread pain, participating in a 4-week
inpatient rehabilitation program, were randomized into two groups: with or
without a smartphone intervention after the rehabilitation. The smartphone
intervention consisted of one face-to-face individual session and 4 weeks of
written communication via a smartphone, consisting of three diaries daily to
elicit pain-related thoughts, feelings, and activities, as well as daily
personalized written feedback based on cognitive behavioral principles from a
therapist. Both groups were given access to an informational website to promote
constructive self-management. Outcomes were measured with self-reported
paper-and-pencil format questionnaires with catastrophizing as the primary
outcome measure. Secondary outcomes included daily functioning and symptom
levels, acceptance of pain, and emotional distress.
RESULTS: By the 11-month follow-up, the favorable between-group differences
previously reported post-intervention and at 5-month follow-up on
catastrophizing, acceptance, functioning, and symptom level were no longer
evident (P>.10). However, there was more improvement in catastrophizing scores
during the follow-up period in the intervention group (M=-2.36, SD 8.41)
compared to the control group (M=.40, SD 7.20), P=.045. Also, per protocol
within-group analysis showed a small positive effect (Cohen's d=.33) on
catastrophizing in the intervention group (P=.04) and no change in the control
group from the smartphone intervention baseline to 11-month follow-up. A
positive effect (Cohen's d=.73) on acceptance was found within the intervention
group (P<.001) but not in the control group. Small to large negative effects
were found within the control group on functioning and symptom levels, emotional
distress, and fatigue (P=.05) from the intervention baseline to the 11-month
follow-up.
CONCLUSION: The long-term results of this randomized trial are ambiguous. No
significant between-group effect was found on the study variables at 11-month
follow-up. However, the within-group analyses, comparing the baseline for the
smartphone intervention to the 11-month data, indicated changes in the desired
direction in catastrophizing and acceptance in the intervention group but not
within the control group. This study provides modest evidence supporting the
long-term effect of the intervention.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01236209;
http://www.clinicaltrials.gov/ct2/show/NCT01236209 (Archived by WebCite at
http://www.webcitation.org/6FF7KUXo0).
DOI: 10.2196/jmir.2442
PMCID: PMC3636011
PMID: 23538392 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/22009847 | 1. Orthop Surg. 2009 Aug;1(3):222-30. doi: 10.1111/j.1757-7861.2009.00038.x.
Association between adolescent idiopathic scoliosis with double curve and
polymorphisms of calmodulin1 gene/estrogen receptor-α gene.
Zhao D(1), Qiu GX, Wang YP, Zhang JG, Shen JX, Wu ZH.
Author information:
(1)Department of Orthopedic Surgery, Peking Union Medical College Hospital,
Beijing, China.
OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNP) of the
calmodulin1 (CALM1) and estrogen receptor-α genes correlate with double curve in
adolescent idiopathic scoliosis (AIS).
METHODS: A total of 67 Chinese patients with AIS with double curve and 100
healthy controls were recruited. Curve pattern and Cobb angle of each patient
were recorded. The Cobb angle is at least 30°. There were 60 patients with Cobb
angle ≥ 40°. According to the apical location of the major curve, there were 40
thoracic curve patients. Four polymorphic loci, including rs12885713 (-16C > T)
and rs5871 in the CALM1 gene and rs2234693 (Pvu II) and rs9340799 (Xba I) in the
estrogen receptor 1 (ER1) gene were analyzed by the ABI3730 genetic analyzer.
RESULTS: The current study indicates that: (i) there are statistical differences
between patients with double curve, with Cobb angle ≥ 40° and with thoracic
curve and healthy controls in the polymorphic distribution of the rs2234693 site
of the ER1 gene, (P= 0.014, 0.0128, 0.0184 respectively); (ii) there is a
difference between patients with double curve and controls in the polymorphic
distribution of the rs12885713 site in the CALM1 gene (P= 0.034); and (iii)
there is a difference between thoracic curve patients and controls in the
polymorphic distribution of the rs5871 site in the CALM1 gene (P= 0.0102).
CONCLUSIONS: Different subtypes of AIS might be related to different SNP. A
combination of CALM1 and ER1 gene polymorphisms might be related to double curve
in patients with AIS. Further study is necessary to confirm these hypotheses.
© 2009 Tianjin Hospital and Blackwell Publishing Asia Pty Ltd.
DOI: 10.1111/j.1757-7861.2009.00038.x
PMCID: PMC6583290
PMID: 22009847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25401082 | 1. |
http://www.ncbi.nlm.nih.gov/pubmed/24328341 | 1. Bioconjug Chem. 2014 Jan 15;25(1):11-7. doi: 10.1021/bc4003844. Epub 2013 Dec
17.
Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl
group of cilengitide by N-oligoethylene glycol (N-OEG) chains.
Fernández-Llamazares AI(1), Adan J, Mitjans F, Spengler J, Albericio F.
Author information:
(1)Institute for Research in Biomedicine (IRB) Barcelona, ‡CIBER-BBN, Networking
Centre on Bioengineering, Biomaterials and Nanomedicine, and ∥Biomed Division,
Leitat Technological Center Institution, Barcelona Science Park , Baldiri Reixac
10, 08028 Barcelona, Spain.
Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed
as a highly active and selective ligand for the αvβ3 and αvβ5 integrin
receptors. We describe the synthesis of three analogues of this peptide in which
the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of
increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively
composed of 2, 11, and 23 ethylene oxide monomer units. The different N-OEG
cyclopeptides and the original peptide were compared with respect to
lipophilicity and biological activity. The N-OEG2 analogue was straightforward
to synthesize in solid phase using an Fmoc-N-OEG2 building block. The syntheses
of the N-OEG11 and N-OEG23 cyclopeptides are hampered by the increased steric
hindrance of the N-substituent, and could only be achieved by segment coupling,
which takes place with epimerization and thus requires extensive product
purification. All the N-OEG analogues were found to be more hydrophobic than the
parent peptide, and their hydrophobicity was systematically enhanced upon
increasing the length of the OEG chain. The N-OEG2 cyclopeptide displayed the
same capacity as Cilengitide to inhibit the integrin-mediated adhesion of HUVEC
endothelial, DAOY gliobastoma, and HT-29 colon cancer cells to their ligands
vitronectin and fibrinogen. The N-OEG11 and N-OEG23 analogues also inhibited
cell adhesion to these immobilized ligands, but their IC50 values dropped by 1
order of magnitude with respect to the parent peptide. These results indicate
that replacement of the backbone N-Me group of Cilengitide by a short N-OEG
chain provides a more lipophilic analogue with a similar biological activity.
Upon increasing the size of the N-OEG chain, liophilicity is enhanced, but
synthetic yields drop and the longer polymer chains may impede targeted binding.
DOI: 10.1021/bc4003844
PMID: 24328341 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24552447 | 1. J Dermatolog Treat. 2015 Feb;26(1):32-6. doi: 10.3109/09546634.2013.878448.
Epub 2014 Feb 20.
Anti-IL-17 phase II data for psoriasis: A review.
Brown G(1), Malakouti M, Wang E, Koo JY, Levin E.
Author information:
(1)University of Arizona College of Medicine , Tucson, AZ , USA .
Abstract Background: Studies investigating the molecular basis of psoriasis have
established the central roles of TNFα, interleukin (IL)-12, IL-22 and IL-23 and
there is increasing evidence that IL-17 plays a critical role in the complex
pathophysiology. Preclinical studies suggest that IL-17 is a desirable
therapeutic target for psoriasis treatment.
METHODS: We reviewed the results of the phase II clinical trials for the
anti-IL-17 agents secukinumab, ixekizumab and brodalumab in order to assess the
efficacy and safety profile of each agent.
RESULTS: By week 12, the proportion of patients reaching Psoriasis Area and
Severity Index (PASI 75) was comparable among the most efficacious dosage
between the different agents (secukinumab 82%, ixekizumab 83% and brodalumab
82%; p<0.001 compared to placebo for all agents). The safety profiles of the
agents were similar with the most frequently reported adverse events of
nasopharyngitis, upper respiratory infections and injection site reaction. A
small percentage of patients experienced low-grade neutropenia that was
predominantly transient and asymptomatic.
CONCLUSION: The anti-IL-17 agents demonstrated a rapid and robust clinical
improvement accompanied by a favorable short-term safety profile. The results of
the phase II trials support the theory that the IL-17 pathway is an essential
target in psoriasis treatment.
DOI: 10.3109/09546634.2013.878448
PMID: 24552447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20421997 | 1. PLoS One. 2010 Apr 21;5(4):e10254. doi: 10.1371/journal.pone.0010254.
Anti-V3 monoclonal antibodies display broad neutralizing activities against
multiple HIV-1 subtypes.
Hioe CE(1), Wrin T, Seaman MS, Yu X, Wood B, Self S, Williams C, Gorny MK,
Zolla-Pazner S.
Author information:
(1)Department of Pathology, New York University Langone School of Medicine, New
York, New York, United States of America. [email protected]
BACKGROUND: The V3 loop of the HIV-1 envelope (Env) glycoprotein gp120 was
identified as the "principal neutralizing domain" of HIV-1, but has been
considered too variable to serve as a neutralizing antibody (Ab) target.
Structural and immunochemical data suggest, however, that V3 contains conserved
elements which explain its role in binding to virus co-receptors despite its
sequence variability. Despite this evidence of V3 conservation, the ability of
anti-V3 Abs to neutralize a significant proportion of HIV-1 isolates from
different subtypes (clades) has remained controversial.
METHODS: HIV-1 neutralization experiments were conducted in two independent
laboratories to test human anti-V3 monoclonal Abs (mAbs) against pseudoviruses
(psVs) expressing Envs of diverse HIV-1 subtypes from subjects with acute and
chronic infections. Neutralization was defined by 50% inhibitory concentrations
(IC(50)), and was statistically assessed based on the area under the
neutralization titration curves (AUC).
RESULTS: Using AUC analyses, statistically significant neutralization was
observed by >or=1 anti-V3 mAbs against 56/98 (57%) psVs expressing Envs of
diverse subtypes, including subtypes A, AG, B, C and D. Even when the 10 Tier 1
psVs tested were excluded from the analysis, significant neutralization was
detected by >or=1 anti-V3 mAbs against 46/88 (52%) psVs from diverse HIV-1
subtypes. Furthermore, 9/24 (37.5%) Tier 2 viruses from the clade B and C
standard reference panels were neutralized by >or=1 anti-V3 mAbs. Each anti-V3
mAb tested was able to neutralize 28-42% of the psVs tested. By IC(50) criteria,
40/98 (41%) psVs were neutralized by >or=1 anti-V3 mAbs.
CONCLUSIONS: Using standard and new statistical methods of data analysis, 6/7
anti-V3 human mAbs displayed cross-clade neutralizing activity and revealed that
a significant proportion of viruses can be neutralized by anti-V3 Abs. The new
statistical method for analysis of neutralization data provides many advantages
to previously used analyses.
