pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/17114343 | 1. Mol Cancer Res. 2006 Nov;4(11):851-9. doi: 10.1158/1541-7786.MCR-06-0090.
NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's
sarcoma.
Kinsey M(1), Smith R, Lessnick SL.
Author information:
(1)The Department of Oncological Sciences, University of Utah, Salt Lake City,
Utah, USA.
A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma,
and myxoid liposarcoma, are associated with recurrent translocation events that
encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a
prototype for this tumor class. Ewing's sarcomas usually harbor the
(11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion
oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key
target genes that are involved in oncogenesis are largely unknown. Although some
target genes have been defined, many of these have been identified in
heterologous model systems with uncertain relevance to the human disease. To
understand the function of EWS/FLI and its targets in a more clinically relevant
system, we used retroviral-mediated RNAi to "knock-down" the fusion protein in
patient-derived Ewing's sarcoma cell lines. By combining transcriptional
profiling data from three of these lines, we identified a conserved
transcriptional response to EWS/FLI. The gene that was most reproducibly
up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan
nuclear receptor with no previously defined role in oncogenesis. We validated
NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary
human tumor samples. Functional studies revealed that ongoing NR0B1 expression
is required for the transformed phenotype of Ewing's sarcoma. These studies
define a new role for NR0B1 in oncogenic transformation and emphasize the
utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells.
DOI: 10.1158/1541-7786.MCR-06-0090
PMID: 17114343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20151946 | 1. J Dtsch Dermatol Ges. 2010 Feb;8(2):99-101. doi:
10.1111/j.1610-0387.2009.07156_supp.x.
New mutation in the CYLD gene within a family with Brooke-Spiegler syndrome.
[Article in English, German]
Scholz IM(1), Nümann A, Froster UG, Helmbold P, Enk AH, Näher H.
Author information:
(1)Department of Dermatology, University of Heidelberg, Germany.
[email protected]
Brooke-Spiegler syndrome is a rare, autosomal dominant disease characterized by
multiple skin appendage tumors caused by various mutations in the CYLD gene on
chromosome 16q12-q13. We describe a family, in which we performed a
molecular-genetic examination and found a new mutation in exon 19 in the CYLD
gene leading to a frameshift. It is important to be aware of this syndrome and
its pathogenesis as its phenotypic features can vary so that apparently
different diseases are caused by the same genetic defect. In addition, there may
be malignant transformation of the generally benign tumors, so that a timely
diagnosis is essential for appropriate monitoring and therapy.
DOI: 10.1111/j.1610-0387.2009.07156_supp.x
PMID: 20151946 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16922728 | 1. Clin Genet. 2006 Sep;70(3):246-9. doi: 10.1111/j.1399-0004.2006.00667.x.
CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple
familial trichoepithelioma syndromes.
Young AL(1), Kellermayer R, Szigeti R, Tészás A, Azmi S, Celebi JT.
Author information:
(1)Department of Dermatology, Columbia University, New York, NY 10032, USA.
Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple
familial trichoepithelioma (MFT), originally described as distinct inherited
disorders, are characterized by a variety of skin appendage neoplasms. Mutations
in the CYLD gene are found in individuals with these syndromes. We describe a
single family with affected members exhibiting either the FC or the MFT
phenotypes associated with a mutation in the CYLD gene. These findings support
the notion that BSS, FC, and MFT represent phenotypic variation of a single
defect. Of interest, one of the affected individuals described in this report
exhibits a severe phenotype illustrating the morbidity of the disorder.
DOI: 10.1111/j.1399-0004.2006.00667.x
PMID: 16922728 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8615372 | 1. Am J Clin Nutr. 1996 May;63(5):842S-5S. doi: 10.1093/ajcn/63.5.842.
Wilson disease and idiopathic copper toxicosis.
Scheinberg IH(1), Sternlieb I.
Author information:
(1)National Center for the Study of Wilson's Disease, St Luke's-Roosevelt
Hospital Center, Columbia University, New York, USA.
The pathogenic agent of both Wilson disease (WD) and non-Indian childhood
cirrhosis (which we term idiopathic copper toxicosis, or ICT) is copper
accumulating to excess in the liver. Inheritance of a pair of alleles of an
autosomal recessive gene on chromosome 13 is necessary and sufficient to cause
such copper accumulation in WD; reducing the dietary intake of copper cannot
prevent the development of WD. In contrast, the lethal accumulations of copper
in children with ICT have been attributed primarily to an increased dietary
intake of copper. However, 64 124 child-year exposures of children under the age
of 6 y to drinking water containing a copper concentration of approximately
125.9 micromol/L (8 mg/L) produced no deaths from any form of liver disease.
Moreover, the ICT of seven infants was attributed primarily to drinking water
containing < 110.2 micromol Cu/L (7 mg/L) despite evidence of the presence of a
genetic defect in three of the patients, one of whom was exclusively breast-fed.
These data suggest that ICT cannot be caused solely by increased dietary intake
of copper and occurs only in children with an identified genetic defect.
DOI: 10.1093/ajcn/63.5.842
PMID: 8615372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21577203 | 1. Oncogene. 2011 Nov 3;30(44):4523-30. doi: 10.1038/onc.2011.163. Epub 2011 May
16.
GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma.
Kuphal S(1), Shaw-Hallgren G, Eberl M, Karrer S, Aberger F, Bosserhoff AK,
Massoumi R.
Author information:
(1)Institute of Pathology, University of Regensburg, Germany.
CYLD is a deubiquitination enzyme that regulates different cellular processes,
such as cell proliferation and cell survival. Mutation and loss of
heterozygosity of the CYLD gene causes development of cylindromatosis, a benign
tumour originating from the skin. Our study shows that CYLD expression is
dramatically downregulated in basal cell carcinoma (BCC), the most common cancer
in humans. Reduced CYLD expression in basal cell carcinoma was mediated by
GLI1-dependent activation of the transcriptional repressor Snail. Inhibition of
GLI1 restored the CYLD expression-mediated Snail signaling pathway, and caused a
significant delay in the G1 to S phase transition, as well as proliferation. Our
data suggest that GLI1-mediated suppression of CYLD has a significant role in
basal cell carcinoma progression.
DOI: 10.1038/onc.2011.163
PMID: 21577203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20607853 | 1. Genes Chromosomes Cancer. 2010 Sep;49(9):803-9. doi: 10.1002/gcc.20789.
Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma.
Schmidt A(1), Schmitz R, Giefing M, Martin-Subero JI, Gesk S, Vater I, Massow A,
Maggio E, Schneider M, Hansmann ML, Siebert R, Küppers R.
Author information:
(1)Institute of Cell Biology (Cancer Research), University of Duisburg-Essen,
Medical School, Essen, Germany.
Survival of the malignant Hodgkin and Reed/Sternberg (HRS) cells in classical
Hodgkin lymphoma (cHL) is dependent on constitutive activation of the nuclear
factor kappaB (NF-kappaB) transcription factor. The deubiquitinating enzyme CYLD
is a negative regulator of NF-kappaB and known to function as a tumor
suppressor. To determine whether CYLD mutations play a role in cHL pathogenesis,
we sequenced the gene in cHL cell lines and microdissected HRS cells obtained
from lymph-node biopsies. A biallelic inactivation by mutations was found in the
cHL cell-line KM-H2. However, the other seven cHL cell lines analyzed and HRS
cells of 10 primary cHL cases did not show any mutations. By interphase
cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase
cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating
decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases.
Our results suggest that biallelic CYLD mutations are rarely involved in cHL
pathogenesis. Nevertheless, it is remarkable that KM-H2 cells, besides the CYLD
mutations, also carry inactivating mutations in the genes of two other NF-kappaB
inhibitors, that is, NFKBIA and TNFAIP3, exemplifying that multiple lesions in
regulators of this signaling pathway can likely cooperatively contribute to the
strong NF-kappaB activity of these cells.
(c) 2010 Wiley-Liss, Inc.
DOI: 10.1002/gcc.20789
PMID: 20607853 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19917957 | 1. Arch Dermatol. 2009 Nov;145(11):1277-84. doi: 10.1001/archdermatol.2009.262.
Tumor mapping in 2 large multigenerational families with CYLD mutations:
implications for disease management and tumor induction.
Rajan N(1), Langtry JA, Ashworth A, Roberts C, Chapman P, Burn J, Trainer AH.
Author information:
(1)MRCP, Institute of Human Genetics, University of Newcastle Upon Tyne,
Newcastle Upon Tyne NE13BZ, England. [email protected]
OBJECTIVES: To comprehensively ascertain the extent and severity of clinical
features in affected individuals from 2 large families with proven heterozygous
mutations in the CYLD locus and to correlate these findings with the 3
appendageal tumor predisposition syndromes (familial cylindromatosis,
Brooke-Spiegler syndrome, and multiple familial trichoepitheliomas) known to be
associated with such germline mutations.
DESIGN: Interfamilial and intrafamilial observational study.
SETTING: Tertiary genetic and dermatology referral center.
PARTICIPANTS: Thirty-four individuals recruited from 2 large multigenerational
families with CYLD mutations. Clinical details, history, and tumor maps were
obtained from all participants; in 18, the information was corroborated by
detailed clinical examination.
MAIN OUTCOME MEASURES: Tumor density, distribution and histologic findings,
associated medical conditions, patient symptoms, and impact of disease on
quality of life.
RESULTS: The severity of penetrance and phenotype varied within families.
Although an approximately equal female to male predisposition was noted, 5 women
and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal. The
average age at onset was 16 years (range, 8-30 years). Symptoms reported by
affected patients included painful tumors (in 12 of 23 patients [52%] who
answered the question), conductive deafness, and sexual dysfunction. Of the 26
surveyed patients, tumors were noted on the scalp in 21 (81%), on the trunk in
18 (69%), and in the pubic area in 11 (42%). Tumor mapping provided clinical
evidence that correlated with hormonally stimulated hair follicles being
particularly vulnerable to loss of heterozygosity and tumor induction.
CONCLUSIONS: The burden of disease at sites other than the head and neck appears
to be underreported in the literature and greatly affects quality of life.
Differentiation between the clinical diagnoses has little prognostic or clinical
utility in genetic counseling, even within individuals from the same family.
Thus, we suggest an encompassing diagnosis of "CYLD cutaneous syndrome."
Finally, the clinical distribution of tumors suggests that hormonal factors may
play an important role in tumor induction in these patients.
DOI: 10.1001/archdermatol.2009.262
PMCID: PMC2935681
PMID: 19917957 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17851586 | 1. J Invest Dermatol. 2008 Mar;128(3):587-93. doi: 10.1038/sj.jid.5701045. Epub
2007 Sep 13.
Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid
681 in CYLD is essential for deubiquitinase activity.
Almeida S(1), Maillard C, Itin P, Hohl D, Huber M.
Author information:
(1)Service of Dermatology, University Hospital Center and University of
Lausanne, Lausanne, Switzerland.
Brooke-Spiegler syndrome, familial cylindromatosis, and familial
trichoepithelioma are autosomal-dominant genetic predispositions for benign
tumors of skin appendages caused by mutations in the CYLD gene localized on
chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific
protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase
(JNK) signaling. We investigated five families affected with these skin
neoplasms and identified four premature stop codons and the novel missense
mutation D681G in a family in which 11 of 12 investigated tumors were
trichoepitheliomas. CYLD protein harboring this missense mutation had a
significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2-
and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha
(TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was
coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin
chains. Aspartic acid 681 is highly conserved in CYLD homologues and other
members of the UBP family, but does not belong to the Cys and His boxes
providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported
previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond
with the C-terminal end of ubiquitin and is important for the enzymatic
activity. These results underline that D681 in CYLD is required for cleavage of
K63-linked polyubiquitin chains.
DOI: 10.1038/sj.jid.5701045
PMID: 17851586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21784908 | 1. Appl Environ Microbiol. 2011 Sep;77(18):6343-9. doi: 10.1128/AEM.05057-11.
Epub 2011 Jul 22.
Defining components of the chromosomal origin of replication of the
hyperthermophilic archaeon Pyrococcus furiosus needed for construction of a
stable replicating shuttle vector.
Farkas J(1), Chung D, DeBarry M, Adams MW, Westpheling J.
Author information:
(1)Department of Genetics, University of Georgia, Athens, GA 30602, USA.
We report the construction of a series of replicating shuttle vectors that
consist of a low-copy-number cloning vector for Escherichia coli and functional
components of the origin of replication (oriC) of the chromosome of the
hyperthermophilic archaeon Pyrococcus furiosus. In the process of identifying
the minimum replication origin sequence required for autonomous plasmid
replication in P. furiosus, we discovered that several features of the origin
predicted by bioinformatic analysis and in vitro binding studies were not
essential for stable autonomous plasmid replication. A minimum region required
to promote plasmid DNA replication was identified, and plasmids based on this
sequence readily transformed P. furiosus. The plasmids replicated autonomously
and existed in a single copy. In contrast to shuttle vectors based on a plasmid
from the closely related hyperthermophile Pyrococcus abyssi for use in P.
furiosus, plasmids based on the P. furiosus chromosomal origin were structurally
unchanged after transformation and were stable without selection for more than
100 generations.
DOI: 10.1128/AEM.05057-11
PMCID: PMC3187180
PMID: 21784908 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15337158 | 1. Trends Microbiol. 2004 Sep;12(9):399-401. doi: 10.1016/j.tim.2004.07.001.
Multiple origins of replication in archaea.
Kelman LM(1), Kelman Z.
Author information:
(1)Montgomery College, 20200 Observation Drive, Germantown, MD 20876, USA.
[email protected]
Until recently, the only archaeon for which a bona fide origin of replication
was reported was Pyrococcus abyssi, where a single origin was identified.
Although several in silico analyses have suggested that some archaeal species
might contain more than one origin, this has only been demonstrated recently.
Two studies have shown that multiple origins of replication function in two
archaeal species. One study identified two origins of replication in the
archaeon Sulfolobus solfataricus, whereas a second study used a different
technique to show that both S. solfataricus and Sulfolobus acidocaldarius have
three functional origins. These are the first reports of archaea having multiple
origins. This finding has implications for research on the mechanisms of DNA
replication and evolution.
DOI: 10.1016/j.tim.2004.07.001
PMID: 15337158 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15024746 | 1. Hum Mutat. 2004 Apr;23(4):400. doi: 10.1002/humu.9231.
CYLD mutation causes multiple familial trichoepithelioma in three Chinese
families.
Zheng G(1), Hu L, Huang W, Chen K, Zhang X, Yang S, Sun J, Jiang Y, Luo G, Kong
X.
Author information:
(1)Health Science Center, Shanghai Institutes of Biological Science, Chinese
Academy of Science and Shanghai Second Medical University, Shanghai, The
People's Republic of China.
Multiple familial trichoepithelioma (MFT) and familial cylindromatosis are two
clinically distinct cancer syndromes. MFT patients developed mostly
trichoepithelioma in the face while cylindromatosis patients developed
cylindromas predominantly (approximately 90%) on the head and neck. However,
multiple familial trichoepithelioma is occasionally associated with familial
cylindromatosis while cylindromatosis patients can also develop
trichoepithelioma. This has led to the speculation that the 2 types of
dermatoses may be caused by dysfunction of a common pathway. Previously, a
candidate MTF locus has been mapped to 9p21 while disease gene for familial
cylindromatosis, the CYLD gene located on 16q21-13 has been identified. Here, we
show that mutations in the CYLD gene are also the genetic basis for three
different Chinese families with MFT. Sequence analysis reveal a single
nucleotide deletion, c.1462delA (P.Ile488fsX9) in exon 9, a nonsense mutation,
c.2128C>T (p. Gln710X) in exon 17, and a missense mutation, c.2822A>T (p.
Asp941Val) in exon 21 in each of the three families respectively. This provides
direct evidence that the mutations in CYLD can cause two clinically distinct
cancer syndromes.
Copyright 2004 Wiley-Liss, Inc.
DOI: 10.1002/humu.9231
PMID: 15024746 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22610954 | 1. Chin J Integr Med. 2013 Mar;19(3):233-40. doi: 10.1007/s11655-012-1089-8. Epub
2012 May 19.
Wilson's disease: update on integrated Chinese and Western medicine.
Li WJ(1), Wang JF, Wang XP.
Author information:
(1)Department of Neurology, Shanghai First People's Hospital, Shanghai Jiao-Tong
University, Shanghai 200080, China.
Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal
recessive inheritance disorder of copper metabolism caused by ATP7B gene
mutation. As WD is an inherited disease of the nervous system that is not
curable; early diagnosis with early and life-long treatment leads to better
prognoses. Currently, the recommended treatment for WD is integrated Chinese and
Western medicine. A number of studies indicate that treatment of integrative
medicine can not only enforce the de-copper effect but also improve liver
function, intelligence, and other factors. This article reviewed in detail the
advantages of WD treated with Chinese and Western medicine together.
DOI: 10.1007/s11655-012-1089-8
PMID: 22610954 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22323744 | 1. Neurology. 2012 Feb 21;78(8):551-6. doi: 10.1212/WNL.0b013e318247ca69. Epub
2012 Feb 8.
Genotype-phenotype relationship in 2 SMA III patients with novel mutations in
the Tudor domain.
Fraidakis MJ(1), Drunat S, Maisonobe T, Gerard B, Pradat PF, Meininger V,
Salachas F.
Author information:
(1)Department of Neurology, Hôpital de la Salpêtrière, Groupement Hospitalier
Universitaire Est Pitié-Salpêtrière, Paris, France.
[email protected]
OBJECTIVE: We report the cases of 2 patients with late-onset spinal muscular
atrophy (SMA) type III, who were hemizygous for SMN1 deletion and carriers of
novel SMN1 intragenic missense mutations, and we investigate the
genotype-phenotype relationship.
METHODS: Patients were tested for SMN1 deletions with standard methodology.
Sequencing of all exons, exon-intron junctions, and flanking sequences of SMN1
by nested PCR was used to detect intragenic point mutations. SMN1 and SMN2
quantification was undertaken to investigate the genotype-phenotype
relationship.
RESULTS: Two novel point mutations were identified in exon 3 of SMN1
(p.Tyr130Cys and p.Tyr130His) in the highly conserved Tudor domain of the Smn
protein.
CONCLUSIONS: The genetic basis of SMA in the rare cases of compound heterozygous
carriers of SMN1 deletions is complex. Small intragenic SMN1 mutations often
lead to severe SMA phenotypes, especially if the point mutations lie in exon 3
that codes for the highly conserved Tudor domain of the Smn protein. Although
both our patients were carriers of intragenic SMN1 mutations in the coding
region of the Tudor domain, they presented with a mild SMA phenotype despite a
low SMN2 copy number. We discuss the possible determinant role of these novel
missense mutations in the phenotypic outcome and compensatory mechanisms that
may account for the genotype-phenotype discrepancy.
DOI: 10.1212/WNL.0b013e318247ca69
PMID: 22323744 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12220455 | 1. Clin Genet. 2002 Aug;62(2):165-8. doi: 10.1034/j.1399-0004.2002.620210.x.
Spinal muscular atrophy in black South Africans: concordance with the universal
SMN1 genotype.
Wilmshurst JM(1), Reynolds L, Van Toorn R, Leisegang F, Henderson HE.
Author information:
(1)Departments of Pediatric Neurology and Chemical Pathology, University of Cape
Town, Red Cross Children's Hospital, Rondebosch, Cape Town, South Africa.
[email protected]
Only one study has reported on the genetic basis of spinal muscular atrophy
(SMA) in South African subjects. This was conducted in the Johannesburg region
and has suggested that black South Africans only (indigenous Africans) differ
from the norm. We have explored this further by DNA studies in 30 unrelated and
racially diverse patients who reside in the Western Cape, and who were assessed
as SMA subjects according to the internationally accepted inclusion criteria for
SMA. These subjects were seen at the neurology clinic at Red Cross Children's
Hospital in Cape Town during the period 1980-2001. Four had the type 1 form of
SMA, 16 had type 2 and 10 had type 3. All patients were found to be homozygous
for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene. Six additional
patients had anterior horn cell disease but were negative for the SMN1 gene
deletion. All six had exclusion features listed in the international guidelines.
This study shows that all patients from the Western Cape, which included 12
black South Africans, are no different genetically or phenotypically from the
internationally recognized form of typical SMA.
DOI: 10.1034/j.1399-0004.2002.620210.x
PMID: 12220455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9073029 | 1. J Neurol Sci. 1997 Jan;145(1):55-61. doi: 10.1016/s0022-510x(96)00240-7.
The relationship of spinal muscular atrophy to motor neuron disease:
investigation of SMN and NAIP gene deletions in sporadic and familial ALS.
Orrell RW(1), Habgood JJ, de Belleroche JS, Lane RJ.
Author information:
(1)Department of Biochemistry, Charing Cross and Westminster Medical School,
London, UK.
Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10%
of cases. Of these familial cases around 20% are associated with mutations of
SOD-1. The genetic basis of the disease in the remaining familial cases, and
genetic risk factors in sporadic cases, are unknown. Recently, the common forms
of spinal muscular atrophy (SMA) have been associated with mutations of the SMN
and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with
both familial and sporadic motor neuron disease show only lower motor neuron
signs, in common with SMA patients, and families containing individuals with
phenotypes of both childhood SMA and adult motor neuron disease have been
reported. We therefore examined the SMA locus as a candidate for ALS, in 54
patients with sporadic motor neuron disease, and 10 single-generation familial
patients (with no evidence of SOD-1 mutations), and in a single patient with
Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were
detected. The difficulties of classification of lower motor neuron presentations
of motor neuron diseases are discussed. The demonstration that mutations
diagnostic of SMA are not found in ALS patients helps distinguish these
conditions.
DOI: 10.1016/s0022-510x(96)00240-7
PMID: 9073029 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12115944 | 1. Muscle Nerve. 2002 Jul;26(1):4-13. doi: 10.1002/mus.10110.
Spinal muscular atrophy: recent advances and future prospects.
Nicole S(1), Diaz CC, Frugier T, Melki J.
Author information:
(1)Molecular Neurogenetics Laboratory, Institut National de la Santé et de la
Recherche Médicale (INSERM), Université d'Evry, E.9913, Genopole, 2 rue Gaston
Crémieux, CP 5724, 91057 Evry, France.
Spinal muscular atrophies (SMA) are characterized by degeneration of lower motor
neurons associated with muscle paralysis and atrophy. Childhood SMA is a
frequent recessive autosomal disorder and represents one of the most common
genetic causes of death in childhood. Mutations of the SMN1 gene are responsible
for SMA. The knowledge of the genetic basis of SMA, a better understanding of
SMN function, and the recent generation of SMA mouse models represent major
advances in the field of SMA. These are starting points towards understanding
the pathophysiology of SMA and developing therapeutic strategies for this
devastating neurodegenerative disease, for which no curative treatment is known
so far.
