A strategy to distinguish similar traditional Chinese medicines by liquid chromatography-mass spectrometry, electronic senses, and gas chromatography-ion mobility spectrometry: Marsdeniae tenacissimae Caulis and Paederiae scandens Caulis as examples.

INTRODUCTION: Marsdeniae tenacissimae Caulis (MTC), a popular traditional Chinese medicine, has been widely used in the treatment of tumor diseases. Paederiae scandens Caulis (PSC), which is similar in appearance to MTC, is a common counterfeit product. It is difficult for traditional methods to effectively distinguish between MTC and PSC. Therefore, there is an urgent need for a rapid and accurate method to identify MTC and PSC. OBJECTIVES: The aim is to distinguish between MTC and PSC by analyzing the differences in nonvolatile organic compounds (NVOCs), taste, odor, and volatile organic compounds (VOCs). METHODS: Liquid chromatography-mass spectrometry (LC-MS) was utilized to analyze the NVOCs of MTC and PSC. Electronic tongue (E-tongue) and electronic nose (E-nose) were used to analyze their taste and odor respectively. Gas chromatography-ion mobility spectrometry (GC-IMS) was applied to analyze VOCs. Finally, multivariate statistical analyses were conducted to further investigate the differences between MTC and PSC, including principal component analysis, orthogonal partial least squares discriminant analysis, discriminant factor analysis, and soft independent modeling of class analysis. RESULTS: The results of this study indicate that the integrated strategy of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis can be effectively applied to distinguish between MTC and PSC. Using LC-MS, 25 NVOCs were identified in MTC, while 18 NVOCs were identified in PSC. The major compounds in MTC are steroids, while the major compounds in PSC are iridoid glycosides. Similarly, the distinct taste difference between MTC and PSC was precisely revealed by the E-tongue. Specifically, the pronounced bitterness in PSC was proven to stem from iridoid glycosides, whereas the bitterness evident in MTC was intimately tied to steroids. The E-nose detected eight odor components in MTC and six in PSC, respectively. The subsequent statistical analysis uncovered notable differences in their odor profiles. GC-IMS provided a visual representation of the differences in VOCs between MTC and PSC. The results indicated a relatively high relative content of 82 VOCs in MTC, contrasted with 32 VOCs exhibiting a similarly high relative content in PSC. CONCLUSION: In this study, for the first time, the combined use of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis has proven to be an effective method for distinguishing between MTC and PSC from multiple perspectives. This approach provides a valuable reference for the identification of other visually similar traditional Chinese medicines.

Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial.

BACKGROUND: This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. METHODS: Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). RESULTS: As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1-2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3-5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. CONCLUSIONS: Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

Oncogenic microRNA-301b regulates tumor repressor dystrobrevin alpha to facilitate cell growth, invasion and migration in esophageal cancer.

BACKGROUND: Esophageal cancer (EC) ranks the eighth in morbidity and the sixth in mortality around the whole world, which is an aggressive malignancy. To authenticate potential therapeutic targets for EC is therefore imperative. Although miR-301b might display changed expression in esophageal adenocarcinoma by utilizing Taqman miRNA profiling analysis, much less is known about the impact of miR-301b in EC. METHODS AND RESULTS: By analyzing the data of 187 cancer tissues and 13 normal samples from TCGA database, we discovered that miR-301b was highly expressed in EC tissues. Then, RT-qPCR determined that miR-301b was up-regulated in EC cell lines (ECA109, JAR, TE-1 and OE33). Besides, miR-301b expression level was higher in ESCC cell line-TE-1 cells and lower in ESCC cell line-ECA109 cells compared to other EC cell lines. Hence, ECA109 cell line was used to up-regulate miR-301b expression while TE-1 cell line was applied to down-regulate miR-301b expression in the subsequent experiments. Additionally, OE33, as an ECA cell line, was applied to upregulate miR-301b expression to reflect the influence of miR-301b overexpression on EC progression. More interestingly, miR-301b appeared to act as a promoting effect on the proliferation of EC cells, which was tested by CCK8. Dystrobrevin alpha (DTNA) was a targeting gene of miR-301b, which was predicted by the websites of miRanda, miRWalk and TargetScan. Additionally, DTNA was low expressed in EC tissues and was an independent predictor of EC. Meanwhile, the low expression of DTNA was related to worse overall survival in EC patients. The Pearson correlation coefficient analyzed that DTNA expression was negatively correlated with miR-301b. Furthermore, RT-qPCR and western blotting assays ulteriorly indicated that DTNA was negatively modulated by miR-301b. The facilitating impact of miR-301b re-expression on ECA109 and OE33 cell growth, invasion and migration was receded by DTNA over-expression, whilst the repressive effect of miR-301b ablation on TE-1 cell growth, invasion and migration was inversed by DTNA silencing. Overexpression of miR-301b accelerated EC cell growth, migration and invasion through targeting DTNA. CONCLUSIONS: Above all, we concluded that miR-301b was concerned with the progression of EC via regulating DTNA, suggesting that miR-301b and its target gene, DTNA, might serve as predictive biomarkers for EC therapy.