DOI: 10.1371/journal.pone.0010254
PMCID: PMC2858080
PMID: 20421997 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Monogram Biosciences, Inc.
served as a contractor in the study. Terri Winn, who is an employee of Monogram
Biosciences, Inc., was involved in the design of the study including the
selection of virus panel and in the analyses of the data. Monogram Biosciences,
Inc. did not fund the study and provided fee-for-service work for performing the
U87 neutralization assay. The authors confirm that this affiliation does not
alter their adherence to the PLoS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/17035933 | 1. Neuropsychopharmacology. 2007 Jan;32(1):153-61. doi: 10.1038/sj.npp.1301216.
Epub 2006 Oct 11.
Placebo-controlled trial comparing intermittent and continuous paroxetine in
premenstrual dysphoric disorder.
Landén M(1), Nissbrandt H, Allgulander C, Sörvik K, Ysander C, Eriksson E.
Author information:
(1)Department of Clinical Neuroscience, Section of Psychiatry St Göran,
Karolinska Institutet, Stockholm, Sweden. [email protected]
Serotonin reuptake inhibitors (SRIs) do not have to be administered continuously
to be effective for premenstrual dysphoric disorder (PMDD), but can be given
during luteal phases only. This is of practical importance, but also of
theoretical interest since it suggests that the onset of action of SRIs is
shorter in PMDD than in, for example depression. In this study, both continuous
and intermittent SRI administration was compared with placebo, with the special
purpose of analyzing if different PMDD symptoms respond differently depending on
the treatment regimen. To this end, women meeting slightly modified DSM-IV
criteria for PMDD (mean+/-SD age, 37+/-6.3 years) were treated for three
menstrual cycles with paroxetine continuously, paroxetine during the luteal
phase only, or placebo, the population completing at least one treatment cycle
comprising 55-56 subjects per group. Continuous treatment with paroxetine
reduced premenstrual symptoms effectively with a response rate of 85%. The
effect size was highest for irritability (1.4) and lowest for lack of energy
(0.5). Intermittent treatment was as effective as continuous treatment in
reducing irritability, affect lability, and mood swings, but had a somewhat
weaker effect on depressed mood and somatic symptoms. The study indicates that
the response rate when treating PMDD with SRIs is high, and that irritability is
a key target symptom. Symptoms such as irritability, affect lability, and mood
swings appear to be more inclined to respond rapidly to SRIs, enabling
intermittent treatment, than are, for example, the somatic symptoms.
DOI: 10.1038/sj.npp.1301216
PMID: 17035933 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20110508 | 1. Science. 2010 Jan 29;327(5965):590-2. doi: 10.1126/science.1179595.
Direct restart of a replication fork stalled by a head-on RNA polymerase.
Pomerantz RT(1), O'Donnell M.
Author information:
(1)The Rockefeller University, Howard Hughes Medical Institute, 1230 York
Avenue, New York, NY 10021, USA.
In vivo studies suggest that replication forks are arrested by encounters with
head-on transcription complexes. Yet, the fate of the replisome and RNA
polymerase (RNAP) after a head-on collision is unknown. We found that the
Escherichia coli replisome stalls upon collision with a head-on transcription
complex, but instead of collapsing, the replication fork remains highly stable
and eventually resumes elongation after displacing the RNAP from DNA. We also
found that the transcription-repair coupling factor Mfd promotes direct restart
of the fork after the collision by facilitating displacement of the RNAP. These
findings demonstrate the intrinsic stability of the replication apparatus and a
previously unknown role for the transcription-coupled repair pathway in
promoting replication past a RNAP block.
DOI: 10.1126/science.1179595
PMCID: PMC2861996
PMID: 20110508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21057525 | 1. Nat Struct Mol Biol. 2010 Dec;17(12):1495-9. doi: 10.1038/nsmb.1924. Epub 2010
Nov 7.
Reciprocal intronic and exonic histone modification regions in humans.
Huff JT(1), Plocik AM, Guthrie C, Yamamoto KR.
Author information:
(1)Department of Cellular and Molecular Pharmacology, University of California,
San Francisco, California, USA.
While much attention has been focused on chromatin at promoters and exons, human
genes are mostly composed of intronic sequences. Analyzing published surveys of
nucleosomes and 41 chromatin marks in humans, we identified histone
modifications specifically associated with 5' intronic sequences,
distinguishable from promoter marks and bulk nucleosomes. These intronic marks
were spatially reciprocal to trimethylated histone H3 Lys36 (H3K36me3),
typically transitioning near internal exons. Several marks transitioned near
bona fide exons, but not near nucleosomes at exon-like sequences. Therefore, we
examined whether splicing affects histone marking. Even with considerable
changes in regulated alternative splicing, histone marks were stable. Notably,
these findings are consistent with exon definition influencing histone marks. In
summary, we show that the location of many intragenic marks in humans can be
distilled into a simple organizing principle: association with 5' intronic or 3'
exonic regions.
DOI: 10.1038/nsmb.1924
PMCID: PMC3057557
PMID: 21057525 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16273408 | 1. Ann Hematol. 2005 Dec;84 Suppl 1:18-24. doi: 10.1007/s00277-005-0019-7.
Clinical experience with decitabine in North American patients with
myelodysplastic syndrome.
Yee KW(1), Jabbour E, Kantarjian HM, Giles FJ.
Author information:
(1)Department of Leukemia, University of Texas M.D. Anderson Cancer Center,
Houston, TX 77030, USA.
Recent evidence demonstrates that epigenetic silencing of genes is associated
with myelodysplasia and that a worse prognosis may be correlated with
hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor
p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at
low doses, acts as a hypomethylating agent and is fivefold to tenfold more
active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved
drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have
demonstrated that decitabine has activity in patients with MDS. Preliminary
results of a phase III multicenter North American trial comparing low-dose
decitabine to supportive care verified that therapy with decitabine resulted in
higher response rates, improved quality of life, and prolonged time to leukemic
transformation and/or death. However, further elucidation of its mechanism of
action is required, as clinical response to decitabine does not correlate with
demethylation of the p15 gene promoter or the repetitive DNA element LINE.
