pubmed_id
stringlengths 39
43
| abstract
stringlengths 3
18k
|
|---|---|
http://www.ncbi.nlm.nih.gov/pubmed/18477895 | 1. Melanoma Res. 2008 Jun;18(3):208-13. doi: 10.1097/CMR.0b013e3283036aa1.
Increased expression of p73Deltaex2 transcript in uveal melanoma with loss of
chromosome 1p.
Kilic E(1), Brüggenwirth HT, Meier M, Naus NC, Beverloo HB, Meijerink JP, Luyten
GP, de Klein A.
Author information:
(1)Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands.
The loss of chromosome 1p and chromosome 3 is associated with metastatic disease
and decreased survival of uveal melanoma (UM) patients. The p53 homologues, p73
and p63, are located on chromosomes 1p and 3q, respectively. Both are able to
activate p53 target genes, resulting in growth arrest, apoptosis and
differentiation. N-terminally truncated isoforms of these genes may act as
dominant negative inhibitors of wild-type p53 and transactivating activity.
Although, p53 is frequently involved in several malignancies it does not play a
major role in UM. Altered expression has been reported for both p63 and p73 in
various malignancies. In this study, fluorescent in-situ hybridization was
performed to identify gains or losses of p63 and p73 loci in UM. The expression
of the different p63 and p73 isoforms was evaluated by reverse transcriptase PCR
followed by Southern blot analysis. Furthermore, the expression pattern of the
various DeltaTAp73 transcripts was analysed in seven primary UMs and 11
UM-derived cell lines using isoform-specific real-time PCR. Our results
indicated that the isoform p73Deltaex2/3 was abundantly expressed and a relative
loss of the p73 locus was associated with the upregulation of p73Deltaex2 and
TAp73 transcripts. N-terminal transactivation forms of both p73 and p63 were
observed in primary and metastasis-derived cell lines, as well as in primary
melanomas, but in only one of the cell lines a DeltaNp63 mRNA transcript was
observed. Our data suggest a potential function of p73 deletion transcripts in
UM progression.
DOI: 10.1097/CMR.0b013e3283036aa1
PMID: 18477895 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18611950 | 1. Nucleic Acids Res. 2008 Aug;36(13):4498-509. doi: 10.1093/nar/gkn414. Epub
2008 Jul 8.
TAp73beta and DNp73beta activate the expression of the pro-survival caspase-2S.
Toh WH(1), Logette E, Corcos L, Sabapathy K.
Author information:
(1)Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer
Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610,
Singapore.
p73, the p53 homologue, exists as a transactivation-domain-proficient TAp73 or
deficient deltaN(DN)p73 form. Expectedly, the oncogenic DNp73 that is capable of
inactivating both TAp73 and p53 function, is over-expressed in cancers. However,
the role of TAp73, which exhibits tumour-suppressive properties in gain or loss
of function models, in human cancers where it is hyper-expressed is unclear. We
demonstrate here that both TAp73 and DNp73 are able to specifically
transactivate the expression of the anti-apoptotic member of the caspase family,
caspase-2(S). Neither p53 nor TAp63 has this property, and only the p73beta
form, but not the p73alpha form, has this competency. Caspase-2 promoter
analysis revealed that a non-canonical, 18 bp GC-rich Sp-1-binding
site-containing region is essential for p73beta-mediated activation. However,
mutating the Sp-1-binding site or silencing Sp-1 expression did not affect
p73beta's transactivation ability. In vitro DNA binding and in vivo chromatin
immunoprecipitation assays indicated that p73beta is capable of directly binding
to this region, and consistently, DNA binding p73 mutant was unable to
transactivate caspase-2(S). Finally, DNp73beta over-expression in neuroblastoma
cells led to resistance to cell death, and concomitantly to elevated levels of
caspase-2(S.) Silencing p73 expression in these cells led to reduction of
caspase-2(S) expression and increased cell death. Together, the data identifies
caspase-2(S) as a novel transcriptional target common to both TAp73 and DNp73,
and raises the possibility that TAp73 may be over-expressed in cancers to
promote survival.
DOI: 10.1093/nar/gkn414
PMCID: PMC2490756
PMID: 18611950 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18075272 | 1. Neurodegener Dis. 2008;5(1):27-31. doi: 10.1159/000109935.
Campath-1H treatment of multiple sclerosis.
Jones JL(1), Coles AJ.
Author information:
(1)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
[email protected]
Campath-1H is a humanised monoclonal antibody that targets CD52, a cell surface
protein expressed on lymphocytes, monocytes and eosinophils. A single dose of
Campath-1H leads to a rapid and profound lymphopenia. Campath-1H has been used
in Cambridge as an experimental treatment of multiple sclerosis for more than 15
years. Here, we summarise our clinical and laboratory findings, describing how
this prototypical 'bench to bedside' therapy continues to inform basic science,
revealing aspects of the pathogenesis of multiple sclerosis and autoimmunity.
Copyright (c) 2008 S. Karger AG, Basel.
DOI: 10.1159/000109935
PMID: 18075272 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16467208 | 1. Blood. 2006 Jun 1;107(11):4549-53. doi: 10.1182/blood-2005-07-2829. Epub 2006
Feb 7.
MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic
trioxide-induced apoptosis.
Lunghi P(1), Costanzo A, Salvatore L, Noguera N, Mazzera L, Tabilio A, Lo-Coco
F, Levrero M, Bonati A.
Author information:
(1)Department of Clinical Sciences, Section of Hemato-Oncology, University of
Parma, Via Gramsci 14, 43100 Parma, Italy.
We found that MEK1 inhibitor PD184352 strikingly increased apoptosis induced by
arsenic trioxide (ATO) in 21 of 25 patients with primary acute myelogenous
leukemia (AML). Isobologram analysis confirmed the synergistic (13 of 25
patients) or additive (8 of 25 patients) nature of this interaction. Moreover,
we demonstrated that the p53-related gene p73 is a molecular target of the
combined treatment in AML blasts. Indeed, ATO modulates the expression of the
p73 gene by inducing the proapoptotic and antiproliferative TAp73 and the
antiapoptotic and proproliferative DeltaNp73 isoforms, thereby failing to
elevate the TA/DeltaNp73 ratio. Conversely, treatment with PD184352 reduces the
level of DeltaNp73 and blunts the arsenic-mediated up-regulation of DeltaNp73,
thus causing an increase in the TA/DeltaNp73 ratio of dual-treated cells. High
doses of ATO induced p53 accumulation in 11 of 21 patients. Combined treatment
resulted in the induction of the proapoptotic p53/p73 target gene p53AIP1
(p53-regulated apoptosis-inducing protein 1) and greatly enhanced the apoptosis
of treated cells.
DOI: 10.1182/blood-2005-07-2829
PMID: 16467208 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17204552 | 1. Endocrinology. 2007 Apr;148(4):1921-7. doi: 10.1210/en.2006-1172. Epub 2007
Jan 4.
Thyronamines are substrates for human liver sulfotransferases.
Pietsch CA(1), Scanlan TS, Anderson RJ.
Author information:
(1)Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska
68105, and University of California, San Francisco 94143, USA.
Sulfotransferases (SULTs) catalyze the sulfation of many endogenous compounds
that include monoamine neurotransmitters, such as dopamine (DA), and thyroid
hormones (iodothyronines). Decarboxylation of iodothyronines results in
formation of thyronamines. In the mouse, thyronamines act rapidly in a
nongenomic fashion to initiate hypothermia and decrease cardiac output and heart
rate. These effects are attenuated after 1-4 h, and metabolism of thyronamines
via sulfation may be a mechanism for termination of thyronamine action. We
carried out this study to test thyronamine (T0AM), 3-iodothyronamine (T1AM),
3,5-diiodothyronamine (T2AM), and 3,5,3'-triiodothyronamine (T3AM) as substrates
for human liver and cDNA-expressed SULT activities. We characterized several
biochemical properties of SULTs using the thyronamines that acted as substrates
for SULT activities in a human liver high-speed supernatant pool (n=3). T1AM led
to the highest SULT activity. Activities with T0AM and T3AM were 10-fold lower,
and there was no detectable activity with T2AM. Thyronamines were then tested as
substrates with eight cDNA-expressed SULTs (1A1, 1A2, 1A3, 1C2, 1E1, 2A1, 2B1a,
and 2B1b). Expressed SULT1A3 had the greatest activity with T0AM, T1AM, and
T3AM, whereas SULT1A1 showed similar activity only with T3AM. Expressed SULT1E1
had low activity with each substrate. T1AM, the most active thyronamine
pharmacologically, was associated with the greatest SULT activity of the
thyronamines tested in the liver pool and in both the expressed SULT1A3 and
SULT1E1 preparations. Our results support the conclusion that sulfation
contributes to the metabolism of thyronamines in human liver and that SULT
activities may regulate the physiological effects of endogenous thyronamines.
DOI: 10.1210/en.2006-1172
PMID: 17204552 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23252497 | 1. Future Microbiol. 2013 Jan;8(1):123-31. doi: 10.2217/fmb.12.132.
Molecular mechanisms driving respiratory syncytial virus assembly.
Shaikh FY(1), Crowe JE Jr.
Author information:
(1)Department of Pathology, Microbiology & Immunology, Vanderbilt University
Medical Center, Nashville, TN 37232, USA.
Respiratory syncytial virus is a single-stranded RNA virus in the
Paramyxoviridae family that preferentially assembles and buds from the apical
surface of polarized epithelial cells, forming filamentous structures that
contain both viral proteins and the genomic RNA. Recent studies have described
both viral and host factors that are involved in ribonucleoprotein assembly and
trafficking of viral proteins to the cell surface. At the cell surface, viral
proteins assemble into filaments that probably require interactions between
viral proteins, host proteins and the cell membrane. Finally, a membrane
scission event must occur to release the free virion. This article will review
the recent literature describing the mechanisms that drive respiratory syncytial
virus assembly and budding.
DOI: 10.2217/fmb.12.132
PMCID: PMC3577052
PMID: 23252497 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed. No writing assistance was utilized
in the production of this manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/15049789 | 1. Pediatr Transplant. 2004 Apr;8(2):106-12. doi:
10.1046/j.1399-3046.2003.00139.x.
Present experience with Campath-1H in organ transplantation and its potential
use in pediatric recipients.
Knechtle SJ(1).
Author information:
(1)Division of Transplantation, Department of Surgery, University of Wisconsin
Medical School, Madison, WI 53792-7375, USA. [email protected]
Campath-1H is a humanized monoclonal antibody directed at CD52 expressed on
lymphocytes and other cells of the immune system. It has been tested extensively
in lymphoid malignancies, autoimmune diseases including rheumatoid arthritis,
multiple sclerosis, and organ transplantation. Although its use in children has
been limited to date, so far it appears to be well tolerated in children.
Currently, studies are being implemented to further assess its safety and
efficacy in pediatric organ transplantation. Immune cell depletion using
Campath-1H appears to be particularly useful in organ transplantation in that
lower doses of maintenance immunosuppressive drugs are needed. This feature is
particularly attractive in children.
DOI: 10.1046/j.1399-3046.2003.00139.x
PMID: 15049789 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17029218 | 1. J Pathol. 2006 Dec;210(4):390-7. doi: 10.1002/path.2066.
The presence of an intronic deletion in p73 and high levels of ZEB1 alter the
TAp73/DeltaTAp73 ratio in colorectal carcinomas.
Domínguez G(1), Peña C, Silva J, García JM, García V, Rodríguez R, Cantos B,
Citores MJ, España P, Bonilla F.
Author information:
(1)Department of Medical Oncology, Hospital Universitario Puerta de Hierro,
Madrid, Spain. [email protected]
TAp73 variants largely mimic p53 suppressor activities, while DeltaTAp73 forms
act as oncogenes through the inactivation of p53 and TAp73. The present study
analysed how TAp73 and DeltaTAp73 levels might be affected by the presence of a
73 bp deletion in a regulatory region of p73. The clinical relevance of this
deletion was also examined. ZEB1 can bind to the region repressing p73
transcription in vitro. The relationship between ZEB1 and p73 variant expression
levels was studied in the context of this deletion and the levels of the ZEB1
cofactors p300 and CtBP. Tumour and normal tissue from 81 colorectal cancer
patients was analysed to evaluate firstly the levels of TAp73, DeltaTAp73
(DeltaEx2p73, DeltaEx2/3p73, and DeltaNp73), ZEB1, p300, and CtBP by
quantitative real-time RT-PCR, and secondly the presence of the 73 bp deletion.
Tumour characteristics were examined in each patient. Suppressor and oncogenic
isoforms of p73 were co-up-regulated in tumour tissues. Overexpression of p73
variants was associated with adverse tumour features. The 73 bp deletion was
present in 40% of the patients and was associated with adverse pathological
parameters of the tumours and also with TAp73 down-regulation. In those cases
harbouring the deletion, the levels of ZEB1 and those of DeltaEx2p73,
DeltaEx2/3p73, and DeltaNp73 correlated directly. Variations in the
concentration of p300 affected the observed correlations between ZEB1 and the
different p73 variants. In conclusion, in colorectal cancer, the 73 bp deletion
in the first intron of the p73 gene and different expression levels of ZEB1 and
p300 may act in concert to affect the ratio of TAp73/DeltaTAp73 forms, favouring
p73 oncogenic variants. In addition, up-regulation of p73 oncogenic isoforms
predicts a poor prognosis based on its relationship with advanced tumour stage.
DOI: 10.1002/path.2066
PMID: 17029218 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23393205 | 1. Neuro Oncol. 2013 Apr;15(4):423-32. doi: 10.1093/neuonc/nos329. Epub 2013 Feb
7.
Prognostic significance of telomerase-associated parameters in glioblastoma:
effect of patient age.
Lötsch D(1), Ghanim B, Laaber M, Wurm G, Weis S, Lenz S, Webersinke G, Pichler
J, Berger W, Spiegl-Kreinecker S.
Author information:
(1)Institute of Cancer Research, Department of Medicine I, Medical University
Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
BACKGROUND: Glioblastoma multiforme (GBM) is a heterogeneous, highly aggressive
primary brain tumor with strongly variable patient survival. Because reliable
prognostic biomarkers are lacking, we investigated the relation between
telomerase-associated parameters and the disease course.
METHODS: Telomerase-associated parameters were determined in 100 GBM tissues and
associated with clinical characteristics and overall survival. Expressions of
telomere length, telomerase activity (TA), and human telomerase reverse
transcriptase (hTERT) were analyzed by quantitative PCR, telomeric repeat
amplification protocol assay, and reverse transcriptase-PCR, respectively.
Mutation status of isocitrate dehydrogenase (IDH)1 was determined by direct
sequencing, and O(6)-methylguanine DNA methyltransferase (MGMT) promoter
methylation by methylation-specific PCR.
RESULTS: Of 100 GBM tissues, 61 were positive for both hTERT mRNA and TA, with a
highly significant correlation between both parameters (linear regression, P <
.0001). Telomere length determination revealed a significant difference between
the hTERT/TA-positive and -negative subgroups, with markedly longer telomeres in
the hTERT/TA-negative cohort (unpaired Student's t-test, P = .0001).
Accordingly, significantly shorter telomeres were detected in GBM tissues
derived from older patients (>60 y at diagnosis, P < .0001). While no
association of telomere parameters with MGMT promoter status was found, all
tumors with IDH1 mutation (6/100) were negative for both hTERT expression and TA
and harbored significantly longer telomeres. Patients with tumors lacking hTERT
expression/TA showed a significant survival benefit (Kaplan-Meier test, both P <
.01), which, however, was based exclusively on the younger patient subgroup (≤60
y, both P < .005; >60 y, both ns).
CONCLUSIONS: Telomerase activation is not an independent prognostic parameter in
GBM but predicts aggressive tumor behavior solely in a younger patient cohort.
DOI: 10.1093/neuonc/nos329
PMCID: PMC3607268
PMID: 23393205 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17671181 | 1. Cancer Res. 2007 Aug 1;67(15):7139-46. doi: 10.1158/0008-5472.CAN-07-0778.
Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in
mice.
Parikh C(1), Subrahmanyam R, Ren R.
Author information:
(1)Rosenstiel Basic Medical Sciences Research Center, Department of Biology,
Brandeis University, Waltham, MA 02454, USA.
RAS proteins are small GTPases that play a central role in transducing signals
that regulate cell proliferation, survival, and differentiation. The RAS
proteins interact with a common set of activators and effectors; however, they
associate with different microdomains of the plasma membrane as well as other
endomembranes and are capable of generating distinct signal outputs. Mutations
that result in constitutive activation of RAS proteins are associated with
approximately 30% of all human cancers; however, different RAS oncogenes are
preferentially associated with different types of human cancer. In myeloid
malignancies, NRAS mutations are more frequent than KRAS mutations, whereas HRAS
mutations are rare. The mechanism underlying the different frequencies of RAS
isoforms mutated in myeloid leukemia is not known. In this study, we compared
the leukemogenic potential of activated NRAS, KRAS, and HRAS in the same bone
marrow transduction/transplantation model system. We found that all three RAS
oncogenes have the ability to induce myeloid leukemias, yet have distinct
leukemogenic strengths and phenotypes. The models established here provide a
system for further studying the molecular mechanisms in the pathogenesis of
myeloid malignancies and for testing targeted therapies.
DOI: 10.1158/0008-5472.CAN-07-0778
PMCID: PMC2662707
PMID: 17671181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20088763 | 1. Curr Med Chem. 2010;17(7):640-50. doi: 10.2174/092986710790416245.
Specific immune intervention with monoclonal antibodies for the treatment of
multiple sclerosis.
Trebst C(1), Voss E, Skripuletz T, Stangel M.
Author information:
(1)Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625
Hannover, Germany. [email protected].
Multiple sclerosis (MS) is considered to be an autoimmune disease leading to
inflammatory demyelination and axonal damage in the central nervous system
(CNS). Current treatments involve non-specific immunosuppression and
immunomodulation. The development of monoclonal antibodies for therapeutic use
allows targeting of specific immune mechanisms. Natalizumab, a monoclonal
antibody directed against alpha4beta1 integrin that plays a crucial role in the
transmigration of immune cells across the blood-brain-barrier, has been licensed
for relapsing-remitting (RR) MS in 2006. Rituximab, directed against CD20
expressed on pre B-cells and B-cells has been tested successfully in a phase II
trial and suggests that several B-cell dependent mechanisms may be relevant to
the mode of action. Alemtuzumab, targeting CD52 expressed on T-cells, B-cells,
monocytes and macrophages, has also shown to be effective in early RRMS and
phase III trials are currently ongoing. Daclizumab binds to CD25, the alpha
chain of the interleukin (IL)-2 receptor, and is also being tested for RRMS.
Beside the clinical data the results from these clinical trials give also new
insights into the pathogenesis of MS. We critically discuss the potential but
also the pitfalls and potential hazards of these new therapeutic strategies.
DOI: 10.2174/092986710790416245
PMID: 20088763 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18469517 | 1. Cell Cycle. 2008 Jun 1;7(11):1587-96. doi: 10.4161/cc.7.11.5894. Epub 2008 Mar
2.
Involvement of N-terminally truncated variants of p73, deltaTAp73, in head and
neck squamous cell cancer: a comparison with p53 mutations.
Faridoni-Laurens L(1), Tourpin S, Alsafadi S, Barrois M, Temam S, Janot F,
Koscielny S, Bosq J, Bénard J, Ahomadegbe JC.
Author information:
(1)UPRESS 3535-IFR54 Univ Paris Sud, Institut Gustave Roussy, Villejuif, France.
p73, a p53-related gene, encodes two classes of isoforms with opposing
functions: (1) a full-length transactivation-competent p73 protein (TAp73) with
tumour suppressor activity; and (2) a group of NH2-terminally truncated,
transactivation-deficient p73 proteins, deltaEx2p73, deltaEx2-3p73, deltaNp73
and deltaN'p73 (collectively named deltaTAp73) with oncogenic activity. In this
study, for the first time, we analyse the deregulations of TAp73 and deltaTAp73
in head and neck squamous cell cancer (HNSCC) and compare them to p53 status. We
found that all the p73 isoforms in HNSCC tissue were upregulated with respect to
those in normal adjacent tissue. Concomitant upregulations of p73 transcripts
were often found in cancer tissue but not in normal tissue. p53 mutations and
p73 transcript alterations are not mutually exclusive. All the HNSCC specimens
studied had at least one p53 mutation and/or one deltaTAp73 transcript
alteration. Although both the deltaNp73 and the TAp73 transcripts were found to
be upregulated in head and neck cancers, the predominant protein in the cancers
analysed was deltaNp73. TAp73, in contrast, was only weakly expressed. This
finding is highly relevant and sheds light on the puzzling question of the
biological significance of TAp73 upregulation in cancers. deltaNp73 protein
levels were significantly overexpressed in HNSCC tissue compared to matched
normal tissue (p = 0.003). Furthermore, a trend was found for better overall
survival in patients with a low expression of deltaNp73. Our results show that
the deregulation of both the p53 and the p73 pathways plays an important role in
inducing head and neck cancers.
DOI: 10.4161/cc.7.11.5894
PMID: 18469517 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18486124 | 1. Eur J Pharmacol. 2008 Jun 10;587(1-3):231-6. doi:
10.1016/j.ejphar.2008.03.055. Epub 2008 Apr 7.
Cardiac effects of trace amines: pharmacological characterization of trace
amine-associated receptors.
Frascarelli S(1), Ghelardoni S, Chiellini G, Vargiu R, Ronca-Testoni S, Scanlan
TS, Grandy DK, Zucchi R.
Author information:
(1)Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa,
Italy.