MiR-1224-5p acts as a tumor suppressor via inhibiting the malignancy of rectal cancer through targeting SLC29A3.

The emphasis of our study was to determine the physiological function of miR-1224-5p in rectal cancer (RC) and its in-depth mechanism. First, the expression of miR-1224-5p in RC tissues was analyzed using public data from the TCGA database. Then, miR-1224-5p expression in RC cell lines SW480 and SW837 was measured using the qRT-PCR assay. The subsequent CCK-8 assay was executed to assess the function of miR-1224-5p in the viability of the RC cell. Bioinformatics prediction prompted that SLC29A3 may be a potential target gene for miR-1224-5p. Western blotting and dual-luciferase reporter assays were performed to affirm the above forecasting. Kaplan-Meier analysis and Cox multivariate analysis were carried out to assess the relationship between SLC29A3 and prognosis. Finally, CCK-8, colony formation assay, and transwell assay were used for functional analysis of miR-1224-5p/ SLC29A3 axis in vitro. MiR-1224-5p was expressed at low levels in RC tissues and cell lines. Up-regulation of miR-1224-5p inhibited SW480 cell viability, while inhibition of miR-1224-5p enhanced the viability of SW837 cells. What is more, we affirmed that miR-1224-5p could direct target SLC29A3, which was expressed at high levels in RC tissues. In addition, SLC29A3 could be used as an independent predictive factor of prognosis in patients with RC, and the higher SLC29A3 expression, the lower survival rate. Finally, cellular functional experiments evidenced that miR-1224-5p mimic can reduce the cell viability, invasion, and migration, while overexpression of SLC29A3 presented an opposite effect. Importantly, co-transfection experiments indicated that SLC29A3 can reverse miR-1224-5p-mediated inhibition in the malignant progression of RC cells. Our work raised the possibility that miR-1224-5p functioned as a tumor suppressor in RC, which achieved its function via targeting SLC29A3.

[Identification of marsdeniae tenacissimae caulis and its adulterants by RAPD].

OBJECTIVE: To identify Marsdeniae Tenacissimae Caulis and its adulterants by RAPD (random amplified polymorphic DNA) and analyze the gene homology of Marsdeniae Tenacissimae Caulis from various habitats. METHODS: General DNA was isolated from Marsdeniae tenacissimae Caulis which were from seven various habitats and its six adulterants by CTAB, the twenty RAPD was used to identify them. RESULTS: Random primer 285 (GGG AAC CCT T) could amplify the gene of Marsdeniae tenacissimae Caulis from various habitats stablely, Marsdeniae tenacissimae Caulis and its adulterants could be identified by primer E01 (CCC AAG GTC C) effectively. CONCLUSION: The method of RAPD can be used to identify Marsdeniae Tenacissimae Caulis and its adulterants, the gene of Marsdeniae tenacissimae Caulis from various habitats have homology.

[Antitumor activities of liposoluble components of caulis Marsdeniae tenocissimae and analysis on its chemical constituents].

OBJECTIVE: To study the antitumor activities of the liposoluble components from caulis Marsdenia tenocissimae and analyze its chemical constituents. METHOD: The supercritical fluid extraction was used to extract the liposoluble components from caulis M. tenocissimae. MIT test was applied to study the anticancer effects of liposoluble components on growth inhibition in human liver cancer line HepG-2 cells, and the chemical constituents were analyzed by gas chromatography/mass spectrometry (GC-MS). RESULT: The liposoluble components of caulis M. tenocissimae have obvious growth inhibitory action to HepG-2 cells. Twenty-four compounds were identified and their relative contents were determined. CONCLUSION: The liposoluble components from caulis M. tenocissimae have antitumor activities, and its pharmacological activity is related to its chemical constituents.

[Chemical constituents of caulis Marsdeniae tenocissimae].

OBJECTIVE: To study the chemical constitutes of caulis Marsdeniae tenocissimae. METHOD: 70% ethanol extracts of caulis M. tenocissimae were isolated and purified by silica gel column chromatography, Sephadex LH-20 chromatography and semi-preparative reversed phase liquid chromatography (RPLC). The compounds were identified on the basis of spectral analysis, including NMR, MS and IR. RESULT: Seven compounds were obtained and identified and their structures were identified as beta-sitosterol (1), condutirol(2), dihydroconduritol(3), betulinic acid(4), lupeol(5), daucosterol(6), 11alpha-O-(2-methylbutyryl)-12beta-O-acetyltenacigeninB(7). CONCLUSION: Compound 4, 5 were isolated from the genus for the first time.

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

BACKGROUND: Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. METHODS: In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. CONCLUSIONS: IBI305 is similar to bevacizumab in terms of efficacy and safety. TRIAL REGISTRATION: Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.