Decitabine appears to upregulate both hypermethylated and nonmethylated genes.
Ongoing studies aim to determine the optimal dose, schedule, and route of
administration of decitabine, and to evaluate whether efficacy can be improved
by using it in combination with other agents, such as histone deacetylase
inhibitors.
DOI: 10.1007/s00277-005-0019-7
PMID: 16273408 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17617896 | 1. Genome Biol. 2007;8(7):R137. doi: 10.1186/gb-2007-8-7-r137.
Comprehensive characterization of the cis-regulatory code responsible for the
spatio-temporal expression of olSix3.2 in the developing medaka forebrain.
Conte I(1), Bovolenta P.
Author information:
(1)Departamento de Neurobiología Celular, Molecular y del Desarrollo, Instituto
Cajal, CSIC, Dr Arce, Madrid 28002, Spain.
BACKGROUND: Embryonic development is coordinated by sets of cis-regulatory
elements that are collectively responsible for the precise spatio-temporal
organization of regulatory gene networks. There is little information on how
these elements, which are often associated with highly conserved noncoding
sequences, are combined to generate precise gene expression patterns in
vertebrates. To address this issue, we have focused on Six3, an important
regulator of vertebrate forebrain development.
RESULTS: Using computational analysis and exploiting the diversity of teleost
genomes, we identified a cluster of highly conserved noncoding sequences
surrounding the Six3 gene. Transgenesis in medaka fish demonstrates that these
sequences have enhancer, silencer, and silencer blocker activities that are
differentially combined to control the entire distribution of Six3.
CONCLUSION: This report provides the first example of the precise regulatory
code necessary for the expression of a vertebrate gene, and offers a unique
framework for defining the interplay of trans-acting factors that control the
evolutionary conserved use of Six3.
DOI: 10.1186/gb-2007-8-7-r137
PMCID: PMC2323233
PMID: 17617896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22819125 | 1. Heart Lung. 2013 Jan-Feb;42(1):77-8. doi: 10.1016/j.hrtlng.2012.05.005. Epub
2012 Jul 17.
Subacute thyroiditis (de Quervain's) due to influenza A: presenting as fever of
unknown origin (FUO).
Cunha BA(1), Berbari N.
Author information:
(1)Infectious Disease Division and Division of General Internal Medicine,
Winthrop-University Hospital, Mineola, New York 11501, USA. [email protected]
Subacute (de Quervain's) thyroiditis is a rare but important cause of fever of
unknown origin. Most cases of subacute thyroiditis are caused by a variety of
viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and
adenovirus. Influenza immunization or infection may cause subacute thyroiditis.
We present the first reported case of a fever of unknown origin due to seasonal
influenza A in a 67-year-old woman.
Copyright © 2013. Published by Mosby, Inc.
DOI: 10.1016/j.hrtlng.2012.05.005
PMID: 22819125 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21816040 | 1. BMC Bioinformatics. 2011 Aug 4;12:323. doi: 10.1186/1471-2105-12-323.
RSEM: accurate transcript quantification from RNA-Seq data with or without a
reference genome.
Li B(1), Dewey CN.
Author information:
(1)Department of Computer Sciences, University of Wisconsin-Madison, Madison,
WI, USA.
BACKGROUND: RNA-Seq is revolutionizing the way transcript abundances are
measured. A key challenge in transcript quantification from RNA-Seq data is the
handling of reads that map to multiple genes or isoforms. This issue is
particularly important for quantification with de novo transcriptome assemblies
in the absence of sequenced genomes, as it is difficult to determine which
transcripts are isoforms of the same gene. A second significant issue is the
design of RNA-Seq experiments, in terms of the number of reads, read length, and
whether reads come from one or both ends of cDNA fragments.
RESULTS: We present RSEM, an user-friendly software package for quantifying gene
and isoform abundances from single-end or paired-end RNA-Seq data. RSEM outputs
abundance estimates, 95% credibility intervals, and visualization files and can
also simulate RNA-Seq data. In contrast to other existing tools, the software
does not require a reference genome. Thus, in combination with a de novo
transcriptome assembler, RSEM enables accurate transcript quantification for
species without sequenced genomes. On simulated and real data sets, RSEM has
superior or comparable performance to quantification methods that rely on a
reference genome. Taking advantage of RSEM's ability to effectively use
ambiguously-mapping reads, we show that accurate gene-level abundance estimates
are best obtained with large numbers of short single-end reads. On the other
hand, estimates of the relative frequencies of isoforms within single genes may
be improved through the use of paired-end reads, depending on the number of
possible splice forms for each gene.
CONCLUSIONS: RSEM is an accurate and user-friendly software tool for quantifying
transcript abundances from RNA-Seq data. As it does not rely on the existence of
a reference genome, it is particularly useful for quantification with de novo
transcriptome assemblies. In addition, RSEM has enabled valuable guidance for
cost-efficient design of quantification experiments with RNA-Seq, which is
currently relatively expensive.
DOI: 10.1186/1471-2105-12-323
PMCID: PMC3163565
PMID: 21816040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15541000 | 1. Neuropathol Appl Neurobiol. 2004 Dec;30(6):601-7. doi:
10.1111/j.1365-2990.2004.00572.x.
Differential expression of alpha-synuclein isoforms in dementia with Lewy
bodies.
Beyer K(1), Lao JI, Carrato C, Mate JL, López D, Ferrer I, Ariza A.
