Objective
Characterise the vaginal metabolome of cervical HPV‐infected and uninfected women.
Design
Cross‐sectional.
Setting
The Center for Health Behavior Research at the University of Maryland ...School of Public Health.
Sample
Thirty‐nine participants, 13 categorised as HPV‐negative and 26 as HPV‐positive (any genotype; HPV+), 14 of whom were positive with at least one high‐risk HPV strain (hrHPV).
Method
Self‐collected mid‐vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing, metabolites by both gas and liquid chromatography mass spectrometry, and 37 types of HPV DNA.
Main outcome measures
Metabolite abundances.
Results
Vaginal microbiota clustered into Community State Type (CST) I (Lactobacillus crispatus‐dominated), CST III (Lactobacillus iners‐dominated), and CST IV (low‐Lactobacillus, ‘molecular‐BV’). HPV+ women had higher biogenic amine and phospholipid concentrations compared with HPV– women after adjustment for CST and cigarette smoking. Metabolomic profiles of HPV+ and HPV− women differed in strata of CST. In CST III, there were higher concentrations of biogenic amines and glycogen‐related metabolites in HPV+ women than in HPV– women. In CST IV, there were lower concentrations of glutathione, glycogen, and phospholipid‐related metabolites in HPV+ participants than in HPV– participants. Across all CSTs, women with hrHPV strains had lower concentrations of amino acids, lipids, and peptides compared with women who had only low‐risk HPV (lrHPV).
Conclusions
The vaginal metabolome of HPV+ women differed from HPV− women in terms of several metabolites, including biogenic amines, glutathione, and lipid‐related metabolites. If the temporal relation between increased levels of reduced glutathione and oxidised glutathione and HPV incidence/persistence is confirmed in future studies, anti‐oxidant therapies may be considered as a non‐surgical HPV control intervention.
Tweetable
Metabolomics study: Vaginal microenvironment of HPV+ women may be informative for non‐surgical interventions.
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Metabolomics study: Vaginal microenvironment of HPV+ women may be informative for non‐surgical interventions.
The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) causes numerous and diverse toxic events via activation of the aryl hydrocarbon receptor, including atrophy of the ...thymus. Exposure to TCDD induces acute thymocyte cell loss, which occurs concomitantly with proliferation arrest and premature emigration of triple negative (TN; CD4-, CD8-, CD3-) T cell progenitors. In this report, we demonstrate that TCDD exposure results in dysregulation of KLF2 (Kruppel-like factor 2) expression in developing thymocytes. The Klf2 gene encodes an Sp1-like zinc finger transcription factor that functions as a central regulator of T lymphocyte proliferation and trafficking. During normal thymocyte development, KLF2 is expressed exclusively in CD4 and CD8 single positive T cells and promotes a nonproliferative, promigratory phenotype. In mice exposed to TCDD, however, the Klf2 gene is prematurely expressed in TN thymocytes. Administration of a 100 μg/kg dose of TCDD results in a ∼15-fold induction of KLF2 as early as the TN2 (CD44+, CD25+) stage of development and immediately precedes acute cell loss in the TN3, TN4, and double positive (CD4+, CD8+) cell stages. Induction of KLF2 occurs within 12 h of TCDD exposure and is fully dependent on expression of the aryl hydrocarbon receptor. In addition, TCDD exposure alters the expression of several factors comprising the KLF2 regulon, including Edg1/S1P1, β7 integrin, CD52, Cdkn2d (cyclin-dependent kinase inhibitor 2D), s100a4, and IL10Rα. These findings indicate that the pollutant TCDD interferes with early thymopoeisis via ectopic expression of the KLF2 regulon.