Trace amine-associated receptors, a novel class of G-protein coupled receptors
which respond to trace amines but not to classical biogenic amines, have been
found to be expressed in heart. Therefore, we investigated the cardiac effects
of the trace amines p-tyramine, beta-phenylethylamine, octopamine, and
tryptamine. Isolated rat hearts were perfused in the presence of trace amines,
monitoring the hemodynamic variables. In addition, radioligand binding
experiments with [3H]-p-tyramine and [125I]-3-iodothyronamine were performed in
rat ventricular tissue. Octopamine, beta-phenylethylamine, and tryptamine
produced a dose-dependent negative inotropic effect as shown by reduced cardiac
output (IC(50)=109 microM, 159 microM, and 242 microM, respectively). In the
same preparation a similar effect was produced by thyronamine and
3-iodothyronamine, with IC(50)=94 microM and 27 microM, respectively. The
negative inotropic effect of octopamine was confirmed in a papillary muscle
preparation. All trace amines except tryptamine increased the heart rate, but
this action could be attributed to their sympathomimetic properties, since it
was abolished by propranolol. The negative inotropic effect of trace amines was
significantly increased by the tyrosine kinase inhibitor genistein. Specific and
saturable binding of [(3)H]-p-tyramine and [125I]-3-iodothyronamine was observed
in ventricular tissue. While [3H]-p-tyramine was displaced by 3-iodothyronamine,
[(125)I]-3-iodothyronamine was not displaced by p-tyramine. In conclusion, trace
amines and thyronamines are negative inotropic agents. Their effect appears to
be mediated by a subtype of trace amine-associated receptor which is
characterized by the rank of potency: 3-iodothyronamine > thyronamine =
octopamine = beta-phenylethylamine, while tryptamine and p-tyramine are
significantly less active.
DOI: 10.1016/j.ejphar.2008.03.055
PMID: 18486124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17047653 | 1. Br J Cancer. 2006 Oct 23;95(8):1062-9. doi: 10.1038/sj.bjc.6603410.
Prognostic value of increase in transcript levels of Tp73 DeltaEx2-3 isoforms in
low-grade glioma patients.
Wager M(1), Guilhot J, Blanc JL, Ferrand S, Milin S, Bataille B, Lapierre F,
Denis S, Chantereau T, Larsen CJ, Karayan-Tapon L.
Author information:
(1)Neurosurgery Department, University Hospital, Poitiers, France.
[email protected]
Glial tumours are a devastating, poorly understood condition carrying a gloomy
prognosis for which clinicians sorely lack reliable predictive parameters
facilitating a sound treatment strategy. Tp73, a p53 family member, expresses
two main classes of isoforms--transactivatory activity (TA)p73 and
DeltaTAp73--exhibiting tumour suppressor gene and oncogene properties,
respectively. The authors examined their expression status in high- and
low-grade adult gliomas. Isoform-specific real-time reverse
transcription-polymerase chain reaction was used for the analysis of Tp73
isoform transcript expression in a series of 51 adult patients harbouring glial
tumours, in order to compare tumour grades with each other, and with
non-tumoural samples obtained from epileptic patients as well. Our data
demonstrate increase of TAp73 and DeltaTAp73 transcript levels at onset and
early stage of the disease. We also show that DeltaEx2-3 isoform expression in
low-grade tumours anticipates clinical and imaging progression to higher grades,
and correlates to the patients' survival. Expression levels of P1 promoter
generated Tp73 isoforms--and particularly DeltaEx2-3--indeed allow for
prediction of the clinical progression of low-grade gliomas in adults. Our data
are the first such molecular biology report regarding low-grade tumours and as
such should be of help for sound decision-making.
DOI: 10.1038/sj.bjc.6603410
PMCID: PMC2360700
PMID: 17047653 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14676279 | 1. J Cell Sci. 2004 Jan 15;117(Pt 2):293-301. doi: 10.1242/jcs.00834.
Differential response of p53 target genes to p73 overexpression in SH-SY5Y
neuroblastoma cell line.
Goldschneider D(1), Blanc E, Raguénez G, Barrois M, Legrand A, Le Roux G,
Haddada H, Bénard J, Douc-Rasy S.
Author information:
(1)Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8126,
39 rue Camille Desmoulins, 94805 Villejuif, France.
p73, the first p53 gene homologue, encodes an array of p73 proteins including
p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73
alpha), two proteins with opposite biological functions. TAp73 alpha can induce
tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as
TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein
is wild-type but known to be excluded from the nucleus, therefore disabling its
function as a tumor suppressor. The present study investigates whether there is
a functional link between p73 isoforms and p53 in neuroblastoma. Experiments
were performed on two neuroblastoma cell lines differing in their p53 status,
e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate
that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y
cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y
cells does forced TAp73 alpha overexpression markedly induce nuclear
accumulation of p53 protein; (iii) p21 protein expression is increased in both
cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is
induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line,
Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser
extent in cells overexpressing Delta N. Taken together our results suggest that
TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not
in NB with mutated p53.
DOI: 10.1242/jcs.00834
PMID: 14676279 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22740507 | 1. J Cell Biochem. 2012 Nov;113(11):3301-12. doi: 10.1002/jcb.24234.
Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic
lateral sclerosis.
van Zundert B(1), Izaurieta P, Fritz E, Alvarez FJ.
Author information:
(1)Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical
Research, Universidad Andres Bello, Avenida Republica 217, Santiago, Chile.
[email protected].
Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused
by dysfunction and degeneration of motor neurons starting in adulthood. Most of
our knowledge about the pathophysiological mechanisms of ALS comes from
transgenic mice models that emulate a subgroup of familial ALS cases (FALS),
with mutations in the gene encoding superoxide dismutase (SOD1). In the more
than 15 years since these mice were generated, a large number of abnormal
cellular mechanisms underlying motor neuron degeneration have been identified,
but to date this effort has led to few improvements in therapy, and no cure.
Here, we consider that this surfeit of mechanisms is best interpreted by current
insights that suggest a very early initiation of pathology in motor neurons,
followed by a diversity of secondary cascades and compensatory mechanisms that
mask symptoms for decades, until trauma and/or aging overloads their protective
function. This view thus posits that adult-onset ALS is the consequence of
processes initiated during early development. In fact, motor neurons in neonatal
mutant SOD mice display important alterations in their intrinsic electrical
properties, synaptic inputs and morphology that are accompanied by subtle
behavioral abnormalities. We consider evidence that human mutant SOD1 protein in
neonatal hSOD1(G93A) mice instigates motor neuron degeneration by increasing
persistent sodium currents and excitability, in turn altering synaptic circuits
that control excessive motor neuron firing and leads to excitotoxicity. We also
discuss how therapies that are aimed at suppressing abnormal neuronal activity
might effectively mitigate or prevent the onset of irreversible neuronal damage
in adulthood. J. Cell. Biochem. 113: 3301-3312, 2012. © 2012 Wiley Periodicals,
Inc.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/jcb.24234
PMCID: PMC3886915
PMID: 22740507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15869731 | 1. Curr Treat Options Oncol. 2005 May;6(3):197-208. doi:
10.1007/s11864-005-0003-4.
Prolymphocytic leukemia.
Absi A(1), Hsi E, Kalaycio M.
Author information:
(1)Taussig Cancer Cancer, The Cleveland Clinic Foundation, 9500 Euclid Avenue
R35, Cleveland OH 44195, USA.
Prolymphocytic leukemia is a rare chronic lymphoproliferative disorder that
includes two subtypes, B cell and T cell, each with its own distinct clinical,
laboratory and pathological features. T-cell prolymphocytic leukemia has an
aggressive course with short median survival and poor response to chemotherapy.
With the use of the purine analogue pentostatin more than half of patients will
have a major response and a minority will have a complete remission, usually
lasting months. With the introduction of alemtuzumab, most patients who
progressed despite treatment with pentostatin had a major response with a
complete remission rate higher than that obtained with pentostatin when used as
a first line. Unfortunately, progression still follows shortly. We recommend
alemtuzumab as initial therapy and offer stem cell transplant (SCT) to selected
young, healthy patients who respond. Although B-cell prolymphocytic leukemia is
also a progressive disease, some patients can achieve a prolonged
progression-free-survival with fludarabine. Patients presenting with massive
splenomegaly may be effectively palliated with splenic irradiation or
splenectomy. Rituximab is a promising agent and further investigations are
warranted to better define its role in treatment of this disorder.
DOI: 10.1007/s11864-005-0003-4
PMID: 15869731 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17076661 | 1. J Neurochem. 2006 Nov;99(3):989-99. doi: 10.1111/j.1471-4159.2006.04142.x.
TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in
primary neurones.
Hooper C(1), Tavassoli M, Chapple JP, Uwanogho D, Goodyear R, Melino G,
Lovestone S, Killick R.
Author information:
(1)King's College London, MRC Centre for Neurodegenerative Research, Institute
of Psychiatry, London, UK.
p73, like Notch, has been implicated in neurodevelopment and in the maintenance
of the mature central nervous system. In this study, by the use of reporter-gene
assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene
transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently
antagonized by exogenously expressed transactivating (TA) p73 splice variants in
SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated
that the inhibitory effects of TAp73 are direct and are not mediated via the
product of a downstream target gene. We found that endogenous TAp73 stabilized
by either c-Abl or cisplatin treatment also potently antagonized
N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting
revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of
split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein
induced by exogenous N1(ICD) expression. Evidence of a direct physical
interaction between N1(ICD) and TAp73alpha was demonstrated by
co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that
TAp73alpha binds the N1(ICD) in a region C-terminal of aa 2094. Interestingly,
DeltaNp73alpha and TAp73alpha(R292H) also co-purified with N1(ICD), but neither
inhibited N1(ICD)/CBF-1-dependent transcription. This suggests that an intact
transactivation (TA) domain and the ability to bind DNA are necessary for TAp73
to antagonize Notch signalling. Finally we found that TAp73alpha reversed the
N1(ICD)-mediated repression of retinoic acid-induced differentiation of SH-SY5Y
neuroblastomas, providing functional evidence for an inhibitory effect of
TAp73alpha on notch signalling. Collectively, these findings may have
ramifications for neurodevelopment, neurodegeneration and oncogenesis.
DOI: 10.1111/j.1471-4159.2006.04142.x
PMID: 17076661 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22562246 | 1. Oncogene. 2013 Mar 14;32(11):1351-62. doi: 10.1038/onc.2012.169. Epub 2012 May
7.
Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in
breast cancer.
Dong C(1), Wu Y, Wang Y, Wang C, Kang T, Rychahou PG, Chi YI, Evers BM, Zhou BP.
Author information:
(1)Department of Molecular and Cellular Biochemistry, The University of Kentucky
College of Medicine, Lexington, KY, USA.
Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT),
is often lost due to promoter DNA methylation in basal-like breast cancer
(BLBC), which contributes to the metastatic advantage of this disease; however,
the underlying mechanism remains unclear. Here, we identified that Snail
interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major
methyltransferase responsible for H3K9me3 that intimately links to DNA
methylation. We demonstrated that the SNAG domain of Snail and the SET domain of
Suv39H1 were required for their mutual interactions. We found that H3K9me3 and
DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We
showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin
promoter for transcriptional repression. Knockdown of Suv39H1 restored
E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in
the inhibition of cell migration, invasion and metastasis of BLBC. Our study not
only reveals a critical mechanism underlying the epigenetic regulation of EMT,
but also paves a way for the development of new treatment strategies against
this disease.
DOI: 10.1038/onc.2012.169
PMCID: PMC3703513
PMID: 22562246 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST The authors declare that
there is no conflict any interest. |
http://www.ncbi.nlm.nih.gov/pubmed/10605118 | 1. Mol Biol Evol. 1999 Dec;16(12):1774-84. doi:
10.1093/oxfordjournals.molbev.a026089.
The phylogeny of land plants inferred from 18S rDNA sequences: pushing the
limits of rDNA signal?
Soltis PS(1), Soltis DE, Wolf PG, Nickrent DL, Chaw SM, Chapman RL.
Author information:
(1)Department of Botany, Washington State University, Pullman 99164-4238, USA.
[email protected]
Previous studies of the phylogeny of land plants based on analysis of 18S
ribosomal DNA (rDNA) sequences have generally found weak support for the
relationships recovered and at least some obviously spurious relationships,
resulting in equivocal inferences of land plant phylogeny. We hypothesized that
greater sampling of both characters and taxa would improve inferences of land
plant phylogeny based on 18S rDNA sequences. We therefore conducted a
phylogenetic analysis of complete (or nearly complete) 18S rDNA sequences for 93
species of land plants and 7 green algal relatives. Parsimony analyses with
equal weighting of characters and characters state changes and parsimony
analyses weighting (1) stem bases half as much as loop bases and (2) transitions
half as much as transversions did not produce substantially different
topologies. Although the general structure of the shortest trees is consistent
with most hypotheses of land plant phylogeny, several relationships,
particularly among major groups of land plants, appear spurious. Increased
character and taxon sampling did not substantially improve the performance of
18S rDNA in phylogenetic analyses of land plants, nor did analyses designed to
accommodate variation in evolutionary rates among sites. The rate and pattern of
18S rDNA evolution across land plants may limit the usefulness of this gene for
phylogeny reconstruction at deep levels of plant phylogeny. We conclude that the
mosaic structure of 18S rDNA, consisting of highly conserved and highly variable
regions, may contain historical signal at two levels. Rapidly evolving regions
are informative for relatively recent divergences (e.g., within angiosperms,
seed plants, and ferns), but homoplasy at these sites makes it difficult to
resolve relationships among these groups. At deeper levels, changes in the
highly conserved regions of small-subunit rDNAs provide signal across all of
life. Because constraints imposed by the secondary structure of the rRNA may
affect the phylogenetic information content of 18S rDNA, we suggest that 18S
rDNA sequences be combined with other data and that methods of analysis be
employed to accommodate these differences in evolutionary patterns, particularly
across deep divergences in the tree of life.
DOI: 10.1093/oxfordjournals.molbev.a026089
PMID: 10605118 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21664427 | 1. Mol Cell Endocrinol. 2011 Jul 20;341(1-2):55-62. doi:
10.1016/j.mce.2011.05.013. Epub 2011 Jun 1.
Effects of the thyroid hormone derivatives 3-iodothyronamine and thyronamine on
rat liver oxidative capacity.
Venditti P(1), Napolitano G, Di Stefano L, Chiellini G, Zucchi R, Scanlan TS, Di
Meo S.
Author information:
(1)Dipartimento delle Scienze Biologiche, Sezione di Fisiologia, Università di
Napoli, I-80134 Napoli, Italy. [email protected]
Thyronamines T(0)AM and T(1)AM are naturally occurring decarboxylated thyroid
hormone derivatives. Their in vivo administration induces effects opposite to
those induced by thyroid hormone, including lowering of body temperature. Since
the mitochondrial energy-transduction apparatus is known to be a potential
target of thyroid hormone and its derivatives, we investigated the in vitro
effects of T(0)AM and T(1)AM on the rates of O(2) consumption and H(2)O(2)
release by rat liver mitochondria. Hypothyroid animals were used because of the
low levels of endogenous thyronamines. We found that both compounds are able to
reduce mitochondrial O(2) consumption and increase H(2)O(2) release. The
observed changes could be explained by a partial block, operated by
thyronamines, at a site located near the site of action of antimycin A. This
hypothesis was confirmed by the observation that thyronamines reduced the
activity of Complex III where the site of antimycin action is located. Because
thyronamines exerted their effects at concentrations comparable to those found
in hepatic tissue, it is conceivable that they can affect in vivo mitochondrial
O(2) consumption and H(2)O(2) production acting as modulators of thyroid hormone
action.
Copyright © 2011. Published by Elsevier Ireland Ltd.
DOI: 10.1016/j.mce.2011.05.013
PMCID: PMC5297583
PMID: 21664427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19295128 | 1. J Cell Sci. 2009 Apr 1;122(Pt 7):1014-24. doi: 10.1242/jcs.028241.
The class I bHLH factors E2-2A and E2-2B regulate EMT.
Sobrado VR(1), Moreno-Bueno G, Cubillo E, Holt LJ, Nieto MA, Portillo F, Cano A.
Author information:
(1)Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de
Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM),
28029 Madrid, Spain.
Functional loss of the cell-cell adhesion molecule E-cadherin is an essential
event for epithelial-mesenchymal transition (EMT), a process that allows cell
migration during embryonic development and tumour invasion. In most carcinomas,
transcriptional repression has emerged as the main mechanism responsible for
E-cadherin downregulation. Here, we report the identification of class I bHLH
factor E2-2 (TCF4/ITF2) as a new EMT regulator. Both isoforms of E2-2 (E2-2A and
E2-2B) induce a full EMT when overexpressed in MDCK cells but without affecting
the tumorigenic properties of parental cells, in contrast to other EMT inducers,
such as Snail1 or class I bHLH E47. E-cadherin repression mediated by E2-2 is
indirect and independent of proximal E-boxes of the promoter. Knockdown studies
indicate that E2-2 expression is dispensable for maintenance of the EMT driven
by Snail1 and E47. Comparative gene-profiling analysis reveals that E2-2 factors
induce similar, yet distinct, genetic programs to that induced by E47 in MDCK
cells. These results, together with the embryonic expression pattern of Tcf4 and
E2A (which encodes E12/E47), support a distinct role for E2-2 and suggest an
interesting interplay between E-cadherin repressors in the regulation of
physiological and pathological EMT processes.
DOI: 10.1242/jcs.028241
PMID: 19295128 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15805007 | 1. Syst Biol. 2005 Feb;54(1):4-20. doi: 10.1080/10635150590906028.
Exploring rate variation among and within sites in a densely sampled tree:
species level phylogenetics of north american tiger beetles (genus cicindela).
Vogler A(1), Cardoso A, Barraclough T.
Author information:
(1)Department of Entomology, The Natural History Museum, London SW7 5BD, United
Kingdom. [email protected]
Species-level phylogenetic studies require fast-evolving nucleotide positions to
resolve relationships among close relatives, but these sites may be highly
homoplastic and perhaps uninformative or even misleading deeper in the tree.
Here we describe a species-level analysis of tiger beetles in the genus
Cicindela (Coleoptera: Cicindelidae) for 132 terminal taxa and 1897 nucleotide
positions from three regions of mtDNA, comprising 75% coverage of species
occurring in North America. Evenly weighted parsimony analysis recovered four
major clades representing radiations confined to North and Central America.
Relationships near the tips were well supported but signal was contradictory at
deeper nodes. Two major categories (3rd positions and all others) can be
distinguished in likelihood analysis of character variation, of which only the
fast-changing 3rd position characters were affected by saturation. However,
their downweighting under a variety of criteria did not improve the tree
topology at basal nodes. There was weak conflict between 3rd and non-3rd
position characters deep in the tree, but support levels declined towards the
root for all categories, even on trees that were reconstructed from 3rd and
non-3rd positions separately. Statistical analysis of parsimony-based character
transitions along branches showed a largely homogeneous distribution of change
along the root-to-tip axis. The comparison of character transitions among the
four major portions of the tree revealed deviations from stochastic distribution
for the non-3rd positions, but not for 3rd positions. Hence, variability of
functionally constrained non-3rd positions differs between clades and may be
dependent on the character states at other sites, consistent with the covarion
model of molecular evolution. The results suggest that some properties of 3rd
positions are less problematic for phylogenetic reconstruction than other
categories despite their high total homoplasy. In densely sampled data sets of
closely related species, the disadvantages of weighting schemes according to
homoplasy levels outweigh the benefits, showing the difficulty of devising
meaningful weighting schemes that are applicable universally throughout the
tree.
DOI: 10.1080/10635150590906028
PMID: 15805007 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17118783 | 1. Cancer Invest. 2006 Nov;24(7):718-25. doi: 10.1080/07357900600981414.
Alemtuzumab in CLL and other lymphoid neoplasms.
Ravandi F(1), O'brien S.
Author information:
(1)Department of Leukemia, University of Texas M.D. Anderson Cancer Center,
Houston, Texas 77030-4095, USA. [email protected]
The recent success of monoclonal antibodies in the treatment of various
hematological and nonhematological cancers is the result of several decades of
research in immune therapy of cancer. The identification of cancer-specific
surface markers has led to the development of numerous monoclonal antibodies
directed at these antigens, which have been associated with variable success in
treating patients with different malignancies. Alemtuzumab, one such monoclonal
antibody, is a humanized antibody directed against CD52. The target antigen is a
small glycosylphosphatidylinositol (GPI)-anchored glycoprotein that is highly
expressed on normal T- and B-lymphocytes and on a large proportion of malignant
lymphoid cells, but not on hematopoietic progenitor cells. A number of clinical
trials have demonstrated the clinical activity of alemtuzumab in chronic
lymphocytic leukemia (CLL), T-cell malignancies such as T-prolymphocytic
leukemia (T-PLL) and cutaneous T-cell lymphoma (CTCL), and have examined its
role as an immunosuppressive agent in transplantation and for the treatment of
autoimmune disorders. Effective antibiotic prophylaxis can limit the incidence
of infections, which are the major side effect associated with the profound
lymphopenia occurring as a result of treatment with this agent.
DOI: 10.1080/07357900600981414
PMID: 17118783 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24434253 | 1. Indian J Med Res. 2013 Oct;138(4):449-60.
New treatment strategies for Alzheimer's disease: is there a hope?
Aprahamian I, Stella F, Forlenza OV(1).
Author information:
(1)Laboratory of Neuroscience (LIM 27) Department & Institute of Psychiatry,
Faculty of Medicine,University of São Paulo, Brazil.
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative
disease, and corresponds to the most common cause of dementia worldwide.
Although not fully understood, the pathophysiology of AD is largely represented
by the neurotoxic events triggered by the beta-amyloid cascade and by
cytoskeletal abnormalities subsequent to the hyperphosphorylation of
microtubule-associated Tau protein in neurons. These processes lead respectively
to the formation of neuritic plaques and neurofibrillary tangles, which are the
pathological hallmarks of the disease. Clinical benefits of the available
pharmacological treatment for AD with antidementia drugs (namely cholinesterase
inhibitors and memantine) are unquestionable, although limited to a temporary,
symptomatic support to cognitive and related functions. Over the past decade,
substantial funding and research have been dedicated to the search and
development of new pharmaceutical compounds with disease-modifying properties.
The rationale of such approach is that by tackling key pathological processes in
AD it may be possible to attenuate or even change its natural history. In the
present review, we summarize the available evidence on the new therapeutic
approaches that target amyloid and Tau pathology in AD, focusing on
pharmaceutical compounds undergoing phase 2 and phase 3 randomized controlled
trials.
PMCID: PMC3868059
PMID: 24434253 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23946506 | 1. J Biochem. 2013 Sep;154(3):219-28. doi: 10.1093/jb/mvt066. Epub 2013 Aug 14.
Endoplasmic reticulum aminopeptidases: biochemistry, physiology and pathology.
Hattori A(1), Tsujimoto M.