Author information:
(1)Department of Pathology, Hospital Universitari Germans Trias i Pujol,
Autonomous University of Barcelona, Barcelona, Spain.
Dementia with Lewy bodies (DLB) is characterized by the widespread presence of
Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is
expressed as two main isoforms (112 and 140), but little is known about their
differential expression in the brain. We compared alpha-synuclein 112 and
alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB
patients, eight Alzheimer disease (AD) patients, and six control subjects.
Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were
determined by real-time polymerase chain reaction with competimer technology
using a LightCycler System. Whereas total alpha-synuclein levels were just
marginally elevated in DLB in comparison with the other groups, alpha-synuclein
112 was seen to be markedly increased in DLB compared with AD cases and
controls. In contrast, alpha-synuclein 140 levels were significantly diminished
in both neurodegenerative disorders in comparison with controls. These results
show differential overexpression of alpha-synuclein 112 in DLB, a finding that
could be of importance in DLB pathogenesis.
DOI: 10.1111/j.1365-2990.2004.00572.x
PMID: 15541000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20301779 | 1. Dyskeratosis Congenita and Related Telomere Biology Disorders.
Savage SA(1), Niewisch MR(2)(3).
In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW,
Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of
Washington, Seattle; 1993–2024.
2009 Nov 12 [updated 2023 Jan 19].
Author information:
(1)Director, Clinical Genetics Branch, Clinical Director, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland
(2)Special Volunteer, Clinical Genetics Branch, Division of Cancer Epidemiology
and Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
(3)Clinical Fellow, Department of Pediatric Hematology and Oncology, Hannover
Medical School, Hannover, Germany
CLINICAL CHARACTERISTICS: Dyskeratosis congenita and related telomere biology
disorders (DC/TBD) are caused by impaired telomere maintenance resulting in
short or very short telomeres. The phenotypic spectrum of telomere biology
disorders is broad and includes individuals with classic dyskeratosis congenita
(DC) as well as those with very short telomeres and an isolated physical
finding. Classic DC is characterized by a triad of dysplastic nails, lacy
reticular pigmentation of the upper chest and/or neck, and oral leukoplakia,
although this may not be present in all individuals. People with DC/TBD are at
increased risk for progressive bone marrow failure (BMF), myelodysplastic
syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell
carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other
findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes,
ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal
telangiectasias, and avascular necrosis of the hips or shoulders. Although most
persons with DC/TBD have normal psychomotor development and normal neurologic
function, significant developmental delay is present in both forms; additional
findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and
bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome
and Coats plus syndrome). Onset and progression of manifestations of DC/TBD
vary: at the mild end of the spectrum are those who have only minimal physical
findings with normal bone marrow function, and at the severe end are those who
have the diagnostic triad and early-onset BMF.
DIAGNOSIS/TESTING: A majority of individuals with DC/TBD have abnormally short
telomeres for their age, as determined by multicolor flow cytometry fluorescence
in situ hybridization (flow-FISH) on lymphocyte subsets. To date, ACD, CTC1,
DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2,
WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause
DC/TBD and to result in very short telomeres. Pathogenic variants in one of
these 16 genes have been identified in approximately 80% of individuals who meet
clinical diagnostic criteria for DC/TBD.
MANAGEMENT: Treatment of manifestations: Treatment is tailored to the
individual. Hematopoietic cell transplantation (HCT) is the only curative
treatment for BMF and leukemia, but long-term outcome has historically been poor
due to treatment toxicity; if a suitable donor is not available, androgen
therapy may be considered for BMF. Treatment of other cancers is tailored to the
type of cancer. Of note, cancer therapy may pose an increased risk for prolonged
cytopenias as well as pulmonary and hepatic toxicity. Treatment of pulmonary
fibrosis is primarily supportive, although lung transplantation may be
considered. Surveillance: For BMF: complete blood count (CBC) annually if normal
and more often if abnormal; annual bone marrow aspirate and biopsy. For those on
androgen therapy: routine monitoring of CBC, liver function, liver ultrasound,
and endocrinology evaluation. For cancer risk: monthly self-examination for
oral, head, and neck cancer; annual cancer screening by an otolaryngologist and
dermatologist; annual gynecologic examination. For pulmonary fibrosis: annual
pulmonary function tests starting either at diagnosis or when the individual can
perform the test (often age ~8 years); bubble echocardiogram to look for
pulmonary arteriovenous malformations if suspected based on clinical symptoms.
Routine dental screening every six months and good oral hygiene are recommended.
Agents/circumstances to avoid: Blood donation by family members if HCT is being
considered; non-leukodepleted and non-irradiated blood products; the combination
of androgens and granulocyte colony-stimulating factor in treatment of BMF (has
been associated with splenic rupture); toxic agents implicated in tumorigenesis
(e.g., smoking, excessive sun exposure). Evaluation of relatives at risk: If a
relative has signs or symptoms suggestive of DC/TBD or is being evaluated as a
potential HCT donor, telomere length testing – or, if the pathogenic variant(s)
in the family are known, molecular genetic testing – is warranted.
GENETIC COUNSELING: The mode of inheritance of DC/TBD varies by gene: X-linked:
DKC1. Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8. Autosomal
dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT. Autosomal
recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53. Genetic counseling
regarding risk to family members depends on accurate diagnosis, determination of
the mode of inheritance in each family, and results of molecular genetic
testing. Once the DC/TBD-related pathogenic variant(s) have been identified in
an affected family member, prenatal and preimplantation genetic testing are
possible.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a
registered trademark of the University of Washington, Seattle. All rights
reserved.