Copyright 2002 Wiley Periodicals, Inc.
DOI: 10.1002/mus.10110
PMID: 12115944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19730223 | 1. Am J Dermatopathol. 2009 Dec;31(8):819-27. doi: 10.1097/DAD.0b013e3181a70eef.
Spectrum of tumors with follicular differentiation in a patient with the
clinical phenotype of multiple familial trichoepitheliomas: a
clinicopathological and molecular biological study, including analysis of the
CYLD and PTCH genes.
Kazakov DV(1), Vanecek T, Nemcova J, Kacerovska D, Spagnolo DV, Mukensnabl P,
Michal M.
Author information:
(1)Department of Pathology, Charles University Medical Faculty Hospital, Pilsen,
Czech Republic. [email protected]
We report a patient with multiple trichoepitheliomas whose biopsy material also
demonstrated a range of other neoplasms with follicular differentiation,
including small nodular trichoblastoma, small nodular basal cell carcinoma
(BCC), and areas resembling infundibulocystic BCC/basaloid follicular hamartoma.
These were all intimately associated with otherwise typical trichoepitheliomas
that dominated the microscopic appearances. Peripheral blood and tumor tissues
of the patient and his 2 daughters, who apparently had a milder phenotype, were
studied for alterations in the CYLD and PTCH genes, but mutations or loss of
heterozygosity was not found in either gene. The occurrence of multiple
follicular neoplasms within a single lesion adds evidence that, although in most
cases BCC and trichoblastoma are distinct lesions, the 2 neoplasms do encompass
a morphological spectrum of follicular differentiation, which is probably more
overtly expressed in syndromic patients.
DOI: 10.1097/DAD.0b013e3181a70eef
PMID: 19730223 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19646678 | 1. Am J Hum Genet. 2009 Aug;85(2):281-9. doi: 10.1016/j.ajhg.2009.07.006. Epub
2009 Jul 30.
Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation
in the VRK1 gene.
Renbaum P(1), Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC,
Levy-Lahad E.
Author information:
(1)Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
The spinal muscular atrophies (SMAs) are a genetically and clinically
heterogeneous group of disorders characterized by degeneration and loss of
anterior horn cells in the spinal cord, leading to muscle weakness and atrophy.
Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as
pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA
variants that include additional clinical manifestations, and its genetic basis
is unknown. We used a homozygosity mapping and positional cloning approach in a
consanguineous family of Ashkenazi Jewish origin and identified a nonsense
mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH.
VRK1, one of three members of the mammalian VRK family, is a serine/threonine
kinase that phosphorylates p53 and CREB and is essential for nuclear envelope
formation. Its identification as a gene involved in SMA-PCH implies new roles
for the VRK proteins in neuronal development and maintenance and suggests the
VRK genes as candidates for related phenotypes.
DOI: 10.1016/j.ajhg.2009.07.006
PMCID: PMC2725266
PMID: 19646678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18806492 | 1. Am J Dermatopathol. 2008 Oct;30(5):472-6. doi: 10.1097/DAD.0b013e31817fb37f.
Spiradenocylindroma-like basaloid carcinoma of the anus and rectum: case report,
including HPV studies and analysis of the CYLD gene mutations.
Kacerovska D(1), Szepe P, Vanecek T, Nemcova J, Michal M, Mukensnabl P, Kazakov
DV.
Author information:
(1)Sikl's Department of Pathology, Charles University, Medical Faculty Hospital,
Pilsen, Czech Republic.
The authors report a case of basaloid carcinoma involving the anus and rectum of
a 57-year-old woman. Microscopically, the tumor showed unusual morphologic
features strongly resembling a spiradenocylindroma because it consisted, in most
parts, of basaloid cell nodules arranged in a jigsaw-puzzle fashion containing
or surrounded by eosinophilic basal membrane material; in addition, there were
intratumoral lymphocytes. The overlying squamous epithelium manifested
dysplastic changes compatible with in situ squamous carcinoma that gradually
became invasive and blended with basaloid cell islands; additionally, there were
koilocytes in the squamous epithelium. A molecular biology study identified
HPV-16 in the lesional tissue. Analysis of the CYLD gene did not prove any
mutation.
DOI: 10.1097/DAD.0b013e31817fb37f
PMID: 18806492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17076267 | 1. Prog Mol Subcell Biol. 2006;44:109-32. doi: 10.1007/978-3-540-34449-0_6.
Spinal muscular atrophy and therapeutic prospects.
Wirth B(1), Brichta L, Hahnen E.
Author information:
(1)Institute of Human Genetics, Institute of Genetics, and Center for Molecular
Medicine Cologne, University of Cologne, Kerpener Str. 34, 50931 Cologne,
Germany.
The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal
recessive neuromuscular disorder, is the loss of function of the survival motor
neuron gene (SMN1). The SMN2 gene, a nearly identical copy of SMN1, has been
detected as a promising target for SMA therapy. Both genes are ubiquitously
expressed and encode identical proteins, but markedly differ in their splicing
patterns: While SMN1 produces full-length (FL)-SMN transcripts only, the
majority of SMN2 transcripts lacks exon 7. Transcriptional SMN2 activation or
modulation of its splicing pattern to increase FL-SMN levels is believed to be
clinically beneficial and therefore a crucial challenge in SMA research. Drugs
such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA that
mainly act as histone deacetylase inhibitors can mediate both: they stimulate
the SMN2 gene transcription and/or restore the splicing pattern, thereby
elevating the levels of FL-SMN2 protein. Preliminary phase II clinical trials
and individual experimental curative approaches SMA patients show promising
results. However, phase III double-blind placebo controlled clinical trials have
to finally prove the efficacy of these drugs.
DOI: 10.1007/978-3-540-34449-0_6
PMID: 17076267 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21598248 | 1. J Pathol. 2011 Jul;224(3):309-21. doi: 10.1002/path.2896. Epub 2011 May 19.
Transition from cylindroma to spiradenoma in CYLD-defective tumours is
associated with reduced DKK2 expression.
Rajan N(1), Burn J, Langtry J, Sieber-Blum M, Lord CJ, Ashworth A.
Author information:
(1)Institute of Human Genetics, University of Newcastle upon Tyne, NE1 3BZ, UK.
[email protected]
Patients carrying heterozygous germline truncating mutations in the CYLD gene
develop multiple primary hair follicle-related tumours. A highly patterned
tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma,
may both develop in the same patient. Furthermore, histological features of both
tumour types have been described within the same tumour specimen. We used
three-dimensional computer-aided reconstruction of these tumours to demonstrate
contiguous growth of cylindromas into spiradenomas, thus suggesting a transition
between the two tumour types. To explore factors that may influence cutaneous
tumour patterning, genome-wide transcriptomic analysis of 32 CYLD-defective
tumours was performed. Overexpression of the Wnt/β-catenin signalling pathway
was observed relative to normal perilesional tissue. Morphometric analysis was
used to investigate the relationship between Wnt pathway-related gene expression
and tumour organization. This revealed an association between reduced Dickkopf 2
(DKK2-a negative regulator of the Wnt/β-catenin signalling pathway) expression
and loss of tumour patterning. Reduced DKK2 expression was associated with
methylation of the DKK2 gene promoter in the majority of tumour samples assayed.
RNA interference-mediated silencing of DKK2 expression in cylindroma primary
cell cultures caused an increase in colony formation, cell viability, and
anchorage-independent growth. Using these data, we propose a model where
epigenetic programming may influence tumour patterning in patients with CYLD
mutations.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by
John Wiley & Sons, Ltd.
DOI: 10.1002/path.2896
PMID: 21598248 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15541090 | 1. Br J Dermatol. 2004 Nov;151(5):1084-6. doi: 10.1111/j.1365-2133.2004.06231.x.
Mild phenotype of familial cylindromatosis associated with an R758X nonsense
mutation in the CYLD tumour suppressor gene.
Oiso N(1), Mizuno N, Fukai K, Nakagawa K, Ishii M.
Author information:
(1)Department of Dermatology, Saiseikai Tondabayashi Hospital, 1-3-36 Koyodai,
Tondabayashi, Osaka 584-0082, Japan. [email protected]
Familial cylindromatosis is a rare dominantly inherited disease characterized by
the development of multiple benign tumours of the skin appendages, including
cylindromas, trichoepitheliomas and spiradenomas. The gene responsible was
positionally cloned recently, and was designated CYLD. We describe a family with
cylindromatosis, in which affected individuals have an inherited R758X nonsense
mutation of CYLD. Affected members of this family manifest a relatively mild
tumour phenotype; the largest tumour was only 30 mm in diameter. Thus far, there
is no evident genotype-phenotype relationship in cylindromatosis, although the
number of families reported with both phenotypic and genotypic data remains
small.
DOI: 10.1111/j.1365-2133.2004.06231.x
PMID: 15541090 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7690557 | 1. Biochem Biophys Res Commun. 1993 Sep 15;195(2):608-15. doi:
10.1006/bbrc.1993.2089.
Inhibition of acid secretion in gastric parietal cells by the
Ca2+/calmodulin-dependent protein kinase II inhibitor KN-93.
Mamiya N(1), Goldenring JR, Tsunoda Y, Modlin IM, Yasui K, Usuda N, Ishikawa T,
Natsume A, Hidaka H.
Author information:
(1)Department of Pharmacology, Nagoya University School of Medicine, Japan.
A novel Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) inhibitor,
KN-93 potently inhibits gastric acid secretion from parietal cells. As
previously reported (1), treatment of parietal cells with a selective inhibitor
of CaM kinase II, KN-62 resulted in the inhibition of cholinergic-stimulated
rabbit parietal cell secretion, whereas it failed to inhibit the histamine and
forskolin response. In contrast effects of carbachol, histamine and forskolin
were significantly inhibited by KN-93 with an IC50 of 0.15, 0.3 and 1 microM,
respectively; these effects occurred without any changes in intracellular cyclic
AMP and Ca2+ levels. In the present study we investigated the mechanism by which
KN-93 acts upon the acid-secreting machinery of gastric parietal cells. Neither
redistribution of the proton pump activity nor the morphological transformation
were affected by KN-93. The drug only weakly inhibited the H+, K(+)-ATPase
activity but strongly dissipated the proton gradient formed in the gastric
membrane vesicles and reduced the volume of luminal space. Thus KN-93 acts at pH
gradient formation whereas KN-62 acts only at CaM Kinase II.
DOI: 10.1006/bbrc.1993.2089
PMID: 7690557 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8939965 | 1. J Biol Chem. 1996 Nov 22;271(47):30149-57. doi: 10.1074/jbc.271.47.30149.
Calcium/calmodulin-dependent protein kinase IIalpha mediates activation of
mitogen-activated protein kinase and cytosolic phospholipase A2 in
norepinephrine-induced arachidonic acid release in rabbit aortic smooth muscle
cells.
Muthalif MM(1), Benter IF, Uddin MR, Malik KU.
Author information:
(1)Department of Pharmacology, College of Medicine, The University of Tennessee
Center for Health Sciences, Memphis, Tennessee 38163, USA.
[email protected]
We have investigated the contribution of Ca2+/calmodulin-dependent protein
kinase II (CaM kinase II) and mitogen-activated protein kinase (MAP kinase) in
norepinephrine (NE)-induced arachidonic acid (AA) release in rabbit aortic
vascular smooth muscle cells (VSMC). NE enhanced release of AA via activation of
cytosolic phospholipase A2 (cPLA2) but not secretory PLA2 in VSMC prelabeled
with [3H]AA. NE (10 microM) enhanced CaM kinase II and MAP kinase activity. In
cells transiently transfected with antisense oligonucleotides complementary to
the translation initiation sites of CaM kinase II and MAP kinase, NE-induced AA
release was inhibited by 100 and 35% respectively. Treatment of cells with
PD-098059, a MAP kinase kinase inhibitor, or with MAP kinase antisense
oligonucleotide reduced NE-induced activation of MAP kinase and cPLA2.
NE-induced MAP kinase and cPLA2 activation was also inhibited in cells treated
with a CaM kinase II inhibitor, KN-93, or with CaM kinase II antisense
oligonucleotide. On the other hand, inhibition of MAP kinase kinase with
PD-098059 or of MAP kinase with antisense oligonucleotides did not alter the
NE-induced increase in CaM kinase II activity. Phosphorylation of MAP kinase and
CaM kinase II by NE, studied by 32P incorporation and immune complex kinase
assays, was inhibited by KN-93. Collectively, these data suggest that CaM kinase
II can activate MAP kinase, which in turn activates cPLA2 to release AA for
prostacyclin synthesis in the rabbit VSMC. This novel pathway for activation of
MAP kinase by CaM kinase II appears to be mediated through stimulation of MAP
kinase kinase. Activation of adrenergic receptors with NE in VSMC caused
translocation of CaM kinase II, MAP kinase, and cPLA2 to the nuclear envelope
only in the presence of extracellular Ca2+. Okadaic acid, which increased
phosphorylation and activity, did not translocate these enzymes. Therefore, it
appears that in rabbit VSMC, NE, by promoting extracellular Ca2+ influx,
increases CaM kinase II activity, leading to activation of MAP kinase and cPLA2
and translocation to the nuclear envelope, resulting in release of AA from the
nuclear envelope for prostacyclin synthesis.
DOI: 10.1074/jbc.271.47.30149
PMID: 8939965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21187407 | 1. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):828-33. doi:
10.1073/pnas.1018022108. Epub 2010 Dec 27.
Beta Ca2+/CaM-dependent kinase type II triggers upregulation of GluA1 to
coordinate adaptation to synaptic inactivity in hippocampal neurons.
Groth RD(1), Lindskog M, Thiagarajan TC, Li L, Tsien RW.
Author information:
(1)Department of Molecular and Cellular Physiology, Stanford University School
of Medicine, Stanford, CA 94305, USA.
Prolonged AMPA-receptor blockade in hippocampal neuron cultures leads to both an
increased expression of GluA1 postsynaptically and an increase in vesicle pool
size and turnover rate presynaptically, adaptive changes that extend beyond
simple synaptic scaling. As a molecular correlate, expression of the β
Ca(2+)/CaM-dependent kinase type II (βCaMKII) is increased in response to
synaptic inactivity. Here we set out to clarify the role of βCaMKII in the
various manifestations of adaptation. Knockdown of βCaMKII by
lentiviral-mediated expression of shRNA prevented the synaptic
inactivity-induced increase in GluA1, as did treatment with the CaM kinase
inhibitor KN-93, but not the inactive analog KN-92. These results demonstrate
that, spurred by AMPA-receptor blockade, up-regulation of βCaMKII promotes
increased GluA1 expression. Indeed, transfection of βCaMKII, but not a
kinase-dead mutant, increased GluA1 expression on dendrites and elevated vesicle
turnover (Syt-Ab uptake), mimicking the effect of synaptic inactivity on both
sides of the synapse. In cells with elevated βCaMKII, relief of
synaptic-activity blockade uncovered an increase in the frequency of miniature
excitatory postsynaptic currents that could be rapidly and fully suppressed by
PhTx blockade of GluA1 receptors. This increased mini frequency involved a
genuine presynaptic enhancement, not merely an increased abundance of synapses.
This finding suggests that Ca(2+) flux through GluA1 receptors may trigger the
acute release of a retrograde messenger. Taken together, our results indicate
that synaptic inactivity-induced increases in βCaMKII expression set in motion a
series of events that culminate in coordinated pre- and postsynaptic adaptations
in synaptic transmission.
DOI: 10.1073/pnas.1018022108
PMCID: PMC3021030
PMID: 21187407 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/19668078 | 1. Am J Dermatopathol. 2009 Oct;31(7):664-73. doi: 10.1097/DAD.0b013e3181a05dad.
A case of Brooke-Spiegler syndrome with a novel germline deep intronic mutation
in the CYLD gene leading to intronic exonization, diverse somatic mutations, and
unusual histology.
Kazakov DV(1), Thoma-Uszynski S, Vanecek T, Kacerovska D, Grossmann P, Michal M.
Author information:
(1)Sikl's Department of Pathology, Charles University Medical Faculty Hospital,
Pilsen, Czech Republic. [email protected]
We present a case of Brooke-Spiegler syndrome with a germline deep intronic
mutation in the CYLD gene leading to intronic exonization. Additionally, diverse
somatic mutations were identified, namely loss of heterozygosity, a recurrent
nonsense mutation, and a sequence mutation causing exon skipping. These somatic
aberrations were identified in 4 different cylindromas that had been removed
from the patient. Additionally, we microscopically studied a spiradenocylindroma
that showed unusual histology, including foci of follicular differentiation. A
deep intronic mutation resulting in exonization and a somatic sequence mutations
causing exon skipping are hitherto unreported genetic mechanisms involving the
CYLD gene in patients with Brooke-Spiegler syndrome.
DOI: 10.1097/DAD.0b013e3181a05dad
PMID: 19668078 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10339583 | 1. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6307-11. doi:
10.1073/pnas.96.11.6307.
A single nucleotide in the SMN gene regulates splicing and is responsible for
spinal muscular atrophy.
Lorson CL(1), Hahnen E, Androphy EJ, Wirth B.
Author information:
(1)Department of Dermatology, New England Medical Center, Tufts University
School of Medicine, Boston, MA 02111, USA.
SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical
question is why only the homozygous loss of SMN1, and not SMN2, results in
spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid
genes and a new SMN1 mutation showed a direct relationship between presence of
disease and exon 7 skipping. We have reported previously that the exon-skipped
product SMNDelta7 is partially defective for self-association and SMN
self-oligomerization correlated with clinical severity. To evaluate
systematically which of the five nucleotides that differ between SMN1 and SMN2
effect alternative splicing of exon 7, a series of SMN minigenes was engineered
and transfected into cultured cells, and their transcripts were characterized.
Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a
translationally silent variance, was necessary and sufficient to dictate exon 7
alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and
protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity
of an exonic enhancer. These findings demonstrate the molecular genetic basis
for the nature and pathogenesis of SMA and illustrate a novel disease mechanism.
Because individuals with SMA retain the SMN2 allele, therapy targeted at
preventing exon 7 skipping could modify clinical outcome.
DOI: 10.1073/pnas.96.11.6307
PMCID: PMC26877
PMID: 10339583 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9596994 | 1. Exp Cell Res. 1998 May 1;240(2):218-27. doi: 10.1006/excr.1997.3925.
CaMK-II inhibition reduces cyclin D1 levels and enhances the association of
p27kip1 with Cdk2 to cause G1 arrest in NIH 3T3 cells.
Morris TA(1), DeLorenzo RJ, Tombes RM.
Author information:
(1)Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth
University, Richmond 23298-0230, USA.
The calmodulin-dependent protein kinase-II (CaMK-II) inhibitor KN-93 has been
shown to reversibly arrest mouse and human cells in the G1 phase of the cell
cycle [Tombes, R. M., Westin, E., Grant. S., and Krystal, G. (1995) Cell Growth
Differ. 6, 1073-1070; Rasmussen, G., and Rasmussen, C. (1995) Biochem. Cell
Biol. 71, 201-207]. The stimulation of Ca(2+)-independent (autonomous) CaMK-II
enzymatic activity, a barometer of in situ activated CaMK-II, was prevented by
the same KN-93 concentrations that cause G1 phase arrest. KN-93 caused the
retinoblastoma protein pRB to become dephosphorylated and the activity of both
cdk2 and cdk4, two potential pRb kinases, to decrease. Neither the activity of
p42MAP kinase, an early response G1 signaling molecule, nor the phosphorylation
status or DNA-binding capability of the transcription factors serum response
factor and cAMP responsive element-binding protein was altered during this G1
arrest. The protein levels of cyclin-dependent kinase 2 (cdk2) and cdk4 were
unaffected during this G1 arrest and the total cellular levels of the cdk
inhibitors p21cip1 and p27kip1 were not increased. Instead, the cdk4 activity
decreases resulting from KN-93 were the result of a 75% decrease in cyclin D1
levels. In contrast, cyclin A and E levels were relatively constant. Cdk2
activity decreases were primarily the result of enhanced p27kip1 association
with cdk2/cyclin E. All of these phenomena were unaffected by KN-93's inactive
analog, KN-92, and were reversible upon KN-93 washout. The kinetics of recovery
from cell cycle arrest were similar to those reported for other G1 phase
blockers. These results suggest a mechanism by which G1 Ca2+ signals could be
linked via calmodulin-dependent phosphorylations to the cell cycle-controlling
machinery through cyclins and cdk inhibitors.
DOI: 10.1006/excr.1997.3925
PMID: 9596994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23694822 | 1. Am J Dermatopathol. 2013 Jun;35(4):445-7. doi: 10.1097/DAD.0b013e31827132af.
Multiple trichoepitheliomas associated with a novel heterozygous mutation in the
CYLD gene as an adjunct to the histopathological diagnosis.
Reuven B(1), Margarita I, Dov H, Ziad K.
Author information:
(1)Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.
[email protected]
Multiple trichoepitheliomas (TEs), especially in the familial setting, have been
associated with germline heterozygous mutations in the CYLD gene. Heterozygous
germline CYLD mutations and loss of heterozygosity of the CYLD gene in the TE
tumor cells have been recently demonstrated in some of the multiple TE cases
irrespective of a family history. The histopathological differential diagnosis
of TE from basal cell carcinoma may be difficult especially in cases with
multiple TEs. Immunohistochemical markers may be used, although some with
conflicting results. We describe a 35-year-old woman with multiple facial TEs,
in whom the molecular genetic analysis revealed a novel heterozygous c.1843delT
mutation in the CYLD gene. This frameshift mutation was also present in a
heterozygous state in the TE tumor cells. The demonstration of a novel CYLD
mutation was used as an adjunct to the histopathological diagnosis in this case.
DOI: 10.1097/DAD.0b013e31827132af
PMID: 23694822 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23404581 | 1. Mol Med Rep. 2013 Apr;7(4):1086-90. doi: 10.3892/mmr.2013.1311. Epub 2013 Feb
6.
PLAG1 and CYLD do not play a role in the tumorigenesis of adenoid cystic
carcinoma.
Daa T(1), Nakamura I, Yada N, Arakane S, Nishida H, Kashima K, Suzuki M,
Yokoyama S.