Author information:
(1)Division of Bioinformatics and Chemical Genomics, Department of System
Chemotherapy and Molecular Sciences, Graduate School of Pharmaceutical Sciences,
Kyoto University, Sakyo, Kyoto 606-8501, Japan. [email protected]
The human endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 proteins were
initially identified as homologues of human placental leucine
aminopeptidase/insulin-regulated aminopeptidase. They are categorized as a
unique class of proteases based on their subcellular localization on the luminal
side of the endoplasmic reticulum. ERAPs play an important role in the
N-terminal processing of the antigenic precursors that are presented on the
major histocompatibility complex (MHC) class I molecules. ERAPs are also
implicated in the regulation of a wide variety of physiological phenomena and
pathogenic conditions. In this review, the current knowledge on ERAPs is
summarized.
DOI: 10.1093/jb/mvt066
PMID: 23946506 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20122289 | 1. Alzheimers Res Ther. 2010 Jan 22;2(1):1. doi: 10.1186/alzrt24.
Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy.
Zotova E(1), Nicoll JA, Kalaria R, Holmes C, Boche D.
Author information:
(1)Division of Clinical Neurosciences, School of Medicine, University of
Southampton, Mailpoint 806, Level D, South Pathology Block, Southampton General
Hospital, Southampton, SO16 6YD, UK. [email protected].
Evidence for the involvement of inflammatory processes in the pathogenesis of
Alzheimer's disease (AD) has been documented for a long time. However, the
inflammation hypothesis in relation to AD pathology has emerged relatively
recently. Even in this hypothesis, the inflammatory reaction is still considered
to be a downstream effect of the accumulated proteins (amyloid beta (Abeta) and
tau). This review aims to highlight the importance of the immune processes
involved in AD pathogenesis based on the outcomes of the two major
inflammation-relevant treatment strategies against AD developed and tested to
date in animal studies and human clinical trials - the use of anti-inflammatory
drugs and immunisation against Abeta.
DOI: 10.1186/alzrt24
PMCID: PMC2874260
PMID: 20122289 |
http://www.ncbi.nlm.nih.gov/pubmed/16026106 | 1. Treat Endocrinol. 2004;3(4):233-44. doi: 10.2165/00024677-200403040-00005.
Subclinical hypothyroidism and cardiovascular risk: a reason to treat?
Palmieri EA(1), Fazio S, Lombardi G, Biondi B.
Author information:
(1)Department of Clinical Medicine, Cardiovascular and Immunological Science,
University Federico II School of Medicine, Naples, Italy.
Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid
stimulating hormone (TSH) with normal levels of free thyroid hormones, is common
in adults, especially in women over 60 years of age. Among individuals with this
condition, up to two-thirds have serum TSH levels between 5-10 mU/L and thyroid
autoantibodies; almost half of them may progress to overt thyroid failure, the
annual percent risk increasing with serum TSH level. There is evidence that
elevated TSH levels in patients with SH do not reflect pituitary compensation to
maintain euthyroidism, but a mild tissue hypothyroidism sensu strictu. When
lasting more than 6-12 months, SH may be associated with an atherogenic lipid
profile, a hypercoagulable state, a subtle cardiac defect with mainly diastolic
dysfunction, impaired vascular function, and reduced submaximal exercise
capacity. The deviation from normality usually increases with serum TSH level
('dosage effect' phenomenon). Restoration of euthyroidism by levothyroxine (LT4)
treatment may correct the lipid profile and cardiac abnormalities, especially in
patients with an initially higher deviation from normality and higher serum TSH
levels. Importantly, a strong association between SH and atherosclerotic
cardiovascular disease, independent of the traditional risk factors, has been
recently reported in a large cross-sectional survey (the Rotterdam Study).
However, whether SH confers a high risk for cardiovascular disease, and whether
LT4 therapy has a long-term benefit that clearly outweighs the risks of
overzealous treatment in these individuals, remain topics of controversy.
Therefore, until randomized, controlled, prospective, and adequately powered
trials provide unequivocal answers to these critical questions, it is advisable
to prescribe LT4 therapy on a case-by-case basis, taking into account the risk
of progressive thyroid failure and the risk of cardiovascular events.
DOI: 10.2165/00024677-200403040-00005
PMID: 16026106 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11098408 | 1. C R Acad Sci III. 2000 Oct;323(10):925-41. doi: 10.1016/s0764-4469(00)01230-0.
Performance of 18S rDNA helix E23 for phylogenetic relationships within and
between the Rotifera-Acanthocephala clades.
Miquelis A(1), Martin JF, Carson EW, Brun G, Gilles A.
Author information:
(1)Laboratoire d'hydrobiologie, UPRES Biodiversité 2202, université de Provence,
Marseille, France.
The species diversity of the phylum Rotifera has been largely studied on the
basis of morphological characters. However, cladistic relationships within this
group are poorly resolved due to extensive homoplasy in morphological traits,
substantial phenotypic plasticity and a poor fossil record. We undertook this
study to determine if a phylogeny based on partial 18S rDNA, which included the
helix E23 of 18S rDNA sequence, was concordant with established taxonomic
relationships within the order Ploimida (class: Monogononta). We also estimated
the level of polymorphism within clones and populations of Ploimida 'species'.
Finally, we included the Cycliophora Symbion pandora as outgroup and the
variable helix E23 region to examine the influence of their signal on the
evolutionary relationships among Acanthocephala, Bdelloidea and Ploimida.
Phylogenetic reconstruction was performed using maximum parsimony, neighbour
joining and maximum likelihood methods. We found 1) that morphologically similar
Ploimida 'species' show vastly different 18S E23 rDNA sequences; 2) inclusion of
the helix E23 of 18S rDNA and its secondary structure analysis results in better
resolution of family level relationships within the Ploimida; 3) an impact of
Symbion pandora as an outgroup with inclusion of the helix E23 on the
relationships between the Rotifera and the Acanthocephala; and 4) partial
incongruence and differential substitution rate between conserved region and
helix E23 region of the 18S rDNA gene depending on the taxomic group studied.
DOI: 10.1016/s0764-4469(00)01230-0
PMID: 11098408 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24416617 | 1. Scientifica (Cairo). 2013;2013:635203. doi: 10.1155/2013/635203. Epub 2013 Dec
12.
Melanoma: from melanocyte to genetic alterations and clinical options.
Bertolotto C(1).
Author information:
(1)INSERM, U1065 (Équipe 1), C3M, 06204 Nice, France ; University of Nice
Sophia-Antipolis, UFR Médecine, 06204 Nice, France.
Metastatic melanoma remained for decades without any effective treatment and was
thus considered as a paradigm of cancer resistance. Recent progress with
understanding of the molecular mechanisms underlying melanoma initiation and
progression revealed that melanomas are genetically and phenotypically
heterogeneous tumors. This recent progress has allowed for the development of
treatment able to improve for the first time the overall disease-free survival
of metastatic melanoma patients. However, clinical responses are still either
too transient or limited to restricted patient subsets. The complete cure of
metastatic melanoma therefore remains a challenge in the clinic. This review
aims to present the recent knowledge and discoveries of the molecular mechanisms
involved in melanoma pathogenesis and their exploitation into clinic that have
recently facilitated bench to bedside advances.
DOI: 10.1155/2013/635203
PMCID: PMC3874946
PMID: 24416617 |
http://www.ncbi.nlm.nih.gov/pubmed/24516336 | 1. Pharmgenomics Pers Med. 2013 Dec 31;7:21-9. doi: 10.2147/PGPM.S37220.
eCollection 2014.
Dabrafenib for treatment of BRAF-mutant melanoma.
Kainthla R(1), Kim KB(2), Falchook GS(3).
Author information:
(1)Department of Internal Medicine, Baylor College of Medicine, Houston, TX,
USA.
(2)Department of Melanoma Medical Oncology, Houston, TX, USA.
(3)Department of Investigational Cancer Therapeutics, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
Melanoma has the highest mortality of all the skin cancer subtypes.
Historically, chemotherapy and immunologic therapies have yielded only modest
results in the treatment of metastatic melanoma. The discovery of prevalent V600
BRAF mutations driving proliferation makes this oncogenic protein an ideal
target for therapy. Dabrafenib, a reversible inhibitor of mutant BRAF kinase,
improved response rates and median progression-free survival in patients with
V600E BRAF-mutant metastatic melanoma, including those with brain metastases.
With a well-tolerated toxicity profile, dabrafenib is effective as a
monotherapy; however, resistance eventually develops in almost all patients. As
a result, current research is exploring the role of combination therapies with
dabrafenib to overcome resistance.
DOI: 10.2147/PGPM.S37220
PMCID: PMC3917541
PMID: 24516336 |
http://www.ncbi.nlm.nih.gov/pubmed/20018455 | 1. Med Hypotheses. 2010 May;74(5):880-3. doi: 10.1016/j.mehy.2009.11.015. Epub
2009 Dec 16.
Serotonin, pregnancy and increased autism prevalence: is there a link?
Hadjikhani N(1).
Author information:
(1)MGH/MIT/HMS Martinos Center for Biomedical Imaging, Charlestown, USA; Brain
Mind Institute, EPFL Lausanne, Switzerland. [email protected]
The prevalence of autism, a neurodevelopmental condition resulting from genetic
and environmental causes, has increased dramatically during the last decade.
Among the potential environmental factors, hyperserotonemia during pregnancy and
its effect on brain development could be playing a role in this prevalence
raise. In the rodent model developed by Whitaker-Azmitia and colleagues,
hyperserotonemia during fetal development results in a dysfunction of the
hypothalamo-pituitary axis, affecting the amygdala as well as pro-social hormone
oxytocin regulation. Dysfunction of the amygdala and abnormal oxytocin levels
may underlie many clinical features of ASD. Selective serotonin reuptake
inhibitors (SSRI) are the most widely used class of antidepressants drugs, and
they are not contraindicated during pregnancy. In this paper, we hypothesize
that increased serotonemia during pregnancy, including due to SSRI intake, could
be one of the causes of the raising prevalence in autism. If our hypothesis is
confirmed, it will not only shed light on one of the possible reason for autism
prevalence, but also offer new preventive and treatment options.
DOI: 10.1016/j.mehy.2009.11.015
PMID: 20018455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24932884 | 1. PLoS One. 2014 Jun 16;9(6):e99725. doi: 10.1371/journal.pone.0099725.
eCollection 2014.
Impact of gene molecular evolution on phylogenetic reconstruction: a case study
in the rosids (Superorder Rosanae, Angiosperms).
Hilu KW(1), Black CM(1), Oza D(1).
Author information:
(1)Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia,
United States of America.
Rate of substitution of genomic regions is among the most debated intrinsic
features that impact phylogenetic informativeness. However, this variable is
also coupled with rates of nonsynonymous substitutions that underscore the
nature and degree of selection on the selected genes. To empirically address
these variables, we constructed four completely overlapping data sets of plastid
matK, atpB, rbcL, and mitochondrial matR genes and used the rosid lineage
(angiosperms) as a working platform. The genes differ in combinations of overall
rates of nucleotide and amino acid substitutions. Tree robustness, homoplasy,
accuracy in contrast to a reference tree, and phylogenetic informativeness are
evaluated. The rapidly evolving/unconstrained matK faired best, whereas
remaining genes varied in degrees of contribution to rosid phylogenetics across
the lineage's 108 million years evolutionary history. Phylogenetic accuracy was
low with the slowly evolving/unconstrained matR despite least amount of
homoplasy. Third codon positions contributed the highest amount of parsimony
informative sites, resolution and informativeness, but magnitude varied with
gene mode of evolution. These findings are in clear contrast with the views that
rapidly evolving regions and the 3rd codon position have inevitable negative
impact on phylogenetic reconstruction at deep historic level due to accumulation
of multiple hits and subsequent elevation in homoplasy and saturation. Relaxed
evolutionary constraint in rapidly evolving genes distributes substitutions
across codon positions, an evolutionary mode expected to reduce the frequency of
multiple hits. These findings should be tested at deeper evolutionary histories.
DOI: 10.1371/journal.pone.0099725
PMCID: PMC4059714
PMID: 24932884 [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/21618162 | 1. Int J Sports Med. 2011 Aug;32(8):644-7. doi: 10.1055/s-0031-1271711. Epub 2011
May 26.
Increased average longevity among the "Tour de France" cyclists.
Sanchis-Gomar F(1), Olaso-Gonzalez G, Corella D, Gomez-Cabrera MC, Vina J.
Author information:
(1)Department of Physiology, Faculty of Medicine, University of Valencia, Spain.
It is widely held among the general population and even among health
professionals that moderate exercise is a healthy practice but long term high
intensity exercise is not. The specific amount of physical activity necessary
for good health remains unclear. To date, longevity studies of elite athletes
have been relatively sparse and the results are somewhat conflicting. The Tour
de France is among the most gruelling sport events in the world, during which
highly trained professional cyclists undertake high intensity exercise for a
full 3 weeks. Consequently we set out to determine the longevity of the
participants in the Tour de France, compared with that of the general
population. We studied the longevity of 834 cyclists from France (n=465), Italy
(n=196) and Belgium (n=173) who rode the Tour de France between the years 1930
and 1964. Dates of birth and death of the cyclists were obtained on December 31
(st) 2007. We calculated the percentage of survivors for each age and compared
them with the values for the pooled general population of France, Italy and
Belgium for the appropriate age cohorts. We found a very significant increase in
average longevity (17%) of the cyclists when compared with the general
population. The age at which 50% of the general population died was 73.5 vs.
81.5 years in Tour de France participants. Our major finding is that repeated
very intense exercise prolongs life span in well trained practitioners. Our
findings underpin the importance of exercising without the fear that becoming
exhausted might be bad for one's health.
© Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0031-1271711
PMID: 21618162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17544610 | 1. Biomed Pharmacother. 2007 Sep;61(8):482-7. doi: 10.1016/j.biopha.2007.04.004.
Epub 2007 May 21.
Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism
during normalization of thyroid function.
Nagasaki T(1), Inaba M, Yamada S, Kumeda Y, Hiura Y, Nishizawa Y.
Author information:
(1)Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City
University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka-city
545-8585, Japan.
OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the population and is
associated with increased cardiovascular morbidity, although this is
controversial. We recently reported a significant increase in brachial-ankle
pulse wave velocity (baPWV), a parameter of arterial stiffening and an
independent predictor for cardiovascular events, in subclinical hypothyroidism.
The current study was performed to assess changes in enhanced baPWV in
subclinical hypothyroidism during normalization of thyroid function.
METHODS: Forty-two subclinical hypothyroid patients (male/female ratio 8/34)
were monitored for changes in baPWV before and after levothyroxine (L-T(4))
replacement therapy.
RESULTS: After attaining euthyroidism, 59.5% and 40.5% of the patients showed
reduction and increase of baPWV, respectively. Baseline baPWV and pulse pressure
were significantly higher in patients with reduced baPWV (1940.3+/-126.4 vs.
1726.4+/-110.4 cm/s, P=0.046; 62.1+/-3.1 vs. 50.7+/-3.7 mmHg, P=0.026,
respectively). Baseline baPWV was significantly correlated with baseline pulse
pressure in both groups, but the change in baPWV was significantly correlated
with baseline pulse pressure only in patients with reduced baPWV (rho=-0.522,
P=0.046). The male/female ratio was significantly lower in patients with reduced
baPWV (4/21 vs. 7/10), and systolic, diastolic and pulse pressures and pulse
rate decreased significantly only in patients with reduced baPWV.
CONCLUSIONS: Our results suggest that L-T(4) replacement therapy may be
especially beneficial in female subclinical hypothyroid patients with high
baseline baPWV and pulse pressure. The beneficial effects of L-T(4) replacement
therapy in decreasing arterial stiffening and thus preventing cardiovascular
disease might be limited to this sub-population.
DOI: 10.1016/j.biopha.2007.04.004
PMID: 17544610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23495208 | 1. Autism Res. 2013 Jun;6(3):149-68. doi: 10.1002/aur.1288. Epub 2013 Mar 14.
Serotonin hypothesis of autism: implications for selective serotonin reuptake
inhibitor use during pregnancy.
Harrington RA(1), Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I.
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD 21205, USA. [email protected]
Serotonin, a neurotransmitter found throughout the brain and body, has long been
of interest in autism. Repeated findings of elevated platelet serotonin levels
in approximately one third of children with autism has led some to believe that
dysfunctional serotonin signaling may be a causal mechanism for the disorder.
Because serotonin is critical to fetal brain development, concerns have arisen
regarding prenatal exposure to substances that manipulate serotonin levels, such
as selective serotonin reuptake inhibitors (SSRIs). This review examines
evidence regarding the serotonin system and autism spectrum disorders (ASD), as
well as what the literature has reported thus far on developmental effects of
prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the
fetus during pregnancy and clinical implications are also discussed. Though the
majority of studies conducted in infants and children suggest prenatal exposure
to SSRIs does not affect neurodevelopment, interpretation must be tempered given
small sample sizes. The only published study that focused on prenatal SSRI
exposure and ASD found an increased risk with exposure to SSRIs, especially
during the first trimester. Obstacles that will be faced in future research are
isolating medication effects from maternal depression and, given the infrequent
occurrence of exposure and outcome, obtaining an adequate sample size. Whether
serotonin is an etiologic factor in ASD, and what it points to as a marker for
subgrouping, remains unclear. Understanding how the development of ASD might be
affected by prenatal factors that influence serotonin levels, such as SSRIs,
could identify modifiable targets for prevention.
© 2013 International Society for Autism Research, Wiley Periodicals, Inc.
DOI: 10.1002/aur.1288
PMID: 23495208 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20189881 | 1. Lancet Neurol. 2010 Apr;9(4):363-72. doi: 10.1016/S1474-4422(10)70043-0. Epub
2010 Feb 26.
11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with
Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind,
placebo-controlled, ascending-dose study.
Rinne JO(1), Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA,
Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M,
Gregg KM, Schenk D, Black R, Grundman M.
Author information:
(1)Turku PET Centre and Clinical Research Services Turku, University of Turku
and Turku University Hospital, Turku, Finland. [email protected]
Comment in
Lancet Neurol. 2010 Apr;9(4):333-5. doi: 10.1016/S1474-4422(10)70055-7.
BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker
of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to
investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal
antibody, would reduce cortical fibrillar amyloid-beta load in patients with
Alzheimer's disease.
METHODS: Patients with mild-to-moderate Alzheimer's disease were randomly
assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to
three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group
was enrolled after safety review of the previous group. Randomisation was by
interactive voice response system; masking was achieved with numbered kit
allocation. Patients, investigators, study site personnel, sponsor staff, and
carers were masked to treatment. Patients received up to six infusions, 13 weeks
apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The
primary outcome was the difference between the pooled bapineuzumab group and the
pooled placebo group in mean change from screening to week 78 in (11)C-PiB
cortical to cerebellar retention ratio averaged across six cortical regions of
interest. Analysis was by modified intention to treat. This study is registered
with EudraCT, number 2004-004120-12; ISRCTN17517446.
FINDINGS: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19
patients in the bapineuzumab group and seven in the placebo group were included
in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention
ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014)
in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo
group. Estimated mean difference in (11)C-PiB retention ratio change from
baseline to week 78 between the bapineuzumab group and the placebo group was
-0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab
group and the placebo group in the individual regions of interest were similar
to the overall mean difference. Adverse events were typically mild to moderate
in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had
transient cerebral vasogenic oedema.
INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical
(11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems
to be useful in assessing the effects of potential Alzheimer's disease
treatments on cortical fibrillar amyloid-beta load in vivo.
FUNDING: Elan Pharmaceuticals and Wyeth Research.
2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(10)70043-0
PMID: 20189881 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10904833 | 1. Herz. 2000 May;25(3):156-60. doi: 10.1007/s000590050001.
Genetics of idiopathic dilated cardiomyopathy.
Arbustini E(1), Morbini P, Pilotto A, Gavazzi A, Tavazzi L.
Author information:
(1)Pathology Department, IRCCS Policlinico S. Matteo, Pavia, Italy.
[email protected] [email protected]
Familial dilated cardiomyopathy (DCM) should be an "evidence-based" diagnosis
derived from clinical and echocardiographic screening of informed and consenting
relatives of index patients, and on the examination of clinical reports for
deceased relatives. Most familial dilated cardiomyopathy pedigrees show an
autosomal pattern of inheritance. Very few of them are X-linked and matrilinear.
Autosomal recessive inheritance is difficult to be assessed in an evidence-based
setting. By linkage analysis, several loci, but no disease gene, have been
identified. At present, few cases of familial dilated cardiomyopathy can benefit
of a molecular diagnosis. The diagnosis of dystrophin defect-related dilated
cardiomyopathy is important for patients and families, especially for carrier
detection. These patients present X-linked inheritance, dominant cardiac
involvement and raised levels of serum creatine phosphokinase. Defects of the
glycoprotein complex associated to dystrophin (DAG) are rare skeletal muscle
diseases with possible cardiac involvement. Mitochondrial diseases, both pure
cardiomyopathies and multiorgan syndromes involving the heart, are associated to
defects of mitochondrial DNA genes or of nuclear genes coding for mitochondrial
proteins. Barth's syndrome develops in male children with granulocytopenia,
dilated cardiomyopathy, and methylglutaconic aciduria. Cardiomyopathies with
atrioventricular block are observed in hemochromatosis, Emery-Dreifuss syndrome,
desmin storage disease, and in isolated familial dilated cardiomyopathy. Actin
defects were recently identified in 2 unrelated patients with familial dilated
cardiomyopathy. Desmin defects were also recently identified in 1 familial
dilated cardiomyopathy. The overall knowledge, although in progression, is still
limited. Clinical family screening identifies familial forms, preclinical cases,
and inheritance pattern. By candidate gene screening, the molecular diagnosis
can be provided for dystrophin, DAG, mitochondrial DNA, actin and desmin gene
defects.
DOI: 10.1007/s000590050001
PMID: 10904833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23970885 | 1. Front Immunol. 2013 Aug 21;4:244. doi: 10.3389/fimmu.2013.00244. eCollection
2013.
Role of T cell receptor affinity in the efficacy and specificity of adoptive T
cell therapies.
Stone JD(1), Kranz DM.
Author information:
(1)Department of Biochemistry, University of Illinois , Urbana, IL , USA.
