Abstract
Objectives To identify the sensitive biomarker to predict the effectiveness of Xue-Fu-Zhu-Yu capsules (XFZYC). Methods This nested case-control study included 5 patients with response to XFZYC in the treatment group, 5 patients with no response to XFZYC also in the treatment group, and 5 patients in the control group treated with placebo who participated in the previous RCT. The mRNAs, miRNAs, lncRNAs, and circRNAs were sequenced by next-generation sequencing and differential-expressed (DE) RNAs were identified if p value ≤ 0.05 and fold change ≥2, bioinformatics analysis was conducted in terms of function annotations and signaling pathways, and then sensitive biomarker was analyzed based on real-time PCR. Results The distributions of clinical characteristics between the selected participants from treatment group and placebo group were well balanced. A total of 1156 DE RNAs, 388 miRNAs, 1954 lncRNAs, and 560 circRNAs were identified, which was associated the mechanism of XFZYC and composed the targeted potential biomarkers for further real-time PCR. The DE RNAs were enriched in KEGG pathways pertaining to pathogenesis of Qi Stagnation and Blood Stasis- (QS & BS-) & associated diseases such as coronary heart disease and digestive diseases. The expression level of FZD8 was significantly higher in response patients than that in nonresponse patients (p = 0.041) and circRNA_13799 significantly lower in response patients than that in nonresponse patients (p = 0.040) based on real-time PCR. Patients with higher expression level of FZD8 with 75% stratification have significantly higher reduction in the questionnaire score (p = 0.010), and the area under the curve (AUC) was 0.765 (95%CI = 0.593–0.936; p = 0.014). Conclusions FZD8 might perform the sensitive biomarker for predicting the effectiveness of XFZYC. However, further prospective cohort study was warranted to confirm the exact specificity and sensitivity of this biomarker.
Highlights
Within the framework of Traditional Chinese Medicine (TCM) theory, TCM practitioners always prescribe the herbal formula or acupuncture therapy according to the differentiation of TCM Zheng [1]
In one of our previous clinical trials to investigate the effects of Xue-Fu-Zhu-Yu capsules (XFZYC), a kind of herbal medicine approved by the China Food and Drug Administration (CFDA), for patients with Qi Stagnation and Blood Stasis (QS&BS), a sort of typical Zheng, where QS&BS diagnosis criteria has been used for participants inclusion, the data of primary outcome in the XFZYC group failed to be within normality and the scatter diagram demonstrated that certain participants receiving XFZYC showed response in effectiveness while some participants indicated nonresponse. is abnormal distribution directly affected the statistical inference of the data and the Evidence-Based Complementary and Alternative Medicine interpretation of the results of the clinical trial, which might lead to the negative conclusion of the trial
In our previous randomized clinical trial (RCT), eligible participants fulfilled the diagnostic criteria for QS&BS pattern whose specificity and sensitivity of diagnosis are 81.91% and 80.35%, respectively [11]; the intervention group was treated with XFZYC, and the control group was placebo with 6 capsules of XFZYC or placebo 2 times daily and the duration was 7 weeks; the primary outcome was the change in the patient-reported QS&BS pattern questionnaire score from baseline to the end of the 7-week intervention. is questionnaire is a well-validated, multidimensional measurement of overall severity of QS&BS pattern [12]. e protocol of this previous trial was registered at the ClinicalTrials.gov (ID: NCT03091634)
Summary
Within the framework of Traditional Chinese Medicine (TCM) theory, TCM practitioners always prescribe the herbal formula or acupuncture therapy according to the differentiation of TCM Zheng [1]. In one of our previous clinical trials to investigate the effects of Xue-Fu-Zhu-Yu capsules (XFZYC), a kind of herbal medicine approved by the China Food and Drug Administration (CFDA), for patients with Qi Stagnation and Blood Stasis (QS&BS), a sort of typical Zheng, where QS&BS diagnosis criteria has been used for participants inclusion, the data of primary outcome in the XFZYC group failed to be within normality and the scatter diagram demonstrated that certain participants receiving XFZYC showed response in effectiveness while some participants indicated nonresponse. Erefore, to find the sensitive biomarker having the capacity to predict the effectiveness of XFZYC is crucial to narrow the scope of targeted population to the exact response population in the clinical trial Sensitive biomarker is just a sort of physiological substance in human body that when present in abnormal amounts in the serum may indicate the presence of disease or predict to what extent patients could respond to the therapy [4]. erefore, to find the sensitive biomarker having the capacity to predict the effectiveness of XFZYC is crucial to narrow the scope of targeted population to the exact response population in the clinical trial
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