Author information:
(1)Department of Diagnostic Pathology, Faculty of Medicine, Oita University,
Oita 879-5593, Japan. [email protected]
The pleiomorphic adenoma gene 1 (PLAG1) gene is activated in a subset of
pleomorphic adenomas of the salivary gland by gene fusion. Germ‑line mutation in
cylindromatosis (CYLD), a tumor suppressor gene, causes familial cylindromatosis
and Brook‑Spiegler syndrome. In the present study, aberrations in PLAG1 and CYLD
were investigated in adenoid cystic carcinoma (ACC) of the salivary gland.
Reverse‑transcription PCR and PCR direct sequencing were performed to detect
gene fusion of PLAG1 and mutation of CYLD in 34 ACC tissues. No PLAG1 fusion was
detected in ACC. However, silent mutation of CYLD was detected in 2 cases of
ACC, but no missense mutation was detected in ACC. These results suggest that
PLAG1 and CYLD do not play a role in ACC tumorigenesis.
DOI: 10.3892/mmr.2013.1311
PMID: 23404581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25888396 | 1. Mol Neurodegener. 2015 Apr 10;10:20. doi: 10.1186/s13024-015-0014-y.
Calcium-responsive transactivator (CREST) protein shares a set of structural and
functional traits with other proteins associated with amyotrophic lateral
sclerosis.
Kukharsky MS(1)(2), Quintiero A(3), Matsumoto T(4), Matsukawa K(5), An H(6),
Hashimoto T(7), Iwatsubo T(8), Buchman VL(9), Shelkovnikova TA(10)(11).
Author information:
(1)School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff,
UK. [email protected].
(2)Institute of Physiologically Active Compounds Russian Academy of Sciences, 1
Severniy proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.
[email protected].
(3)School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff,
UK. [email protected].
(4)Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
[email protected].
(5)Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
[email protected].
(6)School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff,
UK. [email protected].
(7)Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
[email protected].
(8)Department of Neuropathology, The University of Tokyo, Tokyo, Japan.
[email protected].
(9)School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff,
UK. [email protected].
(10)School of Biosciences, Cardiff University, Museum Avenue, CF10 3AX, Cardiff,
UK. [email protected].
(11)Institute of Physiologically Active Compounds Russian Academy of Sciences, 1
Severniy proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.
[email protected].
BACKGROUND: Mutations in calcium-responsive transactivator (CREST) encoding gene
have been recently linked to ALS. Similar to several proteins implicated in ALS,
CREST contains a prion-like domain and was reported to be a component of
paraspeckles.
RESULTS: We demonstrate that CREST is prone to aggregation and co-aggregates
with FUS but not with other two ALS-linked proteins, TDP-43 and TAF15, in
cultured cells. Aggregation of CREST affects paraspeckle integrity, probably by
trapping other paraspeckle proteins within aggregates. Like several other
ALS-associated proteins, CREST is recruited to induced stress granules. Neither
of the CREST mutations described in ALS alters its subcellular localization,
stress granule recruitment or detergent solubility; however Q388stop mutation
results in elevated steady-state levels and more frequent nuclear aggregation of
the protein. Both wild-type protein and its mutants negatively affect neurite
network complexity of unstimulated cultured neurons when overexpressed, with
Q388stop mutation being the most deleterious. When overexpressed in the fly eye,
wild-type CREST or its mutants lead to severe retinal degeneration without
obvious differences between the variants.
CONCLUSIONS: Our data indicate that CREST and certain other ALS-linked proteins
share several features implicated in ALS pathogenesis, namely the ability to
aggregate, be recruited to stress granules and alter paraspeckle integrity. A
change in CREST levels in neurons which might occur under pathological
conditions would have a profound negative effect on neuronal homeostasis.
DOI: 10.1186/s13024-015-0014-y
PMCID: PMC4428507
PMID: 25888396 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11164895 | 1. Mol Immunol. 2000 Aug;37(11):675-83. doi: 10.1016/s0161-5890(00)00087-0.
Calcium-induced ERK activation in human T lymphocytes occurs via p56(Lck) and
CaM-kinase.
Franklin RA(1), Atherfold PA, McCubrey JA.
Author information:
(1)Department of Microbiology and Immunology, East Carolina University School of
Medicine, Brody Building, Greenville, NC 27858, USA. [email protected]
We previously demonstrated that stimulation of human T-lymphocytes with calcium
ionophores induced the phosphorylation and enzymatic activation of ERK2. We now
report on the mechanism by which calcium-ionophore-induced activation of ERK1
and 2 occurs in these cells. The activation of ERK1 and 2 by increases in
intracellular calcium was inhibited by calmidazolium suggesting the involvement
of calmodulin in this response. To further elucidate the mechanism by which
calcium-induced ERK activation occurs, we used the CaM-kinase inhibitor KN-93
and an inactive analog of KN-93 (KN-92). KN-93, but not KN-92, blocked
ionomycin-induced activation of ERK1 and 2 in human T lymphocytes. We previously
demonstrated that stimulation of T lymphocytes with ionomycin or A23187 resulted
in a CaM-kinase-dependent shift in the mobility of p56(Lck). To determine if
p56(Lck) was involved in calcium-induced ERK activation, we stimulated the
p56(Lck) negative Jurkat cell derivatives, J.CaM1.6 and J.CaM1/Rep3, with
ionomycin. In these p56(Lck) negative cell lines, activation of ERK1 and 2 in
response to ionomycin was only minimally detected. When J.CaM1 cells were
reconstituted with p56(Lck), ionomycin induced ERK1 and 2 activation. Treatment
of Jurkat cells with PP2, an inhibitor of p56(Lck), inhibited calcium-induced,
but not PMA-induced, ERK1 and 2 activation. Treatment of Jurkat cells with the
MEK inhibitor PD98059 blocked ionomycin-induced ERK activation, but not the
shift in the mobility of p56(Lck). Our data suggests that increases in
intracellular calcium induce the activation of ERK1 and 2 in human T lymphocytes
via sequential activation of CaM-kinase and phosphorylation of p56(Lck).
DOI: 10.1016/s0161-5890(00)00087-0
PMID: 11164895 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19076795 | 1. Clin Exp Dermatol. 2009 Jan;34(1):77-80. doi:
10.1111/j.1365-2230.2008.02870.x.
A novel splicing mutation of the CYLD gene in a Taiwanese family with multiple
familial trichoepithelioma.
Huang TM(1), Chao SC, Lee JY.
Author information:
(1)Department of Dermatology, National Cheng-Kung University Hospital and
College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease
characterized by numerous skin-coloured papules on the central face. Mutations
in the CYLD gene, which is also the gene responsible for familial
cylindromatosis, have been reported recently. Recent studies indicate that CYLD
is a tumour-suppressor gene. The CYLD protein is a negative regulator of the
activation of transcription factor nuclear factor-kappaB, and loss of CYLD
contributes to oncogenesis. We report a novel splicing mutation (IVS12 + 1
G-->A) in the CYLD gene in a Taiwanese pedigree with MFT, and discuss new
developments in treatment options.
DOI: 10.1111/j.1365-2230.2008.02870.x
PMID: 19076795 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25150498 | 1. Nat Med. 2014 Sep;20(9):1055-61. doi: 10.1038/nm.3664. Epub 2014 Aug 24.
Soluble neuregulin-1 modulates disease pathogenesis in rodent models of
Charcot-Marie-Tooth disease 1A.
Fledrich R(1), Stassart RM(2), Klink A(3), Rasch LM(3), Prukop T(4), Haag L(5),
Czesnik D(5), Kungl T(3), Abdelaal TA(3), Keric N(6), Stadelmann C(7), Brück
W(7), Nave KA(3), Sereda MW(8).
Author information:
(1)1] Department of Neurogenetics, Max Planck Institute of Experimental
Medicine, Göttingen, Germany. [2].
(2)1] Department of Neurogenetics, Max Planck Institute of Experimental
Medicine, Göttingen, Germany. [2] Institute of Neuropathology, University
Medical Center Göttingen, Göttingen, Germany. [3].
(3)Department of Neurogenetics, Max Planck Institute of Experimental Medicine,
Göttingen, Germany.
(4)1] Department of Neurogenetics, Max Planck Institute of Experimental
Medicine, Göttingen, Germany. [2] Institute of Clinical Pharmacology, University
Medical Center Göttingen, Göttingen, Germany.
(5)Department of Clinical Neurophysiology, University Medical Center Göttingen,
Göttingen, Germany.
(6)1] Department of Neurogenetics, Max Planck Institute of Experimental
Medicine, Göttingen, Germany. [2] Department of Neurosurgery, University Medical
Center, Johannes-Gutenberg University of Mainz, Mainz, Germany.
(7)Institute of Neuropathology, University Medical Center Göttingen, Göttingen,
Germany.
(8)1] Department of Neurogenetics, Max Planck Institute of Experimental
Medicine, Göttingen, Germany. [2] Department of Clinical Neurophysiology,
University Medical Center Göttingen, Göttingen, Germany.
Comment in
Nat Med. 2014 Sep;20(9):984-5. doi: 10.1038/nm.3684.
Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22)
underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A),
a disease without a known cure. Although demyelination represents a
characteristic feature, the clinical phenotype of CMT1A is determined by the
degree of axonal loss, and patients suffer from progressive muscle weakness and
impaired sensation. CMT1A disease manifests within the first two decades of
life, and walking disabilities, foot deformities and electrophysiological
abnormalities are already present in childhood. Here, we show in
Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent
differentiation defect during early postnatal development, caused by imbalanced
activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that
enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I
drives diseased Schwann cells toward differentiation and preserves peripheral
nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat
model, when treatment is restricted to early postnatal development, soluble NRG1
effectively overcomes impaired peripheral nerve development and restores axon
survival into adulthood. Our findings suggest a model in which Schwann cell
differentiation within a limited time window is crucial for the long-term
maintenance of axonal support.
DOI: 10.1038/nm.3664
PMID: 25150498 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18039618 | 1. Orv Hetil. 2007 Dec 2;148(48):2275-8. doi: 10.1556/OH.2007.28213.
[Molecular biological virus identification in dilated cardiomyopathy].
[Article in Hungarian]
Tátrai E(1), Ifj Hartyánszky I, Lászik A, Hubay M, Acsády G, Sótonyi P.
Author information:
(1)Semmelweis Egyetem, Altalános Orvostudományi Kar, Igazságügyi Orvostani
Intézet, Budapest.
Enteroviruses have been considered to be the most common cause of acute
myocarditis and possible consequence of dilated cardiomyopathy. Some
publications shed light to the role of other viruses in this disease as well.
Our molecular investigation has demonstrated that adeno- and herpes viruses
might also frequently occur in dilated cardiomyopathy.
AIM: The aim of our study was to screen virus genomes in heart tissues from
heart-transplanted patients to prove their possible role in the pathogenesis of
dilated cardiomyopathy.
METHODS: DNA and RNA were isolated from five regions of the heart muscle.
Amplification for Adenovirus Type 3, Human Herpes Virus Type 6 and Enterovirus
genomes were performed by nested-Polymerase Chain Reaction. Finally the
virus-positive samples were direct sequenced.
RESULTS: In 2 patients Adenovirus Type 3 and in 1 patient both Adenovirus Type 3
and Human Herpes Virus Type 6 were detected. No enteroviruses were found in any
heart tissue.
CONCLUSIONS: In our study the adenovirus genome was found to be the most
frequent virus genome in explanted heart tissues. The identified viral sequences
proved previous viral infection, which could have played a role in the
development of dilated cardiomyopathy. Detection of different viruses in the
myocardium by molecular biological examinations might contribute to adequate
treatment of these patients.
DOI: 10.1556/OH.2007.28213
PMID: 18039618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15175389 | 1. J Neurosci. 2004 Jun 2;24(22):5193-201. doi: 10.1523/JNEUROSCI.0854-04.2004.
Cytoplasmic polyadenylation element binding protein-dependent protein synthesis
is regulated by calcium/calmodulin-dependent protein kinase II.
Atkins CM(1), Nozaki N, Shigeri Y, Soderling TR.
Author information:
(1)Vollum Institute, Oregon Health and Science University, Portland, Oregon
97239, USA.
Phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB)
regulates protein synthesis in hippocampal dendrites. CPEB binds the 3'
untranslated region (UTR) of cytoplasmic mRNAs and, when phosphorylated,
initiates mRNA polyadenylation and translation. We report that, of the protein
kinases activated in the hippocampus during synaptic plasticity,
calcium/calmodulin-dependent protein kinase II (CaMKII) robustly phosphorylated
the regulatory site (threonine 171) in CPEB in vitro. In postsynaptic density
fractions or hippocampal neurons, CPEB phosphorylation increased when CaMKII was
activated. These increases in CPEB phosphorylation were attenuated by a specific
peptide inhibitor of CaMKII and by the general CaM-kinase inhibitor KN-93.
Inhibitors of protein phosphatase 1 increased basal CPEB phosphorylation in
neurons; this was also attenuated by a CaM-kinase inhibitor. To determine
whether CaM-kinase activity regulates CPEB-dependent mRNA translation,
hippocampal neurons were transfected with luciferase fused to a 3' UTR
containing CPE-binding elements. Depolarization of neurons stimulated synthesis
of luciferase; this was abrogated by inhibitors of protein synthesis, mRNA
polyadenylation, and CaMKII. These results demonstrate that CPEB phosphorylation
and translation are regulated by CaMKII activity and provide a possible
mechanism for how dendritic protein synthesis in the hippocampus may be
stimulated during synaptic plasticity.
DOI: 10.1523/JNEUROSCI.0854-04.2004
PMCID: PMC6729187
PMID: 15175389 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18277927 | 1. Pediatr Infect Dis J. 2008 Mar;27(3):241-5. doi: 10.1097/INF.0b013e31815c1b07.
Severe neonatal parechovirus infection and similarity with enterovirus
infection.
Verboon-Maciolek MA(1), Krediet TG, Gerards LJ, de Vries LS, Groenendaal F, van
Loon AM.
Author information:
(1)Department of Neonatology, University Medical Center, Utrecht, The
Netherlands. M. [email protected]
BACKGROUND: Enteroviruses (EV) are an important cause of neonatal disease
including hepatitis, meningoencephalitis, and myocarditis that can lead to death
or severe long-term sequelae. Less is known about severe neonatal infection
caused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were
previously known as echovirus 22 and echovirus 23. They belong to the same
family of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been
associated in 2 recent reports with severe neonatal infection including
involvement of central nervous system.
METHODS: We compared the clinical signs, diagnosis, laboratory data, cerebral
imaging, and neurodevelopmental outcome of 11 neonates with PeV infection with
21 infants with EV infection treated in our hospital between 1994 and 2006. The
diagnosis of EV infection or PeV infection was confirmed by a positive EV and/or
PeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or
stool or a viral culture of stool, nasopharyngeal swab, and/or CSF.
RESULTS: The 32 infants presented with sepsis-like illness and the most frequent
signs were: fever, seizures, irritability, rash, and feeding problems. All
patients received antibiotic treatment. Eleven of 21 infants infected with EV
and 7 of 11 infants infected with PeV were full-term. Differentiation between
the infants infected with EV and PeV on the basis of fever, irritability, rash,
and seizures was not possible. Myocarditis was exclusively seen in 4 patients
infected by EV. Eight of 11 patients with a PeV infection had
meningoencephalitis of whom only 1 infant developed pleocytosis in the CSF.
Serum C-reactive protein and CSF protein values were significantly higher in
infants with EV infection than in those with PeV infection. Cerebral imaging of
all infants with EV or PeV cerebral infection showed mild to severe white matter
abnormalities. In 1 infant with EV infection and 3 infants with PeV infection,
neurodevelopmental delay occurred. Mortality and long-term sequelae were mainly
associated with myocarditis in the infants who were infected with EV (4 of 21).
CONCLUSIONS: It is not possible to distinguish neonatal PeV from EV infection on
the basis of clinical signs. Neonates with PeV or EV infection present with
sepsis-like illness and the most frequent signs are fever, seizures,
irritability, rash, and feeding problems.
DOI: 10.1097/INF.0b013e31815c1b07
PMID: 18277927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7637580 | 1. Brain Res Mol Brain Res. 1995 Jun;30(2):301-11. doi:
10.1016/0169-328x(94)00007-2.
Molecular cloning of cDNA encoding a bovine selenoprotein P-like protein
containing 12 selenocysteines and a (His-Pro) rich domain insertion, and its
regional expression.
Saijoh K(1), Saito N, Lee MJ, Fujii M, Kobayashi T, Sumino K.
Author information:
(1)Department of Public Health, Kobe University School of Medicine, Japan.
When cDNA containing proteins enriched in the bovine cerebellar cortex were
cloned, a clone which seemed to encode a selenoprotein P-like protein was
isolated. The coding nucleotide sequence of its cDNA insert displayed high
homology to rat and human selenoprotein P cDNA but contained 12 rather than 10
TGAs (12 rather than 10 selenocysteines in deduced amino acids), a tandem repeat
of one CACTCC (His-Ser) and seven CATCCCs (His-Pro), and a 3' untranslated
region approximately 890 bases shorter than that of rat liver selenoprotein P.
RT-PCR using a set of primers flanking to the repeat displayed the existence of
mRNA without the repeat. The tandem repeat and its adjacent region consisted of
a similar motif of CAC/TCC/AC/T. Thus, these proteins included a (His-Pro) rich
domain with a slightly negative free energy change irrespective of having the
tandem repeat or not. Such His-Pro repeats reportedly exist in the segmentation
gene paired or homeobox protein Om(1D) of Drosophila. Moreover, both this
selenoprotein P-like protein mRNA and selenoprotein P mRNA were expressed in all
the areas of the brain but most prominently in the cerebellar cortex,
hippocampus, and olfactory bulb. These findings suggest the possibility that
these selenoproteins are major selenium carriers in the brain and play a role in
the morphological response of nerve or glial cells.
DOI: 10.1016/0169-328x(94)00007-2
PMID: 7637580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2641165 | 1. Przegl Epidemiol. 1989;43(4):388-92.
[The search for a viral etiology of myocarditis].
[Article in Polish]
Grodzicka-Królak H, Horbowska-Marzec H, Małkowska E.
The results are presented of serological tests by the neutralization method for
antigens of Coxsackie B group, and by the haemagglutination inhibition method
for three types of parainfluenza and sporadic influenza virus in 529 patients
with myocarditis. In 7 cases the virus was isolated from stools. Virus aetiology
of the disease was confirmed in 23.4% of cases, on average. Raised levels of
antibodies to Coxsackie B antigens were found more frequently than the levels of
antibodies to parainfluenza viruses. Seroconversion was more frequent in
infections by parainfluenza type 3 than type 2. During an influenza epidemic in
5 cases raised levels of antibodies to the epidemic-causing strain were
observed.
PMID: 2641165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17000762 | 1. Mol Cell Biol. 2006 Dec;26(24):9177-84. doi: 10.1128/MCB.00856-06. Epub 2006
Sep 25.
Efficient incorporation of multiple selenocysteines involves an inefficient
decoding step serving as a potential translational checkpoint and ribosome
bottleneck.
Stoytcheva Z(1), Tujebajeva RM, Harney JW, Berry MJ.
Author information:
(1)Department of Cell and Molecular Biology, University of Hawaii at Manoa,
Honolulu, HI 96813, USA.
Selenocysteine is incorporated into proteins via "recoding" of UGA from a stop
codon to a sense codon, a process that requires specific secondary structures in
the 3' untranslated region, termed selenocysteine incorporation sequence (SECIS)
elements, and the protein factors that they recruit. Whereas most selenoprotein
mRNAs contain a single UGA codon and a single SECIS element, selenoprotein P
genes encode multiple UGAs and two SECIS elements. We have identified
evolutionary adaptations in selenoprotein P genes that contribute to the
efficiency of incorporating multiple selenocysteine residues in this protein.
The first is a conserved, inefficiently decoded UGA codon in the N-terminal
region, which appears to serve both as a checkpoint for the presence of factors
required for selenocysteine incorporation and as a "bottleneck," slowing down
the progress of elongating ribosomes. The second adaptation involves the
presence of introns downstream of this inefficiently decoded UGA which confer
the potential for nonsense-mediated decay when factors required for
selenocysteine incorporation are limiting. Third, the two SECIS elements in
selenoprotein P mRNA function with differing efficiencies, affecting both the
rate and the efficiency of decoding different UGAs. The implications for how
these factors contribute to the decoding of multiple selenocysteine residues are
discussed.
DOI: 10.1128/MCB.00856-06
PMCID: PMC1698516
PMID: 17000762 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15569687 | 1. J Biol Chem. 2005 Feb 11;280(6):4321-8. doi: 10.1074/jbc.M407706200. Epub 2004
Nov 29.
Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1
transcriptional activity in cells subjected to intermittent hypoxia.
Yuan G(1), Nanduri J, Bhasker CR, Semenza GL, Prabhakar NR.
Author information:
(1)Department of Physiology & Biophysics, School of Medicine, Case Western
Reserve University, Cleveland, Ohio 44106, USA.
Intermittent hypoxia (IH) occurs in many pathological conditions. However, very
little is known about the molecular mechanisms associated with IH.
Hypoxia-inducible factor 1 (HIF-1) mediates transcriptional responses to
continuous hypoxia. In the present study, we investigated whether IH activates
HIF-1 and, if so, which signaling pathways are involved. PC12 cells were exposed
to either to 20% O2 (non-hypoxic control) or to 60 cycles consisting of 30 s at
1.5% O2, followed by 4 min at 20% O2 (IH). Western blot analysis revealed
significant increases in HIF-1alpha protein in nuclear extracts of cells
subjected to IH. Expression of a HIF-1-dependent reporter gene was increased
3-fold in cells subjected to IH. Although IH induced the activation of ERK1,
ERK2, JNK, PKC-alpha, and PKC-gamma, inhibitors of these kinases and of
phosphatidylinositol 3-kinase did not block HIF-1-mediated reporter gene
expression induced by IH, indicating that signaling via these kinases was not
required. In contrast, addition of the intracellular Ca2+ chelator BAPTA-AM or
the Ca2+/calmodulin-dependent (CaM) kinase inhibitor KN93 blocked reporter gene
activation in response to IH. CaM kinase activity was increased 5-fold in cells
subjected to IH. KN 93 prevented IH-induced transactivation mediated by
HIF-1alpha, and its coactivator p300, which was phosphorylated by CaM kinase II
in vitro. Expression of the HIF-1-regulated gene encoding tyrosine hydroxylase
was induced by IH and this effect was blocked by KN93. These observations
suggest that IH induces HIF-1 transcriptional activity via a novel signaling
pathway involving CaM kinase.