Over the last several years, there has been considerable progress in the
treatment of cancer using gene modified adoptive T cell therapies. Two
approaches have been used, one involving the introduction of a conventional αβ T
cell receptor (TCR) against a pepMHC cancer antigen, and the second involving
introduction of a chimeric antigen receptor (CAR) consisting of a single-chain
antibody as an Fv fragment linked to transmembrane and signaling domains. In
this review, we focus on one aspect of TCR-mediated adoptive T cell therapies,
the impact of the affinity of the αβ TCR for the pepMHC cancer antigen on both
efficacy and specificity. We discuss the advantages of higher-affinity TCRs in
mediating potent activity of CD4 T cells. This is balanced with the potential
disadvantage of higher-affinity TCRs in mediating greater self-reactivity
against a wider range of structurally similar antigenic peptides, especially in
synergy with the CD8 co-receptor. Both TCR affinity and target selection will
influence potential safety issues. We suggest pre-clinical strategies that might
be used to examine each TCR for possible on-target and off-target side effects
due to self-reactivities, and to adjust TCR affinities accordingly.
DOI: 10.3389/fimmu.2013.00244
PMCID: PMC3748443
PMID: 23970885 |
http://www.ncbi.nlm.nih.gov/pubmed/23847357 | 1. Cancer Discov. 2013 Jul;3(7):OF14. doi: 10.1158/2159-8290.CD-NB2013-074. Epub
2013 May 16.
PD-1 inhibitor becomes "breakthrough therapy".
[No authors listed]
Merck's lambrolizumab (MK-3475) monoclonal antibody received "Breakthrough
Therapy" designation from the U.S. Food and Drug Administration in April for
treating patients with advanced melanoma. The designation is one of many signs
of progress in attacking cancer with agents designed for immune checkpoint
blockade.
DOI: 10.1158/2159-8290.CD-NB2013-074
PMID: 23847357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19746166 | 1. PLoS One. 2009 Sep 10;4(9):e6995. doi: 10.1371/journal.pone.0006995.
The 3' region of the chicken hypersensitive site-4 insulator has properties
similar to its core and is required for full insulator activity.
Arumugam PI(1), Urbinati F, Velu CS, Higashimoto T, Grimes HL, Malik P.
Author information:
(1)Division of Experimental Hematology and Cancer Biology, Cincinnati Children's
Hospital Medical Center, Cincinnati, Ohio, USA.
Chromatin insulators separate active transcriptional domains and block the
spread of heterochromatin in the genome. Studies on the chicken hypersensitive
site-4 (cHS4) element, a prototypic insulator, have identified CTCF and USF-1/2
motifs in the proximal 250 bp of cHS4, termed the "core", which provide enhancer
blocking activity and reduce position effects. However, the core alone does not
insulate viral vectors effectively. The full-length cHS4 has excellent
insulating properties, but its large size severely compromises vector titers. We
performed a structure-function analysis of cHS4 flanking lentivirus-vectors and
analyzed transgene expression in the clonal progeny of hematopoietic stem cells
and epigenetic changes in cHS4 and the transgene promoter. We found that the
core only reduced the clonal variegation in expression. Unique insulator
activity resided in the distal 400 bp cHS4 sequences, which when combined with
the core, restored full insulator activity and open chromatin marks over the
transgene promoter and the insulator. These data consolidate the known
insulating activity of the canonical 5' core with a novel 3' 400 bp element with
properties similar to the core. Together, they have excellent insulating
properties and viral titers. Our data have important implications in
understanding the molecular basis of insulator function and design of gene
therapy vectors.
DOI: 10.1371/journal.pone.0006995
PMCID: PMC2736623
PMID: 19746166 [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/15699919 | 1. Kardiologiia. 2004;44(12):31-6.
[Expression of contractile and cytoskeletal proteins in myocardium of patients
with dilated cardiomyopathy.].
[Article in Russian]
Branishte TA(1), Dudnakova TV, Dergilev KV, Severin VV, Naumov VG, Shirinskiĭ
VP, Belenkov IuN.
Author information:
(1)Cardiology Research Complex; ul. Tretiya Cherepkovskaya, 15a, 121552 Moscow,
Russia; Russian State Institute for Transplantation, Moscow.
Dilated cardiomyopathy (DCM) is characterized by enlargement and dilation of all
heart compartments associated with serious decrease of its contractile function.
DCM hallmark is the combination of dystrophic and hypertrophic alterations of
cardiomyocytes. Since the power output of cardiac cells is directly related to
remodeling of their contractile machinery we investigated expression of selected
contractile and cytoskeletal proteins in the left ventricle of DCM patients
using immunoblotting. The content of the recognized protein markers of
cardiomyocyte hypertrophy such as tubulin, desmin and slow skeletal myosin heavy
chain isoform, MHCbeta, was significantly elevated in DCM compared to normal
myocardium. In addition, marked increase in the content of several smooth muscle
proteins (smooth muscle alpha-actin, Myosin Light Chain Kinase, Kinase Related
protein SM22) that are normally expressed in embryonic myocardium, was observed
in DCM hearts. Thus, cardiomyocyte hypertrophy in DCM is associated with
activation of embryonic protein expression program and smooth muscle proteins
could serve as markers of this process. Understanding their involvement in
sarcomere assembly and pathways of their expression activation during cardiac
hypertrophy may bring new insights in treatment of various forms of
cardiomyopathy.
PMID: 15699919 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21596426 | 1. Cell. 2011 May 27;145(5):692-706. doi: 10.1016/j.cell.2011.03.053. Epub 2011
May 19.
Recognition of a mononucleosomal histone modification pattern by BPTF via
multivalent interactions.
Ruthenburg AJ(1), Li H, Milne TA, Dewell S, McGinty RK, Yuen M, Ueberheide B,
Dou Y, Muir TW, Patel DJ, Allis CD.
Author information:
(1)Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University,
1230 York Avenue, New York, NY, 10065, USA.
Little is known about how combinations of histone marks are interpreted at the
level of nucleosomes. The second PHD finger of human BPTF is known to
specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here,
we examine how additional heterotypic modifications influence BPTF binding.
Using peptide surrogates, three acetyllysine ligands are indentified for a
PHD-adjacent bromodomain in BPTF via systematic screening and biophysical
characterization. Although the bromodomain displays limited discrimination among
the three possible acetyllysines at the peptide level, marked selectivity is
observed for only one of these sites, H4K16ac, in combination with H3K4me3 at
the mononucleosome level. In support, these two histone marks constitute a
unique trans-histone modification pattern that unambiguously resides within a
single nucleosomal unit in human cells, and this module colocalizes with these
marks in the genome. Together, our data call attention to nucleosomal patterning
of covalent marks in dictating critical chromatin associations.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2011.03.053
PMCID: PMC3135172
PMID: 21596426 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24089441 | 1. Clin Cancer Res. 2013 Oct 1;19(19):5283-91. doi:
10.1158/1078-0432.CCR-13-2151.
The intersection of immune-directed and molecularly targeted therapy in advanced
melanoma: where we have been, are, and will be.
Sullivan RJ(1), Lorusso PM, Flaherty KT.
Author information:
(1)Authors' Affiliations: Massachusetts General Hospital Cancer Center, Harvard
Medical School, Boston, Massachusetts; and Karmanos Cancer Institute, Wayne
State University, Detroit, Michigan.
In three years, four drugs have gained regulatory approval for the treatment of
metastatic and unresectable melanoma, with at least seven other drugs having
recently completed, currently in, or soon to be in phase III clinical testing.
This amazing achievement has been made following a remarkable increase of
knowledge in molecular biology and immunology that led to the identification of
high-valued therapeutic targets and the clinical development of agents that
effectively engage and inhibit these targets. The discovery of either effective
molecularly targeted therapies or immunotherapies would have led to dramatic
improvements to the standard-of-care treatment of melanoma. However, through
parallel efforts that have showcased the efficacy of small-molecule BRAF and
MAP-ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors,
namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab,
MPDL3280), an opportunity exists to transform the treatment of melanoma
specifically and cancer generally by exploring rational combinations of
molecularly targeted therapies, immunotherapies, and molecular targeted
therapies with immunotherapies. This overview presents the historical context to
this therapeutic revolution, reviews the benefits and limitations of current
therapies, and provides a look ahead at where the field is headed.
©2013 AACR.
DOI: 10.1158/1078-0432.CCR-13-2151
PMCID: PMC4100326
PMID: 24089441 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest: K. Flaherty,
Consultant/Advisory Board, Glaxo Smith Kline, Roche/Genentech, Novartis |
http://www.ncbi.nlm.nih.gov/pubmed/21525025 | 1. Eur Heart J. 2012 Aug;33(15):1954-63. doi: 10.1093/eurheartj/ehr119. Epub 2011
Apr 26.
Regulation of adverse remodelling by osteopontin in a genetic heart failure
model.
Psarras S(1), Mavroidis M, Sanoudou D, Davos CH, Xanthou G, Varela AE,
Panoutsakopoulou V, Capetanaki Y.
Author information:
(1)Cell Biology Division, Center of Basic Research I, Biomedical Research
Foundation, Academy of Athens, Soranou Efessiou 4, Athens 11527, Greece.
AIMS: Desmin, the muscle-specific intermediate filament protein, is a major
target in dilated cardiomyopathy and heart failure in humans and mice. The
hallmarks of desmin-deficient (des(-/-)) mice pathology include pronounced
myocardial degeneration, extended fibrosis, and osteopontin (OPN)
overexpression. We sought to identify the molecular and cellular events
regulating adverse cardiac remodelling in des(-/-) mice and their potential link
to OPN.
METHODS AND RESULTS: In situ hybridization, histology, and immunostaining
demonstrated that inflammatory cells and not cardiomyocytes were the source of
OPN. RNA profile comparison revealed that activation of inflammatory pathways,
sustained by innate immunity mechanisms, predominated among all changes
occurring in degenerating des(-/-) myocardium. The expression of the most highly
up-regulated genes (OPN: 226×, galectin-3: 26×, osteoactivin/Gpnmb/DC-HIL: 160×
and metalloprotease-12: 98×) was associated with heart infiltrating macrophages.
To evaluate the role of OPN, we generated des(-/-)OPN(-/-) mice and compared
their cardiac function and remodelling indices with those of des(-/-).
Osteopontin promoted cardiac dysfunction in this model since des(-/-)OPN(-/-)
mice showed 53% improvement of left ventricular function, paralleled to an up to
44% reduction in fibrosis. The diminished fibrotic response in the absence of
OPN could be partly mediated by a dramatic reduction in myocardial galectin-3
levels, associated with an impaired galectin-3 secretion by OPN-deficient
infiltrating macrophages.
CONCLUSION: Cardiomyocyte death due to desmin deficiency leads to inflammation
and subsequent overexpression of a series of remodelling modulators. Among them,
OPN seems to be a major regulator of des(-/-) adverse myocardial remodelling and
it functions at least by potentiating galectin-3 up-regulation and secretion.
DOI: 10.1093/eurheartj/ehr119
PMID: 21525025 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15572040 | 1. J Mol Cell Cardiol. 2004 Dec;37(6):1097-109. doi: 10.1016/j.yjmcc.2004.07.004.
Genetic modification of the heart: chaperones and the cytoskeleton.
Kumarapeli AR(1), Wang X.
Author information:
(1)Cardiovascular Research Institute and Division of Basic Biomedical Sciences,
University of South Dakota School of Medicine, 1100 E. 21st Street, Sioux Falls,
SD 57105, USA.
In the past decade, genetic modification has been extensively employed to define
(patho)physiological roles of chaperones and the cytoskeleton in the heart,
promoting dramatic advances in this field. Both loss-of-function and
gain-of-function approaches have been used productively. alphaB-Crystallin
(CryAB) is the most abundant small heat shock protein (HSP) in the heart. A
missense mutation (R120G) in CryAB that is linked to human desmin-related
myopathy (DRM), has proved in transgenic (TG) mice to be causative, likely
through compromising the function of both CryAB and desmin filaments and
inducing aberrant protein aggregation. For the molecular chaperones, the
consensus gained is that up-regulation of each of the HSPs in the heart is
protective against insults such as ischemia/reperfusion (I/R) injury. CryAB
modulates protein aggregation of abnormal desmin. With respect to the
cytoskeleton, disruption of the non-sarcomeric actin linkage at the intercalated
discs via overexpressing the VASP-EHV1 domain is sufficient to cause dilated
cardiomyopathy (DCM). Up-regulation of microtubule-associated protein 4 (MAP4)
results in microtubule densification. Myocyte contractile malfunction
characteristic of pressure overload hypertrophy is recapitulated by
cardiac-restricted overexpression of MAP4. In contrast, overexpression of desmin
filaments by itself is not detrimental to the heart. Although loss-of-function
studies have been more limited, ablation of the desmin gene causes mitochondrial
dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function
studies, abnormal desmin aggregation and disruption of the desmin networks
resulting from expression of either mutant desmin or mutant CryAB have been
shown to remodel the heart and compromise cardiac function, suggesting their
synergistic roles in disease pathogenesis.
DOI: 10.1016/j.yjmcc.2004.07.004
PMID: 15572040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19536296 | 1. PLoS One. 2009 Jun 18;4(6):e5956. doi: 10.1371/journal.pone.0005956.
Gene specificity of suppression of transgene-mediated insertional
transcriptional activation by the chicken HS4 insulator.
Desprat R(1), Bouhassira EE.
Author information:
(1)Department of Medicine, Albert Einstein College of Medicine, Bronx, New York,
United States of America.
Insertional mutagenesis has emerged as a major obstacle for gene therapy based
on vectors that integrate randomly in the genome. Reducing the genotoxicity of
genomic viral integration can, in first approximation, be equated with reducing
the risk of oncogene activation, at least in the case of therapeutic payloads
that have no known oncogenic potential, such as the globin genes. An attractive
solution to the problem of oncogene activation is the inclusion of
insulators/enhancer-blockers in the viral vectors. In this study we have used
Recombinase-Mediated Cassette Exchange to characterize the effect of integration
of globin therapeutic cassettes in the presence or absence of the chicken HS4
and three other putative insulators inserted near Stil, Tal1 and MAP17, three
well-known cellular proto-oncogenes in the SCL/Tal1 locus. We show that
insertion of a Locus Control Region-driven globin therapeutic globin transgene
had a dramatic activating effect on Tal1 and Map17, the two closest genes, a
minor effect on Stil, and no effect on Cyp4x1, a non-expressed gene. Of the four
element tested, cHS4 was the only one that was able to suppress this
transgene-mediated insertional transcriptional activation. cHS4 had a strong
suppressive effect on the activation expression of Map17 but has little or no
effect on expression of Tal1. The suppressive activity of cHS4 is therefore
promoter specific. Importantly, the observed suppressive effect of cHS4 on Map17
activation did not depend on its intercalation between the LCR and the Map 17
promoter. Rather, presence of one or two copies of cHS4 anywhere within the
transgene was sufficient to almost completely block the activation of Map17.
Therefore, at this complex locus, suppression of transgene-mediated insertional
transcriptional activation by cHS4 could not be adequately explained by models
that predict that cHS4 can only suppress expression through an enhancer-blocking
activity that requires intercalation between an enhancer and a promoter. This
has important implications for our theoretical understanding of the possible
effects of the insertion of cHS4 on gene therapy vectors. We also show that cHS4
decreased the level of expression of the globin transgene. Therefore, the
benefits of partially preventing insertional gene activation are in part negated
by the lower expression level of the transgene. A cost/benefit analysis of the
utility of incorporation of insulators in gene therapy vectors will require
further studies in which the effects of insulators on both the therapeutic gene
and the flanking genes are determined at a large number of integration sites.
Identification of insulators with minimal promoter specificity would also be of
great value.
DOI: 10.1371/journal.pone.0005956
PMCID: PMC2694267
PMID: 19536296 [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/15970672 | 1. Cell Cycle. 2005 Jul;4(7):919-26. doi: 10.4161/cc.4.7.1824. Epub 2005 Jul 5.
Effector proteins for methylated histones: an expanding family.
Daniel JA(1), Pray-Grant MG, Grant PA.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Virginia
School of Medicine, Charlottesville, Virginia, USA.
Methylation of histone lysine residues in eukaryotic chromatin has been an
exciting area of research ever since the first histone methyltransferase enzyme,
Suv39h, was found to methylate lysine 9 of histone H3 in 2000. Only a year
later, the HP1 chromodomain polypeptide was identified as a recognition module
for this histone modification. Similar to bromodomain-containing proteins that
recognize histone acetylation sites and subsequently stabilize large complexes
to chromatin, effector proteins can also be recruited and stabilized by histone
methylation. Although histone acetylation generally correlates with active
transcription, histone methylation is associated with both the activation and
silencing of transcription, depending on which lysine residue is modified. The
list of proteins that may in fact directly associate with specific methylated
histone lysines is expanding. Since the finding of HP1, many additional proteins
have been shown to bind methylated histone residues. For instance, Polycomb,
Chd1, 53BP1, and Crb2/Rad9 proteins all associate with methylated chromatin in a
unique manner governed by their respective recognition motifs. Here we highlight
recent data on the recognition specificity and biological significance of
proteins that associate with methylated histone lysines.
DOI: 10.4161/cc.4.7.1824
PMID: 15970672 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17049045 | 1. Biochem J. 2007 Feb 15;402(1):125-33. doi: 10.1042/BJ20060907.
Selective recognition of acetylated histones by bromodomains in transcriptional
co-activators.
Hassan AH(1), Awad S, Al-Natour Z, Othman S, Mustafa F, Rizvi TA.
Author information:
(1)Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE
University, P.O. Box 17666, Al-Ain, United Arab Emirates. [email protected]
Bromodomains are present in many chromatin-associated proteins such as the
SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone
acetyltransferase) complexes, and can bind to acetylated lysine residues in the
N-terminal tails of the histones. Lysine acetylation is a histone modification
that forms a stable epigenetic mark on chromatin for bromodomain-containing
proteins to dock and in turn regulate gene expression. In order to better
understand how bromodomains read the 'histone code' and interact with acetylated
histones, we have tested the interactions of several bromodomains within
transcriptional co-activators with differentially acetylated histone tail
peptides and HAT-acetylated histones. Using GST (glutathione S-transferase)
pull-down assays, we show specificity of binding of some bromodomains to
differentially acetylated H3 and H4 peptides as well as HAT-acetylated histones.
Our results reveal that the Swi2/Snf2 bromodomain interacts with various
acetylated H3 and H4 peptides, whereas the Gcn5 bromodomain interacts only with
acetylated H3 peptides and tetra-acetylated H4 peptides. Additionally we show
that the Spt7 bromodomain interacts with acetylated H3 peptides weakly, but not
with acetylated H4 peptides. Some bromodomains such as the Bdf1-2 do not
interact with most of the acetylated peptides tested. Results of the peptide
experiments are confirmed with tests of interactions between these bromodomains
and HAT-acetylated histones. Furthermore, we demonstrate that the Swi2/Snf2
bromodomain is important for the binding and the remodelling activity of the
SWI/SNF complex on hyperacetylated nucleosomes. The selective recognition of the
bromodomains observed in the present study accounts for the broad effects of
bromodomain-containing proteins observed on binding to histones.
DOI: 10.1042/BJ20060907
PMCID: PMC1783998
PMID: 17049045 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26346347 | 1. Core Evid. 2015 Aug 27;10:89-98. doi: 10.2147/CE.S82905. eCollection 2015.
Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary
fibrosis.
Inomata M(1), Nishioka Y(2), Azuma A(1).
Author information:
(1)Department of Pulmonary Medicine and Oncology, Graduate School of Medicine,
Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo.
(2)Department of Respiratory Medicine and Rheumatology, Institute of Health
Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor
prognosis. The molecular mechanisms involved in the progression of IPF are not
fully understood; however, the platelet-derived growth factor (PDGF)/PDGF
receptor pathway is thought to play a critical role in fibrogenesis of the
lungs. Other growth factors, including fibroblast growth factor and vascular
endothelial growth factor, are also thought to contribute to the pathogenesis of
pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases,
including receptors for PDGF, fibroblast growth factor, and vascular endothelial
growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of
nintedanib twice daily showed a trend to slow the decline in lung function and
significantly decrease acute exacerbations in patients with IPF, while showing
an acceptable safety profile. The Phase III INPULSIS trials demonstrated a
significant decrease in the annual rate of decline in forced vital capacity in
IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2
trial, the time to the first acute exacerbation significantly increased in IPF
patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone,
another antifibrotic drug, was shown to limit the decline in pulmonary function
in patients with IPF in the ASCEND trial. Combination therapy with nintedanib
and pirfenidone is anticipated, although further evaluation of its long-term
safety is needed. There is limited evidence for the safety of the combination
therapy although a Phase II trial conducted in Japan demonstrated that
combination therapy with nintedanib and pirfenidone was tolerable for 1 month.
Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have
limited efficacy as single therapies for IPF; therefore, further study of
combination therapy with antifibrotic agents is needed.
DOI: 10.2147/CE.S82905
PMCID: PMC4555978
PMID: 26346347 |
http://www.ncbi.nlm.nih.gov/pubmed/11600725 | 1. Occup Environ Med. 2001 Nov;58(11):702-10. doi: 10.1136/oem.58.11.702.
An epidemiological study of the relations between exposure to organophosphate
pesticides and indices of chronic peripheral neuropathy and neuropsychological
abnormalities in sheep farmers and dippers.
Pilkington A(1), Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, Hurley JF,
Soutar CA.
Author information:
(1)Institute of Occupational Medicine, 8 Roxburgh Place, Edinburgh EH8 9SU, UK.
Comment in
Occup Environ Med. 2001 Nov;58(11):689-90. doi: 10.1136/oem.58.11.689.
OBJECTIVES: To investigate the hypothesis that chronic low level exposure to
organophosphates (OPs) in sheep dips is related to clinically detectable
measures of polyneuropathy.
METHODS: The design was a cross sectional exposure-response study of sheep
dippers and other non-exposed groups. The study group consisted of 612 sheep
dipping farmers, 53 farmers with no sheep dipping experience, and 107 ceramics
workers. Retrospective exposure information was obtained by questionnaire based
on stable and easily identifiable features of sheep dipping found during the
first phase of the study; in particular, estimates of handling concentrate and
splashing with dilute dip. Neurological assessments were based on a standard
neuropathy symptoms questionnaire, and thermal and vibration quantitative
sensory tests.
