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Molecular classification of the placebo effect in nausea.

ABSTRACT: In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

SUBMITTER: Meissner K

PROVIDER: S-EPMC7511022 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular classification of the placebo effect in nausea.

Meissner Karin K Lutter Dominik D von Toerne Christine C Haile Anja A Woods Stephen C SC Hoffmann Verena V Ohmayer Uli U Hauck Stefanie M SM Tschoep Matthias H MH

PloS one 20200923 9

In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins ...[more]

PMID: 32966280

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Project description:IntroductionTactile stimulation during a placebo treatment could enhance its credibility and thereby boost positive treatment expectations and the placebo effect. This experimental study aimed to investigate the interplay between tactile stimulation, expectation, and treatment credibility for the placebo effect in nausea.MethodsNinety healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to one of three groups on the second day after the baseline period: Placebo transcutaneous electrical nerve stimulation (TENS) with tactile stimulation (n = 30), placebo TENS without tactile stimulation (n = 30), or no intervention (n = 30). Placebo TENS was performed for 20 min at a dummy acupuncture point on both forearms. Expected and perceived nausea severity and further symptoms of motion sickness were assessed at baseline and during the evaluation period. At the end of the experiment, participants in the placebo groups guessed whether they had received active or placebo treatment.ResultsExpected nausea decreased significantly more in the placebo groups as compared to the no treatment control group (interaction day × group, F = 6.60, p = 0.003, partial η2 = 0.20), with equal reductions in the two placebo groups (p = 1.0). Reduced expectation went along with a significant placebo effect on nausea (interaction day × group, F = 22.2, p < 0.001, partial η2 = 0.35) with no difference between the two placebo groups (p = 1.0). Twenty-three out of 29 participants in the tactile placebo group (79%) but only 14 out of 30 participants (47%) in the non-tactile placebo group believed that they had received the active intervention (p = 0.015). Bang's blinding index (BI) indicated random guessing in the non-tactile placebo group (BI = 0; 95% CI, -0.35 to 0.35) and non-random guessing in the direction of an "opposite guess" in the tactile placebo group (BI = -0.52; 95% CI, -0.81 to -0.22).ConclusionTactile stimulation during placebo TENS did not further enhance positive treatment expectations and the placebo effect in nausea but increased the credibility of the intervention. Further trials should investigate the interaction between perceived treatment assignment, expectation, and the placebo effect during the course of a trial.

Project description:Transcriptomic profiling Background Cholangiocarcinoma accounts for 5-10% of primary hepatic cancers. The etiology is unclear and patients are often diagnosed without risk factors. Resection is the only curative treatment although patients frequently remain undiagnosed until advanced stage of disease. Methods To construct molecular classification of cholangiocarcinoma, we profiled the transcriptomes of 104 freshly-frozen tumors and 59 matched non-cancerous livers obtained from Australia, Europe and the United States. We also performed mutational analysis of KRAS, EGFR and BRAF, and used laser-capture microdissection to obtain independent gene expression profiles for epithelial and stromal compartments in a subset of tumors. The selected target genes were validated by western blotting and immunohistochemistry. Results Transcriptomic profiling classified cholangiocarcinoma into two distinct subclasses defined by survival (P<0.0007) and early recurrence (P<0.001). Applying leave-one-out cross-validation, we optimized the prognostic classifier to 238 genes which were positively enriched in the epithelial tumor compartment. A deregulated HER2 network was associated with the epithelial compartment which also showed a frequent overexpression of Ki67, EGFR, MET and pRPS6 whereas inflammatory cytokines were enriched in tumor stroma specifically in patients with poor prognosis. KRAS mutations were found in 24.6% of patients with poor disease outcome. Conclusion Our study presents new insights into pathogenesis of cholangiocarcinoma and stratification of the patients according to survival and recurrence. Identification of a subgroup of patients among the poor prognostic cohort characterized by KRAS mutations and oncogenic-addiction may provide a novel therapeutic opportunity for this treatment-refractory malignancy. Profiling of individual cholangiocarcinomas and non-cancerous matched surrounding livers using normal bile ducts as reference

Project description:BackgroundDoxylamine-pyridoxine is recommended as a first line treatment for nausea and vomiting during pregnancy and it is commonly prescribed. We re-analysed the findings of a previously reported superiority trial of doxylamine-pyridoxine for the treatment of nausea and vomiting during pregnancy using the clinical study report obtained from Health Canada.Methods and findingsWe re-analysed individual level data for a parallel arm randomized controlled trial that was conducted in six outpatient obstetrical practices in the United States. Pregnant women between 7 and 14 weeks of gestation with moderate nausea and vomiting of pregnancy symptoms. The active treatment was a tablet containing both doxylamine 10 mg and pyridoxine 10 mg taken between 2 and 4 times per day for 14 days depending on symptoms. The control was an identical placebo tablet taken using the same instructions. The primary outcome measure was improvement in nausea and vomiting of symptoms scores using the 13-point pregnancy unique quantification of emesis scale between baseline and 14 days using an ANCOVA. 140 participants were randomized into each group. Data for 131 active treatment participants and 125 control participants were analysed. On the final day of the trial, 101 active treatment participants and 86 control participants provided primary outcome measures. There was greater improvement in symptoms scores with doxylamine-pyridoxine compared with placebo (0.73 points; 95% CI 0.21 to 1.25) when last observation carried forward imputation was used for missing data but the difference is not statistically significant using other approaches to missing data (e.g. 0.38; 95% CI -0.08 to 0.84 using complete data).ConclusionsThere is a trend towards efficacy for nausea and vomiting symptoms with doxylamine-pyridoxine compared with placebo but the statistical significance of the difference depends on the method of handling missing data and the magnitude of the difference suggests that there is no clinically important benefit employing the prespecified minimal clinically important difference or "expected difference" of 3 points.Trial registrationClinical Trial NCT00614445.

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Molecular classification of the placebo effect in nausea.

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Molecular classification of the placebo effect in nausea.

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