PMID: 20301779 |
http://www.ncbi.nlm.nih.gov/pubmed/4072955 | 1. Am J Clin Nutr. 1985 Dec;42(6):1201-5. doi: 10.1093/ajcn/42.6.1201.
Influences of "normal" and "prudent" diets on biliary and serum lipids in
healthy women.
Kohlmeier M, Stricker G, Schlierf G.
The differential effect of two diets, taken in synchrony with the menstrual
cycles for 2 wk each, on serum and bile lipids was investigated in young healthy
women. The "normal" diet was high in cholesterol and total fat, and low in
polyunsaturated fat and fiber; the "prudent" diet contained a high proportion of
polyunsaturated fat and fiber, but was low in cholesterol and total fat; there
was little difference in energy content. Both in whole serum and in low-density
lipoprotein the concentrations of cholesterol and apolipoprotein B were almost
30% lower with the "prudent" than with the "normal" diet; HDL-cholesterol was
16.3% lower. Triglycerides were increased, only in the very-low-density
lipoproteins while cholesterol and apolipoprotein B did not change much in this
fraction. The risk to acquire cholesterol gallstones was not less with the use
of the "prudent" diet as originally expected. While using the "prudent" diet
five of the women had slightly higher lithogenic indices, in two there were much
higher values (greater than 25%), and only in three the lithogenic index was
unchanged or slightly lower than with the "normal" diet.
DOI: 10.1093/ajcn/42.6.1201
PMID: 4072955 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10668797 | 1. RNA. 2000 Jan;6(1):41-54. doi: 10.1017/s1355838200991167.
Specific HDV RNA-templated transcription by pol II in vitro.
Filipovska J(1), Konarska MM.
Author information:
(1)The Rockefeller University, New York, New York 10021, USA.
RNA polymerase II is implicated in the RNA-templated RNA synthesis during
replication of viroids and Hepatitis Delta Virus (HDV); however, neither the RNA
template nor protein factor requirements for this process are well defined. We
have developed an in vitro transcription system based on HeLa cell nuclear
extract (NE), in which a segment of antigenomic RNA corresponding to the
left-hand tip region of the HDV rod-like structure serves as a template for
efficient and highly specific RNA synthesis. Accumulation of the unique RNA
product is highly sensitive to alpha-amanitin in HeLa NE and only partially
sensitive to this drug in NE from PMG cells that contain an allele of the
alpha-amanitin-resistant subunit of pol II, strongly suggesting pol II
involvement in this reaction. Detailed analysis of the RNA product revealed that
it represents a chimeric molecule composed of a newly synthesized transcript
covalently attached to the 5' half of the RNA template. Selection of the start
site for transcription is remarkably specific and depends on the secondary
structure of the RNA template, rather than on its primary sequence. Some
features of this reaction resemble the RNA cleavage-extension process observed
for pol II-arrested complexes in vitro. A possible involvement of the described
reaction in HDV replication is discussed.
DOI: 10.1017/s1355838200991167
PMCID: PMC1369892
PMID: 10668797 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8145639 | 1. Mol Microbiol. 1994 Jan;11(1):155-64. doi: 10.1111/j.1365-2958.1994.tb00297.x.
Structure and heterologous expression of the Ustilago maydis viral toxin KP4.
Park CM(1), Bruenn JA, Ganesa C, Flurkey WF, Bozarth RF, Koltin Y.
Author information:
(1)Department of Biological Sciences, State University of New York at Buffalo
14260.
Killer toxins are polypeptides secreted by some fungal species that kill
sensitive cells of the same or related species. In the best-characterized cases,
they function by creating new pores in the cell membrane and disrupting ion
fluxes. Immunity or resistance to the toxins is conferred by the preprotoxins
(or products thereof) or by nuclear resistance genes. In several cases, the
toxins are encoded by one or more genomic segments of resident double-stranded
RNA viruses. The known toxins are composed of one to three polypeptides, usually
present as multimers. We have further characterized the KP4 killer toxin from
the maize smut fungus Ustilago maydis. This toxin is also encoded by a single
viral double-stranded RNA but differs from other known killer toxins in several
respects: it has no N-linked glycosylation either in the precursor or in the
mature polypeptide, it is the first killer toxin demonstrated to be a single
polypeptide, and it is not processed by any of the known secretory proteinases
(other than the signal peptidase). It is efficiently expressed in a heterologous
fungal system.
DOI: 10.1111/j.1365-2958.1994.tb00297.x
PMID: 8145639 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20613874 | 1. PLoS One. 2010 Jun 29;5(6):e11333. doi: 10.1371/journal.pone.0011333.
Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human
and mice glial cells.
Hervouet E(1), Lalier L, Debien E, Cheray M, Geairon A, Rogniaux H, Loussouarn
D, Martin SA, Vallette FM, Cartron PF.
Author information:
(1)Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe
labellisée Ligue Nationale Contre le Cancer, Nantes, France.
Global DNA hypomethylation is a hallmark of cancer cells, but its molecular
mechanisms have not been elucidated. Here, we show that the disruption of
Dnmt1/PCNA/UHRF1 interactions promotes a global DNA hypomethylation in human
gliomas. We then demonstrate that the Dnmt1 phosphorylations by Akt and/or PKC
abrogate the interactions of Dnmt1 with PCNA and UHRF1 in cellular and acellular
studies including mass spectrometric analyses and the use of primary cultured
patient-derived glioma. By using methylated DNA immunoprecipitation, methylation
and CGH arrays, we show that global DNA hypomethylation is associated with genes
hypomethylation, hypomethylation of DNA repeat element and chromosomal
instability. Our results reveal that the disruption of Dnmt1/PCNA/UHRF1
interactions acts as an oncogenic event and that one of its signatures (i.e. the
low level of mMTase activity) is a molecular biomarker associated with a poor
prognosis in GBM patients. We identify the genetic and epigenetic alterations
which collectively promote the acquisition of tumor/glioma traits by human
astrocytes and glial progenitor cells as that promoting high proliferation and
apoptosis evasion.