DOI: 10.1074/jbc.M407706200
PMID: 15569687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24062268 | 1. Indian J Pediatr. 2014 Feb;81(2):158-64. doi: 10.1007/s12098-013-1203-8. Epub
2013 Sep 24.
Cushing syndrome.
Bista B(1), Beck N.
Author information:
(1)Department of Pediatrics, Texas Tech University Health Sciences Center, 3601
- 4th Street, Mail Stop 9406, Lubbock, TX, 79430, USA.
Cushing syndrome is the constellation of signs and symptoms caused by protracted
exposure to glucocorticoids. The most common cause of Cushing syndrome in
children and adolescents is exogenous administration of glucocorticoids.
Presenting features commonly include weight gain, growth retardation, hirsutism,
obesity, striae, acne and hypertension. Almost invariably, linear growth is
severely diminished, a factor which may be useful in differentiating between
childhood obesity and Cushing syndrome. Diagnostic approaches are based on
distinguishing between adrenocorticotropic hormone (ACTH)-dependent and
ACTH-independent etiologies, and consideration of the most likely diagnosis by
age. Treatment modality is dependent upon etiology. After cure, important
components of care include attention to linear growth, pubertal progression and
body composition.
DOI: 10.1007/s12098-013-1203-8
PMID: 24062268 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8199011 | 1. Int J Exp Pathol. 1994 Apr;75(2):99-110.
Characterization of a murine model of myocarditis induced by a reactivated
coxsackievirus B3.
Zhang H(1), Yousef GE, Ouyang X, Archard LC.
Author information:
(1)Department of Biochemistry, Charing Cross and Westminster Medical School,
London, UK.
A transfection-reactivated Coxsackievirus B3 (rCVB3), from a full-length cDNA
clone of Nancy strain, has previously been shown to be as cardiovirulent as the
wild-type virus. Myocarditis induced by this genetically defined virus was
compared in SWR mice with the traditional Balb/c model. SWR mice inoculated with
rCVB3 developed more severe myocarditis but less severe pancreatitis than Balb/c
mice. In contrast to the poor general health and frequent mortality of Balb/c
mice following CVB3 infection, the body weight of SWR mice was not affected by
CVB3 inoculation and no mortality occurred at titres of 10(2)-10(7) plaque
forming units (PFU). Typical myocarditis developed in SWR mice 7 days post
infection. Myocarditic foci consisting of necrotic myocardial fibres and
mononuclear cell infiltrates resolved by day 30, similar to that observed in
Balb/c. However, SWR mice were more sensitive to rCVB3-induced myocarditis than
were Balb/c mice: mild myocarditis was induced (4/4) by as low as 10(2) PFU of
the virus (ID50 < 10(1.5) PFU), and more severe myocarditis was seen at higher
PFU of virus in a dose-dependent manner. The SWR model was tested with
attenuated variants derived from cardiovirulent rCVB3. The ID50 for myocarditis
was 10(7) PFU for a large plaque-size attenuant and 10(6) PFU for a minute
plaque-size attenuant, indicating loss of cardiovirulence by a factor of more
than 10(4)-10(5). rCVB3-induced SWR mouse is a sensitive and reliable model for
myocarditis. It is useful in assessing the cardiovirulence of different CVB3
variants and evaluating the efficacies of anti-viral therapies. It will allow
follow-up study after high dose infection with cardiovirulent rCVB3.
PMCID: PMC2002107
PMID: 8199011 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12877753 | 1. BMC Neurol. 2003 Jul 23;3:5. doi: 10.1186/1471-2377-3-5. Epub 2003 Jul 23.
Variable expression of cerebral cavernous malformations in carriers of a
premature termination codon in exon 17 of the Krit1 gene.
Lucas M(1), Costa AF, García-Moreno JM, Solano F, Gamero MA, Izquierdo G.
Author information:
(1)Molecular Biology Services of the Virgen Macarena University Hospital, Avda
Dr, Fedriani sn, 41009 Sevilla, Spain. [email protected]
BACKGROUND: Cerebral cavernous malformations (CCM) present as either sporadic or
autosomal dominant conditions with incomplete penetrance of symptoms.
Differences in genetic and environmental factors might be minimized among
first-degree relatives. We therefore studied clinical expression in a family
with several affected members.
METHODS: We studied a three-generation family with the onset of CCM as a
cerebral haemorrhage in the younger (four-year-old) sibling. Identification and
enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the
whole brains. Genetic analysis comprised SCCP, sequencing and restriction
polymorphism of the Krit1 gene in the proband and at risk relatives.
RESULTS: The phenotypes of cerebral cavernous malformations (CCMs) in carriers
of Krit1 mutations were very variable. We identified a novel frameshift mutation
caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a
premature TAA triplet and predicts the truncating phenotype Y634X. A very
striking finding was the absence of both clinical symptoms and CCMs in the
eldest sibling harbouring the 1902insA.
CONCLUSIONS: Patients in this family, harbouring the same mutation, illustrate
the very variable clinical and radiological expression of a Krit1 mutation. The
early and critical onset in the proband contrasts with minor clinical findings
in affected relatives. This consideration is important in genetic counselling.
DOI: 10.1186/1471-2377-3-5
PMCID: PMC184376
PMID: 12877753 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24466005 | 1. PLoS One. 2014 Jan 23;9(1):e86286. doi: 10.1371/journal.pone.0086286.
eCollection 2014.
Mutation prevalence of cerebral cavernous malformation genes in Spanish
patients.
Mondéjar R(1), Solano F(1), Rubio R(1), Delgado M(1), Pérez-Sempere A(2),
González-Meneses A(3), Vendrell T(4), Izquierdo G(5), Martinez-Mir A(6), Lucas
M(1).
Author information:
(1)Servicio de Biología Molecular, Hospital Universitario Virgen Macarena,
Facultad de Medicina, Sevilla, Spain.
(2)Servicio de Neurología, Hospital Universitario de Alicante, Alicante, Spain.
(3)Unidad de Dismorfología, Hospital Universitario Virgen del Rocío, Sevilla,
Spain.
(4)Unidad de Genética, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
(5)Servicio de Neurología, Hospital Universitario Virgen Macarena, Facultad de
Medicina, Sevilla, Spain.
(6)Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del
Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
OBJECTIVE: To study the molecular genetic and clinical features of cerebral
cavernous malformations (CCM) in a cohort of Spanish patients.
METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct
sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic
cases of CCM patients of Spanish extraction. When available, RNA studies were
performed seeking for alternative or cryptic splicing.
RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated
proteins, were identified in 29 familial forms and in three sporadic cases. The
repertoire includes six novel non-sense and frameshift mutations in CCM1 and
CCM3. We also found four missense mutations, one of them located at the third
NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon
6. We found four genomic deletions with the loss of the whole CCM2 gene in one
patient and a partial loss of CCM1and CCM2 genes in three other patients. Four
families had mutations in CCM3. The results include a high frequency of intronic
variants, although most of them localize out of consensus splicing sequences.
The main symptoms associated to clinical debut consisted of cerebral
haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM
with Noonan and Chiari syndromes and delayed menarche is reported.
CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations
in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic
patients). The results include 13 new mutations of CCM genes and the main
clinical symptoms that deserves consideration in molecular diagnosis and genetic
counselling of cerebral cavernous malformations.
DOI: 10.1371/journal.pone.0086286
PMCID: PMC3900513
PMID: 24466005 [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/11310633 | 1. Ann Neurol. 2001 Apr;49(4):529-32.
Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous
malformations.
Lucas M(1), Costa AF, Montori M, Solano F, Zayas MD, Izquierdo G.
Author information:
(1)Servicio de Biología Molecular, Hospital Universitario Virgen Macarena,
Seville, Spain. [email protected]
Mutations in the Kritl gene have been recently discovered as the cause of
hereditary cerebral cavernous angioma. We sought the possibility that de novo,
noninherited mutations of Kritl also cause cavernous angioma. A patient with two
cerebral malformations carries a heterozygous deletion of two base pairs
(741delTC) in exon VI of the Kritl gene. The deletion initiates a frameshift
mutation that, 23 amino acids downstream, encodes a TAA stop triplet replacing a
CAT triplet of histidine at exon VII (H271X). Magnetic resonance images of the
parents were normal, neither parent carries the 741delTC mutation, and both bear
the wild-type sequence of exon VI. These findings document a de novo germline
mutation in Kritl gene that causes cerebral cavernous malformations.
PMID: 11310633 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20080130 | 1. Biochim Biophys Acta. 2010 Mar;1803(3):386-95. doi:
10.1016/j.bbamcr.2010.01.005. Epub 2010 Jan 15.
Chk2 splice variants express a dominant-negative effect on the wild-type Chk2
kinase activity.
Berge EO(1), Staalesen V, Straume AH, Lillehaug JR, Lønning PE.
Author information:
(1)Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway;
Section of Oncology, Institute of Medicine, University of Bergen, N-5021 Bergen,
Norway.
While the majority of RNA transcripts from protein-encoding genes in the human
genome are subject to physiological splicing, pathological splicing is
increasingly reported in cancer tissue. Previously, we identified >90 different
splice variants of Chk2, a gene encoding a serine/threonine kinase propagating
the DNA damage signal by phosphorylating and activating several downstream
substrates like p53, Cdc25A, and Cdc25C involved in cell cycle arrest and
apoptosis. While alternative splice forms of other genes have been reported to
exert a dominant-negative effect on the wild-type molecules, the function of
Chk2 splice protein variants is still unclear. Here we evaluated the function of
four Chk2 splice proteins for which mRNA splice variants were identified in
human breast carcinomas. These splice variants were stably expressed as nuclear
proteins. Two splice forms (Chk2Delta4 and Chk2del(2-3)) expressed kinase
activity while variants Chk2Delta11 and Chk2isoI were essentially kinase
inactive. Independent of intrinsic kinase activity, each splice variant impaired
wild-type Chk2 activity through heterodimerization. Based on our findings, we
suggest alternative splicing as a possible novel mechanism for repression of the
Chk2 wild-type function.
Copyright 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2010.01.005
PMID: 20080130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1662507 | 1. Biochem Biophys Res Commun. 1991 Dec 31;181(3):968-75. doi:
10.1016/0006-291x(91)92031-e.
The newly synthesized selective Ca2+/calmodulin dependent protein kinase II
inhibitor KN-93 reduces dopamine contents in PC12h cells.
Sumi M(1), Kiuchi K, Ishikawa T, Ishii A, Hagiwara M, Nagatsu T, Hidaka H.
Author information:
(1)Department of Pharmacology, Nagoya University School of Medicine, Japan.
We reported that one of the isoquinolinesulfonamide derivatives, KN-62, is a
potent and specific inhibitor of Ca2+/calmodulin-dependent protein kinase II
(CaMKII) (Tokumitsu, H., Chijiwa, T., Hagiwara, M., Mizutani, A., Terasawa, M.
and Hidaka, H. (1990) J. Biol. Chem. 265, 4315-4320). We have now investigated
the inhibitory property of a newly synthesized methoxybenzenesulfonamide, KN-93,
on CaMKII activity in situ and in vitro. KN-93 elicited potent inhibitory
effects on CaMKII phosphorylating activity with an inhibition constant of 0.37
microM but this compound had no significant effects on the catalytic activity of
cAMP-dependent protein kinase, Ca2+/phospholipid dependent protein kinase,
myosin light chain kinase and Ca(2+)-phosphodiesterase. KN-93 also inhibited the
autophosphorylation of both the alpha- and beta-subunits of CaMKII. Kinetic
analysis indicated that KN-93 inhibits CaMKII, in a competitive fashion against
calmodulin. To evaluate the regulatory role of CaMKII on catecholamine
metabolism, we examined the effect of KN-93 on dopamine (DA) levels in PC12h
cells. The DA levels decreased in the presence of KN-93. Further, the tyrosine
hydroxylase (TH) phosphorylation induced by KCl or acetylcholine was
significantly suppressed by KN-93 in PC12h cells while events induced by
forskolin or 8-Br-cAMP were not affected. These results suggest that KN-93
inhibits DA formation by modulating the reaction rate of TH to reduce the
Ca(2+)-mediated phosphorylation levels of the TH molecule.
DOI: 10.1016/0006-291x(91)92031-e
PMID: 1662507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22513374 | 1. Development. 2012 Jun;139(11):1921-30. doi: 10.1242/dev.078543. Epub 2012 Apr
18.
The regenerative capacity of the zebrafish heart is dependent on TGFβ signaling.
Chablais F(1), Jazwinska A.
Author information:
(1)Unit of Anatomy, Department of Medicine, University of Fribourg, Rte A.
Gockel 1, 1700 Fribourg, Switzerland.
Mammals respond to a myocardial infarction by irreversible scar formation. By
contrast, zebrafish are able to resolve the scar and to regenerate functional
cardiac muscle. It is not known how opposing cellular responses of fibrosis and
new myocardium formation are spatially and temporally coordinated during heart
regeneration in zebrafish. Here, we report that the balance between the
reparative and regenerative processes is achieved through Smad3-dependent TGFβ
signaling. The type I receptor alk5b (tgfbr1b) is expressed in both fibrotic and
cardiac cells of the injured heart. TGFβ ligands are locally induced following
cryoinjury and activate the signaling pathway both in the infarct area and in
cardiomyocytes in the vicinity of the trauma zone. Inhibition of the relevant
type I receptors with the specific chemical inhibitor SB431542 qualitatively
altered the infarct tissue and completely abolished heart regeneration. We show
that transient scar formation is an essential step to maintain robustness of the
damaged ventricular wall prior to cardiomyocyte replacement. Taking advantage of
the reversible action of the inhibitor, we dissected the multifunctional role of
TGFβ signaling into three crucial processes: collagen-rich scar deposition,
Tenascin C-associated tissue remodeling at the infarct-myocardium interface, and
cardiomyocyte proliferation. Thus, TGFβ signaling orchestrates the beneficial
interplay between scar-based repair and cardiomyocyte-based regeneration to
achieve complete heart regeneration.
DOI: 10.1242/dev.078543
PMID: 22513374 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14993139 | 1. Circulation. 2004 Mar 16;109(10):1250-8. doi:
10.1161/01.CIR.0000118493.13323.81. Epub 2004 Mar 1.
Cardiovascular magnetic resonance assessment of human myocarditis: a comparison
to histology and molecular pathology.
Mahrholdt H(1), Goedecke C, Wagner A, Meinhardt G, Athanasiadis A, Vogelsberg H,
Fritz P, Klingel K, Kandolf R, Sechtem U.
Author information:
(1)Division of Cardiology, Robert Bosch Medical Center, Stuttgart, Germany.
[email protected]
BACKGROUND: Myocarditis can occasionally lead to sudden death and may progress
to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is
difficult to recognize clinically and the diagnostic tools available are
unsatisfactory, new strategies to diagnose myocarditis are needed.
METHODS AND RESULTS: Cardiovascular MR imaging (CMR) was performed in 32
patients who were diagnosed with myocarditis by clinical criteria. To determine
whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was
taken from the region of contrast enhancement and submitted to histopathologic
analysis. Follow-up was performed 3 month later. Contrast enhancement was
present in 28 patients (88%) and was usually seen with one or several foci in
the myocardium. Foci were most frequently located in the lateral free wall. In
the 21 patients in whom biopsy was obtained from the region of contrast
enhancement, histopathologic analysis revealed active myocarditis in 19 patients
(parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in
the remaining 11 patients, in whom biopsy could not be taken from the region of
contrast enhancement, active myocarditis was found in one case only (HHV6). At
follow-up, the area of contrast enhancement decreased from 9+/-11% to 3+/-4% of
left ventricular mass as the left ventricular ejection fraction improved from
47+/-19% to 60+/-10%.
CONCLUSIONS: Contrast enhancement is a frequent finding in the clinical setting
of suspected myocarditis and is associated with active inflammation defined by
histopathology. Myocarditis occurs predominantly in the lateral free wall.
Contrast CMR is a valuable tool for the evaluation and monitoring of
inflammatory heart disease.
DOI: 10.1161/01.CIR.0000118493.13323.81
PMID: 14993139 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23293297 | 1. Development. 2013 Feb 1;140(3):660-6. doi: 10.1242/dev.088526.
In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers
of heart regeneration.
Choi WY(1), Gemberling M, Wang J, Holdway JE, Shen MC, Karlstrom RO, Poss KD.
Author information:
(1)Department of Cell Biology and Howard Hughes Medical Institute, Duke
University Medical Center, Durham, NC 27710, USA.
Adult mammalian cardiomyocytes have little capacity to proliferate in response
to injury, a deficiency that underlies the poor regenerative ability of human
hearts after myocardial infarction. By contrast, zebrafish regenerate heart
muscle after trauma by inducing proliferation of spared cardiomyocytes,
providing a model for identifying manipulations that block or enhance these
events. Although direct genetic or chemical screens of heart regeneration in
adult zebrafish present several challenges, zebrafish embryos are ideal for
high-throughput screening. Here, to visualize cardiomyocyte proliferation events
in live zebrafish embryos, we generated transgenic zebrafish lines that employ
fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. We
then performed a chemical screen and identified several small molecules that
increase or reduce cardiomyocyte proliferation during heart development. These
compounds act via Hedgehog, Insulin-like growth factor or Transforming growth
factor β signaling pathways. Direct examination of heart regeneration after
mechanical or genetic ablation injuries indicated that these pathways are
activated in regenerating cardiomyocytes and that they can be pharmacologically
manipulated to inhibit or enhance cardiomyocyte proliferation during adult heart
regeneration. Our findings describe a new screening system that identifies
molecules and pathways with the potential to modify heart regeneration.
DOI: 10.1242/dev.088526
PMCID: PMC3561784
PMID: 23293297 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25451273 | 1. Biochem Biophys Res Commun. 2014 Dec 5;455(1-2):98-106. doi:
10.1016/j.bbrc.2014.10.105.
Surveying genetic variants and molecular phylogeny of cerebral cavernous
malformation gene, CCM3/PDCD10.
Kumar A, Bhandari A, Goswami C.
The three cerebral cavernous malformations (CCMs) genes namely CCM1/KRIT1,
CCM2/MGC4607 and CCM3/PDCD10 have been identified for which mutations cause
cerebral cavernous malformations. However, the protein products of these genes
involved in forming CCM signaling, are still poorly understood imposing an
urgent need to understand these genes and their signaling processes in details.
So far involvement of CCM3/PDCD10 in the cavernous angioma has been
characterized from biochemical and biophysical analyses. However, there is no
comprehensive study illustrating the phylogenetic history and comprehensive
genetic variants of CCM3/PDCD10. Herein, we explored the phylogenetic history
and genetic variants of CCM3/PDCD10 gene. Synteny analyses revealed that
CCM3/PDCD10 gene shared same genomic loci from Drosophila to human and the gene
structure of CCM3/PDCD10 is conserved from human to Branchiostoma floridae for
about 500 MYs with some changes in sea urchin and in insects. The conserved
CCM3/PDCD10 is characterized by presence of indels in the N-terminal
dimerization domain. We identified 951 CCM3/PDCD10 variants by analysis of 1092
human genomes with top three variation classes belongs to 84% SNPs, 6.9%
insertions and 6.2% deletions. We identified 22 missense mutations in the human
CCM3/PDCD10 protein and out of which three mutations are deleterious. We also
identified four stop-codon gaining mutations at the positions E34*, E68*, E97*
and E140*, respectively. This study is the first comprehensive analysis of the
CCM3/PDCD10 gene based on phylogenetic origin and genetic variants. This study
corroborates that the evolution of CCM proteins with tubular organization
evolvements by endothelial cells.
DOI: 10.1016/j.bbrc.2014.10.105
PMID: 25451273 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22993035 | 1. J Clin Endocrinol Metab. 2012 Dec;97(12):4515-23. doi: 10.1210/jc.2012-2556.
Epub 2012 Sep 19.
Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency.
Verge CF(1), Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T,
Hameed S, Hamilton J, Weiss RE, Refetoff S.
Author information:
(1)Department of Endocrinology, Sydney Children's Hospital, Randwick, NSW 2031,
Australia.
Comment in
J Clin Endocrinol Metab. 2012 Dec;97(12):4362-5. doi: 10.1210/jc.2012-3759.
CONTEXT: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell
membrane transporter. MCT8 deficiency causes severe psychomotor retardation and
abnormal thyroid tests. The great majority of affected children cannot walk or
talk, and all have elevated serum T(3) levels, causing peripheral tissue
hypermetabolism and inability to maintain weight. Treatment with thyroid hormone
is ineffective. In Mct8-deficient mice, the thyroid hormone analog,
diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and
could be an effective alternative to thyroid hormone treatment in humans.
OBJECTIVE: The objective of the study was to evaluate the effect and efficacy of
DITPA in children with MCT8 deficiency.
METHODS: This was a multicenter report of four affected children given DITPA on
compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25
months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d
(2.1-2.4 mg/kg · d), given in three divided doses.
RESULTS: DITPA normalized the elevated serum T(3) and TSH when the dose reached
1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The
following significant changes were also observed: decline in SHBG (in all
subjects), heart rate (in three of four), and ferritin (in one of four).
Cholesterol increased in two subjects. There was no weight loss and weight gain
occurred in two. None of the treated children required a gastric feeding tube or
developed seizures. No adverse effects were observed.
CONCLUSION: DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and
reduces the hypermetabolism and the tendency for weight loss. The effects of
earlier commencement and long-term therapy remain to be determined.
DOI: 10.1210/jc.2012-2556
PMCID: PMC3513545
PMID: 22993035 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24481819 | 1. J Cell Sci. 2014 Feb 15;127(Pt 4):701-7. doi: 10.1242/jcs.138388. Epub 2014
Jan 30.
Cerebral cavernous malformation proteins at a glance.
Draheim KM(1), Fisher OS, Boggon TJ, Calderwood DA.
Author information:
(1)Department of Pharmacology, Yale University School of Medicine, New Haven, CT
06520-8066, USA.
Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2
(also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause
cerebral cavernous malformations (CCMs). These abnormalities are characterized
by dilated leaky blood vessels, especially in the neurovasculature, that result
in increased risk of stroke, focal neurological defects and seizures. The three
CCM proteins can exist in a trimeric complex, and each of these essential
multi-domain adaptor proteins also interacts with a range of signaling,
cytoskeletal and adaptor proteins, presumably accounting for their roles in a
range of basic cellular processes including cell adhesion, migration, polarity
and apoptosis. In this Cell Science at a Glance article and the accompanying
poster, we provide an overview of current models of CCM protein function
focusing on how known protein-protein interactions might contribute to cellular
phenotypes and highlighting gaps in our current understanding.