RESULTS: Adjusted for confounders there was a weak positive association between
cumulative exposure to OPs and neurological symptoms, the significance of which
was dependent on the inclusion of a few individual workers with extremely high
exposure. There was no evidence of an association between cumulative exposure
and the thermal or vibration sensory thresholds. However, separating the effects
of exposure intensity and duration showed a higher prevalence of symptoms,
primarily of a sensory type, among sheep dippers who handled the OP concentrate.
There was also evidence that sensory and vibration thresholds were higher among
concentrate handlers, the highest exposed group of dippers.
CONCLUSIONS: The findings showed a strong association between exposure to OP
concentrate and neurological symptoms, but a less consistent association with
sensory thresholds. There was only weak evidence of a chronic effect of low dose
cumulative exposure to OPs. It is suggested that long term health effects may
occur in at least some sheep dippers exposed to OPs over a working life,
although the mechanisms are unclear.
DOI: 10.1136/oem.58.11.702
PMCID: PMC1740069
PMID: 11600725 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2279154 | 1. BMJ. 1990 Dec 22-29;301(6766):1409-11. doi: 10.1136/bmj.301.6766.1409.
Longevity of men capable of prolonged vigorous physical exercise: a 32 year
follow up of 2259 participants in the Dutch eleven cities ice skating tour.
van Saase JL(1), Noteboom WM, Vandenbroucke JP.
Author information:
(1)Department of Clinical Epidemiology, Leiden University Hospital, The
Netherlands.
OBJECTIVE: To compare the long term survival of a group of athletes taking
prolonged vigorous physical exercise to that of the general population.
DESIGN: Follow up of a cohort of participants in the Dutch eleven cities ice
skating tour (a race and recreational tour) over a distance of 200 kilometers.
SETTING: Data on participation from the organising committee and data on
mortality from all municipalities in The Netherlands.
SUBJECTS: 2259 Male athletes.
MAIN OUTCOME MEASURES: Comparison of all cause mortality in male participants in
the tour with that in the general population of The Netherlands.
RESULTS: The standardised mortality ratio for all participants during 32 years
of follow up was 0.76 (95% confidence interval 0.68 to 0.85), and 0.90 (0.48 to
1.44) for participants in the race, and 0.72 (0.60 to 0.86) for participants in
the recreational tour who finished within the time limit.
CONCLUSIONS: The capacity for prolonged and vigorous physical exercise,
particularly if the exercise is recreational, is a strong indicator of
longevity.
DOI: 10.1136/bmj.301.6766.1409
PMCID: PMC1679864
PMID: 2279154 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21181474 | 1. World J Surg. 2011 Mar;35(3):563-7. doi: 10.1007/s00268-010-0878-5.
Laparoscopic organ-sparing resection of von Hippel-Lindau disease-associated
pancreatic neuroendocrine tumors.
von Dücker L(1), Walz MK, Voss C, Arnold G, Eng C, Neumann HP.
Author information:
(1)Department of Nephrology and General Medicine, University Medical Center,
Albert Ludwigs University, Hugstetter Strasse 55, 79106 Freiburg, Germany.
BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are a characteristic
feature of the tumor syndromes multiple endocrine neoplasia type 1 (MEN-1) and
von Hippel-Lindau disease (VHL). With VHL, about 10% of the patients exhibit
PNETs by age 40 years. Metastatic potential is high if the tumors have grown to
>3 cm in diameter. Optimal surgical treatment is still a challenge.
METHODS: We report three cases, all women, ages 22, 30, and 39 years,
respectively, who had known VHL, confirmed by classic organ manifestations and
germline mutations of the VHL gene. All were diagnosed, in an asymptomatic
stage, with solid tumors of the pancreatic tail or tail/corpus area measuring
2.9-5.6 cm diameter. All accepted the offer of laparoscopic organ-sparing
removal of the tumors.
RESULTS: In all three cases, the tumor was entirely removed. In two cases,
resection of the spleen was also necessary as dissection of the tumor from the
major splenic vessels was impossible. Operating time was 215-365 min, and blood
loss was 200-700 ml. Histolopathology revealed benign PNETs in two cases, but
the third patient had regional lymph node metastases. There were no
complications, and the hospital stay was 4-7 days.
CONCLUSIONS: Organ-sparing laparoscopic surgery is an important option for
treating VHL-associated PNETs of the pancreatic tail.
DOI: 10.1007/s00268-010-0878-5
PMID: 21181474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23724846 | 1. N Engl J Med. 2013 Jul 11;369(2):134-44. doi: 10.1056/NEJMoa1305133. Epub 2013
Jun 2.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
Hamid O(1), Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P,
Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM,
Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC,
Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A.
Author information:
(1)Angeles Clinic and Research Institute, Los Angeles, CA, USA.
Erratum in
N Engl J Med. 2018 Nov 29;379(22):2185. doi: 10.1056/NEJMx180040.
Comment in
N Engl J Med. 2013 Jul 11;369(2):187-9. doi: 10.1056/NEJMe1305484.
Nat Rev Clin Oncol. 2013 Jul;10(7):365. doi: 10.1038/nrclinonc.2013.98.
BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of
T-cell effector mechanisms that limits immune responses against cancer. We
tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in
patients with advanced melanoma.
METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per
kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in
patients with advanced melanoma, both those who had received prior treatment
with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor
responses were assessed every 12 weeks.
RESULTS: A total of 135 patients with advanced melanoma were treated. Common
adverse events attributed to treatment were fatigue, rash, pruritus, and
diarrhea; most of the adverse events were low grade. The confirmed response rate
across all dose cohorts, evaluated by central radiologic review according to the
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95%
confidence interval [CI], 25 to 44), with the highest confirmed response rate
observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95%
CI, 38 to 66). The response rate did not differ significantly between patients
who had received prior ipilimumab treatment and those who had not (confirmed
response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively).
Responses were durable in the majority of patients (median follow-up, 11 months
among patients who had a response); 81% of the patients who had a response (42
of 52) were still receiving treatment at the time of analysis in March 2013. The
overall median progression-free survival among the 135 patients was longer than
7 months.
CONCLUSIONS: In patients with advanced melanoma, including those who had had
disease progression while they had been receiving ipilimumab, treatment with
lambrolizumab resulted in a high rate of sustained tumor regression, with mainly
grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov
number, NCT01295827.).
DOI: 10.1056/NEJMoa1305133
PMCID: PMC4126516
PMID: 23724846 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25628503 | 1. P T. 2015 Jan;40(1):33-5.
Pharmaceutical approval update.
Gohil K.
Meningococcal group B vaccine (Trumenba) to prevent more types of invasive
meningococcal disease; antihemophilic factor (recombinant), porcine sequence
(Obizur) to treat bleeding from acquired hemophilia A; and pirfenidone (Esbriet)
and nintedanib (Ofev) for idiopathic pulmonary fibrosis.
PMCID: PMC4296588
PMID: 25628503 |
http://www.ncbi.nlm.nih.gov/pubmed/23907003 | 1. Eur J Cancer. 2013 Sep;49(14):2968-71. doi: 10.1016/j.ejca.2013.07.001. Epub
2013 Jul 29.
Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1
receptor monoclonal antibodies.
Robert C(1), Soria JC, Eggermont AM.
Author information:
(1)Gustave Roussy Comprehensive Cancer Center, 114 Rue Edouard Vaillant, 94800
Villejuif/Paris-Sud, France.
Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed
the landscape in oncology in 2013. The most mature results have been obtained in
advanced melanoma patients. They indicate important response rates and high
quality responses or prolonged duration. Also in renal cancer and in lung cancer
remarkable activity has been demonstrated. Thus it is clear that these
antibodies have a very broad potential and trials in many tumour types are being
initiated. Breaking tolerance at the tumour site is a potent phenomenon and the
potential for synergy with other checkpoint inhibitors such as ipilimumab have
also been demonstrated in 2013. Long term tumour control now seems achievable
and thus the concept of a clinical cure is emerging by modulation of the immune
system. These antibodies bring immunotherapy to the forefront and indicate that
immune-modulation will be a key component of therapeutic strategies from now on.
Because of all these reasons PD-1/PD-L1 antibodies are considered 'drug of the
year'.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ejca.2013.07.001
PMID: 23907003 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19079407 | 1. JNMA J Nepal Med Assoc. 2008 Oct-Dec;47(172):251-8.
Organophosphorus poisoning.
Paudyal BP(1).
Author information:
(1)Department of Medicine, Patan Hospital, Lalitpur. [email protected]
Acute poisoning by organophosphorus (OP) compounds is a major global clinical
problem, with thousands of deaths occurring every year. Most of these pesticide
poisoning and subsequent deaths occur in developing countries following a
deliberate self ingestion of the poison. Metacid (Methyl parathion) and Nuvan
(Dichlorovos) are commonly ingested OP pesticides; Dimethoate, Profenofos, and
Chlorpyrifos are other less frequently ingested compounds in Nepal. The toxicity
of these OP pesticides is due to the irreversible inhibition of
acetylcholinesterase (AChE) enzyme leading to accumulation of acetylcholine and
subsequent over-activation of cholinergic receptors in various parts of the
body. Acutely, these patients present with cholinergic crisis; intermediate
syndrome and delayed polyneuropathy are other sequel of this form of poisoning.
The diagnosis depends on the history of exposure to these pesticides,
characteristic manifestations of toxicity and improvements of the signs and
symptoms after administration of atropine. The supportive treatment of OP
poisoning includes the same basic principles of management of any acutely
poisoned patient i.e., rapid initial management of airways, breathing, and
circulation. Gastric lavage and activated charcoal are routinely used
decontamination procedures, but their value has not been conclusively proven in
this poisoning. Atropine is the mainstay of therapy, and can reverse the life
threatening features of this acute poisoning. However, there are no clear cut
guidelines on the dose and duration of atropine therapy in OP poisoning.
Cholinesterase reactivators, by regenerating AChE, can reverse both the
nicotinic and muscarinic effects; however, this benefit has not been translated
well in clinical trials. All these facts highlight that there are many
unanswered questions and controversies in the management of OP poisoning and
there is an urgent need for research on this aspect of this common and deadly
poisoning.
PMID: 19079407 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25248327 | 1. Acta Neurochir (Wien). 2014 Dec;156(12):2315-24. doi:
10.1007/s00701-014-2234-2. Epub 2014 Sep 24.
Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for
fluorescence-guided resections in pediatric brain tumors: a European survey.
Stummer W(1), Rodrigues F, Schucht P, Preuss M, Wiewrodt D, Nestler U, Stein M,
Artero JM, Platania N, Skjøth-Rasmussen J, Della Puppa A, Caird J, Cortnum S,
Eljamel S, Ewald C, González-García L, Martin AJ, Melada A, Peraud A, Brentrup
A, Santarius T, Steiner HH; European ALA Pediatric Brain Tumor Study Group.
Author information:
(1)Department of Neurosurgery, Universitätsklinikum Münster,
Albert-Schweitzer-Campus 1, 48149, Münster, Germany,
[email protected].
BACKGROUND: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is
approved for fluorescence-guided resections of adult malignant gliomas. Case
reports indicate that 5-ALA can be used for children, yet no prospective study
has been conducted as of yet. As a basis for a study, we conducted a survey
among certified European Gliolan users to collect data on their experiences with
children.
METHODS: Information on patient characteristics, MRI characteristics of tumors,
histology, fluorescence qualities, and outcomes were requested. Surgeons were
further asked to indicate whether fluorescence was "useful", i.e., leading to
changes in surgical strategy or identification of residual tumor. Recursive
partitioning analysis (RPA) was used for defining cohorts with high or low
likelihoods for useful fluorescence.
RESULTS: Data on 78 patients <18 years of age were submitted by 20 centers.
Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five
anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III
(80 %). Fluorescence was found inconsistently useful in PNETs (three of seven;
43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %)
and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors
showed tumors with supratentorial location, strong contrast enhancement and
first operation to have a likelihood of useful fluorescence of 64.3 %, as
opposed to infratentorial tumors with first surgery (23.1 %).
CONCLUSIONS: Our survey demonstrates 5-ALA as being used in pediatric brain
tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial
tumors. These data indicate controlled studies to be necessary and also provide
a basis for planning such a study.
DOI: 10.1007/s00701-014-2234-2
PMCID: PMC4232748
PMID: 25248327 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16140621 | 1. Environ Health Perspect. 2005 Sep;113(9):1160-3. doi: 10.1289/ehp.7374.
Pesticide exposure alters follicle-stimulating hormone levels in Mexican
agricultural workers.
Recio R(1), Ocampo-Gómez G, Morán-Martínez J, Borja-Aburto V, López-Cervante M,
Uribe M, Torres-Sánchez L, Cebrián ME.
Author information:
(1)Sección Externa de Toxicología, Centro de Investigación y de Estudios
Avanzados del Instituto Politécnico Nacional, México DF, México.
Organophosphorous pesticides (OPs) are suspected of altering reproductive
function by reducing brain acetylcholinesterase activity and monoamine levels,
thus impairing hypothalamic and/or pituitary endocrine functions and gonadal
processes. Our objective was to evaluate in a longitudinal study the association
between OP exposure and serum levels of pituitary and sex hormones. Urinary OP
metabolite levels were measured by gas-liquid chromatography, and serum
pituitary and sex hormone levels by enzymatic immunoassay and radioimmunoassay
in 64 men. A total of 147 urine and blood samples were analyzed for each
parameter. More than 80% of the participants had at least one OP metabolite in
their urine samples. The most frequent metabolite found was diethylthiophosphate
(DETP; 55%), followed by diethylphosphate (DEP; 46%), dimethylthiophosphate
(DMTP; 32%), and dimethyldithiophosphate (DMDTP; 31%). However, the metabolites
detected at higher concentrations were DMTP, DEP, DMDTP, and dimethylphosphate.
There was a high proportion of individuals with follicle-stimulating hormone
(FSH) concentrations outside the range of normality (48%). The average FSH serum
levels were higher during the heavy pesticide spraying season. However, a
multivariate analysis of data collected in all periods showed that serum FSH
levels were negatively associated with urinary concentrations of both DMTP and
DMDTP, whereas luteinizing hormone (LH) was negatively associated with DMTP. We
observed no significant associations between estradiol or testosterone serum
levels with OP metabolites. The hormonal disruption in agricultural workers
presented here, together with results from experimental animal studies, suggests
that OP exposure disrupts the hypothalamic-pituitary endocrine function and also
indicates that FSH and LH are the hormones most affected.
DOI: 10.1289/ehp.7374
PMCID: PMC1280395
PMID: 16140621 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1665780 | 1. Electromyogr Clin Neurophysiol. 1991 Dec;31(8):507-11.
The neurophysiologic examination in organophosphate ester poisoning. Case report
and review of the literature.
Van den Neucker K(1), Vanderstraeten G, De Muynck M, De Wilde V.
Author information:
(1)Department of Physical Medicine and Rehabilitation, Ghent University
Hospital, Belgium.
A 65-year-old woman who has been admitted after organophosphate-induced
poisoning (Fenthion), develops pareses as a result of neuromuscular junctional
dysfunction 7 days post-exposure. These findings are consistent with an
intermediate syndrome, which may appear within 24 to 96 hours of exposure and
subsides after 5 to 18 days. Delayed polyneuropathy develops within 1 to 3 weeks
and abates after 6 to 12 months. A distal axonopathy can be demonstrated.
Several authors have attempted EMG monitoring of pesticide-workers in
agricultural and industrial settings. The electrophysiologic examination is an
important diagnostic adjunct in the development and course of muscle paresis
following organophosphate-ester poising.
PMID: 1665780 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10483922 | 1. Brain Res Bull. 1999 Aug;49(6):441-51. doi: 10.1016/s0361-9230(99)00081-7.
Persistent Borna disease virus infection of neonatal rats causes brain regional
changes of mRNAs for cytokines, cytokine receptor components and neuropeptides.
Plata-Salamán CR(1), Ilyin SE, Gayle D, Romanovitch A, Carbone KM.
Author information:
(1)Division of Molecular Biology, School of Life and Health Sciences, University
of Delaware, Newark, USA. [email protected]
Borna disease virus (BDV) replicates in brain cells. The neonatally infected rat
with BDV exhibits developmental-neuromorphological abnormalities, neuronal
cytolysis, and multiple behavioral and physiological alterations. Here, we
report on the levels of interleukin-1beta (IL-1beta), IL-1 receptor antagonist
(IL-1Ra), tumor necrosis factor-alpha (TNF-alpha), transforming growth
factor-beta1 (TGF-beta1), IL-1 receptor type I (IL-1RI), IL-1 receptor accessory
protein (IL-1R AcP) I and II, glycoprotein 130, and various neuropeptide mRNAs
in the cerebellum, parieto-frontal cortex, hippocampus and hypothalamus of
BDV-infected rats at 7 and 28 days postintracerebral BDV inoculation. The data
show that cytokine and neuropeptide mRNA components are abnormal and
differentially modulated in brain regions. IL-1beta, TNF-alpha and TGF-beta1
mRNA levels were up-regulated in all brain regions following BDV inoculation.
The same cerebellar samples from BDV-infected animals exhibited the highest
levels of IL-1beta, IL-1Ra, TNF-alpha, IL-1RI, and IL-1R AcP II mRNA expression.
The profiles of IL-1beta, IL-1Ra, TNF-alpha, and TGF-beta1 mRNA induction in the
cerebellar samples were highly intercorrelated, indicating an association among
cytokine ligand mRNAs. Cytokine mRNA induction was differentially up-regulated
among brain regions, except for TGF-beta1. Specificity of transcriptional
changes in response to BDV infection is also suggested by the up-regulation of
cytokine and neuropeptide Y mRNAs associated with down-regulation of
pro-opiomelanocortin, and with no change of IL-1R AcPI, dynorphin and leptin
receptor mRNAs in the same brain region samples. Other data also show a
differential mRNA component modulation in distinct brain regions obtained from
the same rats depending on the stage of BDV infection. The conclusion of these
studies is that cytokines may play a role in the neuropathophysiology of
neonatally BDV-infected rats.
DOI: 10.1016/s0361-9230(99)00081-7
PMID: 10483922 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18780003 | 1. Hand (N Y). 2009 Mar;4(1):84-7. doi: 10.1007/s11552-008-9126-y. Epub 2008 Aug
26.
Delayed neuropathy due to organophosphate insecticide injection in an attempt to
commit suicide.
Ergün SS(1), Oztürk K, Su O, Gürsoy EB, Uğurad I, Yüksel G.
Author information:
(1)Department of Plastic and Reconstructive Surgery, Vakif Gureba Hospital,
Istanbul, Turkey. [email protected]
Organophosphates (OPs) are commonly used as pesticides throughout the world.
Exposures to OPs cause a significant number of poisonings and deaths every year.
Organophosphate-induced delayed polyneuropathy is a sensory-motor distal
axonopathy which usually occurs after exposure of certain OP insecticides.
Neuropathies due to ingestion of OPs have rarely been reported in the
literature. Moreover, until now, there is no report of a patient developing
organophosphorus injection-induced delayed neuropathy in the literature. We
report a patient with serious organophosphorus-induced delayed neuropathy due to
malathion injection. The patient was a 32-year-old female who self-injected
undetermined amounts of malathion over the median nerve trace on the forearm
crease in a suicide attempt which resulted in peripheral neuropathy.
DOI: 10.1007/s11552-008-9126-y
PMCID: PMC2654942
PMID: 18780003 |
http://www.ncbi.nlm.nih.gov/pubmed/20181287 | 1. Genome Biol. 2010;11(2):R22. doi: 10.1186/gb-2010-11-2-r22. Epub 2010 Feb 25.
ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end
tag sequencing.
Li G(1), Fullwood MJ, Xu H, Mulawadi FH, Velkov S, Vega V, Ariyaratne PN,
Mohamed YB, Ooi HS, Tennakoon C, Wei CL, Ruan Y, Sung WK.
Author information:
(1)Computational and Mathematical Biology, Genome Institute of Singapore, 60
Biopolis Street, Singapore, 138672, Republic of Singapore.
Chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) is a
new technology to study genome-wide long-range chromatin interactions bound by
protein factors. Here we present ChIA-PET Tool, a software package for automatic
processing of ChIA-PET sequence data, including linker filtering, mapping tags
to reference genomes, identifying protein binding sites and chromatin
interactions, and displaying the results on a graphical genome browser. ChIA-PET
Tool is fast, accurate, comprehensive, user-friendly, and open source (available
at http://chiapet.gis.a-star.edu.sg).
DOI: 10.1186/gb-2010-11-2-r22
PMCID: PMC2872882
PMID: 20181287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8647196 | 1. Eur J Immunol. 1996 Jun;26(6):1222-7. doi: 10.1002/eji.1830260606.
Structure and chromosomal location of the mouse interleukin-12 p35 and p40
subunit genes.
Tone Y(1), Thompson SA, Babik JM, Nolan KF, Tone M, Raven C, Waldmann H.
Author information:
(1)Sir William Dunn School of Pathology, University of Oxford, GB.
Interleukin-12 (IL-12) is a heterodimeric cytokine composed of p35 and p40
subunits and is required for induction of T helper 1 (Th1) responses. Knowledge
of how the IL-12 gene is regulated will permit an understanding of
susceptibility and resistance to pathogenic microbes and to autoiummune
diseases. In this report, we provide the gene structures, nucleotide sequences
and chromosomal assignment for the p35 and p40 subunits of mouse IL-12. The p35
and p40 subunit genes are distributed over 8 kb and 14 kb, and map to
chromosomes 3 and 11, respectively. The p35 subunit gene consists of eight
exons, including a 5'-noncoding exon that was defined by sequence comparison of
genomic DNA with the 5'ends of novel cDNA molecules. Transcription of p35 mRNA
can start from the first exon but can also initiate further downstream.
Potential transcription regulatory elements, AP1, AP2, AP3, NF-kB and GATA
recognition sequences, are located within 523 bp upstream of the p35 gene;
however, no TATA box was identified. The p40 subunit gene consists of eight
exons. A TATA box is located 30 bp upstream from the transcription start site,
and AP1, AP3, GATA, and Pu.1 recognition sequences are located within 690 bp
upstream of the p40 gene. An AGTTTCTACTTT sequence, which acts as an
interferon-gamma response element in the promoter of the major
histocompatibility complex class I gene, was also found upstream of the p40
gene.
DOI: 10.1002/eji.1830260606
PMID: 8647196 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12447847 | 1. Semin Hematol. 2002 Oct;39(4 Suppl 3):12-9. doi: 10.1053/shem.2002.36923.
