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41.
The hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in 6-
thioguanine (TG) resistant T-lymphocytes is a useful target for the study
of somatic in vivo mutagenesis, since it provides information about a broad
spectrum of mutation. Mutations in the hprt coding region were studied in
124 TG-resistant T-cell clones from 38 healthy, non- smoking male donors
from a previously studied population of bus maintenance workers,
fine-mechanics and laboratory personnel. Their mean age was 43 years (range
23-64) and their hprt mutant frequency was 9.3 +/- 5.2 x 10(-6) (mean +/-
SD, range 1.4-22.6 x 10(-6)). Sequence analysis of hprt cDNA identified 115
unique mutations; 76% were simple base substitutions, 10% were +/-1 bp
frameshifts, and 10% were small deletions within exons (3-52 bp). In
addition, two tandem base substitutions and one complex mutation were
observed. Simple base substitutions were observed at 55 (20%) of 281 sites
known to be mutable in the hprt coding sequence. The distribution of these
mutations was significantly different than would be expected based upon a
Poisson distribution (P < 0.0001), suggesting the existence of
'hotspots'. All of the 87 simple base substitutions occurred at known
mutable sites, but eight were substitutions of a kind that have not
previously been reported at these sites. The most frequently mutated sites
were cDNA positions 197 and 146, with six and five independent mutations
respectively. Four mutations were observed at position 131, and three each
at positions 143, 208, 508 and 617. Transitions (52%) were slightly more
frequent than tranversions (48%), and mutations at GC base pairs (56%) more
common than mutations at AT base pairs (44%). GC > AT was the most
common type of base pair substitution (37%). The majority of the mutations
at GC base pairs (78%) occurred at sites with G in the non-transcribed
strand. All but one of eight mutations at CpG- sites were of the kind
expected from deamination of methylated cytosine. Deletion of a single base
pair (-1 frameshift) was three times more frequent than insertion of a
single bp (+1 frameshift). Almost half (6/13) of the small (3-52 bp)
deletions within the coding sequence clustered in the 5' end of exon 2.
Short repeats and other sequence motifs that have been associated with
replication error were found in the flanking regions of most of the
frameshifts and small deletions. However, several differences in the local
sequence context between +/-1 frameshift and deletion mutations were also
noticed. The present results identify positions 197, 146 and possibly 131
as hotspots for base substitution mutations, and confirm previously
reported hotspots at positions 197, 508 and 617. In addition, the earlier
notion of a deletion hotspot in the 5'end of exon 2 was confirmed. The
observations of these mutational cluster regions in different human
populations suggest that they are due to endogeneous mechanisms of
mutagenesis, or to ubiquitous environmental influences. The emerging
background spectrum of somatic in vivo mutation in the human hprt gene
provides a useful basis for comparisons with radiation or chemically
induced mutational spectra, as well as with gene mutations in human tumors.
相似文献
42.
43.
Phenobarbital and clofibrate, two non-genotoxic carcinogens, have been
investigated regarding the relationship between reactive oxygen species,
antioxidant enzyme expression and apoptosis in primary cultures of rat
hepatocytes. Low toxicity concentrations, 200 and 100 microg/ml for
phenobarbital and clofibrate respectively, were used to examine their
effect on spontaneous or transforming growth factor beta1
(TGFbeta1)-induced apoptosis and on the expression of antioxidant defence
enzymes (superoxide dismutases and catalase). The increased incidence of
apoptotic nuclei was visualized in TGFbeta1-treated cultures with the
fluorescent dye Hoechst 33258 and was quantified under all experimental
conditions by measurement of the hypodiploid peak in DNA histograms
obtained by flow cytometry. Both substances, when added separately to
hepatocyte cultures and incubated for 24 and 48 h, significantly diminished
spontaneous apoptosis and exhibited a slight suppression of
TGFbeta1-induced apoptosis. Endogenous peroxide production by hepatocytes
increased with TGFbeta1, phenobarbital or clofibrate and the increase was
greater with phenobarbital and in the presence of TGFbeta1 with both drugs.
Gene expression of catalase and Mn- and Cu,Zn superoxide dismutases (SOD)
was evaluated by northern blot analysis of hepatocytes incubated in the
presence of phenobarbital or clofibrate with or without TGFbeta1 and the
following differences were detected: phenobarbital induced a significant
decrease in both dismutases (to 56%, P < 0.05, and 55%, P < 0.05, for
Mn- and Cu,Zn-SOD respectively) and a 2-fold increase (P < 0.01) in
catalase; clofibrate induced a slight decrease in both SODs and a 4-fold
increase (P < 0.05) in catalase; TGFbeta1 significantly decreased to 37%
(P < 0.05) expression of catalase while not significantly affecting
expression of both SODs. We conclude that inhibition of spontaneous
apoptosis induced by either phenobarbital or clofibrate is accompanied by
increases in the endogenous levels of peroxides and by significant
induction of catalase gene expression. Furthermore, the lack of effect of
both compounds on TGFbeta1-induced apoptosis could be a consequence of the
inability of these two compounds to counteract the depressing effect of
TGFbeta1 on expression of catalase.
相似文献
44.
45.
46.
AM Halefoglu 《Journal of Medical Imaging and Radiation Oncology》2005,49(3):242-245
A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula. 相似文献
47.
Charles J. Woodrow Sabina Dahlstr?m Richard Cooksey Jennifer A. Flegg Hervé Le Nagard France Mentré Claribel Murillo Didier Ménard Fran?ois Nosten Kanlaya Sriprawat Lise Musset Neils B. Quashie Pharath Lim Rick M. Fairhurst Sam L. Nsobya Veronique Sinou Harald Noedl Bruno Pradines Jacob D. Johnson Philippe J. Guerin Carol H. Sibley Jacques Le Bras 《Antimicrobial agents and chemotherapy》2013,57(7):3121-3130
Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50s) were determined by a modified sigmoid Emax model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC50s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs. 相似文献
48.
Jacqueline AM Smith DL Patil OT Daniels Y-S Ding J-D Gallezot S Henry KHS Kim S Kshirsagar WJ Martin GP Obedencio E Stangeland PR Tsuruda W Williams RE Carson ST Patil 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(2)
Background:
Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.Methods:
We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.Results:
TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [11C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [11C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.Conclusions:
These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. 相似文献49.
50.
Monika Oláhová Tobias B Haack Charlotte L Alston Jessica AC Houghton Langping He Andrew AM Morris Garry K Brown Robert McFarland Zofia MA Chrzanowska-Lightowlers Robert N Lightowlers Holger Prokisch Robert W Taylor 《European journal of human genetics : EJHG》2015,23(7):935-939
Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene. 相似文献