DOI: 10.1242/jcs.138388
PMCID: PMC3924200
PMID: 24481819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20592472 | 1. J Clin Invest. 2010 Aug;120(8):2795-804. doi: 10.1172/JCI39679. Epub 2010 Jul
1.
CCM3 signaling through sterile 20-like kinases plays an essential role during
zebrafish cardiovascular development and cerebral cavernous malformations.
Zheng X(1), Xu C, Di Lorenzo A, Kleaveland B, Zou Z, Seiler C, Chen M, Cheng L,
Xiao J, He J, Pack MA, Sessa WC, Kahn ML.
Author information:
(1)Department of Medicine and Cardiovascular Institute, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cerebral cavernous malformation is a common human vascular disease that arises
due to loss-of-function mutations in genes encoding three intracellular adaptor
proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3.
CCM1, CCM2, and CCM3 interact biochemically in a pathway required in endothelial
cells during cardiovascular development in mice and zebrafish. The downstream
effectors by which this signaling pathway regulates endothelial function have
not yet been identified. Here we have shown in zebrafish that expression of
mutant ccm3 proteins (ccm3Delta) known to cause cerebral cavernous malformation
in humans confers cardiovascular phenotypes identical to those associated with
loss of ccm1 and ccm2. CCM3Delta proteins interacted with CCM1 and CCM2, but not
with other proteins known to bind wild-type CCM3, serine/threonine protein
kinase MST4 (MST4), sterile 20-like serine/threonine kinase 24 (STK24), and
STK25, all of which have poorly defined biological functions. Cardiovascular
phenotypes characteristic of CCM deficiency arose due to stk deficiency and
combined low-level deficiency of stks and ccm3 in zebrafish embryos. In cultured
human endothelial cells, CCM3 and STK25 regulated barrier function in a manner
similar to CCM2, and STKs negatively regulated Rho by directly activating
moesin. These studies identify STKs as essential downstream effectors of CCM
signaling in development and disease that may regulate both endothelial and
epithelial cell junctions.
DOI: 10.1172/JCI39679
PMCID: PMC2912181
PMID: 20592472 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18030062 | 1. J Cardiovasc Pharmacol. 2007 Nov;50(5):526-34. doi:
10.1097/FJC.0b013e318142bdf2.
Regulation of gene expression in rats with heart failure treated with the
thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) and the combination
of DITPA and captopril.
Maitra N(1), Adamson C, Greer K, Klewer S, Hoying J, Bahl JJ, Goldman S, Morkin
E.
Author information:
(1)Department of Sarver Heart Center, University of Arizona, Tucson, AZ, USA.
We have used an oligonucleotide microarray to identify genes that are affected
by congestive heart failure and those influenced by treatment with DITPA and
DITPA in combination with captopril using a rat postinfarction model. The most
striking result when comparing heart failure to sham operation was that all of
the mitochondrial and metabolic enzymes affected were down regulated. When
comparing heart failure with DITPA treatment, most of the down regulated
metabolic genes were returned toward normal. When comparing heart failure with
heart failure animals treated with DITPA and captopril, metabolic enzymes were
no longer significantly downregulated. DITPA treatment and the combination of
DITPA and captopril show that the metabolic enzymes were no longer down
regulated. This represents a substantial improvement in the energy- generating
capacity of the heart. These results indicate that the actions of DITPA and the
combination of DITPA and captopril in heart failure can be partially explained
by differences in gene activation.
DOI: 10.1097/FJC.0b013e318142bdf2
PMID: 18030062 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10710355 | 1. Am J Physiol Heart Circ Physiol. 2000 Mar;278(3):H862-70. doi:
10.1152/ajpheart.2000.278.3.H862.
DITPA prevents the blunted contraction-frequency relationship in myocytes from
infarcted hearts.
Litwin SE(1), Zhang D, Roberge P, Pennock GD.
Author information:
(1)Cardiovascular Division, Veterans Affairs Medical Center, and University of
Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
[email protected]
Loss of the positive force-frequency relationship is a characteristic finding in
failing hearts. The mechanisms of this change are not well understood.
Myocardial infarction (MI) was induced in rabbits to produce left ventricular
(LV) dysfunction. Beginning 1 day after MI, a subgroup of rabbits received
diiodothyropropionic acid (DITPA) (3.75 mg x kg(-1) x day(-1) sc) for 3 wk. We
measured contractions, Ca(2+) transients, action potentials, and sarcoplasmic
reticulum (SR) Ca(2+) content at different stimulation rates in single LV
myocytes. The shortening-frequency relationship was markedly flattened in MI
myocytes compared with control myocytes. In addition, Ca(2+) transients, action
potentials, and contractions were prolonged. Myocytes from DITPA-treated MI
rabbits had preserved inotropic responses to increased stimulation rate and
normal duration of action potentials and Ca(2+) transients. SR Ca(2+) content
increased significantly when stimulation rate was increased from 0.5 to 2.0 Hz
in control myocytes but did not change significantly in MI myocytes. Myocytes
from DITPA-treated MI rabbits had a greater frequency-dependent increase in SR
Ca(2+) content compared with the untreated MI rabbits. Thus single myocytes from
infarcted rabbit hearts have frequency-dependent abnormalities of contractility,
Ca(2+) cycling, and action potential repolarization. The flattened
contraction-frequency relationship can be partially explained by an attenuation
of the normal enhancement of SR Ca(2+) content that occurs when stimulation rate
is increased. Chronic DITPA administration after MI largely prevents the
development of these abnormalities.
DOI: 10.1152/ajpheart.2000.278.3.H862
PMID: 10710355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10749704 | 1. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1105-16. doi:
10.1152/ajpheart.2000.278.4.H1105.
The thyroid hormone analog DITPA restores I(to) in rats after myocardial
infarction.
Wickenden AD(1), Kaprielian R, You XM, Backx PH.
Author information:
(1)Departments of Physiology and Medicine and The Center for Cardiovascular
Research, University Health Network, University of Toronto, Toronto, Ontario,
Canada M5G 2C4.
Previous studies have established that reductions in repolarizing currents occur
in heart disease and can contribute to life-threatening arrhythmias in
myocardium. In this study, we investigated whether the thyroid hormone analog 3,
5-diiodothyropropionic acid (DITPA) could restore repolarizing transient outward
K(+) current (I(to)) density and gene expression in rat myocardium after
myocardial infarction (MI). Our findings show that I(to) density was reduced
after MI (14.0 +/- 1.0 vs. 10.2 +/- 0.9 pA/pF, sham vs. post-MI at +40 mV). mRNA
levels of Kv4.2 and Kv4.3 genes were decreased but Kv1.4 mRNA levels were
increased post-MI. Corresponding changes in Kv4.2 and Kv1.4 protein were also
observed. Chronic treatment of post-MI rats with 10 mg/kg DITPA restored I(to)
density (to 15.2 +/- 1.1 pA/pF at +40 mV) as well as Kv4.2 and Kv1.4 expression
to levels observed in sham-operated controls. Other membrane currents (Na(+),
L-type Ca(2+), sustained, and inward rectifier K(+) currents) were unaffected by
DITPA treatment. Associated with the changes in I(to) expression, action
potential durations (current-clamp recordings in isolated single right
ventricular myocytes and monophasic action potential recordings from the right
free wall in situ) were prolonged after MI and restored with DITPA treatment.
Our results demonstrate that DITPA restores I(to) density in the setting of MI,
which may be useful in preventing complications associated with I(to)
downregulation.
DOI: 10.1152/ajpheart.2000.278.4.H1105
PMID: 10749704 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25086949 | 1. BMC Neurol. 2014 Aug 3;14:158. doi: 10.1186/s12883-014-0158-3.
A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous
malformations.
Lanfranconi S, Ronchi D, Ahmed N, Civelli V, Basilico P, Bresolin N, Comi GP,
Corti S(1).
Author information:
(1)Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico,
Milan, Italy. [email protected].
BACKGROUND: Cerebral cavernous malformations are relatively rare vascular
disorders that may affect any part of the central nervous system. This
presentation has been associated with heterozygous mutations in CCM1/KRIT1,
CCM2/malcavernin and CCM3/PDCD10. We aimed to investigate the genetic defect
underlying multiple cerebral and vertebral cavernous malformations in a
multigenerational Italian family.
CASE PRESENTATION: The proband is a 49-year-old man who underwent cerebral MRI
in his thirties for persistent haeadache and tingling in his left arm and leg
and was diagnosed with multiple supratentorial cavernous angiomas. A right
frontal angioma with radiological evidence of a recent bleeding was surgically
removed when he was 39 years old and he was thereafter asymptomatic. Magnetic
resonance imaging revealed multiple cerebral cavernous malformations in seven
members of his familily. Four subjects were asymptomatic. Other family mambers
displayed heterogeneous clinical features including seizures and recurrent brain
haemorrhages. Sequence analysis in the proband disclosed a novel heterozygous
nucleotide substitution (c.263-10A > G) in intron 5 of CCM1. This variant is
predicted to create an abnormal acceptor splice site and segregated in affected
relatives available for molecular screening. The analysis of CCM1 transcript in
proband's lymphocytes confirmed the partial retention of intron 3 resulting in a
premature termination codon.
CONCLUSIONS: Our findings demonstrate that c.263-10A > G mutation is associated
with cerebral cavernous malformations. A better knowledge of the
disease-associated phenotype may lead to an early diagnosis and to an
appropriate clinical surveillance in affected patients.
DOI: 10.1186/s12883-014-0158-3
PMCID: PMC4236643
PMID: 25086949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10474790 | 1. Coron Artery Dis. 1999 Sep;10(6):395-9. doi: 10.1097/00019501-199909000-00008.
Thyroid hormone and thyroid hormone analogues in the treatment of heart failure.
Spooner PH(1), Morkin E, Goldman S.
Author information:
(1)Department of Internal Medicine, Tucson Veterans Administration Medical
Center, AZ 85723, USA. [email protected]
The thyroid hormone analogue DITPA is a promising potential new treatment for
heart failure. Although the mechanism of action is incompletely determined, it
is clear that DITPA improves systolic as well as diastolic function. It is also
clear that the effects of DITPA are intrinsic to the muscle and not the result
of changes in the structure or geometry of the left ventricle. On the basis of
these experimental studies, we applied to the USA Food and Drug Administration
for an Investigational New Drug application to study the use of DITPA in
patients. These studies are currently in progress. While we await the outcome of
these clinical trials, it is important to emphasize that even if the end-point
is not a new drug to treat heart failure, our investigations are based on a
systematic evaluation integrating biochemistry and physiology. We believe that
this is the way to approach the problem of developmental pharmacology.
DOI: 10.1097/00019501-199909000-00008
PMID: 10474790 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9618233 | 1. J Mol Cell Cardiol. 1998 May;30(5):923-32. doi: 10.1006/jmcc.1998.0671.
A thyroid hormone analog stimulates angiogenesis in the post-infarcted rat
heart.
Tomanek RJ(1), Zimmerman MB, Suvarna PR, Morkin E, Pennock GD, Goldman S.
Author information:
(1)Department of Anatomy, University of Iowa, Iowa City 52242, USA.
In view of the evidence that thyroid hormone administration has angiogenic
effects on the hypertrophic myocardium, we tested the hypothesis that the
capillary supply in the hypertrophic myocardium surviving infarction would be
improved by administration of the thyroid hormone analog, diiodothyroproprionic
acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to
rats for 10 days following experimental infarction of the left ventricle (LV).
Morphometric methods were used to assess capillarity and myocyte cross-sectional
area in three regions of the left ventricle: (1) border (next to the scar of
infarction); (2) adjacent (next to the border); and (3) remote (interventricular
septum). Infarct size ranged from 20-85% of the LV free-wall, and both groups
had similar mean infarct size. Capillary length density (LV) was significantly
higher in the remote region of the treated group than in the MI-saline rats. LV
in the border region, which experienced the most marked increase in cardiocyte
cross-sectional area, was not significantly lower than in the other regions,
indicating a more marked angiogenic response. In hearts with large infarcts (>
or = 40%) LV in the border region was higher in the DITPA group than in the
non-treated rats. In the MI-DITPA group, cardiocyte size in the border region
was positively correlated with that of the other regions, which contrasts with
the negative correlations noted for the MI-saline rats. These data suggest that
DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied
myocardium surviving a myocardial infarction, and (2) is selectively effective
in the border region of hearts with large infarcts.
DOI: 10.1006/jmcc.1998.0671
PMID: 9618233 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19903697 | 1. Clin Appl Thromb Hemost. 2010 Jun;16(3):288-93. doi: 10.1177/1076029609348315.
Epub 2009 Nov 10.
Human platelet aggregation and degranulation is induced in vitro by L-thyroxine,
but not by 3,5,3'-triiodo-L-thyronine or diiodothyropropionic acid (DITPA).
Mousa SS(1), Davis FB, Davis PJ, Mousa SA.
Author information:
(1)Pharmaceutical Research Institute, Albany College of Pharmacy and Health
Sciences, Rensselaer, New York 12144, USA. [email protected]
The endogenous thyroid hormones L-thyroxine (T(4)) and
3,5,3'-triiodo-L-thyronine (T(3)) induce angiogenesis via an endothelial cell
iodothyronine receptor on integrin alphaVbeta3. This receptor also exists on
platelets. Diiodothyropropionic acid (DITPA) and GC-1, a noniodinated thyroid
hormone analog, also induce angiogenesis. Here we examined the effects of
iodothyronines (L-T(4) vs L-T(3)) and analogs DITPA and GC-1 on human platelet
function. Subthreshold aggregation of platelets obtained from healthy human
donors was induced with collagen. Platelet activation (proaggregation) and
adenosine triphosphate (ATP) secretion (degranulation) induced by L-T( 4),
L-T(4)-agarose, L-T(3), DITPA, or GC-1 were determined simultaneously. Platelet
aggregation and ATP secretion induced by a subthreshold level of collagen were
enhanced 3-fold by either L-T(4) or L-T( 4)-agarose (0.01 micromol/L) as
compared to control, whereas, L-T( 3), DITPA, or GC-1 had no effect under the
same conditions. The platelet proaggregatory and degranulation effects of L-T(4)
were blocked by the alphavbeta3 antagonist XT199 (0.1 micromol/ L) and by
tetraiodothyroacetic acid (tetrac; 0.1 micromol/L). Tetrac inhibits binding of
thyroid hormone analogs to the receptor on alphavbeta3 and lacks thyromimetic
activity at this site; thus, the proaggregatory action of L-T(4) likely involves
the cell surface receptor on integrin alphavbeta3. The thyroid hormone receptor
(TR) on human platelets but not endothelial cells distinguishes among
iodothyronines, reflecting quantitative differences in integrin sites on
endothelial cells and platelets or qualitative differences in the
phospholipids/protein microenvironment of endothelial and platelet membranes
that can affect integrin function. Additional studies in different populations
with larger sample sizes are warranted to determine the impact of the current
findings on clinical interventions.
DOI: 10.1177/1076029609348315
PMID: 19903697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12414442 | 1. Am J Physiol Heart Circ Physiol. 2003 Feb;284(2):H613-8. doi:
10.1152/ajpheart.00449.2002. Epub 2002 Oct 31.
DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary
arteriolar growth.
Wang X(1), Zheng W, Christensen LP, Tomanek RJ.
Author information:
(1)Department of Anatomy and Cell Biology and The Cardiovascular Center,
University of Iowa, Iowa City 52242, USA.
Previous studies from our laboratory and those of others have shown thyroxine to
be a stimulator of coronary microvascular growth. The present study tested the
hypothesis that 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog
with inotropic but not chronotopic characteristics, is angiogenic in the
nonischemic heart. Daily injections (3.75 mg/kg sc) of DITPA to Sprague-Dawley
rats affected protein increases in vascular endothelial growth factor
(VEGF)(164), VEGF(188,) basic fibroblast growth factor (bFGF) (FGF-2),
angiopoietin-1, and Tie-2 during the first few days of treatment. After 3 wk of
treatment, arteriolar length density and the relative number of terminal
arterioles (<10 microm diameter) increased in the left ventricle as determined
by image analysis of perfuse-fixed hearts. These findings occurred in hearts
that did not undergo changes in mass nor in increases in capillary length
density. We conclude that DITPA, which is known to improve ventricular function
after infarction, is angiogenic in normal nonischemic hearts.
DOI: 10.1152/ajpheart.00449.2002
PMID: 12414442 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17612639 | 1. Can J Physiol Pharmacol. 2007 Mar-Apr;85(3-4):311-8. doi: 10.1139/y07-011.
Thyroid hormone analog, diiodothyropropionic acid (DITPA), exerts beneficial
effects on chamber and cellular remodeling in cardiomyopathic hamsters.
Kuzman JA(1), Tang Y, Vogelsang KA, Said S, Anderson BE, Morkin E, Gerdes AM.
Author information:
(1)Cardiovascular Research Institute, Sanford Research, University of South
Dakota, 1100 East 21st Street, Sioux Falls, SD 57105, USA.
Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that is currently
in phase II clinical trials. However, there have not been any studies to
comprehensively analyze its effect on myocyte morphology. In addition, long-term
studies with DITPA have not been done. This study compares the effects of DITPA
with L-thyroxine (T4) on chamber remodeling, cardiac function, cellular
morphology, cardiac blood flow, and protein expression. Normal and
cardiomyopathic hamsters were treated with T4 or DITPA for 2 months. At the end
of the treatment, echos, hemodynamics, coronary blood flow, cell morphology, and
protein expression data were collected. Both T4 and DITPA treatment reduced
chamber diameter during diastole, suggesting attenuated chamber dilatation in
cardiomyopathic hamsters. Wall thickness also tended to increase, which was
supported by cell morphology data in which DITPA significantly increased
cross-sectional growth of myocytes specifically in the minor dimension, which is
oriented transmurally. T4 and DITPA also increased myocardial blood flow both at
baseline and after maximal dilation. This suggests there was increased
angiogenesis or reduced loss of arterioles. Both T4 and DITPA had beneficial
effects on chamber remodeling, which was most likely due to beneficial changes
in cell shape and improved vascular supply.
DOI: 10.1139/y07-011
PMID: 17612639 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1403782 | 1. J Pharmacol Exp Ther. 1992 Oct;263(1):163-9.
Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with
inotropic selectivity.
Pennock GD(1), Raya TE, Bahl JJ, Goldman S, Morkin E.
Author information:
(1)Department of Cardiology, Tucson Veterans Administration Medical Center,
Arizona.
Thyroid hormone exerts a strong positive inotropic action on the heart and
induces alpha-myosin heavy chain (MHC) gene expression. 3,5-Diiodothyropropionic
acid (DITPA), a carboxylic acid analog with low metabolic activity, was observed
to induce alpha-MHC mRNA in heart cell culture with EC50 approximately 5 x
10(-7) M. To determine if the compound has positive inotropic actions, the
effects of DITPA and L-thyroxine on heart rate, left ventricular pressures, left
ventricular dP/dt, myosin isoenzymes and hepatic alpha-glycerolphosphate
dehydrogenase activity were compared in hypothyroid rats. Binding affinities of
DITPA and triiodothyronine for bacterially expressed alpha-1 and beta-1 thyroid
hormone receptors (TRs) also were determined. Over the dosage range of 150 to
1500 micrograms/100 g, DITPA produced increases in left ventricular dP/dt
comparable to those obtained with L-thyroxine at dosages of 1.5 to 15
micrograms/100 g, but with significantly less tachycardia. The increase in
alpha-MHC mRNA was about the same with both compounds whereas alpha-MHC protein
content and GPDH activity increased less with DITPA. These differences could not
be explained by preferential binding of DITPA to TR subtypes. Because heart rate
is a major determinant of myocardial oxygen consumption, DITPA is able to
achieve increased cardiac performance at lower myocardial oxygen costs.
PMID: 1403782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11453427 | 1. J Neurosurg. 2001 Jul;95(1 Suppl):25-32. doi: 10.3171/spi.2001.95.1.0025.
Tarlov cysts: a study of 10 cases with review of the literature.
Voyadzis JM(1), Bhargava P, Henderson FC.
Author information:
(1)Department of Neurosurgery and Pathology, Georgetown University Medical
Center, Washington, DC, USA.
Comment in
J Neurosurg. 2002 Sep;97(2 Suppl):271; author reply 271-2. doi:
10.3171/spi.2002.97.2.0271.
OBJECT: Tarlov or perineurial cysts are lesions of the nerve root most often
found in the sacral region. Although there is agreement that asymptomatic Tarlov
cysts should be followed, it is still debated whether patients with symptomatic
Tarlov cysts should be treated surgically. The authors assessed the outcome and
efficacy of cyst wall resection in 10 patients with symptomatic Tarlov cysts.
The medical literature is reviewed, theories of origin are evaluated, and
suggestions as to their cause and pathogenesis are offered.
METHODS: Ten consecutive patients harboring symptomatic Tarlov cysts were
treated by the senior author between 1989 and 1999. All patients were assessed
for neurological deficits and pain by neurological examination and visual analog
scale, respectively. Computerized tomography myelography was performed in all
patients to diagnose delayed filling of the cysts. A sacral laminectomy with
resection of the sacral cyst or cysts was performed in all patients. Resected
material from eight of 10 patients was submitted for histopathological
evaluation. Seven (70%) of 10 patients obtained complete or substantial
resolution of their symptoms, with an average follow up of 31.7 months. All of
these patients had Tarlov cysts larger than 1.5 cm in diameter, producing
radicular pain or bladder and bowel dysfunction. Three (30%) of 10 patients
experienced no significant improvement. All three patients harbored Tarlov cysts
smaller than 1.5 cm in diameter, producing nonradicular pain. Histopathological
examination was performed on specimens from eight of 10 patients, which
demonstrated nerve fibers in 75% of cases, ganglion cells in 25% of cases, and
evidence of old hemorrhage in half.
CONCLUSIONS: Large cysts (> 1.5 cm) and the presence of associated radicular
symptoms strongly correlate with excellent outcome. Tarlov cysts may result from
increased hydrostatic pressure and trauma.
DOI: 10.3171/spi.2001.95.1.0025
PMID: 11453427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19110185 | 1. J Minim Invasive Gynecol. 2009 Jan-Feb;16(1):78-80. doi:
10.1016/j.jmig.2008.09.580.
Beware the Tarlov cyst.
Hirst JE(1), Torode H, Sears W, Cousins MJ.
Author information:
(1)North Shore Private Hospital, St Leonards, Australia. [email protected]
Tarlov cysts are sacral perineural cysts. This case report describes the
clinical course after biopsy of a very large Tarlov cyst via laparoscopy, which
was thought preoperatively to be an adnexal mass. It serves as a warning against
attempting biopsy or resection of these lesions.