DOI: 10.1371/journal.pone.0011333
PMCID: PMC2894052
PMID: 20613874 [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/12753603 | 1. Wound Repair Regen. 2003 May-Jun;11(3):213-9. doi:
10.1046/j.1524-475x.2003.11310.x.
Impaired healing of nitrogen mustard wounds in CXCR2 null mice.
Milatovic S(1), Nanney LB, Yu Y, White JR, Richmond A.
Author information:
(1)Department of Cancer Biology, Vanderbilt University School of Medicine, and
Department of Veterans Affairs, Nashville, Tennessee 37232, USA.
To examine the significance of chemokine activation of CXCR2 in wound healing
after chemical burn, cutaneous injury was created by topical application of
nitrogen mustard on CXCR2 wild type (+/+), heterozygous (+/-), and knockout
(-/-) mice. Wounds were analyzed histologically for neutrophil and monocyte
infiltration and for reepithelialization at postwound days 4, 7, and 10.
Neutrophil recruitment to the wound site was reduced through postwound day 7 in
CXCR2 -/- mice as indicated by myeloperoxidase assay and by visual quantitation.
Because there is always concern that mice with targeted deletion of a specific
receptor may undergo developmental adaptations to offset the loss of the
receptor, we also accessed chemical wound repair in the presence of a small
molecule antagonist of CXCR2. Dietary supplementation with a CXCR2 antagonist
(SB-265610) during the wound repair process also markedly delayed healing
parameters in CXCR2 +/+ mice, even greater than treatment with glucocorticoids.
These parallel studies further establish that mice deficient in CXCR2 function
exhibit delayed cutaneous wound healing that may be primarily linked to impaired
neutrophil recruitment after chemical burn with nitrogen mustard. Thus, there
may be a potential therapeutic benefit of treating nitrogen mustard-induced skin
lesions with agonists of CXCR2 to facilitate the wound repair process.
DOI: 10.1046/j.1524-475x.2003.11310.x
PMCID: PMC2667443
PMID: 12753603 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18228241 | 1. Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):918-26. doi:
10.1002/ajmg.b.30698.
Autism spectrum conditions in myotonic dystrophy type 1: a study on 57
individuals with congenital and childhood forms.
Ekström AB(1), Hakenäs-Plate L, Samuelsson L, Tulinius M, Wentz E.
Author information:
(1)Department of Pediatrics, Northern Alvsborg County Hospital, Trollhättan,
Sweden. [email protected]
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder, caused by an
expansion of a CTG triplet repeat in the DMPK gene. The aims of the present
study were to classify a cohort of children with DM1, to describe their
neuropsychiatric problems and cognitive level, to estimate the size of the CTG
expansion, and to correlate the molecular findings with the neuropsychiatric
problems. Fifty-seven children and adolescents (26 females; 31 males) with DM1
(CTG repeats > 40) were included in the study. The following instruments were
used: Autism Diagnostic Interview-Revised (ADI-R), 5-15, Griffiths Mental
Development Scales, and the Wechsler Scales. Based on age at onset and
presenting symptoms, the children were divided into four DM1 groups; severe
congenital (n = 19), mild congenital (n = 18), childhood (n = 18), and classical
DM1 (n = 2). Forty-nine percent had an autism spectrum disorder (ASD) and
autistic disorder was the most common diagnosis present in 35% of the subjects.
Eighty-six percent of the individuals with DM1 had mental retardation (MR), most
of them moderate or severe MR. ASD was significantly correlated with the DM1
form; the more severe the form of DM1, the higher the frequency of ASD. The
frequency of ASD increased with increasing CTG repeat expansions. ASD and/or
other neuropsychiatric disorders such as attention deficit hyperactivity
disorder, and Tourette's disorder were found in 54% of the total DM1 group. In
conclusion, awareness of ASD comorbidity in DM1 is essential. Further studies
are warranted to elucidate the molecular etiology causing neurodevelopmental
symptoms such as ASD and MR in DM1.
2008 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.b.30698
PMID: 18228241 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25348719 | 1. Mol Cell Biol. 2015 Jan;35(1):211-23. doi: 10.1128/MCB.01054-14. Epub 2014 Oct
27.
Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is
essential for maintenance of homogeneously active mitochondria during neonatal
heart development.
Ishihara T(1), Ban-Ishihara R(1), Maeda M(2), Matsunaga Y(3), Ichimura A(1),
Kyogoku S(4), Aoki H(5), Katada S(6), Nakada K(6), Nomura M(7), Mizushima N(8),
Mihara K(9), Ishihara N(10).
Author information:
(1)Department of Protein Biochemistry, Institute of Life Science, Kurume
University, Kurume, Japan.
(2)Department of Protein Biochemistry, Institute of Life Science, Kurume
University, Kurume, Japan Department of Physiology and Cell Biology, Tokyo
Medical and Dental University, Tokyo, Japan.
(3)Department of Physiology and Cell Biology, Tokyo Medical and Dental
University, Tokyo, Japan.
(4)Department of Medicine, Division of Cardiovascular Medicine, Kurume
University School of Medicine, Kurume, Japan.
(5)Cardiovascular Research Institute, Kurume University, Kurume, Japan.
(6)Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki,
Japan.
(7)Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka,
Japan.
