Thymic stromal lymphopoietin, a cytokine, has been implicated in allergic sensitization and post-sensitization effector pathways. In this study, an antibody interrupting TSLP signaling improved ...lab-induced early and late asthmatic responses without modifying baseline airway obstruction.
Asthma is a chronic inflammatory disease of the airways that is characterized by recurrent episodes of wheezing, breathlessness, chest tightness, and cough. The cause of this disorder is multifactorial and is influenced by both genetic and environmental mechanisms,
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with environmental allergens as an important cause.
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Inhalation of allergens by patients with atopic asthma induces some of the manifestations of asthma, including reversible airflow obstruction, airway hyperresponsiveness, and eosinophilic and basophilic airway inflammation. Allergen-inhalation challenge has become the predominant model for the evaluation of asthmalike responses in many species.
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Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that . . .
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, ...recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.
In psoriasis, only limited overlap between sets of genes identified as differentially expressed (psoriatic lesional vs. psoriatic non-lesional) was found using statistical and fold-change cut-offs. ...To provide a framework for utilizing prior psoriasis data sets we sought to understand the consistency of those sets.
Microarray expression profiling and qRT-PCR were used to characterize gene expression in PP and PN skin from psoriasis patients. cDNA (three new data sets) and cRNA hybridization (four existing data sets) data were compared using a common analysis pipeline. Agreement between data sets was assessed using varying qualitative and quantitative cut-offs to generate a DEG list in a source data set and then using other data sets to validate the list. Concordance increased from 67% across all probe sets to over 99% across more than 10,000 probe sets when statistical filters were employed. The fold-change behavior of individual genes tended to be consistent across the multiple data sets. We found that genes with <2-fold change values were quantitatively reproducible between pairs of data-sets. In a subset of transcripts with a role in inflammation changes detected by microarray were confirmed by qRT-PCR with high concordance. For transcripts with both PN and PP levels within the microarray dynamic range, microarray and qRT-PCR were quantitatively reproducible, including minimal fold-changes in IL13, TNFSF11, and TNFRSF11B and genes with >10-fold changes in either direction such as CHRM3, IL12B and IFNG.
Gene expression changes in psoriatic lesions were consistent across different studies, despite differences in patient selection, sample handling, and microarray platforms but between-study comparisons showed stronger agreement within than between platforms. We could use cut-offs as low as log10(ratio) = 0.1 (fold-change = 1.26), generating larger gene lists that validate on independent data sets. The reproducibility of PP signatures across data sets suggests that different sample sets can be productively compared.
Nonsteroidal anti-inflammatory drugs (NSAIDs), used for the treatment of pain and inflammation, are eliminated primarily through conjugation with polar sugar moieties to form glucuronides. ...Glucuronidation is catalyzed by the UDP-glucuronosyltransferases (UGT) superfamily. An inverse relationship may exist between glucuronidation activity and NSAID efficacy; however, specific UGTs catalyzing conjugation of the structurally diverse NSAIDs have yet to be identified systematically. Therefore, NSAID glucuronidation activity by 12 individually expressed UGTs was investigated by liquid chromatography-tandem mass spectrometry. The relative rates of NSAID glucuronidation varied among UGT enzymes examined, demonstrating specificity of the individual UGTs toward selected NSAIDs. Kinetic parameters were determined for expressed UGT Supersomes and compared with parameters determined in pooled human liver microsomes (HLMs). Comparison of K(m) values suggested roles for UGTs 1A3 and 2B7 in indene glucuronidation and UGTs 1A9, 2B4, and 2B7 in profen glucuronidation. Inhibitory studies in pooled HLMs support the role of UGTs 1A1, 1A3, 1A9, 2B4, and 2B7 in the glucuronidation of ibuprofen, flurbiprofen, and ketoprofen. Bilirubin did not inhibit indomethacin or diclofenac glucuronidation, suggesting that UGT1A1 was not involved in catalysis. Imipramine did not inhibit glucuronidation of sulindac, sulindac sulfone, indomethacin, or naproxen in pooled HLMs, suggesting that UGT1A3 was not a principal hepatic catalyst. Nevertheless, multiple UGT enzymes, most notably UGTs 1A1, 1A9, 2B4, and 2B7, seem to be involved in the hepatic catalysis of NSAID glucuronidation.
Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing
enzymes have been shown to affect risk of colorectal neoplasia ...and other malignancies. Using data from a population-based
incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the
reduced folate carrier ( RFC ), thymidylate synthase ( TS ), methionine synthase ( MTR ), and 5,10-methylenetetrahydrofolate reductase ( MTHFR ) and colon cancer risk. The TS enhancer region ( TSER ) variant was associated with a reduced risk among men 2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence
interval, 0.6-0.98 but not women. When combined genotypes for both TS polymorphisms ( TSER and 3′-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically
significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated
reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression
were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least
one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings
from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to
colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects
of dietary intakes and genetic variability in folate metabolism.
Prostaglandin H synthase 2 (PTGS2) or cyclooxygenase-2 (COX-2) has been shown to play a key role in the regulation of inflammation,
and its inhibition is associated with a reduced risk of colon ...cancer. The PTGS2 ( COX-2 ) −765G > C promoter variant is located in a putative SP1 binding site and reduces PTGS2 expression. In a Minnesota-based
case-control study of cases with adenomatous ( n = 494) or hyperplastic polyps ( n = 186) versus polyp-free controls ( n = 584), we investigated the role of the PTGS2 −765G > C promoter polymorphism. Multiple logistic regression analysis was used, adjusting for age, body mass index, caloric
intake, alcohol, fiber, sex, hormone use, and smoking. For colorectal adenoma, odds ratios (OR) compared with PTGS2 −765GG as reference were GC 1.00 95% confidence interval (95% CI), 0.74-1.35 and CC 0.53 (95% CI, 0.22-1.28). For hyperplastic
polyps, the comparable adjusted odds ratios were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05-1.11). Risk associated
with the −765G > C variant differed by aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use. Among nonusers of
aspirin or other NSAIDs, the CC genotype conferred a significant decrease in risk of adenoma (OR, 0.26; 95% CI, 0.07-0.89).
Use of aspirin or other NSAIDs reduced risk of adenoma only among those with the −765GG (wild type) and possibly −765CG genotypes
(OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% CI, 0.40-1.02, respectively). These data suggest that COX-2 expression or activity
may be beneficially suppressed, and risk of colorectal polyps reduced, by aspirin or other NSAIDs in PTGS2 −765GG (wild type) individuals and by the −765 CC variant genotype in nonusers of NSAIDs.
Databases
of expressed sequence tags (EST) can be used to screen rapidly for
potential polymorphisms in candidate proteins. As part of this study,
we screened the gene for the enzyme thymidylate ...synthase (TS). TS is
important physiologically because it is essential for the synthesis of
deoxythymidylate, a nucleotide required for DNA synthesis and repair.
TS is also a major target for cancer chemotherapeutic drugs, especially
the widely used 5-fluorouracil. Using sequence alignment of ESTs, we
identified a candidate 6-bp variation at bp 1494 in the 3′-untranslated
region of the TS mRNA. This sequence
variation occurred in 21 of 34 aligned ESTs at this location, including
ESTs from various tissue sources. The presence of this polymorphism was
confirmed in a Caucasian population ( n = 95) by
polymerase chain restriction amplification/RFLP analysis. The allele
frequency of the 6-bp deletion was found to be 0.29 (wild-type +6 bp/+6
bp, 48%; +6 bp/−6 bp, 44%; −6 bp/−6 bp, 7%). Although the
function of this polymorphism has not yet been investigated, the
3′-untranslated region of a gene can play a role in mRNA stability and
translation. This study illustrates an approach to polymorphism
discovery in candidate enzymes of physiological interest by searches of
publicly available sequence data, a rapid and inexpensive method. The
potential functional relevance of the common 6-bp deletion in the
TS gene needs to be investigated, because this enzyme is
plausibly of major importance not only in cancer treatment but also in
cancer prevention.