DOI: 10.1016/j.jmig.2008.09.580
PMID: 19110185 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18353884 | 1. Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1504-9. doi:
10.1152/ajpregu.00027.2008. Epub 2008 Mar 19.
Effects of thyroidectomy, T4, and DITPA replacement on brain blood vessel
density in adult rats.
Schlenker EH(1), Hora M, Liu Y, Redetzke RA, Morkin E, Gerdes AM.
Author information:
(1)Basic Biomedical Sciences, Sanford School of Medicine of the University of
South Dakota, Vermillion, SD 57069, USA. [email protected]
In hypothyroid patients, altered microvascular structure and function may affect
mood and cognitive function. We hypothesized that adult male hypothyroid rats
will have significantly lower forebrain blood vessel densities (BVD) than
euthyroid rats and that treatment with 3,5-diiothyroprionic acid (DITPA) (a
thyroid hormone analog) or thyroxine (T(4)) will normalize BVDs. The euthyroid
group received no thyroidectomy or treatment. The other three groups received
thyroidectomies and pellets. The hypothyroid group received a placebo pellet,
the DITPA group received an 80-mg DITPA-containing pellet, and the T(4) group
received a 5.2-mg T(4) slow-release pellet for 6 wk. Body weights, cardiac
function, and body temperatures were measured. A monoclonal antiplatelet
endothelial cell adhesion antibody was used to visualize blood vessels. The
euthyroid group averaged body weights of 548 +/- 54 g, while the hypothyroid
group averaged a body weight of 332 +/- 19 g (P value < 0.001). Relative to the
euthyroid group, the DITPA-treated group was significantly lighter (P value <
0.05), while the T(4)-treated group was comparable in body weight to the
euthyroid group. The same trends were seen with body temperature and cardiac
function with the largest difference between the euthyroid and hypothyroid
groups. BVD in the euthyroid group was 147 +/- 12 blood vessels/mm(2) and in
hypothyroid group 69 +/- 5 blood vessels/mm(2) (P = 0.013) but similar among the
euthyroid, DITPA, and T(4) groups. These results show that hypothyroidism
decreased BVD in adult rat forebrain regions. Moreover, DITPA and T(4) were
efficacious in preventing effects of hypothyroidism on cardiac function and BVD.
DOI: 10.1152/ajpregu.00027.2008
PMID: 18353884 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15454853 | 1. J Cardiovasc Pharmacol. 2004 Oct;44(4):453-9. doi:
10.1097/01.fjc.0000140206.81804.33.
Thyroid hormone analog, DITPA, improves endothelial nitric oxide and
beta-adrenergic mediated vasorelaxation after myocardial infarction.
Spooner PH(1), Thai HM, Goldman S, Gaballa MA.
Author information:
(1)Cardiology Section, Southern Arizona VA Healthcare System, Tucson, AZ, USA.
This study was designed to determine if the thyroid hormone analog 3,5
diiodothyropropionic acid (DITPA), now in clinical trials for heart failure,
alters endothelial function after myocardial infarction (MI). Three weeks after
MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g
subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV)
end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change
MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3
versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus
3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the
acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and
isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The
increases in vasorelaxation were blocked with l-NAME and restored with
L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in
aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity
units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In
endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P <
0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg
protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein.
The thyroid analog DITPA enhances endothelial nitric oxide and
beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the
vasculature.
DOI: 10.1097/01.fjc.0000140206.81804.33
PMID: 15454853 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9069582 | 1. Proc Assoc Am Physicians. 1997 Mar;109(2):136-45.
The effects of a thyroid hormone analog on left ventricular performance and
contractile and calcium cycling proteins in the baboon.
Hoit BD(1), Pawloski-Dahm CM, Shao Y, Gabel M, Walsh RA.
Author information:
(1)Division of Cardiology, University of Cincinnati Medical Center, OH, USA.
To determine the biochemical and related functional effects of the thyroid
analog diiodothyroproprionic acid (DITPA) on primate myocardium, we examined,
both before and after 23 days of DITPA (3.75 mg/kg): myosin heavy-chain (MHC)
isoforms and sarcoplasmic reticulum (SR) calcium cycling proteins; left
ventricular (LV) function; and the LV force-frequency relation in four baboons
chronically instrumented with sonomicrometers and micromanometers. The
force-frequency relation was measured as the response of isovolumic contraction
(dP/dtmax) to incremental pacing and the critical heart rate (HRcrit) as the
rate at which dP/dtmax reached its maximum. DITPA increased basal LV dPt/dtmax
(3,300 +/- 378 versus 2,943 +/- 413 mm Hg/sec; p = .09), and velocity of
circumferential shortening (1.13 +/- 0.30 versus 0.76 +/- 0.30 circ/sec; p <
.01), decreased the basal time constant of isovolumic relaxation (24.2 +/- 1.6
versus 29.9 +/- 2.5 msec; p < .05), and increased the HRcrit (203 +/- 19 versus
168 +/- 20 bpm; p < .05), without effecting significant changes in either basal
heart rate (119 +/- 14 versus 111 +/- 17 bpm) or systolic blood pressure (137
+/- 14 versus 126 +/- 8 mm Hg). Quantitative immunoblotting revealed significant
decreases in both phospholamban and the ratio of phospholamban to SR Ca2+
adenosine triphosphatase in DITPA-treated animals when compared to four
untreated controls. By contrast, alpha-MHC isoform was undetectable in both
DITPA treated and control baboons. Thus, DITPA favorably alters the
stoichiometry between the SR calcium pump and its inhibitor, phospholamban, and
has positive inotropic and lusitropic effects in the normal primate left
ventricle, which may be useful in the treatment of heart failure. Unlike thyroid
hormone, these changes occur in the absence of detectable alpha-MHC isoform
protein expression and without an increase in heart rate.
PMID: 9069582 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15543491 | 1. Am J Hum Genet. 2005 Jan;76(1):42-51. doi: 10.1086/426952. Epub 2004 Nov 12.
Mutations within the programmed cell death 10 gene cause cerebral cavernous
malformations.
Bergametti F(1), Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P,
Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker
F, Tremoulet M, Tournier-Lasserve E; Société Française de Neurochirurgie.
Author information:
(1)INSERM E365, Faculté de Médecine Lariboisiere, Hôpital Lariboisière,
Assistance Publique-Hôpitaux de Paris, 10 avenue de Verdun, 75010 Paris, France.
Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations
characterized by abnormally enlarged capillary cavities without intervening
brain parenchyma. They cause seizures and cerebral hemorrhages, which can result
in focal neurological deficits. Three CCM loci have been mapped, and
loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607
(CCM2) genes. We report herein the identification of PDCD10 (programmed cell
death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27
within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We
hypothesized that genomic deletions might occur at the CCM3 locus, as reported
previously to occur at the CCM2 locus. Through high-density microsatellite
genotyping of 20 families, we identified, in one family, null alleles that
resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and
D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that
the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six
additional distinct deleterious mutations within PDCD10, one of the five known
genes mapped within this interval, were identified in seven families. Three of
these mutations were nonsense mutations, and two led to an aberrant splicing of
exon 9, with a frameshift and a longer open reading frame within exon 10. The
last of the six mutations led to an aberrant splicing of exon 5, without
frameshift. Three of these mutations occurred de novo. All of them cosegregated
with the disease in the families and were not observed in 200 control
chromosomes. PDCD10, also called "TFAR15," had been initially identified through
a screening for genes differentially expressed during the induction of apoptosis
in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and
invertebrates. Its implication in cerebral cavernous malformations strongly
suggests that it is a new player in vascular morphogenesis and/or remodeling.
DOI: 10.1086/426952
PMCID: PMC1196432
PMID: 15543491 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12145478 | 1. Cardiology. 2002;97(4):218-25. doi: 10.1159/000063110.
Pilot studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone
analog, in the treatment of congestive heart failure.
Morkin E(1), Pennock G, Spooner PH, Bahl JJ, Underhill Fox K, Goldman S.
Author information:
(1)Department of Cardiology, Southern Arizona Veterans Administration Health
Care System and Sarver Heart Center, University of Arizona, 1501 N. Campbell
Avenue, Tucson, AZ 85724, USA. [email protected]
After an initial safety study in 7 normal volunteers, a randomized double-blind
comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in
19 patients with moderately severe congestive failure. In heart failure patients
receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and
systemic vascular resistance index was decreased (p = 0.02). Systolic cardiac
function was unchanged but isovolumetric relaxation time was decreased
significantly, suggesting improvement in diastolic function. Total serum
cholesterol (p = 0.005) and triglycerides (p = 0.01) also were decreased
significantly. DITPA could represent a useful new agent for treatment of
congestive heart failure.
Copyright 2002 S. Karger AG, Basel
DOI: 10.1159/000063110
PMID: 12145478 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11040100 | 1. J Mol Cell Cardiol. 2000 Nov;32(11):1939-53. doi: 10.1006/jmcc.2000.1225.
Prevention of abnormal sarcoplasmic reticulum calcium transport and protein
expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid
(DITPA).
Pennock GD(1), Spooner PH, Summers CE, Litwin SE.
Author information:
(1)Department of Medicine, Southern Arizona Veterans Affairs Health Care System
and University of Arizona Sarver Heart Center, Tucson, Arizona, USA.
[email protected]
Heart failure of diverse causes is associated with abnormalities of sarcoplasmic
reticulum (SR) Ca(2+)transport. The purpose of this study was to determine
whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA),
prevents abnormal Ca(2+)transport and expression of SR proteins associated with
post-infarction heart failure. New Zealand White rabbits were randomly assigned
to circumflex artery ligation or sham operation, and to DITPA administration
(3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3
weeks, echo-Doppler and LV hemodynamic measurements were performed. From
ventricular tissue, single myocyte shortening and relaxation were determined,
and Ca(2+)transport was measured in homogenates and SR-enriched microsomes.
Levels of mRNA and protein content were determined for the SR Ca(2+)-ATPase
(SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and
calsequestrin. The administration of DITPA improved LV contraction and
relaxation and improved myocyte shortening in infarcted animals. The
improvements in LV and myocyte function were associated with increases in
V(max)for SR Ca(2+)transport in both homogenates and microsomes. Also, DITPA
prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2
post-infarction, without measurable changes in mRNA levels. The thyroid hormone
analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and
prevents the downregulation of SR proteins associated with post-infarction heart
failure. The specific effects of DITPA on post-infarction SR Ca(2+)transport and
the expression of SR proteins make this compound a potentially useful
therapeutic agent for LV systolic and/or diastolic dysfunction.
Copyright 2000 Academic Press.
DOI: 10.1006/jmcc.2000.1225
PMID: 11040100 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10758434 | 1. Rev Esp Med Nucl. 2000 Feb;19(1):25-8. doi: 10.1016/s0212-6982(00)71865-9.
[Scintigraphic pattern in a case of Tarlov cyst].
[Article in Spanish]
Infante JR(1), González FM, Vallejo JA, Torres-Avisbal M, Pacheco MC, Contreras
P, Arias MC, Latre JM.
Author information:
(1)Servicio de Medicina Nuclear, Hospital Universitario Reina Sofía, Córdoba,
14008, España.
We report the case of a 40-year-old man remitted to our department with a
history of lower back pain and sciatica with no history of trauma. The
laboratory analyses showed normal values whereas plain radiographs showed a
sacrum rarefaction area. A 99mTc-MDP bone scintigraphy was performed to evaluate
the lumbosacral area. Planar images did not show any abnormality. SPECT images
revealed photopenic abnormality in the second sacral vertebral right hemibody,
with no peripherally increased radiotracer accumulation. Subsequent MRI and CT
myelography demonstrated the nature of the photopenic area as secondary to
vertebral erosion by sacral perineurial cyst (Tarlov cyst).
DOI: 10.1016/s0212-6982(00)71865-9
PMID: 10758434 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8353891 | 1. Circulation. 1993 Sep;88(3):1289-98. doi: 10.1161/01.cir.88.3.1289.
Combination treatment with captopril and the thyroid hormone analogue
3,5-diiodothyropropionic acid. A new approach to improving left ventricular
performance in heart failure.
Pennock GD(1), Raya TE, Bahl JJ, Goldman S, Morkin E.
Author information:
(1)Department of Internal Medicine, Tucson Veterans Administration Medical
Center, AZ.
BACKGROUND: An agent that improves left ventricular (LV) performance by
non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart
failure. We have shown earlier that the thyroid hormone analogue
3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters
transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid
rats with substantially less effect on heart rate and metabolism than thyroid
hormone, which makes it a selective cardiotonic agent.
METHODS AND RESULTS: To determine whether DITPA might be useful in treating
heart failure, we compared chronic treatment with normal saline, captopril (2
g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L)
in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both
DITPA/captopril and captopril treatment decreased LV end-diastolic pressure
compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3
mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36%
increase in resting cardiac index (P < .05) and shifted the cardiac function
curve upward and to the left, indicative of enhanced myocardial performance.
Also, DITPA/captopril compared with captopril treatment or control produced an
increase in the rate of LV relaxation, as manifested by a decrease in tau, the
time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds,
P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/-
232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV
mass, LV systolic pressure, or peripheral resistance relative to captopril
treatment (P > .05).
CONCLUSIONS: The combination of DITPA and captopril improved cardiac output,
increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent
than captopril treatment in the rat postinfarction model of heart failure. Use
of a cardiotonic analogue of thyroid hormone represents a new approach to
improving LV performance and may be a useful adjunct to afterload reduction for
the treatment of heart failure.
DOI: 10.1161/01.cir.88.3.1289
PMID: 8353891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25216402 | 1. J Neurosurg Spine. 2014 Nov;21(5):833-6. doi: 10.3171/2014.8.SPINE148. Epub
2014 Sep 12.
Pelvic pain from a giant presacral Tarlov cyst successfully obliterated using
aneurysm clips in a patient with Marfan syndrome.
Wang B(1), Moon SJ, Olivero WC, Wang H.
Author information:
(1)Departments of 1 Internal Medicine and.
Patients with Marfan syndrome used to succumb early in life from cardiovascular
complications. With the current rapid advance in medical and surgical care, such
patients may now have near-normal longevities. Consequently, rare late-life
complications are emerging in these patients and represent challenges to
clinicians for their diagnoses and treatments. The authors report a rare case of
pelvic pain and genital prolapse from a giant presacral Tarlov cyst in a
67-year-old patient with Marfan syndrome. This 67-year-old Caucasian female
presented with progressively severe pelvic pain, intermittent explosive
diarrhea, and dysuria. Physical and bimanual examination demonstrated genital
prolapse and a nontender, cyst-like mass fixed in the midline. She underwent
ultrasound, CT, and eventually MRI evaluations that led to the diagnosis of a
giant (6.7 × 6.4 × 6.6 cm) Tarlov cyst originating from the right S-2 nerve root
sleeve/sacral foramen with intrapelvic extension. She underwent S1-S2 and S2-S3
laminectomy with obliteration of the Tarlov cyst using aneurysm clips.
Postoperatively, her pelvic pain and bowel symptoms resolved and the bladder
symptoms improved. The 3-month follow-up CT of abdomen/pelvis demonstrated
resolution of the cyst. The present case illustrates that clinicians caring for
elderly patients with Marfan syndrome need to increasingly recognize such
unusual late-life complications. Also, these large Tarlov cysts can be simply
and effectively obliterated with aneurysm clips.
DOI: 10.3171/2014.8.SPINE148
PMID: 25216402 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25701170 | 1. Lancet Oncol. 2015 Mar;16(3):338-48. doi: 10.1016/S1470-2045(15)70027-6. Epub
2015 Feb 18.
Orteronel plus prednisone in patients with chemotherapy-naive metastatic
castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre,
phase 3, randomised, placebo-controlled trial.
Saad F(1), Fizazi K(2), Jinga V(3), Efstathiou E(4), Fong PC(5), Hart LL(6),
Jones R(7), McDermott R(8), Wirth M(9), Suzuki K(10), MacLean DB(11), Wang
L(11), Akaza H(12), Nelson J(13), Scher HI(14), Dreicer R(15), Webb IJ(16), de
Wit R(17); ELM-PC 4 investigators.
Collaborators: Troon S, Underhill C, Dittrich C, Krainer M, Kramer G, Loidl W,
Pummer K, Belyakovskiy V, Polyakov S, Goeminne JC, Hoekx L, Luyten D, Van Poppel
H, Werbrouck P, Azambuja A, Barrios C, Brust L, Cabral Filho S, Carcano F, Cruz
F, Damião R, Delgado G, Diógenes Â, Dzik C, Faccio A, de Faria G, Faulhaber A,
Fernandes H, Ferreira U, Filho R, Franke F, Girotto G, Koff W, Kussumoto C,
Malzyner A, de Moraes A, Padílha S, de Pádua C, Pinto L, Portella M, Reiriz A,
da Silva Teixeira V, Vieiralves L, Dimitrov B, Dudov A, Micheva R, Petrov P,
Taskova V, Carmel M, Casey R, Chin J, Jacobson A, Jansz G, Kapoor A, Kinahan T,
Love W, Martin AG, Saad F, Trachtenberg J, Webster T, Acevedo Gaete A, Arén
Frontera O, Leyton Naranjo R, Miranda Benabarre A, Pastor Arroyo P, Neira Reyes
L, Ramirez Pinto G, Restrepo Molina J, Grgic M, Babjuk M, Domes L, Jansa J,
Lukes M, Pavlik I, Zachoval R, Kahu J, Tamm T, Marttila T, Tammela T, Vaarala M,
Vitanen J, Bompas E, Colombel M, Delva R, Deplanque G, Fizazi K, Flechon A,
Giroux J, Joly F, Lechevallier E, Mottet Auselo N, Priou F, Roubaud G, Roupret
M, Spaeth D, De La Taille A, Tourani JM, Feyerabend S, De Geeter P, Geiges G,
Gleißner J, Hammerer P, Klotz T, Kuczyk M, Marin J, Schrader A, Stenzl A,
Steuber T, Wirth M, Efstathiou E, Georgoulias V, Hatzimouratidis K, Kalofonos H,
Papandreou C, Thanos A, Leung KC, Ng C, Farkas L, Pintér J, McDermott R,
Sullivan F, Berger R, Gabizon A, Gez E, Rosenbaum E, Sella A, Semenisty V, Tavdy
E, Alabiso O, Ciuffreda L, Fratino L, Sternberg C, Tubaro A, Akakura K, Arai Y,
Egawa S, Fujimoto H, Ichikawa T, Kakehi Y, Kitamura H, Maniwa A, Miyanaga N,
Mizokami A, Nakatani T, Nishimura K, Niwakawa M, Sato F, Sugiyama T, Suzuki H,
Suzuki K, Takahashi S, Tomita Y, Ueda T, Uemura H, Yamaguchi R, Yokomizo A,
Yoshimura K, Brize A, Litavnience D, Vjaters E, Jankevicius F, Jievaltas M,
Jocys G, Ulys A, Calvo Domínguez D, González Perez J, de Leon Jaen S, Pérez O,
Rodriguez Rivera J, Valdés A, Blaisse R, Hamberg A, Loosveld O, Los M, Van Oort
I, de la Rosette J, De Vries P, Vrijhof H, de Wit R, Costello S, Davidson P,
Fong C, Gilling P, Neill M, Abrill Mendoza G, Cano Rivera J, Garcia Ahumada S,
Huaringa Leiva R, Pazos Franco A, Jablonska Z, Kmieciak R, Coelho J, Sousa N,
Bucuras C, Cebotaru C, Ciuleanu T, Jinga V, Anatolyevich I, Yurievich P, Hiang
T, Sing N, Balaz V, Brezovsky M, Kliment J, Mikulas J, Mincik I, Sokol R, Botha
M, Hart G, Kraus P, Landers G, Malan J, Bellmunt J, Castellano D, Climent Duran
M, Veiga F, González B, Pérez Gracia J, Valderrama B, Provencio M, Damber JE,
Häggman M, Nyman C, Berthold D, Fischer N, Popescu R, Stenner F, Chang YH, Ou
YC, Tsai YC, Wu HC, Wu TL, Bondarenko I, Ivashchenko P, Kobets V, Pasiechnikov
S, Semenukha V, Sernyak Y, Stus V, Bahl A, Birtle A, Chowdhury S, Crabb S, Dixit
S, Elliott P, Hoskin P, Jones R, Khoo V, MacDonald A, Malik Z, O'Sullivan J,
Simms M, Stockdale A, Agarwal N, Alter R, Anderson TC, Bailen J, Berry W, Bidair
M, Clark W, Cohn AL, Crawford E, DiSimone C, Feliciano L, Fleming MT, Forero L,
Friday B, Fruehauf JP, Gelmann E, George D, Gignac G, Given R, Gullo J,
Hainsworth J, Hajdenberg J, Haluschak JJ, Hamid O, Hammers H, Hart LL, Hussain
A, Hutson TE, Ibrahim E, Jain SK, Khojasteh A, Kohli M, Lara PN Jr, Lilly M,
Lipton A, Mackey DW, Mao SS, Mehta AR, Modiano MR, Morris M, Muscato JJ,
Nordquist LT, Richards DA, Ryan C, Sartor AO, Schnadig ID, Sieber PR, Singal R,
Smith F, Somer B, Srkalovic G, Tagawa S, Tan W, Twardowski P, Van Veldhuizen PJ,
Vogelzang N, Watkins DL, Wertheim M, Wong YN, Zhang J.
Author information:
(1)Centre Hospitalier de l'Université de Montréal/CRCHUM, Montréal, QC, Canada.
Electronic address: [email protected].
(2)Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
(3)Universitatea de Medicina si Farmacie, Bucharest, Romania.
(4)University of Athens Medical School, Athens, Greece.
(5)Auckland City Hospital, Auckland, New Zealand.
(6)Florida Cancer Specialists, Fort Myers, FL, USA.
(7)Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
(8)The Adelaide and Meath Hospital, Incorporating the National Children's
Hospital, Dublin, Ireland.
(9)University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
(10)Gunma University Graduate School of Medicine, Gunma, Japan.
(11)Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited, Cambridge, MA, USA.
(12)The University of Tokyo Research Center for Advanced Science and Technology,
Tokyo, Japan.
(13)University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
(14)Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
(15)Cleveland Clinic, Cleveland, OH, USA.
(16)Millennium Pharmaceuticals, Inc, Cambridge, MA, USA.
(17)Erasmus University Medical Center, Rotterdam, Netherlands.
Comment in
Lancet Oncol. 2015 Mar;16(3):247-9. doi: 10.1016/S1470-2045(15)70071-9.