(8)Department of Physiology and Cell Biology, Tokyo Medical and Dental
University, Tokyo, Japan Department of Biochemistry and Molecular Biology,
Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
(9)Department of Protein Biochemistry, Institute of Life Science, Kurume
University, Kurume, Japan Department of Molecular Biology, Graduate School of
Medical Science, Kyushu University, Fukuoka, Japan.
(10)Department of Protein Biochemistry, Institute of Life Science, Kurume
University, Kurume, Japan Department of Physiology and Cell Biology, Tokyo
Medical and Dental University, Tokyo, Japan [email protected].
Mitochondria are dynamic organelles, and their fusion and fission regulate
cellular signaling, development, and mitochondrial homeostasis, including
mitochondrial DNA (mtDNA) distribution. Cardiac myocytes have a specialized
cytoplasmic structure where large mitochondria are aligned into tightly packed
myofibril bundles; however, recent studies have revealed that mitochondrial
dynamics also plays an important role in the formation and maintenance of
cardiomyocytes. Here, we precisely analyzed the role of mitochondrial fission in
vivo. The mitochondrial fission GTPase, Drp1, is highly expressed in the
developing neonatal heart, and muscle-specific Drp1 knockout (Drp1-KO) mice
showed neonatal lethality due to dilated cardiomyopathy. The Drp1 ablation in
heart and primary cultured cardiomyocytes resulted in severe mtDNA nucleoid
clustering and led to mosaic deficiency of mitochondrial respiration. The
functional and structural alteration of mitochondria also led to immature
myofibril assembly and defective cardiomyocyte hypertrophy. Thus, the dynamics
of mtDNA nucleoids regulated by mitochondrial fission is required for neonatal
cardiomyocyte development by promoting homogeneous distribution of active
mitochondria throughout the cardiomyocytes.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
DOI: 10.1128/MCB.01054-14
PMCID: PMC4295379
PMID: 25348719 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15565817 | 1. Cancer Invest. 2004;22(4):588-603. doi: 10.1081/cnv-200027144.
The tuberous sclerosis complex genes in tumor development.
Mak BC(1), Yeung RS.
Author information:
(1)Department of Surgery, University of Washington, Seattle, Washington 98195,
USA.
The study of hereditary tumor syndromes has laid a solid foundation toward
understanding the genetic basis of cancer. One of the latest examples comes from
the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses,
TSC is characterized by the appearance of benign tumors, most notably in the
central nervous system, kidney, heart, lung, and skin. While classically
described as "hamartomas," the pathology of the lesions has features suggestive
of abnormal cellular proliferation, size, differentiation, and migration.
Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma).
The genetic basis of this disease has been attributed to mutations in one of two
unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either
gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm.
The functions of the TSC1 and TSC2 gene products, hamartin and tuberin,
respectively, have remained ill defined until recently. Genetic, biochemical,
and biologic analyses have highlighted their role as negative regulators of the
mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK,
mediates mTOR activity by coordinating inputs from growth factors and energy
availability in the control of cell growth, proliferation, and survival.
Emerging evidence also suggests that the TSC 1/2 complex may play a role in
modulating the activity of beta-catenin and TGFbeta. These findings provide
novel functional links between the TSC genes and other tumor suppressors
responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and
familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon,
endometrium, and breast have ties to these genes, highlighting the potential
role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor,
has potent antitumoral activities in preclinical models of TSC and is currently
undergoing phase I/II clinical studies.
DOI: 10.1081/cnv-200027144
PMID: 15565817 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17258731 | 1. Gastroenterology. 2007 Feb;132(2):667-78. doi: 10.1053/j.gastro.2006.12.008.
Epub 2006 Dec 3.
Hepatitis C virus continuously escapes from neutralizing antibody and T-cell
responses during chronic infection in vivo.
von Hahn T(1), Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, McKeating JA.
Author information:
(1)Center for the Study of Hepatitis C, The Rockefeller University, New York,
New York 10021, USA. [email protected]
Comment in
Gastroenterology. 2007 Feb;132(2):801-5. doi: 10.1053/j.gastro.2007.01.010.
BACKGROUND & AIMS: Broadly reactive neutralizing antibodies (nAbs) and
multispecific T-cell responses are generated during chronic hepatitis C virus
(HCV) infection and yet fail to clear the virus. This study investigated the
development of autologous nAb and HCV-glycoprotein-specific T-cell responses and
their effects on viral sequence evolution during chronic infection in order to
understand the reasons for their lack of effectiveness.
METHODS: Numerous E1E2 sequences were amplified and sequenced from serum samples
collected over a 26-year period from patient H, a uniquely well-characterized,
chronically infected individual. HCV pseudoparticles (HCVpp) expressing the
patient-derived glycoproteins were generated and tested for their sensitivity to
neutralization by autologous and heterologous serum antibodies.
RESULTS: A strain-specific nAb response developed early in infection (8 weeks
postinfection), whereas cross-reactive antibodies able to neutralize
HCVpp-bearing heterologous glycoproteins developed late in infection (>33 wk
postinfection). The humoral response continuously failed to neutralize viruses
bearing autologous glycoprotein sequences that were present in the serum at a
given time. The amplified glycoprotein sequences displayed high variability,
particularly in regions corresponding to defined linear B-cell epitopes.
Mutations in defined neutralizing epitopes were associated with a loss of
recognition by monoclonal antibodies against these epitopes and with decreased
neutralization of corresponding HCVpp. Viral escape from CD4 and CD8 T-cell
responses also was shown for several novel epitopes throughout the glycoprotein
region.
CONCLUSIONS: During chronic infection HCV is subjected to selection pressures
from both humoral and cellular immunity, resulting in the continuous generation
of escape variants.
DOI: 10.1053/j.gastro.2006.12.008
PMID: 17258731 [Indexed for MEDLINE] |