Monoclonal antibody therapies in leukemias.
Tallman MS(1).
Author information:
(1)Division of Hematology-Oncology, Northwestern University Medical School,
Robert H Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA.
Significant advances in the development of monoclonal antibodies (unconjugated)
and monoclonal antibodies conjugated to potent toxins or cytotoxic agents
(immunoconjugates) have enabled improved targeting of leukemic cells with
acceptable toxicities. Gemtuzumab ozogamicin, a calicheamicin-conjugated
anti-CD33 monoclonal antibody, has demonstrated substantial efficacy in patients
with acute myeloid leukemia (AML) and has induced remissions in patients with
favorable-, intermediate-, and poor-risk cytogenetics. The immunoconjugate
BL-22, comprised of an anti-CD22 monoclonal antibody fused to a fragment of
pseudomonas exotoxin PE38, has produced high response rates in patients with
purine analog-resistant hairy cell leukemia. Campath-1H (Wellcome, Beckenham,
UK, and Ilex Oncology, San Antonio, TX), an anti-CD52 monoclonal antibody, has
demonstrated significant activity in patients with previously untreated,
relapsed, or refractory chronic lymphocytic leukemia (CLL), as well as in
patients with T-cell prolymphocytic leukemia. The anti-CD20 monoclonal antibody
rituximab also is effective in treating CLL and is being evaluated in
combination with chemotherapeutic agents (cyclophosphamide) and fludarabine.
Monoclonal antibodies may sensitize cells to chemotherapy. The optimal role of
targeted therapy with monoclonal antibodies and immunoconjugates in acute and
chronic leukemias has not yet been determined, but these novel therapies are
beginning to fulfill their promise.
Copyright 2002, Elsevier Science (USA). All rights reserved.
DOI: 10.1053/shem.2002.36923
PMID: 12447847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19275513 | 1. Expert Rev Anticancer Ther. 2009 Mar;9(3):365-71. doi:
10.1586/14737140.9.3.365.
T-cell prolymphocytic leukemia.
Khot A(1), Dearden C.
Author information:
(1)Department of Hemato-Oncology, Royal Marsden Hospital, London, UK.
[email protected]
T-cell prolymphocytic leukemia is a rare post-thymic lymphoid disorder, which
has distinctive clinical, morphologic, immunophenotypic and cytogenetic
features. It has previously been associated with an aggressive course, poor
response to conventional chemotherapy and a short median survival. Treatment
with purine analogs and the monoclonal antibody alemtuzumab has resulted in
significantly higher response rates and increased survival. However, responses
are transient and allogeneic hematopoietic progenitor-cell transplantation
remains the only potential curative option. The proportion of patients eligible
for transplant is low, owing to the older age group of patients, and
nonmyeloablative transplantation is a promising alternative that needs to be
explored.
DOI: 10.1586/14737140.9.3.365
PMID: 19275513 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15143168 | 1. Mol Cell Biol. 2004 Jun;24(11):4734-42. doi: 10.1128/MCB.24.11.4734-4742.2004.
Bromodomain factor 1 (Bdf1) is phosphorylated by protein kinase CK2.
Sawa C(1), Nedea E, Krogan N, Wada T, Handa H, Greenblatt J, Buratowski S.
Author information:
(1)Department of Biological Chemistry and Molecular Pharmacology, Harvard
Medical School, Boston, MA 02115, USA.
Bromodomain factor 1 (Bdf1) associates with Saccharomyces cerevisiae TFIID and
corresponds to the C-terminal half of higher eukaryotic TAF1. It also associates
with the SWR-C complex, which is important for Htz1 deposition. Bdf1 binds
preferentially to acetylated histone H4. Bdf1 is phosphorylated, but the
mechanism and significance of this modification have been unclear. Two distinct
regions within Bdf1 are phosphorylated; one is just C terminal to the
bromodomains and the other is near the C terminus. Mutational analysis shows
that phosphorylation is necessary for Bdf1 function in vivo. Endogenous protein
kinase CK2 purifies with Bdf1 and phosphorylates both domains. A similar
mechanism may be responsible for phosphorylation of the C-terminal region of
mammalian TAF1. These findings suggest that CK2 phosphorylation of Bdf1 may
regulate RNA polymerase II transcription and/or chromatin structure.
DOI: 10.1128/MCB.24.11.4734-4742.2004
PMCID: PMC416403
PMID: 15143168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25767391 | 1. Ther Clin Risk Manag. 2015 Mar 3;11:359-70. doi: 10.2147/TCRM.S69716.
eCollection 2015.
Update on therapeutic management of idiopathic pulmonary fibrosis.
Tzouvelekis A(1), Bonella F(2), Spagnolo P(3).
Author information:
(1)Department of Internal Medicine, Section of Pulmonary, Critical Care and
Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
(2)Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University Hospital,
University of Duisburg-Essen, Germany.
(3)Medical University Clinic, Canton Hospital Baselland and University of Basel,
Liestal, Switzerland.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive diffuse
parenchymal lung disease of unknown origin, with a mortality rate exceeding that
of many cancers. The diagnostic process is complex and relies on the clinician
integrating clinical, laboratory, radiological, and histological data. In the
last decade, major advances in our understanding of the pathogenesis of IPF have
shifted the paradigm from a primarily inflammatory process evolving to fibrosis
to a condition driven by aberrant wound healing following alveolar epithelial
cell injury that results in scarring of the lung, architectural distortion, and
irreversible loss of function. Improved understanding of disease pathogenesis
has led to the identification of several therapeutic targets and the design of
high-quality clinical trials evaluating novel compounds. However, the results of
these studies have been mostly disappointing, probably due to the plethora of
mediators, growth factors, and signaling pathways involved in the fibrotic
process. Most recently, pirfenidone and nintedanib, two compounds with
pleiotropic anti-fibrotic properties, have been proven effective in reducing
functional decline and disease progression in IPF. This is a major breakthrough.
Nevertheless, we still have a long way to go. In fact, neither pirfenidone nor
nintedanib is a cure for IPF, and most patients continue to progress despite
treatment. As such, comprehensive care of patients with IPF, including
management of concomitant conditions and physical debility, as well as timely
referral for lung transplantation, remains essential. Several agents with a high
potential are currently being tested, and many more are ready for clinical
trials. Their completion is critical for achieving the ultimate goal of curing
patients with IPF.
DOI: 10.2147/TCRM.S69716
PMCID: PMC4354471
PMID: 25767391 |
http://www.ncbi.nlm.nih.gov/pubmed/24834811 | 1. Respir Med. 2014 Jul;108(7):1023-30. doi: 10.1016/j.rmed.2014.04.011. Epub
2014 Apr 29.
Design of the INPULSIS™ trials: two phase 3 trials of nintedanib in patients
with idiopathic pulmonary fibrosis.
Richeldi L(1), Cottin V(2), Flaherty KR(3), Kolb M(4), Inoue Y(5), Raghu G(6),
Taniguchi H(7), Hansell DM(8), Nicholson AG(8), Le Maulf F(9), Stowasser S(10),
Collard HR(11).
Author information:
(1)National Institute for Health Research Southampton Respiratory Biomedical
Research Unit and University of Southampton, University Road, Southampton SO17
1BJ, UK. Electronic address: [email protected].
(2)Louis Pradel Hospital, University of Lyon, 28 Avenue du Doyen Lepine, 69677
Bron Cedex, Lyon, France.
(3)University of Michigan Health System, 1500 E. Medical Center Drive, 3916
Taubman Center, Ann Arbor, MI 48109-0360, USA.
(4)McMaster University, Department of Medicine, Pathology & Molecular Medicine,
50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.
(5)National Hospital Organization Kinki-Chuo Chest Medical Center, Department of
Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, 1180
Nagasone-cho, Kita-Ku, Sakai City, Osaka 591-8555, Japan.
(6)University of Washington, Seattle, WA 98105, USA.
(7)Tosei General Hospital, Department of Respiratory Medicine and Allergy, 160
Nishioiwake-cho, Seto, Aichi 489-8642, Japan.
(8)Royal Brompton and Harefield Hospital NHS Foundation Trust and National Heart
and Lung Institute, Imperial College, Sydney Street, London SW3 6NP, UK.
(9)Boehringer Ingelheim France S.A.S., 12, rue André Huet - B.P. 292, 51060
Reims Cedex, France.
(10)Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216 Ingelheim,
Germany.
(11)University of California San Francisco, 505 Parnassus Avenue, San Francisco,
CA 94131, USA.
BACKGROUND: Nintedanib is in clinical development as a treatment for idiopathic
pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that
nintedanib 150 mg twice daily had clinical benefits with an acceptable safety
profile.
METHODS: The INPULSIS™ trials are replicate Phase III, randomized, double-blind,
studies comparing the efficacy and safety of nintedanib 150 mg twice daily with
placebo in patients with IPF. Eligible patients were aged ≥40 years with a
diagnosis of IPF within 5 years before randomization who had undergone a chest
high-resolution computed tomography (HRCT) scan within 1-year before screening,
and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing
capacity for carbon monoxide of 30-79% predicted. Participants were randomized
3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the
annual rate of decline in FVC. The key secondary endpoints are change from
baseline in the total score on the St. George's Respiratory Questionnaire (a
measure of health-related quality of life) over 52 weeks and time to first acute
exacerbation.
RESULTS: Enrolment of 1066 patients in 24 countries was completed in September
2012. Results will be reported in the first half of 2014.
CONCLUSION: The INPULSIS™ trials will determine the efficacy of nintedanib in
patients with IPF, including its impact on disease progression as defined by
decline in FVC, acute exacerbations and health-related quality of life. In
addition, they will characterise the adverse event profile of nintedanib in this
patient population.
TRIAL REGISTRATION: Registered at ClinicalTrials.gov (identifiers: NCT01335464
and NCT01335477).
Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.rmed.2014.04.011
PMID: 24834811 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19675515 | 1. Neuro Endocrinol Lett. 2009;30(2):209-14.
Radioiodine therapy in patients with amiodarone-induced thyrotoxicosis (AIT).
Czarnywojtek A(1), Czepczynski R, Ruchala M, Wasko R, Zgorzalewicz-Stachowiak M,
Szczepanek E, Zamyslowska H, Bartkowiak Z, Florek E, Sowinski J.
Author information:
(1)Department of Endocrinology, Metabolism and Internal Medicine, Poznan
University of Medical Sciences, Poland. [email protected]
INTRODUCTION: Amiodarone (AM) is frequently used in the therapy of patients with
cardiac disorders. However, due to high iodine content, it has side effects on
thyroid function. The use of radioiodine therapy (RIT) in amiodarone-induced
thyrotoxicosis (AIT) with low radioactive iodine uptake (RAIU) is still
controversial. In these patients therapeutic choices for refractory disease
include surgery, antithyroid drugs, or glu ocorticosteriods.
AIM: The aim of the study was to evaluate the efficacy of RIT in patients
presenting AIT and low RAIU in two-year follow-up.
PATIENTS AND METHODS: 40 patients (25 men and 15 women) aged from 63 to 83 years
(x +/- SD: 66.2 +/- 5.0 years; median: 65 years) treated with RIT were included
into the study. In these patients AM therapy was essential for the underlying
heart disorder, while surgery, antithyroid drugs or glucocorticosteroids, were
contraindicated. Forty seven patients with toxic multinodular goiter (TMNG) (39
women and 8 men), matched for age (67 +/- 12 yr; range 54-89 yr), were enrolled
into the study as a comparative group. The diagnostic procedures included
baseline thyroid function tests (thyrothropin - TSH, free triiodothyronine - fT3
and free thyroxine - fT4 levels), thyroid autoantibodies measurement
(antithyroglobulin autoantibodies - TgAb, antithyroid peroxidase autoantibodies
- TPOAb, anti-TSH receptor autoantibodies - TRAb), thyroid ultrasonography,
thyroid scintiscan and RAIU assessment.
RESULTS: Serum values of TSH, TgAb, TPOAb and TRAb were undetectable in both
groups. In patients with AIT fT4 level was 18.7 to 38.7 pmol/l (mean: 27.1 +/-
5.8) and fT3 concentration was 3.9 to 5.6 pmo/l (mean: 5.7 +/- 1.4), while in
TMNG patients level of fT4 was 31.5 to 22.2 pmol/l (mean: 25,3 +/- 5,8) and fT3
concentration was 3.8 to 4,2 pmo/l (mean: 4,2 +/- 0,2). Mean RAIU values after
5h and 24h in AIT patients were 2.3 +/- 0.5 and 3.1 +/- 0.9%, while in TMNG
patients were 18,0 +/- 3,8 and 35,7 +/- 9,1%, respectively. A significant
difference (p<0.001) between 5h and 24h RAIU in AIT compared to TMNG was noted.
In all patients with AIT, a dose of 800 MBq of 131I was administered. During
two-year-observation recurrence of hyperthyroidism was observed in two patients
(5%) with TMNG. These patients received a second radioiodine dose 16.2 +/- 15
months later (the mean re-treatment dose was 735.93 +/- 196.1 MBq). In
comparison, none of the patients with AIT required a second 131I dose and only
one patient (2.5%) 6 months after ablative 131I dose needed anti-thyroid
medication. Transient hypothyroidism was observed in only two patients (5%) with
AIH, though was not observed in TMNG. During follow-up time, no sudden deaths in
AIT patients were observed; one patient was diagnosed with prostate cancer, and
in one patient acute toxic hepatitis after AM occurred.
CONCLUSION: RIT may be a safe and useful method of AIT therapy in patients with
low RAIU, in whom other treatment methods are contraindicated.
PMID: 19675515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21494614 | 1. PLoS One. 2011 Apr 8;6(4):e18674. doi: 10.1371/journal.pone.0018674.
Methylation and loss of Secreted Frizzled-Related Protein 3 enhances melanoma
cell migration and invasion.
Ekström EJ(1), Sherwood V, Andersson T.
Author information:
(1)Cell and Experimental Pathology, Department of Laboratory Medicine, Lund
University, Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
BACKGROUND: Wnt signaling is important in development and can also contribute to
the initiation and progression of cancer. The Secreted Frizzled Related Proteins
(SFRPs) constitute a family of Wnt modulators, crucial for controlling Wnt
signaling. Here we investigate the expression and role of SFRP3 in melanoma.
METHODOLOGY/PRINCIPAL FINDINGS: We show that SFRP3 mRNA is down-regulated in
malignant melanoma tumors as compared to normal/benign tissue. Furthermore, we
found that SFRP3 expression was lost in the malignant melanoma cell lines,
A2058, HTB63 and A375, but not in the non-transformed melanocyte cell line,
Hermes 3A. Methylated CpG rich areas were detected in the SFRP3 gene in melanoma
cell lines and their SFRP3 expression could be restored using the demethylating
agent, 5'aza-deoxycytidine. Addition of recombinant SFRP3 to melanoma cells had
no effect on viable cell numbers, but decreased cell migration and invasion.
Wnt5a signaling has been shown to increase the migration and invasion of
malignant melanoma cells, and high expression of Wnt5a in melanoma tumors has
been connected to a poor prognosis. We found that recombinant SFRP3 could
inhibit Wnt5a signaling, and that it inhibited melanoma cell migration and
invasion in a Wnt5a-dependent manner.
CONCLUSION/SIGNIFICANCE: We conclude that SFRP3 functions as a melanoma
migration and invasion suppressor by interfering with Wnt5a signaling.
DOI: 10.1371/journal.pone.0018674
PMCID: PMC3072980
PMID: 21494614 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: TA and VS are shareholders
of WntResearch. This does not alter the authors' adherence to all the PLoS ONE
policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/17188616 | 1. J Pediatr. 2007 Jan;150(1):62-5. doi: 10.1016/j.jpeds.2006.10.060.
Thyroid morphology and subclinical hypothyroidism in children and adolescents
with Williams syndrome.
Cambiaso P(1), Orazi C, Digilio MC, Loche S, Capolino R, Tozzi A, Faedda A,
Cappa M.
Author information:
(1)Department of Pediatric Medicine, Endocrinology Unit, Bambino Gesù Children's
Hospital, IRRCS, Rome, Italy. [email protected]
OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid
abnormalities in young patients with Williams syndrome (WS).
STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years
of age) underwent evaluation of thyroid function by means of thyroid-stimulating
hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed
in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were
measured in all patients with abnormal thyroid function tests.
RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had
subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The
prevalence of patients with subclinical hypothyroidism was significantly higher
in the younger patients. Ultrasonography revealed morphological or volumetric
abnormalities of the thyroid gland in 67.5% of patients; these abnormalities
were more frequently observed in the older children.
CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in
young children with WS. The great majority of patients with WS >10 years, either
with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we
suggest yearly monitoring of thyroid function and sonographic studies at least
once in patients with WS. Treatment should be reserved for the patients with
overt hypothyroidism or for those whose thyroid function shows signs of
progressive deterioration.
DOI: 10.1016/j.jpeds.2006.10.060
PMID: 17188616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17107865 | 1. Environ Health Perspect. 2006 Nov;114(11):1763-9. doi: 10.1289/ehp.9062.
Potential uses of biomonitoring data: a case study using the organophosphorus
pesticides chlorpyrifos and malathion.
Barr DB(1), Angerer J.
Author information:
(1)National Center for Environmental Health, Centers for Disease Control and
Prevention, Atlanta, Georgia, USA. [email protected]
BACKGROUND: Organophosphorus pesticides such as chlorpyrifos and malathion are
widely used insecticides. They do not bioaccumulate appreciably in humans and
are rapidly metabolized and excreted in the urine. In nonoccupational settings,
exposures to these pesticides are typically sporadic and short-lived because the
pesticides tend to degrade in the environment over time; however, dietary
exposures may be more chronic. Biologic monitoring has been widely used to
assess exposures, susceptibility, and effects of chlorpyrifos and malathion;
thus, the information base on these compounds is data rich. For biomonitoring of
exposure, chlorpyrifos and malathion have been measured in blood, but most
typically their urinary metabolites have been measured. For assessing early
effects and susceptibility, cholinesterase and microsomal esterase activities,
respectively, have been measured.
OBJECTIVES: Although many biologic monitoring data have been generated and
published on these chemicals, their interpretation is not straightforward. For
example, exposure to environmental degradates of chlorpyrifos and malathion may
potentially increase f urinary metabolite levels, thus leading to overestimation
of exposure. Also, the temporal nature of the exposures makes the evaluation of
both exposure and effects difficult. We present an overview of the current
biomonitoring and other relevant data available on exposure to chlorpyrifos and
malathion and the use of these data in various environmental public health
applications.
DOI: 10.1289/ehp.9062
PMCID: PMC1665422
PMID: 17107865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23872122 | 1. World Neurosurg. 2013 Dec;80(6):759-765.e3. doi: 10.1016/j.wneu.2013.07.010.
Epub 2013 Jul 18.
Part I: The application of the h-index to groups of individuals and departments
in academic neurosurgery.
Khan N(1), Thompson CJ, Choudhri AF, Boop FA, Klimo P Jr.
Author information:
(1)College of Medicine, University of Tennessee Health Science Center, Memphis,
Tennessee, USA.
OBJECTIVE: The h-index was introduced as a means of quantifying the contribution
a researcher makes to the scientific literature. We evaluated the h-index for
academic neurosurgeons to assess the various methods of calculation and to
determine whether the h-index can be used to differentiate groups of individuals
by various classifications.
METHODS: The h-index was calculated for all neurosurgeons from 10 institutions
ranked highly by 2012 U.S. News & World Report plus the authors' institution via
Scopus. The h-index also was calculated manually to evaluate its accuracy. The
average h-index was calculated for groups on the basis of sex, academic rank,
years in practice, institution, and subspecialty. Cumulative and mean h-indices
were calculated for each department.
RESULTS: The median h-index for the 188 neurosurgeons was 16 (mean, 19.71;
range, 0-61). There was a positive association between the h-index, academic
rank, and years posttraining. There was a significant difference between the
"manually calculated" and automated h-indices, particularly for more senior
physicians. The difference in h-index between men and women was not
statistically significant. Among subspecialties, vascular surgeons had the
greatest average h-index and general neurosurgeons had the lowest. There were
significant shifts in departmental rankings when the cumulative or mean
departmental indices were compared with the U.S. News & World Report rankings.
CONCLUSION: Application of the h-index as a bibliometric in neurosurgery can
distinguish academic productivity on the basis of academic rank, years
posttraining, and neurosurgical subspecialties. The application of the h-index
to compare departments is problematic and, at this time, not reliable.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.wneu.2013.07.010
PMID: 23872122 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21432383 | 1. Environ Health Prev Med. 2006 May;11(3):102-7. doi: 10.1265/ehpm.11.102.
Ocular toxicity from pesticide exposure: A recent review.
Jaga K(1), Dharmani C.
Author information:
(1)Department of Psychiatry, Mount Sinai School of Medicine, 51 Eiler Lane,
10533, Irvington, New York, USA, [email protected].
Toxic effects on eyes result from exposure to pesticides via inhalation,
ingestion, dermal contact and ocular exposure. Exposure of unprotected eyes to
pesticides results in the absorption in ocular tissue and potential ocular
toxicity. Recent literature on the risks of ocular toxicity from pesticide
exposure is limited.Ocular toxicity from pesticide exposure, including the
dose-response relationship, has been studied in different animal species.
Cholinesterase enzymes have been detected in animal ocular tissue, with evidence
of organophosphate-induced inhibition. Pathological effects of pesticides have
been observed in conjunctiva, cornea, lens, retina and the optic nerve.
Pesticide exposure has been associated with retinopathy in agricultural workers
and wives of farmers who used pesticides. Saku disease, an optico-autonomic
peripheral neuropathy, has been described in Japan in people living in an area
where organophosphates were used. Pesticide exposure is also associated with
abnormal ocular movements.Progressive toxic ocular effects leading to defective
vision are a serious health concern. Agricultural workers are at high risk of
exposure to pesticides and associated ocular toxicity. Primary prevention is the
appropriate method of protecting eyes from pesticide-related damage. This
includes improved eye safety and care in workplaces, and effective pesticide
regulation for maintenance of public eye health.
DOI: 10.1265/ehpm.11.102
PMCID: PMC2723220
PMID: 21432383 |
http://www.ncbi.nlm.nih.gov/pubmed/12883107 | 1. Psychosom Med. 2003 Jul-Aug;65(4):571-81. doi:
10.1097/01.psy.0000074003.35911.41.