BACKGROUND: Orteronel is an investigational, partially selective inhibitor of
CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic
target for metastatic castration-resistant prostate cancer. We assessed
orteronel in chemotherapy-naive patients with metastatic castration-resistant
prostate cancer.
METHODS: In this phase 3, double-blind, placebo-controlled trial, we recruited
patients with progressive metastatic castration-resistant prostate cancer and no
previous chemotherapy from 324 study centres (ie, hospitals or large urologic or
group outpatient offices) in 43 countries. Eligible patients were randomly
assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone
twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done
centrally with an interactive voice response system and patients were stratified
by region (Europe, North America, and not Europe or North America) and the
presence or absence of radiographic disease progression at baseline. The two
primary endpoints were radiographic progression-free survival and overall
survival, determined in the intention-to-treat population. This trial is
registered with ClinicalTrials.gov, number NCT01193244.
FINDINGS: From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for
eligibility. Of those, 1560 were randomly assigned to receive either orteronel
plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff
date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up
for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median
radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with
orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone
(hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up
of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI
28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not
estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The
most common grade 3 or worse adverse events were increased lipase (137 [17%] of
784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients
in the placebo plus prednisone group), increased amylase (77 [10%] vs nine
[1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27
[4%]). Serious adverse events were reported in 358 [46%] patients receiving
orteronel plus prednisone and in 292 [38%] patients receiving placebo plus
prednisone.
INTERPRETATION: In chemotherapy-naive patients with metastatic
castration-resistant prostate cancer, radiographic progression-free survival was
prolonged with orteronel plus prednisone versus placebo plus prednisone.
However, no improvement was noted in the other primary endpoint, overall
survival. Orteronel plus prednisone was associated with increased toxic effects
compared with placebo plus prednisone. On the basis of these and other data,
orteronel is not undergoing further development in metastatic
castration-resistant prostate cancer.
FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(15)70027-6
PMID: 25701170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20644507 | 1. J Vis Exp. 2010 Jul 2;(41):2034. doi: 10.3791/2034.
PAR-CliP--a method to identify transcriptome-wide the binding sites of RNA
binding proteins.
Hafner M(1), Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P,
Rothballer A, Ascano M, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell
S, Zavolan M, Tuschl T.
Author information:
(1)Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology,
Rockefeller University, USA.
RNA transcripts are subjected to post-transcriptional gene regulation by
interacting with hundreds of RNA-binding proteins (RBPs) and microRNA-containing
ribonucleoprotein complexes (miRNPs) that are often expressed in a cell-type
dependently. To understand how the interplay of these RNA-binding factors
affects the regulation of individual transcripts, high resolution maps of in
vivo protein-RNA interactions are necessary. A combination of genetic,
biochemical and computational approaches are typically applied to identify
RNA-RBP or RNA-RNP interactions. Microarray profiling of RNAs associated with
immunopurified RBPs (RIP-Chip) defines targets at a transcriptome level, but its
application is limited to the characterization of kinetically stable
interactions and only in rare cases allows to identify the RBP recognition
element (RRE) within the long target RNA. More direct RBP target site
information is obtained by combining in vivo UV crosslinking with
immunoprecipitation followed by the isolation of crosslinked RNA segments and
cDNA sequencing (CLIP). CLIP was used to identify targets of a number of RBPs.
However, CLIP is limited by the low efficiency of UV 254 nm RNA-protein
crosslinking, and the location of the crosslink is not readily identifiable
within the sequenced crosslinked fragments, making it difficult to separate
UV-crosslinked target RNA segments from background non-crosslinked RNA fragments
also present in the sample. We developed a powerful cell-based crosslinking
approach to determine at high resolution and transcriptome-wide the binding
sites of cellular RBPs and miRNPs that we term PAR-CliP
(Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation)
(see Fig. 1A for an outline of the method). The method relies on the
incorporation of photoreactive ribonucleoside analogs, such as 4-thiouridine
(4-SU) and 6-thioguanosine (6-SG) into nascent RNA transcripts by living cells.
Irradiation of the cells by UV light of 365 nm induces efficient crosslinking of
photoreactive nucleoside-labeled cellular RNAs to interacting RBPs.
Immunoprecipitation of the RBP of interest is followed by isolation of the
crosslinked and coimmunoprecipitated RNA. The isolated RNA is converted into a
cDNA library and deep sequenced using Solexa technology. One characteristic
feature of cDNA libraries prepared by PAR-CliP is that the precise position of
crosslinking can be identified by mutations residing in the sequenced cDNA. When
using 4-SU, crosslinked sequences thymidine to cytidine transition, whereas
using 6-SG results in guanosine to adenosine mutations. The presence of the
mutations in crosslinked sequences makes it possible to separate them from the
background of sequences derived from abundant cellular RNAs. Application of the
method to a number of diverse RNA binding proteins was reported in Hafner et al.
DOI: 10.3791/2034
PMCID: PMC3156069
PMID: 20644507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20080837 | 1. J Clin Endocrinol Metab. 2010 Mar;95(3):1349-54. doi: 10.1210/jc.2009-1209.
Epub 2010 Jan 15.
Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body
mass index, and serum lipoproteins: a pilot prospective, randomized, controlled
study.
Ladenson PW(1), McCarren M, Morkin E, Edson RG, Shih MC, Warren SR, Barnhill JG,
Churby L, Thai H, O'Brien T, Anand I, Warner A, Hattler B, Dunlap M, Erikson J,
Goldman S.
Author information:
(1)Department of Endocrinology and Metabolism, John Hopkins University, 1830
East Monument Street, Suite 333, Baltimore, Maryland 21287-0003, USA.
[email protected]
CONTEXT: Widespread thyroid hormone actions offer the possibility of developing
selective thyromimetic analogs with salutary metabolic properties. Consequently,
effects of diiodothyropropionic acid (DITPA) on body weight, serum lipoproteins,
and bone metabolism markers were studied in a prospective, controlled,
double-blind 24-wk trial, which was primarily designed to assess treatment of
stable chronic heart failure.
DESIGN: Eighty-six patients (aged 66 +/- 11 yr, mean +/- sd) were randomized
(1:2) to placebo or an escalating DITPA dose (90 to 180, 270, and 360 mg/d) over
8 wk until serum TSH was less than 0.02 mU/liter. Patients were studied at 2, 4,
6, 8, 16, and 24 wk and after 4 wk off study drug. Only 21 DITPA-treated and 27
placebo patients completed the full 24 wk of therapy.
RESULTS: DITPA therapy lowered serum TSH levels and, to a lesser extent, serum
T(3) and T(4), but there were no differences in clinical manifestations of
thyrotoxicosis or hypothyroidism. Serum total and low-density lipoprotein
cholesterol levels both decreased on DITPA; there was a transient decrease in
triglycerides and no change in high-density lipoprotein cholesterol. DITPA
therapy was associated with significant reduction in body weight, 12.5 lb at 24
wk. Increases in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels
were consistent with increased bone turnover on DITPA.
CONCLUSION: This investigation of DITPA actions demonstrated its efficacy in
reducing body weight and lowering total and low-density lipoprotein cholesterol
levels. However, DITPA's adverse effects at doses used resulted in a high
dropout rate and potentially dangerous skeletal actions were observed.
DOI: 10.1210/jc.2009-1209
PMID: 20080837 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22686547 | 1. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14. doi: 10.1007/BF03261927.
Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors.
Golightly LK(1), Drayna CC, McDermott MT.
Author information:
(1)University of Colorado Hospital, Aurora, CO 80045, USA.
[email protected]
Erratum in
Clin Pharmacokinet. 2012 Dec;51(12):831.
Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently
unique form of disease management for persons with type 2 diabetes mellitus. The
aim of this review is to compare the clinical pharmacokinetics of available
DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and
vildagliptin) for the purpose of identifying potential selection preferences
according to individual patient variables and co-morbidities. DPP-4 inhibitors
are readily absorbed orally. Following oral ingestion, absorption occurs mainly
in the small intestine, with median times to maximum (peak) plasma concentration
ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from
approximately 30% with linagliptin to 75-87% for all others. Numerical
differences in maximum (peak) plasma drug concentrations and areas under the
plasma concentration-time curve among the DPP-4 inhibitors vary by an order of
magnitude. However, functional capacity measured in terms of glucose-lowering
ability remains comparable among all available DPP-4 inhibitors. Distribution of
DPP-4 inhibitors is strongly influenced by both lipophilicity and protein
binding. Apparent volumes of distribution (V(d)) for most agents range from 70
to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread
distribution into tissues. Binding to target proteins in plasma and peripheral
tissues exerts a major influence upon broadening linagliptin distribution. DPP-4
inhibitor metabolism is widely variable, with reported terminal half-lives
ranging from approximately 3 to more than 200 hours. Complex relationships
between rates of receptor binding and dissociation appear to strongly influence
the durations of action of those DPP-4 inhibitors with comparatively shorter
half-lives. Durations of activity often are not reflective of clearance and,
with the exception of vildagliptin which may be administered either once daily
in the evening or twice daily, these medications are effective when used with a
once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are
largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With
the exception of the primary hydroxylated metabolite of saxagliptin, which is
2-fold less potent than its parent molecule, metabolic products of hepatic
biotransformation are minimally active and none appreciably contribute to either
the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has
been shown to inhibit or to induce hepatic CYP-mediated drug metabolism.
Accordingly, the number of clinically significant drug-drug interactions
associated with these agents is minimal, with only saxagliptin necessitating
dose adjustment if administered concurrently with medications that strongly
inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large
majority (85%) of the absorbed dose eliminated in faeces via biliary excretion.
Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of
each dose eliminated as unchanged parent compound in the urine. Systematic
reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors
in patients with type 2 diabetes generally is similar. Apart from these
generalizations, pharmacokinetic distinctions that potentially influence product
selection are tentative. When considered in total, data reviewed in this report
suggest that the best overall balance between potency and the clinical
pharmacokinetic characteristics of distribution, metabolism and elimination may
be observed with linagliptin followed closely by vildagliptin, saxagliptin,
sitagliptin and alogliptin.
DOI: 10.1007/BF03261927
PMID: 22686547 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19506112 | 1. Circulation. 2009 Jun 23;119(24):3093-100. doi:
10.1161/CIRCULATIONAHA.108.834424. Epub 2009 Jun 8.
DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart
failure: phase II trial veterans affairs cooperative study.
Goldman S(1), McCarren M, Morkin E, Ladenson PW, Edson R, Warren S, Ohm J, Thai
H, Churby L, Barnhill J, O'Brien T, Anand I, Warner A, Hattler B, Dunlap M,
Erikson J, Shih MC, Lavori P.
Author information:
(1)Cardiology Section (1-111C), Southern Arizona VA Health Care System, 3601 S
6th Ave, Tucson, AZ 85723, USA. [email protected]
Comment in
Circulation. 2010 Mar 16;121(10):e240; author reply e241. doi:
10.1161/CIR.0b013e3181d77f5e.
BACKGROUND: In animal studies and a pilot trial in patients with congestive
heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA)
had beneficial hemodynamic effects.
METHODS AND RESULTS: This was a phase II multicenter, randomized,
placebo-controlled, double-blind trial of New York Heart Association class II to
IV congestive heart failure patients randomized (2:1) to DITPA or placebo and
treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to
placebo). The primary objective was to assess the effect of DITPA on a composite
congestive heart failure end point that classifies patients as improved,
worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA
was poorly tolerated, which obscured the interpretation of congestive heart
failure-specific effects. Fatigue and gastrointestinal complaints, in
particular, were more frequent in the DITPA group. DITPA increased cardiac index
(by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol
(-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb).
Thyroid-stimulating hormone was suppressed in patients given DITPA, which
reflects its thyromimetic effect; however, no symptoms or signs of potential
hypothyroidism or thyrotoxicosis were seen.
CONCLUSIONS: DITPA improved some hemodynamic and metabolic parameters, but there
was no evidence for symptomatic benefit in congestive heart failure.
DOI: 10.1161/CIRCULATIONAHA.108.834424
PMID: 19506112 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24793580 | 1. Nutr Metab Cardiovasc Dis. 2014 Jul;24(7):689-97. doi:
10.1016/j.numecd.2014.01.017. Epub 2014 Mar 5.
Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of
randomized clinical trials.
Monami M(1), Dicembrini I(2), Mannucci E(3).
Author information:
(1)Section of Geriatric and Medicine, Careggi Teaching Hospital, Via delle
Oblate 4, 50141 Florence, Italy.
(2)Obesity Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141
Florence, Italy; Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4,
50141 Florence, Italy.
(3)Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141
Florence, Italy. Electronic address: [email protected].
BACKGROUND & AIMS: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of
Vascular Outcomes Recorded in patients with diabetes mellitus--Thrombolysis in
Myocardial Infarction-53) reported a significant increase in the risk of
hospitalizations for heart failure in patients treated with saxagliptin in
comparison with placebo. Aim of the present meta-analysis is the systematic
collection and synthesis of information on treatment-emergent cases of acute
heart failure described in randomized clinical trials with DPP4.
DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for
"vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and
"dutogliptin" was performed, collecting all randomized clinical trials on humans
up to October 1st, 2013. Studies were included if they satisfied the following
criteria: i) randomized trials, ii) duration ≥24 weeks; iii) on type 2 diabetes;
iv) comparison of DPP4i with placebo or active drugs. The principal outcome was
the effect of DPP4i on the incidence of acute heart failure. A total of 84
eligible trials was identified. The overall risk of acute heart failure was
higher in patients treated with DPP4i in comparison with those treated with
placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; p = 0.015). When trials
with non-cardiovascular outcomes were analysed separately no signal of risk was
detectable.
CONCLUSION: Available data from RCTs suggest that DPP4i could be associated with
an increased risk of heart failure, without any clear evidence of differences
among drugs of the class. Although it is plausible that the risk is greater in
some sub-populations of patients, current evidence is not yet sufficient to
identify susceptible patients.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.numecd.2014.01.017
PMID: 24793580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21500969 | 1. Expert Opin Investig Drugs. 2011 Jun;20(6):723-32. doi:
10.1517/13543784.2011.576667. Epub 2011 Apr 18.
Small molecule dipeptidylpeptidase IV inhibitors under investigation for
diabetes mellitus therapy.
Gallwitz B(1).
Author information:
(1)Eberhard-Karls-University, Dept Medicine IV, Otfried-Müller-Str. 10, 72076
Tübingen, Germany. [email protected]
INTRODUCTION: A recent treatment advance for type 2 diabetes is the oral therapy
with DPP IV inhibitors. New substances of this class are in development in order
to increase alternatives for treating this important metabolic disease. The
reader will gain detailed pharmacological and clinical information on
alogliptin, dutogliptin and linagliptin and will learn how these DPP IV
inhibitors may widen the whole drug class. Possible special indications for the
various DPP IV inhibitors are discussed.
AREAS COVERED: The DPP IV inhibitors and their current role in type 2 diabetes
are highlighted. Preclinical and clinical studies of the novel DPP IV inhibitors
alogliptin, dutogliptin and linagliptin, including published data since 2007,
are presented and a comparison of these compounds is made.
EXPERT OPINION: The efficacy and safety profile of DPP IV inhibitors are
promising and advantageous so far. In contrast to sulfonylureas, DPP IV
inhibitors do not have an intrinsic risk for causing hypoglycemia and they are
body weight neutral. Their tolerability profile is good and no specific adverse
reactions have been reported. Experience so far suggests that there are no
safety issues associated with inhibition of DPP IV activity by itself. Novel DPP
IV inhibitors with distinct properties may offer alternative choices within this
drug class.
DOI: 10.1517/13543784.2011.576667
PMID: 21500969 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24793219 | 1. Diabetes Ther. 2014 Jun;5(1):341-4. doi: 10.1007/s13300-014-0066-y. Epub 2014
May 3.
Testing the therapeutic equivalence of alogliptin, linagliptin, saxagliptin,
sitagliptin or vildagliptin as monotherapy or in combination with metformin in
patients with type 2 diabetes.
Messori A(1), Fadda V, Maratea D, Trippoli S, Marinai C.
Author information:
(1)HTA Unit, ESTAV Toscana Centro, Regional Health Service, 50100, Florence,
Italy, [email protected].
BACKGROUND: In studying the therapeutic evidence of innovative drug treatments,
increasing attention is being devoted to differentiating between results that
indicate no significant differences among the treatments under examination ("no
proof of difference") and results that demonstrate the therapeutic equivalence
among the treatments ("proof of no difference").
AIM: Our analysis was aimed at evaluating the degree of therapeutic equivalence
for dipeptidylpeptidase-4 (DPP-4) inhibitors given in type 2 diabetes as
monotherapy or in combination with metformin.
METHODS: Equivalence was determined by developing a standard Forest plot that
incorporated the information on margins previously reported in randomized trials
on these agents. The end point was HbA1c change from baseline; the equivalence
margin was set at ±0.25% change in HbA1c. The clinical material was obtained
from a systematic review on this topic.
RESULTS: Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but
not saxagliptin) met the equivalence criterion when compared with one another.
Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and
vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the
equivalence criterion.
CONCLUSIONS: Considering the most recent therapeutic guidelines, our results are
of interest particularly as regards the information on DPP-4 inhibitors in
combination with metformin. Four of the five DPP-4 inhibitors under examination
clearly showed to have the same effectiveness; the fifth agent-alogliptin-failed
to meet the equivalence criterion, but only because its superiority could not be
excluded.
DOI: 10.1007/s13300-014-0066-y
PMCID: PMC4065299
PMID: 24793219 |
http://www.ncbi.nlm.nih.gov/pubmed/22106978 | 1. Curr Med Res Opin. 2011 Nov;27 Suppl 3:57-64. doi:
10.1185/03007995.2011.602964.
Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized
clinical trials.
Monami M(1), Dicembrini I, Martelli D, Mannucci E.
Author information:
(1)Section of Geriatric Cardiology and Medicine, Department of Cardiovascular
Medicine, Careggi Teaching Hospital, Florence, Italy.
OBJECTIVE: Dipeptidyl peptidase-4 inhibitors (DPP4i) have been recently
associated with increased risk of pancreatitis and cancer. The aim of the
present meta-analysis of randomized clinical trials is the assessment of the
effect of DPP4i on the incidence of major cardiovascular events (MACE), cancer,
and pancreatitis.
RESEARCH DESIGN AND METHODS: An extensive Medline and Embase search for
'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and
'dutogliptin' was performed, collecting all randomized clinical trials on humans
up to March 1, 2011. The present meta-analysis was therefore performed including
all randomized clinical trials with a duration of at least 24 weeks, enrolling
patients with type 2 diabetes, comparing DPP4i with either placebo or active
drugs. Completed but still unpublished trials were identified through a search
of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines
Agency website.
RESULTS: Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and
comparators, respectively, were included, reporting 176 malignancies, 257 MACE,
and 22 pancreatitis. DPP4i, compared with placebo or other treatment, were
associated with a similar risk of cancer (MH-OR 1.020 [0.742-1.402]; p = 0.90)
and pancreatitis (0.786 [0.357-1.734], p = 0.55), and with a reduced risk of
MACE (MH-OR 0.689 [0.528-0.899], p = 0.006).
CONCLUSIONS: The present meta-analysis seems to exclude any relevant short term
effect of DPP4i on the incidence of cancer and suggest a possible protection
from cardiovascular events. This result should be interpreted with caution, as
those events were not the principal endpoint, the trial duration was short, and
the characteristics of patients included could be different from routine
clinical practice.
DOI: 10.1185/03007995.2011.602964
PMID: 22106978 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21431099 | 1. Drugs Today (Barc). 2011 Feb;47(2):99-107. doi: 10.1358/dot.2011.47.2.1583163.
Alogliptin for the treatment of type 2 diabetes.
White JR(1).
Author information:
(1)Department of Pharmacotherapy, Washington State University, Spokane, WA, USA.
[email protected]
The pharmacologic management of type 2 diabetes has changed dramatically in the
past two decades. We have moved from a situation of only having two choices,
insulin and sulfonylureas, to a position of myriad choices from 11 categories of
medications (insulin, sulfonylureas, biguanides, α-glucosidase inhibitors,
gliptins (dipeptidyl peptidase 4 [DPP IV] inhibitors), bromocriptine,
glucagon-like peptide analogues, thiazolidinediones, glinides, amylin analogues
and bile acid sequestrants. One of the most recent additions to this list are
the DPP IV inhibitors commonly known as gliptins. Currently, there are four DPP
IV inhibitors available in various countries-alogliptin, sitagliptin,
vildagliptin and saxagliptin (1). Of these, two have been approved for clinical
use in the United States: sitagliptin and saxagliptin. Additionally,
linagliptin, vildagliptin and alogliptin are currently in phase III development
in the United States while studies with another DPP IV inhibitor, dutogliptin,
have been terminated (2). Alogliptin was approved for use in Japan under the
trade name Nesina® in April 2010 (3). This manuscript will review alogliptin,
its chemistry, pharmacokinetics/pharmacodynamics, drug interactions, clinical
trials and its current state of FDA review. Preclinical animal data have been
reviewed elsewhere and will not be outlined in this manuscript. The interested
reader is referred to those recent reviews (4, 5).
Copyright 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
DOI: 10.1358/dot.2011.47.2.1583163
PMID: 21431099 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24186878 | 1. Diabetes Care. 2013 Dec;36(12):4015-21. doi: 10.2337/dc13-0663. Epub 2013 Nov
1.
Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an
active-controlled, parallel-group, randomized, 78-week open-label extension
study in patients with type 2 diabetes.
Ferrannini E(1), Berk A, Hantel S, Pinnetti S, Hach T, Woerle HJ, Broedl UC.
Author information:
(1)Corresponding author: Ele Ferrannini, [email protected].
OBJECTIVE: To investigate the long-term safety and efficacy of empagliflozin, a
sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients
with type 2 diabetes.
RESEARCH DESIGN AND METHODS: In this randomized, open-label, 78-week extension
study of two 12-week, blinded, dose-finding studies of empagliflozin
(monotherapy and add-on to metformin) with open-label comparators, 272 patients
received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg
empagliflozin (166 as add-on to metformin), 56 patients received metformin, and
56 patients received sitagliptin as add-on to metformin.