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) serves as a prototype for a range of environmental toxicants and as a pharmacologic probe to study signal transduction by the ...aryl hydrocarbon receptor (AHR). Despite a detailed understanding of how TCDD exposure leads to the transcriptional up-regulation of cytochrome P450-dependent monooxygenases, we know little about how compounds like TCDD lead to a variety of AHR-dependent toxic end points such as liver pathology, terata, thymic involution, and cancer. Using an acute exposure protocol and the toxic response of the mouse liver as a model system, we have begun a detailed microarray analysis to describe the transcriptional changes that occur after various TCDD doses and treatment times. Through correlation analysis of time- and dose-dependent toxicological end points, we are able to identify coordinately responsive transcriptional events that can be defined as primary transcriptional events and downstream events that may represent mechanistically linked sequelae or that have potential as biomarkers of toxicity.
NicVAX, a nicotine vaccine (3′AmNic‐rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether ...dosages and frequency of administration are associated with increased Ab response. This randomized, double‐blinded, placebo‐controlled multicenter clinical trial (N = 301 smokers) tested the results of 200‐ and 400‐µg doses administered four or five times over a period of 6 months, as compared with placebo. 3′AmNic‐rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14–6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five‐injection, 400‐µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3′AmNic‐rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.
Clinical Pharmacology & Therapeutics (2011) 89 3, 392–399. doi:10.1038/clpt.2010.317
Trials of antidepressant medications for smoking cessation have had mixed results. We conducted a double-blind, placebo-controlled trial of a sustained-release form of bupropion for smoking ...cessation. We excluded smokers with current depression, but not those with a history of major depression. The 615 subjects were randomly assigned to receive placebo or bupropion at a dose of 100, 150, or 300 mg per day for seven weeks. The target quitting date (or "target quit date") was one week after the beginning of treatment. Brief counseling was provided at base line, weekly during treatment, and at 8, 12, 26, and 52 weeks. Self-reported abstinence was confirmed by a carbon monoxide concentration in expired air of 10 ppm or less.
At the end of seven weeks of treatment, the rates of smoking cessation as confirmed by carbon monoxide measurements were 19.0 percent in the placebo group, 28.8 percent in the 100-mg group, 38.6 percent in the 150-mg group, and 44.2 percent in the 300-mg group (P<0.001). At one year the respective rates were 12.4 percent, 19.6 percent, 22.9 percent, and 23.1 percent. The rates for the 150-mg group (P=0.02) and the 300-mg group (P=0.01) -- but not the 100-mg group (P=0.09) -- were significantly better than those for the placebo group. Among the subjects who were continuously abstinent through the end of treatment, the mean absolute weight gain was inversely associated with the dose (a gain of 2.9 kg in the placebo group, 2.3 kg in 100-mg and 150-mg groups, and 1.5 kg in the 300-mg group; P= 0.02). No effects of treatment were observed on depression scores as measured serially by the Beck Depression Inventory. Thirty-seven subjects stopped treatment prematurely because of adverse events; the frequency was similar among all groups.
A sustained-release form of bupropion was effective for smoking cessation and was accompanied by reduced weight gain and minimal side effects. Many participants in all groups were smoking at one year.
Letter to the Editor, BJOG Exchange Borgogna, JLC; Shardell, MD; Santori, EK ...
BJOG : an international journal of obstetrics and gynaecology,
03/2020, Letnik:
127, Številka:
6
Journal Article
To identify predictors of smoking abstinence at the end of medication use that could assist in the optimal use of a sustained-release (SR) form of bupropion for treating cigarette smokers.
A ...double-blind, placebo-controlled, dose-response trial.
Multicenter (three sites) study conducted in the United States.
Six hundred fifteen healthy men and women (> or = 18 years of age) who were smoking > or = 15 cigarettes per day and who were motivated to stop smoking.
Random assignment of patients to placebo or SR bupropion treatment, 100, 150, or 300 mg/d, for 7 weeks (total duration of study was 52 weeks: 7 weeks of treatment and 45 weeks of follow-up).