Mindfulness-based stress reduction in relation to quality of life, mood,
symptoms of stress, and immune parameters in breast and prostate cancer
outpatients.
Carlson LE(1), Speca M, Patel KD, Goodey E.
Author information:
(1)Department Psychosocial Resources, Tom Baker Cancer Centre, Calgary, Alberta,
Canada. [email protected]
OBJECTIVES: This study investigated the relationships between a
mindfulness-based stress reduction meditation program for early stage breast and
prostate cancer patients and quality of life, mood states, stress symptoms,
lymphocyte counts, and cytokine production.
METHODS: Forty-nine patients with breast cancer and 10 with prostate cancer
participated in an 8-week MBSR program that incorporated relaxation, meditation,
gentle yoga, and daily home practice. Demographic and health behavior variables,
quality of life (EORTC QLQ C-30), mood (POMS), stress (SOSI), and counts of NK,
NKT, B, T total, T helper, and T cytotoxic cells, as well as NK and T cell
production of TNF, IFN-gamma, IL-4, and IL-10 were assessed pre- and
postintervention.
RESULTS: Fifty-nine and 42 patients were assessed pre- and postintervention,
respectively. Significant improvements were seen in overall quality of life,
symptoms of stress, and sleep quality. Although there were no significant
changes in the overall number of lymphocytes or cell subsets, T cell production
of IL-4 increased and IFN-gamma decreased, whereas NK cell production of IL-10
decreased. These results are consistent with a shift in immune profile from one
associated with depressive symptoms to a more normal profile.
CONCLUSIONS: MBSR participation was associated with enhanced quality of life and
decreased stress symptoms in breast and prostate cancer patients. This study is
also the first to show changes in cancer-related cytokine production associated
with program participation.
DOI: 10.1097/01.psy.0000074003.35911.41
PMID: 12883107 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15126284 | 1. Ann N Y Acad Sci. 2004 Apr;1011:61-8. doi: 10.1007/978-3-662-41088-2_7.
Mitochondrial nucleoid and transcription factor A.
Kanki T(1), Nakayama H, Sasaki N, Takio K, Alam TI, Hamasaki N, Kang D.
Author information:
(1)Department of Clinical Chemistry and Laboratory Medicine, Kyushu University
Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
Nuclear DNA is tightly packed into nucleosomal structure. In contrast, human
mitochondrial DNA (mtDNA) had long been believed to be rather naked because
mitochondria lack histone. Mitochondrial transcription factor A (TFAM), a member
of a high mobility group (HMG) protein family and a first-identified
mitochondrial transcription factor, is essential for maintenance of
mitochondrial DNA. Abf2, a yeast counterpart of human TFAM, is abundant enough
to cover the whole region of mtDNA and to play a histone-like role in
mitochondria. Human TFAM is indeed as abundant as Abf2, suggesting that TFAM
also has a histone-like architectural role for maintenance of mtDNA. When human
mitochondria are solubilized with non-ionic detergent Nonidet-P40 and then
separated into soluble and particulate fractions, most TFAM is recovered from
the particulate fraction together with mtDNA, suggesting that human mtDNA forms
a nucleoid structure. TFAM is tightly associated with mtDNA as a main component
of the nucleoid.
DOI: 10.1007/978-3-662-41088-2_7
PMID: 15126284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16042503 | 1. Toxicol Rev. 2005;24(1):37-49. doi: 10.2165/00139709-200524010-00003.
Organophosphate-induced delayed polyneuropathy.
Lotti M(1), Moretto A.
Author information:
(1)Department of Environmental Medicine and Public Health, University of Padua,
Padova, Italy. [email protected]
Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity
resulting from exposure to certain organophosphorus (OP) esters. It is
characterised by distal degeneration of some axons of both the peripheral and
central nervous systems occurring 1-4 weeks after single or short-term
exposures. Cramping muscle pain in the lower limbs, distal numbness and
paraesthesiae occur, followed by progressive weakness, depression of deep tendon
reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs
include high-stepping gait associated with bilateral foot drop and, in severe
cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In
time, there might be significant recovery of the peripheral nerve function but,
depending on the degree of pyramidal involvement, spastic ataxia may be a
permanent outcome of severe OPIDP. Human and experimental data indicate that
recovery is usually complete in the young. At onset, the electrophysiological
changes include reduced amplitude of the compound muscle potential, increased
distal latencies and normal or slightly reduced nerve conduction velocities. The
progression of the disease, usually over a few days, may lead to
non-excitability of the nerve with electromyographical signs of denervation.
Nerve biopsies have been performed in a few cases and showed axonal degeneration
with secondary demyelination. Neuropathy target esterase (NTE) is thought to be
the target of OPIDP initiation. The ratio of inhibitory powers for
acetylcholinesterase and NTE represents the crucial guideline for the
aetiological attribution of OP-induced peripheral neuropathy. In fact,
pre-marketing toxicity testing in animals selects OP insecticides with
cholinergic toxicity potential much higher than that to result in OPIDP.
Therefore, OPIDP may develop only after very large exposures to insecticides,
causing severe cholinergic toxicity. However, this was not the case with certain
triaryl phosphates that were not used as insecticides but as hydraulic fluids,
lubricants and plasticisers and do not result in cholinergic toxicity. Several
thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate
have been reported, whereas the number of cases of OPIDP as a result of OP
insecticide poisoning is much lower. In this article, we mainly discuss OP
pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos,
isofenphos, methamidophos, mipafox, trichlorfon, trichlornat,
phosphamidon/mevinphos and by certain carbamates. We also discuss case reports
where neuropathies were not convincingly attributed to fenthion, malathion,
omethoate/dimethoate, parathion and merphos. Finally, several observational
studies on long-term, low-level exposures to OPs that sometimes reported mild,
inconsistent and unexplained changes of unclear significance in peripheral
nerves are briefly discussed.
DOI: 10.2165/00139709-200524010-00003
PMID: 16042503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19830044 | 1. Cases J. 2009 Jul 22;2:8018. doi: 10.4076/1757-1626-2-8018.
Dental erosion caused by gastroesophageal reflux disease: a case report.
Cengiz S(1), Cengiz MI, Saraç YS.
Author information:
(1)Prosthetic Dentistry, Private Practice, Samsun, Turkey. [email protected]
INTRODUCTION: Chronic regurgitation of gastric acids in patients with
gastroesophageal reflux disease may cause dental erosion, which can lead in
combination with attrition or bruxism to extensive loss of coronal tooth tissue.
CASE PRESENTATION: This clinical report describes treatment of severe tooth wear
of a gastroesophageal reflux disease patient who is 54-year-old Turkish male
patient. After his medical treatment, severe tooth wear, bruxism and decreased
vertical dimensions were determined. The vertical dimension was re-established
and maxillary and mandibular anterior and posterior teeth were prepared for
metal-ceramic restorations. Metal-ceramic fixed partial dentures were fabricated
as full mouth restorations for both maxillary and mandibular arches because of
splinting all teeth. And then maxillary stabilization splint was fabricated for
his bruxism history.
CONCLUSION: Significant loss of coronal tooth structure must taken into
consideration. Gastroesophageal reflux disease by itself or in combination with
attrition, abrasion or bruxism may be responsible for the loss. An extensive
diagnostic evaluation is essential for the medical and dental effects of the
problem.
DOI: 10.4076/1757-1626-2-8018
PMCID: PMC2740145
PMID: 19830044 |
http://www.ncbi.nlm.nih.gov/pubmed/8468724 | 1. J Natl Cancer Inst. 1993 Apr 21;85(8):658-62. doi: 10.1093/jnci/85.8.658.
Pentostatin in prolymphocytic leukemia: phase II trial of the European
Organization for Research and Treatment of Cancer Leukemia Cooperative Study
Group.
Döhner H(1), Ho AD, Thaler J, Stryckmans P, Sonneveld P, de Witte T, Lechner K,
Lauria F, Bödewadt-Radzun S, Suciu S, et al.
Author information:
(1)Medizinische Klinik, University of Heidelberg, Federal Republic of Germany.
BACKGROUND: B-cell prolymphocytic leukemias or T-cell prolymphocytic leukemias
are aggressive variants of chronic lymphoid leukemias. The small studies
conducted to date have shown median survival durations of approximately 3 years
for patients who have B-cell prolymphocytic leukemia and 7.5 months for those
who have T-cell prolymphocytic leukemia, compared with about 8 years for
patients who have chronic lymphocytic leukemia. In chronic lymphocytic leukemia,
chemotherapy consisting of alkylating agents such as cyclophosphamide and
chlorambucil combined with prednisone has achieved overall response rates of 50%
to 70%, but this regimen has resulted in response rates of less than 25% in
prolymphocytic leukemia. Pentostatin (2'-deoxycoformycin; DCF) is a purine
analogue that has shown activity in treatment of chronic lymphoid malignancies.
PURPOSE: This prospective phase II trial by the Leukemia Cooperative Group of
the European Organization for Research and Treatment of Cancer was performed to
assess the activity and toxicity of DCF in prolymphocytic leukemia.
METHODS: Twenty patients with B-cell or T-cell prolymphocytic leukemia were
given DCF at a dosage of 4 mg/m2 intravenously once a week for 3 weeks, then
every other week for three doses. Patients who had at least partial response
received maintenance therapy once a month for a maximum of 6 months. Fourteen
patients had B-cell prolymphocytic leukemia, and six had T-cell prolymphocytic
leukemia, as evidenced by morphologic and immunologic criteria; three were
previously untreated, eight had been given one or two chemotherapeutic regimens,
and nine had been given more than two.
RESULTS: One patient died of an unknown cause during the first 6 weeks of
treatment, and one died of disseminated toxoplasmosis during the period of
maintenance therapy, 5 months after achieving partial remission. Nine (45%
response rate) of the 20 patients achieved partial remission, including seven
(50%) of 14 with B-cell prolymphocytic leukemia and two (33%) of six with T-cell
prolymphocytic leukemia. The median duration of response was 9 months (range,
2-30 months); for patients with B-cell prolymphocytic leukemia, the median
remission duration was 12 months. No complete remission was observed. Toxic
effects included nausea and vomiting (30%), infections (30%), and transient
increase in liver enzymes (35%) and in creatinine (20%) levels. Eight patients
experienced thrombocytopenia, the major hematologic toxic effect; four had grade
3 or 4 toxic effects.
CONCLUSION: DCF is active in prolymphocytic leukemia, even as salvage therapy in
patients who had received multiple prior chemotherapeutic regimens.
IMPLICATIONS: Trials using DCF or other purine analogues alone or in combination
with standard chemotherapeutic agents in front-line or salvage therapy are
warranted to improve the prognosis of patients with prolymphocytic leukemia.
DOI: 10.1093/jnci/85.8.658
PMID: 8468724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15952730 | 1. J Proteome Res. 2005 May-Jun;4(3):837-45. doi: 10.1021/pr049750o.
Evaluation of protein depletion methods for the analysis of total-, phospho- and
glycoproteins in lumbar cerebrospinal fluid.
Ogata Y(1), Charlesworth MC, Muddiman DC.
Author information:
(1)Mayo Proteomics Research Center and Department of Biochemistry and Molecular
Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
A proper sample preparation, in particular, abundant protein removal is crucial
in the characterization of low-abundance proteins including those harboring
post-translational modifications. In human cerebrospinal fluid (CSF),
approximately 80% of proteins originate from serum, and removal of major
proteins is necessary to study brain-derived proteins that are present at low
concentrations for successful biomarker and therapeutic target discoveries for
neurological disorders. In this study, phospho- and glycoprotein specific
fluorescent stains and mass spectrometry were used to map proteins from CSF on
two-dimensional gel electropherograms after immunoaffinity based protein
removal. Two protein removal methods were evaluated: batch mode with avian IgY
antibody microbeads using spin filters and HPLC multiple affinity removal
column. Six abundant proteins were removed from CSF: human serum albumin (HSA),
transferrin, IgG, IgA, IgM, and fibrinogen with batch mode, and HSA,
transferrin, IgG, IgA, antitrypsin, and haptoglobin with column chromatography.
2D gels were compared after staining for phospho-, glyco- and total proteins.
The column format removed the major proteins more effectively and approximately
50% more spots were visualized when compared to the 2D gel of CSF without
protein depletion. After protein depletion, selected phospho- and glycoprotein
spots were identified using mass spectrometry in addition to some of the spots
that were not visualized previously in nondepleted CSF. Fifty proteins were
identified from 66 spots, and among them, 12 proteins (24%) have not been
annotated in previously published 2D gels.
DOI: 10.1021/pr049750o
PMID: 15952730 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14654909 | 1. Oncol Rep. 2004 Jan;11(1):93-5.
Thalidomide prolongs disease stabilization after conventional therapy in
patients with recurrent glioblastoma.
Morabito A(1), Fanelli M, Carillio G, Gattuso D, Sarmiento R, Gasparini G.
Author information:
(1)Division of Medical Oncology, 'San Filippo Neri' Hospital, Rome, Italy.
Thalidomide shows antiangiogenic activity and it has been successfully employed
in various tumors. Considering the poor therapeutic options for glioblastoma and
the role of angiogenesis in malignant glioma cells growth, we investigated the
therapeutic activity of thalidomide in patients affected by recurrent
glioblastoma. Inclusion criteria were: recurrent glioblastoma pretreated with
surgery and radiotherapy, age >/=18 years, adequate performance status,
hematological, renal, and hepatic functions. Exclusion criteria included severe
underlying diseases, neuropathy or concurrent radiotherapy. Eighteen patients
entered the study, 17 of whom were assessable for toxicity and response. Most of
patients were pretreated with chemotherapy (77.8%). Thalidomide was well
tolerated: the most common side effects were constipation (76.5% of patients),
somnolence (47%), and peripheral neuropathy (11.8%). One minimal response (MR)
and 8 stable disease (SD) were observed, with an overall clinical benefit of
52.9%. Median time to progression and median overall survival (OS) for
responders was 25 weeks (range 12-40) and 36 weeks (range 16-64), respectively.
In conclusion, thalidomide induces modest side effects and it may be considered
a valid therapeutic option for patients with recurrent glioblastoma.
PMID: 14654909 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16720000 | 1. Ann R Coll Surg Engl. 2006 May;88(3):284-8. doi: 10.1308/003588406X98685.
PSA testing: are patients aware of what lies ahead?
Lamplugh M(1), Gilmore P, Quinlan T, Cornford P.
Author information:
(1)Department of Urological Surgery, Royal Liverpool Hospital, Liverpool, UK.
[email protected]
INTRODUCTION: Screening for prostate cancer with serum prostate specific antigen
(PSA) remains a controversial topic. The UK NHS Executive has issued extensive
guidance stressing the importance of adequate counselling prior to performing
this test. This study aims to assess men's knowledge of the PSA test at the time
of their referral and their attitude towards screening.
PATIENTS AND METHODS: A total of 219 men referred to urology via the 'fast
track' prostate cancer service were recruited into the study. Of these, 191 were
referred from primary care and 28 from secondary care. All men completed a
questionnaire regarding their knowledge and expectation of the test.
RESULTS: The response rate for completed questionnaires was 100%. Overall, 91
(41.5%) men were aware that their PSA had been performed prior to referral and
only 79 (36%) men understood why the test was being done. Patients referred from
secondary care appeared to be better informed. Despite these figures, 175 (80%)
men said they would recommend PSA testing to a friend or colleague, and 196
(89%) men said the test should be broadly publicised.
CONCLUSIONS: Nearly two-thirds of the men referred to urology with an elevated
PSA were unaware that they had even had their PSA done. Information about the
limitations of PSA testing and the consequence of a positive test result had
been deficient. Informed counselling for the PSA test should form part of the
consultation of any physician intending to undertake this test whether for lower
urinary tract symptoms or for prostate cancer screening.
DOI: 10.1308/003588406X98685
PMCID: PMC1963666
PMID: 16720000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23314528 | 1. Rev Neurosci. 2013;24(2):115-23. doi: 10.1515/revneuro-2012-0071.
The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of
Parkinson's disease: a review of in vivo models.
Sato H(1), Kato T, Arawaka S.
Author information:
(1)Department of Neurology, Yamagata University Faculty of Medicine, Yamagata,
Japan.
Parkinson's disease is the most common neurodegenerative movement disorder. The
motor impairments of Parkinson's disease are caused by the loss of dopaminergic
neurons in the substantia nigra and associated with the appearance of fibrillar
aggregates of α-synuclein (α-syn) called Lewy bodies. Approximately 90% of α-syn
deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast,
only 4% or less of total α-syn is phosphorylated at this residue in the normal
brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads
to the formation of Lewy bodies and dopaminergic neurodegeneration in
Parkinson's disease. Our laboratory and others have performed experiments using
in vivo models of Parkinson's disease to elucidate the role of increased Ser129
phosphorylation in α-syn neurotoxicity. However, there has been a lack of
consistency among these models. In this review, we summarize the main findings
regarding the relationship between Ser129 phosphorylation and α-syn
neurotoxicity, and examine the differences among models. We further discuss the
role of Ser129 phosphorylation in α-syn aggregation and the future directions to
test the potential of Ser129 phosphorylation as a therapeutic target for slowing
the progression of Parkinson's disease.
DOI: 10.1515/revneuro-2012-0071
PMID: 23314528 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19966852 | 1. Oncogene. 2010 Feb 18;29(7):1062-72. doi: 10.1038/onc.2009.371. Epub 2009 Dec
7.
PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream
enhancer element.
Bonadies N(1), Neururer Ch, Steege A, Vallabhapurapu S, Pabst T, Mueller BU.
Author information:
(1)Department of Internal Medicine and Clinical Research, University Hospital
Bern, University of Bern, Bern, Switzerland.
The majority of patients with acute myeloid leukemia (AML) still die of their
disease, and novel therapeutic concepts are needed. Timely expression of the
hematopoietic master regulator PU.1 is crucial for normal development of myeloid
and lymphoid cells. Targeted disruption of an upstream regulatory element (URE)
located several kb upstream in the PU.1 promoter decreases PU.1 expression
thereby inducing AML in mice. In addition, suppression of PU.1 has been observed
in specific subtypes of human AML. Here, we identified nuclear factor-kappaB
(NF-kappaB) to activate PU.1 expression through a novel site within the URE. We
found sequence variations of this particular NF-kappaB site in 4 of 120 AML
patients. These variant NF-kappaB sequences failed to mediate activation of
PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through
these variant sequences was also lost. Finally, AML patients with such variant
sequences had suppressed PU.1 mRNA expression. This study suggests that changes
of a single base pair in a distal element critically affect the regulation of
the tumor suppressor gene PU.1 thereby contributing to the development of AML.
DOI: 10.1038/onc.2009.371
PMID: 19966852 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24316222 | 1. Mol Cell. 2014 Jan 9;53(1):88-100. doi: 10.1016/j.molcel.2013.11.004. Epub
2013 Dec 5.
Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect.
Yang F(1), Zhang H(1), Mei Y(2), Wu M(3).
Author information:
(1)Hefei National Laboratory for Physical Sciences at Microscale and School of
Life Sciences, University of Science and Technology of China, Hefei, Anhui
230027, China.
(2)Hefei National Laboratory for Physical Sciences at Microscale and School of
Life Sciences, University of Science and Technology of China, Hefei, Anhui
230027, China. Electronic address: [email protected].
(3)Hefei National Laboratory for Physical Sciences at Microscale and School of
Life Sciences, University of Science and Technology of China, Hefei, Anhui
230027, China. Electronic address: [email protected].
Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism
remains largely unclear. It is also not known if lncRNAs are involved in the
contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21 is
a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis.
Hypoxia/HIF-1α-induced lincRNA-p21 is able to bind HIF-1α and VHL and thus
disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated
HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the
existence of a positive feedback loop between HIF-1α and lincRNA-p21 that
promotes glycolysis under hypoxia. The ability of lincRNA-p21 to promote tumor
growth is validated in mouse xenograft models. Together, these findings suggest
that lincRNA-p21 is an important player in the regulation of the Warburg effect
and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2013.11.004
PMID: 24316222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15901832 | 1. Mol Biol Cell. 2005 Aug;16(8):3488-500. doi: 10.1091/mbc.e04-11-1029. Epub
2005 May 18.
Cathepsin B regulates the intrinsic angiogenic threshold of endothelial cells.
Im E(1), Venkatakrishnan A, Kazlauskas A.
Author information:
(1)Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114,
USA.
The lysosomal protease cathepsin B has been implicated in a variety of
pathologies including pancreatitis, tumor angiogenesis, and neuronal diseases.
We used a tube formation assay to investigate the role of cathepsin B in
angiogenesis. When cultured between two layers of collagen I, primary
endothelial cells formed tubes in response to exogenously added VEGF.
Overexpressing cathepsin B reduced the VEGF-dependent tube response, whereas
pharmacologically or molecularly suppressing cathepsin B eliminated the
dependence on exogenous VEGF. However, tube formation still required VEGF
receptor activity, which suggested that endothelial cells generated VEGF.
Indeed, VEGF mRNA and protein was detectable in cells treated with cathepsin B
inhibitor, which correlated with a rise in the level of HIF-1alpha. In addition
to boosting the level of proangiogenic factors, blocking cathepsin B activity
reduced the amount of the antiangiogenic protein endostatin. Thus endothelial
cells have the intrinsic capacity to generate pro- and antiangiogenic agents.
These observations complement and expand our appreciation of how endothelial
cell-derived proteases regulate angiogenesis.
DOI: 10.1091/mbc.e04-11-1029
PMCID: PMC1182291
PMID: 15901832 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23965803 | 1. Oncotarget. 2013 Sep;4(9):1427-37. doi: 10.18632/oncotarget.1155.
Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by
down-regulating H3K9me3 and heterochromatin.
Chen B(1), Yu M, Chang Q, Lu Y, Thakur C, Ma D, Yi Z, Chen F.
Author information:
(1)Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy,
Wayne State University, 259 Mack Avenue, Detroit, MI, USA.