Acetylsalicylic acid (aspirin) is a common nonsteroidal anti-inflammatory drug used for treatment of pain and arthritis. In the body, acetylsalicylic acid is rapidly deacetylated to form salicylic ...acid. Both compounds have been proposed as anti-inflammatory agents. Major metabolites of salicylic acid are its acyl and phenolic glucuronide conjugates. Formation of these conjugates, catalyzed by UDP-glucuronosyltransferases (UGTs), decreases the amount of pharmacologically active salicylic acid present. We aimed to identify the UGTs catalyzing the glucuronidation of salicylic acid using both heterologously expressed enzymes and pooled human liver microsomes (HLMs) and to develop a liquid chromatography-tandem mass spectrometry method to quantify glucuronidation activity of UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17 Supersomes. All UGTs tested, except 1A4, 2B15, and 2B17, catalyzed salicylic acid phenolic and acyl glucuronidation. Ratios of salicylic acid phenolic to acyl glucuronide formation varied more than 12-fold from 0.5 for UGT1A6 to 6.1 for UGT1A1. These results suggest that all UGTs except 1A4, 2B15, and 2B17 might be involved in the glucuronidation of salicylic acid in vivo. From comparisons of apparent Km values determined in pooled HLMs and in expressed UGTs, UGT2B7 was suggested as a likely catalyst of salicylic acid acyl glucuronidation, whereas multiple UGTs were suggested as catalysts of phenolic glucuronidation. The results of this UGT screening may help target future evaluation of the effects of UGT polymorphisms on response to aspirin in clinical and population-based studies.
Several modifiable lifestyle factors, such as physical activity, obesity, and postmenopausal hormone use, have been associated
with colorectal cancer risk. It has been hypothesized that some or all ...of these factors may mediate their effects through
alterations in insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBP). To evaluate the role of IGFs in colorectal
cancer, we examined the relationship of two common genetic polymorphisms in IGF-1 (a cytosine-adenosine dinucleotide repeat) and IGFBP-3 (a G → C single nucleotide polymorphism) with colorectal cancer risk, as well as their potential modification by physical
activity, body mass index (BMI), and postmenopausal hormone use. Subjects included 782 male and female colorectal cancer cases
diagnosed between 1998 and 2002 and reported to the statewide registry in the metropolitan Seattle area, and 503 age- and
sex-matched cancer-free population controls. Colorectal cancer was modestly associated with having an IGF-1 genotype other than homozygous for 19 repeats (odds ratio, 1.3; 95% confidence interval, 1.0-1.6) and having the GG IGFBP-3 genotype (odds ratio, 1.3; 95% confidence interval, 1.0-1.8). There was evidence that IGF-1 genotype modified the relationship between BMI and colorectal cancer among women, such that high BMI increased risk of colorectal
cancer only among those with the 19/19 genotype ( P interaction = 0.02). IGFBP-3 genotype was also a significant effect modifier of the relationship between risk factors and colorectal cancer: The positive
association between BMI and colorectal cancer was observed only among men ( P interaction < 0.01) and women ( P interaction = 0.06) with the GG genotype; the inverse association between postmenopausal hormone use and colorectal cancer was observed only among women
with the GG genotype ( P = 0.01) and the inverse association between physical activity and colorectal cancer was observed only among men who carried
the C allele ( P < 0.01). The current study provides some support for a role of IGFs in colorectal cancer etiology, particularly in mediating
the relationship of common risk factors (physical activity, BMI, and postmenopausal hormone use).
OBJECTIVESIn vivo, aspirin (acetylsalicylic acid) is rapidly deacetylated to form salicylic acid, which then undergoes primary or secondary glucuronidation catalyzed by UDP-glucuronosyltransferases ...(UGTs). The variant UGT1A6*2 (T181A, R184S) is associated with altered enzyme function. Our objective was to compare salicylic acid glucuronidation in individuals with different UGT1A6 genotypes.
METHODSFollowing orally dosing with 650 mg aspirin, saliva and urine samples were collected over a period of 24 h from healthy individuals with homozygous wild-type UGT1A6 *1/*1 (n=19) and homozygous variant UGT1A6 *2/*2 (T181A, R184S) (n=9) genotypes.
RESULTSNo statistically significant differences were observed in salivary pharmacokinetic parameters. Urinary excretion of the sum of aspirin and its metabolites (salicyluric acid, salicyluric acid phenolic glucuronide, salicyl phenolic glucuronide, salicyl acyl glucuronide, salicylic acid) during the early period of 2–4 h of collection was significantly lower in UGT1A6 *1/*1 than in UGT1A6 *2/*2 individuals. Further, UGT1A6 *1/*1 individuals excreted a lower percentage of aspirin and its metabolites in the first 12 h and a greater percentage after 12 h than UGT1A6 *2/*2 individuals.
CONCLUSIONSThe variant UGT1A6*2 or polymorphisms in other UGTs that are in linkage disequilibrium with UGT1A6*2 may confer more rapid glucuronidation of salicylic acid than the wild-type UGT1A6 *1/*1.
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