RESULTS: Changes from baseline in HbA1c at week 90 were -0.34 to -0.63% (-3.7 to
-6.9 mmol/mol) with empagliflozin, -0.56% (-6.1 mmol/mol) with metformin, and
-0.40% (-4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week
90 were -2.2 to -4.0 kg with empagliflozin, -1.3 kg with metformin, and -0.4 kg
with sitagliptin. Adverse events (AEs) were reported in 63.2-74.1% of patients
on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or
moderate in intensity. Hypoglycemic events were rare in all treatment groups,
and none required assistance. AEs consistent with genital infections were
reported in 3.0-5.5% of patients on empagliflozin, 1.8% on metformin, and none
on sitagliptin. AEs consistent with urinary tract infections were reported in
3.8-12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on
sitagliptin.
CONCLUSIONS: Long-term empagliflozin treatment provided sustained glycemic and
weight control and was well tolerated with a low risk of hypoglycemia in
patients with type 2 diabetes.
DOI: 10.2337/dc13-0663
PMCID: PMC3836134
PMID: 24186878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19345254 | 1. Biochim Biophys Acta. 2009 Nov;1790(11):1441-7. doi:
10.1016/j.bbagen.2009.03.026. Epub 2009 Apr 1.
Selenoprotein P-expression, functions, and roles in mammals.
Burk RF(1), Hill KE.
Author information:
(1)Division of Gastroenterology, Hepatology, and Nutrition, Department of
Medicine, 1030C Medical Research Building IV, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232-0252, USA. [email protected]
Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The
larger N-terminal domain contains 1 selenocysteine residue in a redox motif and
the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1
isoforms of varying lengths occur but quantitation of them has not been
achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the
liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein
receptor family, binds Sepp1 and facilitates its uptake into the testis and
retention of its selenium by the brain. Megalin, another lipoprotein receptor,
facilitates uptake of filtered Sepp1 into proximal tubule cells of the kidney.
Thus, Sepp1 serves in homeostasis and distribution of selenium. Mice with
deletion of Sepp1 suffer greater morbidity and mortality from infection with
Trypanosoma congolense than do wild-type mice. Mice that express only the
N-terminal domain of Sepp1 have the same severity of illness as wild-type mice,
indicating that the protective function of Sepp1 against the infection resides
in the N-terminal (redox) domain. Thus, Sepp1 has several functions. In
addition, plasma Sepp1 concentration falls in selenium deficiency and,
therefore, it can be used as an index of selenium nutritional status.
DOI: 10.1016/j.bbagen.2009.03.026
PMCID: PMC2763998
PMID: 19345254 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16825496 | 1. Blood. 2006 Nov 1;108(9):2950-6. doi: 10.1182/blood-2006-03-010553. Epub 2006
Jul 6.
Expression levels of CD38 in T cells predict course of disease in male patients
with B-chronic lymphocytic leukemia.
Tinhofer I(1), Rubenzer G, Holler C, Hofstaetter E, Stoecher M, Egle A, Steurer
M, Greil R.
Author information:
(1)Laboratory of Immunological and Molecular Cancer Research, 3rd Medical Dept
at the Salzburg University Hospital, Muellner Hauptstrasse 48, A-5020 Salzburg,
Austria. [email protected]
CD38 expression of tumor cells has been identified as an important prognostic
factor in B-cell chronic lymphocytic leukemia (B-CLL). Although CD38 is involved
in effector functions of T cells, the prognostic value of CD38+ T cells has not
yet been addressed in B-CLL. In the present study, CD38-expression levels in
B-CLL cells and T cells from 204 patients were analyzed by flow cytometry and
correlated with clinical and molecular risk parameters. CD38 expression
significantly differed in the neoplastic clone from patients with low versus
advanced stage, irrespective of the sex of patients. In contrast, CD38
expression was generally higher in T cells from female compared with male
patients but only increased in male patients in a stage-dependent manner. In
male patients, combined analysis of CD38 in T cells and B-CLL cells identified 4
subgroups with significantly different treatment-free survival. Multivariate
analysis including Rai stage and molecular risk parameters of the neoplastic
clone identified CD38-expression levels in T cells as an independent prognostic
factor in male patients. Combined analysis of CD38 in B-CLL and T cells is
superior in predicting outcome of male B-CLL patients than either parameter
alone. Further studies are needed to elucidate the underlying mechanisms of the
sex-specific role of CD38+ T cells in B-CLL.
DOI: 10.1182/blood-2006-03-010553
PMID: 16825496 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19127482 | 1. Leuk Lymphoma. 2009 Jan;50(1):68-79. doi: 10.1080/10428190802541807.
Analysis of chronic lymphotic leukemia transcriptomic profile: differences
between molecular subgroups.
Jantus Lewintre E(1), Reinoso Martín C, Montaner D, Marín M, José Terol M,
Farrás R, Benet I, Calvete JJ, Dopazo J, García-Conde J.
Author information:
(1)Molecular Haematology Laboratory, Prince Felipe Research Centre, Valencia,
Spain. [email protected]
Comment in
Leuk Lymphoma. 2009 Jan;50(1):10-1. doi: 10.1080/10428190802678625.
B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with
a variable clinical course. Patients with unmutated IgV(H) gene show a shorter
progression-free and overall survival than patients with immunoglobulin heavy
chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations
identify a subgroup of patients with high risk of progression. Gene expression
was analysed in 36 early-stage patients using high-density microarrays. Around
150 genes differentially expressed were found according to IgV(H) mutations,
whereas no difference was found according to BCL6 mutations. Functional
profiling methods allowed us to distinguish KEGG and gene ontology terms showing
coordinated gene expression changes across subgroups of CLL. We validated a set
of differentially expressed genes according to IgV(H) status, scoring them as
putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are
the ones with at least equal or superior performance to ZAP70 which is actually
the most used surrogate marker of IgV(H) status.
DOI: 10.1080/10428190802541807
PMID: 19127482 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25860270 | 1. Rev Med Chil. 2015 Jan;143(1):63-8. doi: 10.4067/S0034-98872015000100008.
[Safety and efficacy of Vildagliptin in real life Chilean diabetic patients].
[Article in Spanish]
Godoy J G, Gutiérrez V, Montecinos M, Yenes A.
BACKGROUND: Vildagliptin is a dipeptidyl peptidase IV inhibitor (DPP4i). Its
efficacy and safety of DPP4i in Chilean real life type 2 diabetic (T2D) patients
is not well known.
AIM: To assess the safety profile and effectiveness of 12 weeks of treatment
with Vildagliptin for glycemic control in T2D Chilean patients with a poor
glycemic control.
PATIENTS AND METHODS: Retrospective assessment of the effects of Vildagliptin
treatment during 12 weeks in 103 T2D patients aged 29 to 92 years (47% males).
The main outcomes were changes in glycosylated hemoglobin and the occurrence of
adverse effects.
RESULTS: After 12 weeks of Vildagliptin use, glycosylated hemoglobin decreased
from 8.3 ± 1.4 to 7.2 ± 1.1% (p < 0.01). Fasting plasma glucose and the number
of hypoglycemic events also decreased significantly. No significant weight
change was observed. The treatment had good compliance, tolerance and patient
satisfaction.
CONCLUSIONS: Vildagliptin treatment reduced glycosylated hemoglobin by 1.1% and
was well tolerated in this group of diabetic patients.
DOI: 10.4067/S0034-98872015000100008
PMID: 25860270 [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/20102100 | 1. Coll Antropol. 2009 Dec;33(4):1401-3.
Symptomatic sacral perineurial (Tarlov) cysts.
Sajko T(1), Kovać D, Kudelić N, Kovac L.
Author information:
(1)Department of Neurosurgery, University Hospital Sestre milosrdnice, Zagreb,
Croatia. [email protected]
Sacral perineurial (Tarlov) cysts are rare lesions. Over a seven year period
4000 patients underwent surgery for lumbar disk herniation. In three patients
neurological symptoms were caused by large sacral perineurial cysts. Methods of
choice for diagnosis of Tarlov cysts are lumbosacral magnetic resonance imaging
and computerized tomography myelography. The majority of Tarlov cysts are
asymptomatic. In case of large (> or = 1.5 cm) and symptomatic perineurial cyst,
as in three patients reported in this article, microsurgical treatment was
successful. Although rare, perineurial (Tarlov) cysts must be taken into
consideration when approaching to patient with low back and radicular pain.
Authors review the medical literature, pathological and pathophysiological
features and treatment options of sacral perineurial cysts.
PMID: 20102100 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19506735 | 1. Curr Genomics. 2008 Nov;9(7):466-74. doi: 10.2174/138920208786241199.
Clinical utility of microarrays: current status, existing challenges and future
outlook.
Li X(1), Quigg RJ, Zhou J, Gu W, Nagesh Rao P, Reed EF.
Author information:
(1)Clinical Microarray Core, Department of Pathology & Laboratory Medicine,
University of California at Los Angeles, 1000 Veteran Ave., Los Angeles, CA
90095, USA.
Microarray-based clinical tests have become powerful tools in the diagnosis and
treatment of diseases. In contrast to traditional DNA-based tests that largely
focus on single genes associated with rare conditions, microarray-based tests
are ideal for the study of diseases with underlying complex genetic causes.
Several microarray based tests have been translated into clinical practice such
as MammaPrint and AmpliChip CYP450. Additional cancer-related microarray-based
tests are either in the process of FDA review or under active development,
including Tissue of Tumor Origin and AmpliChip p53. All diagnostic microarray
testing is ordered by physicians and tested by a Clinical Laboratories
Improvement Amendment-certified (CLIA) reference laboratory. Recently, companies
offering consumer based microarray testing have emerged. Individuals can order
tests online and service providers deliver the results directly to the clients
via a password-protected secure website. Navigenics, 23andMe and deCODE Genetics
represent pioneering companies in this field. Although the progress of these
microarray-based tests is extremely encouraging with the potential to
revolutionize the recognition and treatment of common diseases, these tests are
still in their infancy and face technical, clinical and marketing challenges. In
this article, we review microarray-based tests which are currently approved or
under review by the FDA, as well as the consumer-based testing. We also provide
a summary of the challenges and strategic solutions in the development and
clinical use of the microarray-based tests. Finally, we present a brief outlook
for the future of microarray-based clinical applications.
DOI: 10.2174/138920208786241199
PMCID: PMC2691672
PMID: 19506735 |
http://www.ncbi.nlm.nih.gov/pubmed/23136353 | 1. Ann Pharmacother. 2012 Nov;46(11):1453-69. doi: 10.1345/aph.1R041. Epub 2012
Nov 7.
Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes:
meta-analysis.
Park H(1), Park C, Kim Y, Rascati KL.
Author information:
(1)Health Outcomes and Pharmacy Practice Division, College of Pharmacy, The
University of Texas, Austin, TX, USA.
BACKGROUND: An up-to-date assessment of dipeptidyl peptidase-4 (DPP-4)
inhibitors is needed to include newly available data.
OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibitors, including
sitagliptin, saxagliptin, vildagliptin, and linagliptin, in type 2 diabetes.
METHODS: We conducted a search of MEDLINE for randomized controlled trials
(RCTs) of DPP-4 inhibitors in type 2 diabetes through November 2011, using the
key terms sitagliptin, saxagliptin, vildagliptin, and linagliptin. We also
searched for completed, but unpublished, trials at relevant web sites. RCTs were
selected for meta-analysis if they (1) compared DPP-4 inhibitors with placebo or
an antihyperglycemic agent; (2) had study duration of 12 or more weeks; (3) had
1 or more baseline and posttreatment efficacy and/or safety outcome; and (4)
were published in English.
RESULTS: In 62 evaluated articles, DPP-4 inhibitors lowered hemoglobin A(1c)
(A1C) significantly more than placebo (weighted mean difference [WMD] -0.76%;
95% CI -0.83 to -0.68); however, heterogeneity was substantial (I(2) = 82%).
Exclusion of Japanese trials (n = 7) resulted in a reduction of heterogeneity
(I(2) = 59%). In the non-Japanese RCTs (n = 55), DPP-4 inhibitors were
associated with a reduction in A1C (WMD -0.65%; 95% CI -0.71 to -0.60) but
higher risk of hypoglycemia (odds ratio [OR] 1.30; 95% CI 1.00 to 1.68) compared
to placebo. The 7 Japanese-specific RCTs showed a greater reduction in A1C (WMD
-1.67%; 95% CI -1.89 to -1.44) and a nonsignificant increase in risk of
hypoglycemia (OR 1.41; 95% CI 0.51 to 3.88) with DPP-4 inhibitors versus
placebo. When comparing DPP-4 inhibitors to active comparators, the I(2) was
still high after deleting Japanese studies. In these 17 active comparator
trials, there was no significant difference in A1C reduction (WMD 0.04%; 95% CI
-0.09 to 0.16) or risk of hypoglycemia (OR 0.60; 95% CI 0.22 to 1.61) for DPP-4
inhibitors compared to other antihyperglycemics. There were similar odds of any
or serious adverse events with DPP-4 inhibitors compared to placebo, but a
decreased risk compared to other antihyperglycemics.
CONCLUSIONS: DPP-4 inhibitors were associated with a reduction in A1C with
comparable safety profiles compared to placebo, but no significant difference in
A1C compared to other hyperglycemics. Differences in efficacy and safety were
observed between Japanese and non-Japanese patients.
DOI: 10.1345/aph.1R041
PMID: 23136353 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15759228 | 1. Arch Phys Med Rehabil. 2005 Mar;86(3):453-62. doi: 10.1016/j.apmr.2004.05.016.
Predictors of outcome in prolonged posttraumatic disorders of consciousness and
assessment of medication effects: A multicenter study.
Whyte J(1), Katz D, Long D, DiPasquale MC, Polansky M, Kalmar K, Giacino J,
Childs N, Mercer W, Novak P, Maurer P, Eifert B.
Author information:
(1)Moss Rehabilitation Research Institute/Albert Einstein Healthcare Network,
Philadelphia, PA, USA. [email protected]
OBJECTIVES: To develop predictive models of recovery from the vegetative state
(VS) and minimally conscious state (MCS) after traumatic brain injury (TBI) and
to gather preliminary evidence on the impact of various psychotropic medications
on the recovery process to support future randomized controlled trials. Design
Longitudinal observational cohort design, in which demographic information,
injury and acute care history, neuroimaging data, and an initial Disability
Rating Scale (DRS) score were collected at the time of study enrollment. Weekly
follow-up data, consisting of DRS score, current psychoactive medications, and
medical complications, were gathered until discharge from inpatient
rehabilitation.
SETTING: Seven acute inpatient rehabilitation facilities in the United States
and Europe with specialized programs for treating patients in the VS and MCS.
PARTICIPANTS: People with TBI (N=124) who were in the VS or MCS 4 to 16 weeks
after injury.
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: DRS score at 16 weeks after injury and time until
commands were first followed (among those participants demonstrating no command
following at study enrollment). Results DRS score at enrollment, time between
injury and enrollment, and rate of DRS change during the first 2 weeks of
poststudy observation were all highly predictive of both outcomes. No variables
related to injury characteristics or lesions on neuroimaging were significant
predictors. Of the psychoactive medications, amantadine hydrochloride was
associated with greater recovery and dantrolene sodium was associated with less
recovery, in terms of the DRS score at 16 weeks but not the time until commands
were followed. More detailed analysis of the timing of functional improvement,
with respect to the initiation of amantadine provided suggestive, but not
definitive, evidence of the drug's causal role.
CONCLUSIONS: These findings show the feasibility of improving outcome prediction
from the VS and MCS using readily available clinical variables and provide
suggestive evidence for the effects of amantadine and dantrolene, but these
results require confirmation through randomized controlled trials.
DOI: 10.1016/j.apmr.2004.05.016
PMID: 15759228 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18786252 | 1. BMC Med Genomics. 2008 Sep 11;1:39. doi: 10.1186/1755-8794-1-39.
Identification of a gene signature in cell cycle pathway for breast cancer
prognosis using gene expression profiling data.
Liu J(1), Campen A, Huang S, Peng SB, Ye X, Palakal M, Dunker AK, Xia Y, Li S.
Author information:
(1)Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285,
USA. [email protected]
BACKGROUND: Numerous studies have used microarrays to identify gene signatures
for predicting cancer patient clinical outcome and responses to chemotherapy.
However, the potential impact of gene expression profiling in cancer diagnosis,
prognosis and development of personalized treatment may not be fully exploited
due to the lack of consensus gene signatures and poor understanding of the
underlying molecular mechanisms.
METHODS: We developed a novel approach to derive gene signatures for breast
cancer prognosis in the context of known biological pathways. Using unsupervised
methods, cancer patients were separated into distinct groups based on gene
expression patterns in one of the following pathways: apoptosis, cell cycle,
angiogenesis, metastasis, p53, DNA repair, and several receptor-mediated
signaling pathways including chemokines, EGF, FGF, HIF, MAP kinase, JAK and
NF-kappaB. The survival probabilities were then compared between the patient
groups to determine if differential gene expression in a specific pathway is
correlated with differential survival.
RESULTS: Our results revealed expression of cell cycle genes is strongly
predictive of breast cancer outcomes. We further confirmed this observation by
building a cell cycle gene signature model using supervised methods. Validated
in multiple independent datasets, the cell cycle gene signature is a more
accurate predictor for breast cancer clinical outcome than the previously
identified Amsterdam 70-gene signature that has been developed into a FDA
approved clinical test MammaPrint.
CONCLUSION: Taken together, the gene expression signature model we developed
from well defined pathways is not only a consistently powerful prognosticator
but also mechanistically linked to cancer biology. Our approach provides an
alternative to the current methodology of identifying gene expression markers
for cancer prognosis and drug responses using the whole genome gene expression
data.
DOI: 10.1186/1755-8794-1-39
PMCID: PMC2551605
PMID: 18786252 |
http://www.ncbi.nlm.nih.gov/pubmed/22429011 | 1. Curr Diabetes Rev. 2012 May;8(3):169-82. doi: 10.2174/157339912800564007.
An update in incretin-based therapy: a focus on dipeptidyl peptidase--4
inhibitors.
Irons BK(1), Weis JM, Stapleton MR, Edwards KL.
Author information:
(1)Ambulatory Care Texas Tech University Health Sciences Center, School of
Pharmacy, 3601 4th St. Lubbock, TX 79430, USA. [email protected]
Dipeptidyl peptidase -4 inhibitors represent a novel way to augment the incretin
system and one of the newest class of medications in the treatment of type 2
diabetes mellitus. Their mechanism of action is to decrease the inactivation of
glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, both
of which are involved in maintaining euglycemia subsequent to carbohydrate
intake. Currently investigated agents include sitagliptin, vildagliptin,
saxagliptin, linagliptin, and alogliptin. Each agent has been shown to provide
significant improvements in glycemic control compared to placebo. They are
effective when added to other oral diabetes agents and in the cases of
sitagliptin, vildagliptin, and alogliptin in addition to insulin. These agents
may not provide as significant improvement in glucose concentrations as some
other medications including metformin, thiazolidinediones, or glucagon-like
peptide 1 agonists. The lack of head to head clinical data comparing the various
dipeptidyl peptidase 4 inhibitors does not allow for specific recommendations if
one agent is more effective or safer than another within the class. Their side
effect profile suggests they are very well tolerated and have few drug
interactions. For patients with mildly elevated glucose concentrations, they are
therapeutic options in both drug-naive patients as well as those not optimally
controlled on other diabetes medications.
DOI: 10.2174/157339912800564007
PMID: 22429011 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12374778 | 1. FASEB J. 2002 Oct;16(12):1558-66. doi: 10.1096/fj.02-0072com.
Stem cell differentiation requires a paracrine pathway in the heart.
Behfar A(1), Zingman LV, Hodgson DM, Rauzier JM, Kane GC, Terzic A, Pucéat M.
Author information:
(1)CNRS UPR1086, Centre de Recherches de Biochimie Macromoléculaire,
Montpellier, France.
Members of the transforming growth factor beta1 (TGF-beta) superfamily--namely,
TGF-beta and BMP2--applied to undifferentiated murine embryonic stem cells
up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription
factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with
these growth factors demonstrated an increased potential for cardiac
differentiation with a significant increase in beating areas and enhanced
myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells
engineered to express a fluorescent protein under the control of a cardiac
promoter differentiated into fluorescent ventricular myocytes beating in
synchrony with host cells, a process significantly enhanced by TGF-beta or BMP2.
In vitro, disruption of the TGF-beta/BMP signaling pathways by
latency-associated peptide and/or noggin prevented differentiation of stem
cells. In fact, only host cells that secrete a TGF-beta family member induced a
cardiac phenotype in stem cells. In vivo, transplantation of stem cells into
heart also resulted in cardiac differentiation provided that TGF-beta/BMP2
signaling was intact. In infarcted myocardium, grafted stem cells differentiated
into functional cardiomyocytes integrated with surrounding tissue, improving
contractile performance. Thus, embryonic stem cells are directed to
differentiate into cardiomyocytes by signaling mediated through TGF-beta/BMP2, a
cardiac paracrine pathway required for therapeutic benefit of stem cell
transplantation in diseased heart.
DOI: 10.1096/fj.02-0072com
PMID: 12374778 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26150355 | 1. Biochem Biophys Res Commun. 2015 Aug 28;464(3):685-91. doi:
10.1016/j.bbrc.2015.06.164. Epub 2015 Jul 3.
LMAN1 (ERGIC-53) is a potential carrier protein for matrix metalloproteinase-9
glycoprotein secretion.
Duellman T(1), Burnett J(1), Shin A(1), Yang J(2).
Author information:
(1)Department of Anesthesiology, University of Wisconsin School of Medicine and
Public Health, Madison, WI 53705, USA.
(2)Department of Anesthesiology, University of Wisconsin School of Medicine and
Public Health, Madison, WI 53705, USA. Electronic address: [email protected].
Matrix metalloproteinase-9 (MMP-9) is a secreted glycoprotein with a major role
in shaping the extracellular matrix and a detailed understanding of the
secretory mechanism could help identify methods to correct diseases resulting
from dysregulation of secretion. MMP-9 appears to follow a canonical secretory
pathway through a quality control cycle in the endoplasmic reticulum (ER) before
transport of the properly folded protein to the Golgi apparatus and beyond for
secretion. Through a complementation assay, we determined that LMAN1, a
well-studied lectin-carrier protein, interacts with a secretion-competent
N-glycosylated MMP-9 in the ER while N-glycosylation-deficient
secretion-compromised MMP-9 does not. In contrast, co-immunoprecipitation
demonstrated protein interaction between LMAN1 and secretion-compromised
N-glycosylation-deficient MMP-9. MMP-9 secretion was reduced in the LMAN1
knockout cell line compared to control cells confirming the functional role of
LMAN1. These observations support the role of LMAN1 as a lectin-carrier protein
mediating efficient MMP-9 secretion.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2015.06.164
PMCID: PMC4697752
PMID: 26150355 [Indexed for MEDLINE] |