Mineral dust-induced gene (mdig) had been linked to the development of human
lung cancers associated with environmental exposure to mineral dust, tobacco
smoke or other carcinogens. In the present studies, we demonstrated that the
overexpression of mdig in A549 adenocarcinomic human alveolar type II epithelial
cells decreases the heterochromatin conformation of the cells and de-represses
the transcription of genes in the tandemly repeated DNA regions. Although mdig
can only cause a marginal decrease of the total histone H3 lysine 9
trimethylation (H3K9me3), a significant reduction of H3K9me3 in the promoter
region of H19, the paternally imprinted but maternally expressed gene
transcribing a large intergenic non-coding RNA (lincRNA), was observed in the
cells with mdig overexpression. Silencing mdig by either shRNA or siRNA not only
increased the level of H3K9me3 in the promoter region of H19 but also attenuated
the transcription of H19 long non-coding RNA. Demethylation assays using
immunoprecipitated mdig and histone H3 peptide substrate suggested that mdig is
able to remove the methyl groups from H3K9me3. Clinically, we found that higher
levels of mdig and H19 expression correlate with poorer survival of the lung
cancer patients. Taken together, our results imply that mdig is involved in the
regulation of H3K9me3 to influence the heterochromatin structure of the genome
and the expression of genes important for cell growth or transformation.
DOI: 10.18632/oncotarget.1155
PMCID: PMC3824531
PMID: 23965803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18400281 | 1. Urology. 2008 Dec;72(6):1324-8. doi: 10.1016/j.urology.2008.01.015. Epub 2008
Apr 8.
A dietary intervention for recurrent prostate cancer after definitive primary
treatment: results of a randomized pilot trial.
Carmody J(1), Olendzki B, Reed G, Andersen V, Rosenzweig P.
Author information:
(1)Division of Preventive and Behavioral Medicine, University of Massachusetts
Medical School, Worcester, Massachusetts 01655, USA. [email protected]
OBJECTIVES: Considerable evidence has shown that diet can affect both the
incidence and the progression of prostate cancer. The objective of this study
was to determine whether men in this situation could make a change to a diet
emphasizing plant-based foods and fish and to examine the effect on quality of
life (QOL) and prostate-specific antigen (PSA) velocity.
METHODS: A total of 36 men and their partners were randomly assigned to attend a
series of 11 dietary and cooking classes that also integrated mindfulness
practice as a support in making the change or a wait-list control group.
Assessments were made of dietary intake, QOL, and PSA at baseline, after
intervention (11 weeks), and 3 months after intervention.
RESULTS: The intervention group showed significant reductions in the consumption
of saturated fat and increased consumption of vegetable proteins with
accompanying reductions in animal proteins, including dairy products. They also
showed increased QOL. Although no significant change was found in the rate of
PSA increase between the two groups, the mean PSA doubling time for the
intervention group was substantially longer at the 3-month follow-up visit than
that of the controls.
CONCLUSIONS: Men with a increasing PSA level after primary treatment were able
to make a change to a prostate-healthy diet, accompanied by increases in QOL. No
significant difference was found in the log PSA slope between the two groups;
however, the PSA doubling time increased substantially in the intervention group
compared with that in the controls. Future trials should examine the effect of
the prostate-healthy diet with a larger sample of men for a longer period.
DOI: 10.1016/j.urology.2008.01.015
PMID: 18400281 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12209593 | 1. Int J Cancer. 2002 Sep 1;101(1):86-94. doi: 10.1002/ijc.10566.
Serum levels of angiogenin, basic fibroblast growth factor and endostatin in
patients receiving intensive chemotherapy for acute myelogenous leukemia.
Glenjen N(1), Mosevoll KA, Bruserud Ø.
Author information:
(1)Section for Hematology, Department of Medicine, Haukeland University Hospital
and the University of Bergen, Norway. [email protected]
Angiogenesis seems to be important both in the pathogenesis of acute myelogenous
leukemia (AML) and for the susceptibility of AML blasts to chemotherapy. Recent
clinical studies even suggest that antiangiogenic therapy can induce disease
control in patients with AML relapse. In this context we have investigated the
profile of the systemic component of angiogenic regulation in AML by
characterizing the serum levels of (i) the angiogenic regulators angiogenin,
basic fibroblast growth factor (bFGF) and endostatin; (ii) the endothelial cell
marker soluble (s) E-selectin. Patients with untreated AML had increased levels
of angiogenin, endostatin and sE-selectin, whereas the levels of bFGF were not
significantly altered. The systemic levels of the proangiogenic bFGF, the
antiangiogenic endostatin and the endothelial cell marker sE-selectin showed
significant correlations, whereas angiogenin and sE-selectin levels were not
correlated. Furthermore, intensive chemotherapy resulted in decreased systemic
levels of the 2 proangiogenic mediators angiogenin and bFGF, whereas endostatin
levels remained high after treatment. Although angiogenin normally is a part of
the acute phase reaction, its systemic levels were not altered when patients
with chemotherapy-induced cytopenia developed complicating bacterial infections.
Our results suggest that intensive chemotherapy can modulate the systemic
component of angiogenic regulation in AML patients.
Copyright 2002 Wiley-Liss, Inc.
DOI: 10.1002/ijc.10566
PMID: 12209593 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19726741 | 1. J Am Acad Orthop Surg. 2009 Sep;17(9):572-81. doi:
10.5435/00124635-200909000-00004.
Marfan syndrome.
Shirley ED(1), Sponseller PD.
Author information:
(1)Naval Medical Center Portsmouth, VA, USA.
Marfan syndrome is a variable autosomal dominant disorder; most cases result
from mutations of fibrillin-1. Diagnosis is guided by the Ghent nosology. The
condition may manifest in the cardiovascular and ocular systems. Musculoskeletal
manifestations include scoliosis, dural ectasia, protrusio acetabuli, and
ligamentous laxity. Compared with patients with idiopathic scoliosis, patients
with Marfan syndrome tend to have scoliosis that progresses at a faster rate and
is more resistant to bracing; undergo scoliosis surgery complicated by greater
blood loss, pseudarthrosis, and additional curvature; and have more frequent
occurrences of dural ectasia, which may cause headaches, leg pain, or perineal
pain. Protrusio acetabuli may result in hip joint arthritis and may require
valgus osteotomy or total hip arthroplasty.
DOI: 10.5435/00124635-200909000-00004
PMID: 19726741 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18230650 | 1. J Cell Sci. 2008 Feb 15;121(Pt 4):514-21. doi: 10.1242/jcs.013557. Epub 2008
Jan 29.
Functional interactions between phosphatase POPX2 and mDia modulate RhoA
pathways.
Xie Y(1), Tan EJ, Wee S, Manser E, Lim L, Koh CG.
Author information:
(1)School of Biological Sciences, Nanyang Technological University, Singapore,
Republic of Singapore.
Rho GTPases and their downstream effectors regulate changes in the actin
cytoskeleton that underlie cell motility and adhesion. They also participate,
with RhoA, in the regulation of gene transcription by activating serum response
factor (SRF)-mediated transcription from the serum response element (SRE).
SRF-mediated transcription is also promoted by several proteins that regulate
the polymerization or stability of actin. We have previously identified a family
of PP2C phosphatases, POPXs, which can dephosphorylate the CDC42/RAC-activated
kinase PAK and downregulate its enzymatic and actin cytoskeletal activity. We
now report that POPX2 interacts with the formin protein mDia1 (DIAPH1). This
interaction is enhanced when mDia1 is activated by RhoA. The binding of POPX2 to
mDia1 or to an mDia-containing complex greatly decreases the ability of mDia1 to
activate transcription from the SRE. We propose that the interaction between
mDia1 and POPX2 (PPM1F) serves to regulate both the actin cytoskeleton and
SRF-mediated transcription, and to link the CDC42/RAC1 pathways with those of
RhoA.
DOI: 10.1242/jcs.013557
PMID: 18230650 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17932119 | 1. J Med Genet. 2008 Feb;45(2):87-92. doi: 10.1136/jmg.2007.051896. Epub 2007 Oct
11.
Assignment of two loci for autosomal dominant adolescent idiopathic scoliosis to
chromosomes 9q31.2-q34.2 and 17q25.3-qtel.
Ocaka L(1), Zhao C, Reed JA, Ebenezer ND, Brice G, Morley T, Mehta M, O'Dowd J,
Weber JL, Hardcastle AJ, Child AH.
Author information:
(1)Department of Cardiological Sciences, St George's Medical School, University
of London, UK.
BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common form of
spinal deformity, affecting up to 4% of children worldwide. Familial inheritance
of AIS is now recognised and several potential candidate loci have been found.
METHODS: We studied 25 multi-generation AIS families of British descent with at
least 3 affected members in each family. A genomewide screen was performed using
microsatellite markers spanning approximately 10-cM intervals throughout the
genome. This analysis revealed linkage to several candidate chromosomal regions
throughout the genome. Two-point linkage analysis was performed in all families
to evaluate candidate loci. After identification of candidate loci, two-point
linkage analysis was performed in the 10 families that segregated, to further
refine disease intervals.
RESULTS: Significant linkage was obtained in a total of 10 families: 8 families
to the telomeric region of chromosome 9q, and 2 families to the telomeric region
of 17q. A significant LOD score was detected at marker D9S2157 Z(max) = 3.64 (
theta= 0.0) in a four-generation family (SC32). Saturation mapping of the 9q
region in family SC32 defined the critical disease interval to be flanked by
markers D9S930 and D9S1818, spanning approximately 21 Mb at 9q31.2-q34.2. In
addition, seven other families segregated with this locus on 9q. In two
multi-generation families (SC36 and SC23) not segregating with the 9q locus, a
maximum combined LOD score of Z(max) = 4.08 ( = 0.0) was obtained for marker
AAT095 on 17q. Fine mapping of the 17q candidate region defined the AIS critical
region to be distal to marker D17S1806, spanning approximately 3.2 Mb on
chromosome 17q25.3-qtel.
CONCLUSION: This study reports a common locus for AIS in the British population,
mapping to a refined interval on chromosome 9q31.2-q34.2 and defines a novel AIS
locus on chromosome 17q25.3-qtel.
DOI: 10.1136/jmg.2007.051896
PMID: 17932119 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18288611 | 1. Neurochem Res. 2008 Jul;33(7):1332-40. doi: 10.1007/s11064-008-9588-x. Epub
2008 Feb 21.
Structural and quantitative comparison of cerebrospinal fluid glycoproteins in
Alzheimer's disease patients and healthy individuals.
Sihlbom C(1), Davidsson P, Sjögren M, Wahlund LO, Nilsson CL.
Author information:
(1)Department of Medical Chemistry and Cell Biology, Institute of Biomedicine,
Sahlgrenska Academy at Goteborg University, 440, SE-405 30 Goteborg, Sweden.
[email protected]
Glycoproteins in cerebrospinal fluid (CSF) are altered in Alzheimer's Disease
(AD) patients compared to control individuals. We have utilized albumin
depletion prior to 2D gel electrophoresis to enhance glycoprotein concentration
for image analysis as well as structural glycoprotein determination without
glycan release using mass spectrometry (MS). The benefits of a direct
glycoprotein analysis approach include minimal sample manipulation and retention
of structural details. A quantitative comparison of gel-separated glycoprotein
isoforms from twelve AD patients and twelve control subjects was performed with
glycoprotein-specific and total protein stains. We have also compared glycoforms
in pooled CSF obtained from AD patients and control subjects with mass
spectrometry. One isoform of alpha1-antitrypsin showed decreased glycosylation
in AD patients while another glycosylated isoform of an unassigned protein was
up-regulated. Protein expression levels of alpha1-antitrypsin were decreased,
while the protein levels of apolipoprotein E and clusterin were increased in AD.
No specific glycoform could be specifically assigned to AD.
DOI: 10.1007/s11064-008-9588-x
PMID: 18288611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18289149 | 1. Psychiatry Clin Neurosci. 2008 Feb;62(1):109-14. doi:
10.1111/j.1440-1819.2007.01785.x.
Six-month paroxetine treatment of premenstrual dysphoric disorder: continuous
versus intermittent treatment protocols.
Wu KY(1), Liu CY, Hsiao MC.
Author information:
(1)Department of Psychiatry, Chang Gung Memorial Hospital and Chang Gung
University School of Medicine, Tao-yuan, Taiwan.
AIMS: Several trials have proved the efficacy of selective serotonin re-uptake
inhibitors (SSRI) in the treatment of premenstrual dysphoric disorder (PMDD) in
Western society. The SSRI can be administered continuously throughout the entire
cycle or intermittently from ovulation to the onset of menstruation (luteal
phase). The purpose of the present study was to compare continuous and
intermittent paroxetine treatment in oriental PMDD women during 6 months follow
up.
METHODS: Thirty-six subjects were evaluated and drug free for two menstrual
cycles, and they received daily paroxetine (20 mg) for two further full cycles.
They were then randomly divided into continuous or intermittent treatment groups
(n = 16, 14) over the next four cycles. Responses were assessed every 2 weeks.
Outcome measures included scores on the Prospective Record of the Impact and
Severity of Menstrual Symptomatology (PRISM) calendar, Hamilton Rating Scale for
Depression/Anxiety (HAMD/HAMA), and the Clinical Global Impression scale (CGI).
RESULTS: All these women had significant improvements in the HAMA, HAMD, CGI,
and PRISM calendar. The rate of response to paroxetine treatment lay between 50%
and 78.6% in the continuous-treatment group, and 37.5-93.8% in the
intermittent-treatment group, as determined at the study end-point. Limitations
of the present study included the open-label design and the incorporation of a
limited sample size.
CONCLUSIONS: The present results indicate that paroxetine is effective in both
continuous and intermittent treatment of oriental PMDD women, and that the
effects of active treatment lasted for six consecutive treatment menstrual
cycles.
DOI: 10.1111/j.1440-1819.2007.01785.x
PMID: 18289149 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17702698 | 1. Cancer Res. 2007 Aug 15;67(16):7665-74. doi: 10.1158/0008-5472.CAN-06-4666.
Production of Wnt inhibitors by myeloma cells: potential effects on canonical
Wnt pathway in the bone microenvironment.
Giuliani N(1), Morandi F, Tagliaferri S, Lazzaretti M, Donofrio G, Bonomini S,
Sala R, Mangoni M, Rizzoli V.
Author information:
(1)Hematology and Bone Marrow Transplantation Center, Department of Internal
Medicine and Biomedical Science, University of Parma, Parma, Italy.
[email protected]
Osteoblast impairment occurs within multiple myeloma cell infiltration into the
bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is
involved in osteoblast formation through the stabilization of dephosphorylated
beta-catenin and its nuclear translocation. The effects of multiple myeloma
cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear.
In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors,
Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple
myeloma cells. However, although multiple myeloma cells or multiple myeloma bone
marrow plasma affected expression of genes in the canonical Wnt signaling and
inhibited beta-catenin stabilization in murine osteoprogenitor cells, they
failed to block the canonical Wnt pathway in human mesenchymal or
osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor
cells did not blunt the inhibitory effect of multiple myeloma cells on
osteoblast formation. Consequently, despite the higher Wnt antagonist bone
marrow levels in osteolytic multiple myeloma patients compared with
nonosteolytic ones, beta-catenin immunostaining was not significantly different.
Our results support the link between the production of Wnt antagonists by
multiple myeloma cells and the presence of bone lesions in multiple myeloma
patients but show that myeloma cells do not inhibit canonical Wnt signaling in
human bone microenvironment.
DOI: 10.1158/0008-5472.CAN-06-4666
PMID: 17702698 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18412540 | 1. Biotechnol Appl Biochem. 2009 Feb;52(Pt 2):159-66. doi: 10.1042/BA20080015.
Development of affinity columns for the removal of high-abundance proteins in
cerebrospinal fluid.
Ramström M(1), Zuberovic A, Grönwall C, Hanrieder J, Bergquist J, Hober S.
Author information:
(1)Department of Proteomics, School of Biotechnology, AlbaNova University
Center, Royal Institute of Technology (KTH), SE-106 91 Stockholm, Sweden.
Various approaches for removal of high-abundance components in body fluids are
currently available. While most methods are constructed for plasma depletion,
there is a need for body-fluid-specific strategies. The aim of the present study
was to design an affinity matrix suitable for the depletion of high-abundance
proteins in CSF (cerebrospinal fluid). Hence, molecules with specific affinity
towards proteins present at high concentration in CSF were desired. Affibody
molecules are specific binders of small size that have shown high stability
under various conditions and are therefore good candidates for such a matrix.
The protein composition in CSF resembles that in plasma. However, 20% of the
proteins are brain-derived and are therefore present in higher proportions in
CSF than in plasma, whereas larger plasma-derived proteins are less abundant in
CSF. Therefore five high-abundance CSF proteins were chosen for the design of a
CSF-specific depletion setup. Affibody molecules with specificity towards HSA
(human serum albumin), IgG, transferrin and transthyretin were combined in an
affinity column. In addition, polyclonal antibodies against cystatin C were
coupled to chromatographic beads and packed in a separate column. Highly
reproducible and efficient removal of the five target proteins was observed. The
proportion of depleted proteins were estimated to be 99, 95, 74, 92 and 83% for
HSA, IgG, transferrin, transthyretin and cystatin C respectively. SDS/PAGE
analysis was used for monitoring and identifying proteins in native CSF,
depleted CSF samples and the captured fractions. Moreover, shotgun proteomics
was used for protein identification in native as well as depleted CSF and the
achieved data were compared. Enhanced identification of lower-abundance
components was observed in the depleted fraction, in terms of more detected
peptides per protein.
DOI: 10.1042/BA20080015
PMID: 18412540 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9516420 | 1. J Biol Chem. 1998 Mar 27;273(13):7268-76. doi: 10.1074/jbc.273.13.7268.
The biochemical and phenotypic characterization of Hho1p, the putative linker
histone H1 of Saccharomyces cerevisiae.
Patterton HG(1), Landel CC, Landsman D, Peterson CL, Simpson RT.
Author information:
(1)Department of Biochemistry and Molecular Biology, Pennsylvania State
University, University Park, Pennsylvania 16802, USA. [email protected]
There is currently no published report on the isolation and definitive
identification of histone H1 in Saccharomyces cerevisiae. It was, however,
recently shown that the yeast HHO1 gene codes for a predicted protein homologous
to H1 of higher eukaryotes (Landsman, D. (1996) Trends Biochem. Sci. 21,
287-288; Ushinsky, S. C., Bussey, H. , Ahmed, A. A., Wang, Y., Friesen, J.,
Williams, B. A., and Storms, R. K. (1997) Yeast 13, 151-161), although there is
no biochemical evidence that shows that Hho1p is, indeed, yeast histone H1. We
showed that purified recombinant Hho1p (rHho1p) has electrophoretic and
chromatographic properties similar to linker histones. The protein forms a
stable ternary complex with a reconstituted core di-nucleosome in vitro at molar
rHho1p:core ratios up to 1. Reconstitution of rHho1p with H1-stripped chromatin
confers a kinetic pause at approximately 168 base pairs in the micrococcal
nuclease digestion pattern of the chromatin. These results strongly suggest that
Hho1p is a bona fide linker histone. We deleted the HHO1 gene and showed that
the strain is viable and has no growth or mating defects. Hho1p is not required
for telomeric silencing, basal transcriptional repression, or efficient
sporulation. Unlike core histone mutations, a hho1Delta strain does not exhibit
a Sin or Spt phenotype. The absence of Hho1p does not lead to a change in the
nucleosome repeat length of bulk chromatin nor to differences in the in vivo
micrococcal nuclease cleavage sites in individual genes as detected by primer
extension mapping.
DOI: 10.1074/jbc.273.13.7268
PMID: 9516420 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15751610 | 1. J Pediatr Endocrinol Metab. 2005 Feb;18(2):205-7. doi:
10.1515/jpem.2005.18.2.205.
Growth hormone deficiency in a child with Williams-Beuren syndrome. The response
to growth hormone therapy.
Xekouki P(1), Fryssira H, Maniati-Christidi M, Amenta S, Karavitakis EM,
Kanaka-Gantenbein C, Dacou-Voutetakis C.
Author information:
(1)Endocrine Unit, First Department of Pediatrics, Athens University Medical
School, Athens, Greece.
Pre- and postnatal growth retardation of unknown pathogenesis is a common
clinical feature in patients with Williams-Beuren syndrome (WBS). However,
growth hormone deficiency (GHD) has not been considered a major cause of growth
retardation. There is only one patient in the literature with confirmed GHD who
responded well to human growth hormone (hGH) therapy. We report a female infant
with confirmed WBS who, through provocative testing, was found to have GHD and
who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of
12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years.
The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated
levels of prolactin and the response of hGH to growth hormone releasing hormone
(GHRH) administration are indicative of a hypothalamic rather than pituitary
defect. In conclusion, GH deficiency might contribute to the growth failure in a
number of patients with WBS and in such cases hGH therapy will most likely
improve final height.
DOI: 10.1515/jpem.2005.18.2.205
PMID: 15751610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9814660 | 1. Curr Opin Hematol. 1998 Nov;5(6):483-7. doi: 10.1097/00062752-199811000-00022.
Diagnosis and treatment of cytomegalovirus infection.
Hebart H(1), Einsele H.
Author information:
(1)Medizinische Klinik und Poliklinik, Abteilung II, Tübingen, Germany.
Cytomegalovirus (CMV) infection remains a major cause of morbidity and mortality
in recipients of an allogeneic stem cell transplant (SCT). Due to the broad
application of antiviral prophylaxis and preemptive therapy, a decrease in
early-onset and a subsequent increase in late-onset CMV disease has been
observed. New data on the latency state and reactivation of CMV have been
presented, the role of T-cell responses in the control of CMV further
substantiated, and viral immune escape mechanisms described in more detail.
Sensitive diagnostic assays using nucleic acid amplification and hybridization
techniques have been commercialized and will allow standardization of CMV
diagnostics in antiviral drug trials. Quantification of the viral load will be
increasingly considered for initiation and, in patients with persistence of high
viral titers despite antiviral therapy, screening for antiviral drug resistance.
Clinical data are emerging to show that, apart from ganciclovir, foscarnet can
be given safely even after allogeneic SCT. Additional drugs like lobucavir and
cidofovir have been used for specific indications. Interactions of
immunosuppressive drugs and antiviral compounds of clinical relevance have been
described. Thus, therapeutic drug monitoring and targeted antiviral drug dosing
will become standard practice in antiviral treatment strategies in patients
following allogeneic SCT.
DOI: 10.1097/00062752-199811000-00022
PMID: 9814660 [Indexed for MEDLINE] |