Logistic regression was used to identify predictors of abstinence at the end of the medication phase. Univariate predictors included the following: bupropion dose (p < 0.001); older age (p = 0.024); lower number of cigarettes smoked per day (cpd) (p < 0.001); lower Fagerström Tolerance Questionnaire score (p = 0.011); longest time previously abstinent that was < 24 h or > 4 weeks (p < 0.001); absence of other smokers in the household (p = 0.021); greater number of previous stop attempts (p = 0.019); and study site (p = 0.004). Multivariate predictors of abstinence at the end of the medication phase were the following: higher bupropion dose (p < 0.001); lower number of cpd (p < 0.001); longest time previously abstinent from smoking (p = 0.002); male gender (p = 0.014); and study site (p = 0.021).
Bupropion SR therapy was effective in treating cigarette smokers independently of all other characteristics studied. Lower smoking rate, brief periods (ie, < 24 h) or long periods (ie, > 4 weeks) of abstinence with previous attempts to stop smoking, and male gender were predictive of better outcomes, independent of the dose of bupropion that was used.
ABSTRACT
Aims Most relapse episodes occur when smokers are confronted with craving provoked by situational cues. Current nicotine gum can help relieve cue‐provoked cravings, but faster effects may ...result in more rapid relief. We tested a prototype formulation of a new rapid‐release nicotine gum (RRNG) that provides more rapid release and absorption of nicotine, for its ability to provide faster and better craving relief compared to current nicotine polacrilex gum (NPG).
Design Random assignment to RRNG or NPG, used during a smoking cue provocation procedure.
Participants and setting A total of 319 smokers were exposed to a smoking cue in the laboratory by being asked to light but not smoke a cigarette of their preferred brand. Subjects then chewed a piece of 2 mg RRNG (n = 159) or 2 mg NPG (n = 160) according to randomized assignment.
Measurements Craving assessments were completed at regular intervals before and after cue exposure (baseline, pre‐cue, and 3, 6, 9, 12, 15, 18, 21, 25, 30 and 35 minutes after the cue).
Findings Smokers chewing RRNG showed significantly lower craving than NPG subjects starting with the first assessment at 3 minutes (P < 0.025). Repeated‐measures ANOVA revealed a significant treatment × time interaction (P < 0.05)—craving scores dropped more rapidly in RRNG subjects compared to NPG subjects. Survival analyses also indicated superiority of RRNG in achieving more rapid self‐reported meaningful relief (P < 0.05) and complete relief (P < 0.05) of craving.
Conclusions Rapid‐release nicotine gum reduced cue‐provoked craving more rapidly compared to NPG, and thus merits further study in cessation efficacy trials.
The cDNAs for the four murine aryl hydrocarbon (Ah) receptor alleles were cloned and sequenced, and the deduced amino acid sequences were compared. The Ahb-1 allele encodes a protein of 805 amino ...acids, the Ahd and Ahb-2 alleles encode proteins of 848 amino acids, and the Ahb-3 allele encodes a protein of 883 amino acids. The alleles differ by eight point mutations in the common open reading frame (the initial 805 amino acids) and by additional sequences at the carboxyl end. The amino halves of the proteins, containing a spliced leader sequence, a basic helix-loop-helix motif, and two 50-amino acid repeats (PAAS), have identical sequences except for a single amino acid change in the second PAAS box. The Ahd allele, which has a lower ligand binding affinity, differs from the Ahb-2 receptor by only two amino acids. Mutagenesis experiments with these cloned cDNAs, using in vitro transcription and translation and 2-125Iiodo-7,8-dibromodibenzo-p-dioxin binding, indicate that the low ligand binding affinity of the Ahd allele is attributable to a valine at residue 375; changing this amino acid to an alanine, as in the Ahb-2 protein, enhances the affinity 4-fold. For in vitro translated Ahb-1 and Ahb-2 alleles the Kd values were approximately 6-10 pM and for Ahd the Kd value was approximately 37 pM. Using 5' truncation and mutations to produce 3' translation truncation sites, we mapped the ligand binding region for the Ahb-1 allele.
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