Serum metabolomic analysis reveals key metabolites in drug treatment of central precocious puberty in female children.

Precocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl-tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid-biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.

A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study.

INTRODUCTION: The therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473). METHODS: A total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations. RESULTS: Vaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months. CONCLUSION: Our study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.

Identification of active compounds from Caesalpinia sappan L. extracts suppressing IL-6 production in RAW 264.7 cells by PLS.

ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia sappan L. is distributed in Southeast Asia and also used as herbal medicine for the treatment of various diseases such as burning sensations, leprosy, dysentery, osteoarthritis and rheumatoid arthritis (RA). The overproduction of IL-6 plays an important role in the prognosis of RA, but the active compounds from the extracts of Caesalpinia sappan L. suppressing IL-6 production remain unknown. AIMS OF THE STUDY: Identifying the main active compounds of Caesalpinia sappan L. extracts inhibiting the IL-6 production in LPS-stimulated RAW 264.7 cells by partial least squares (PLS). MATERIALS AND METHODS: Sixty-four samples with different proportions of compounds were prepared from Caesalpinia sappan L. by supercritical CO2 fluid extraction (SCFE) and refluxing. Each of 64 samples was applied to RAW 264.7 cells with LPS to evaluate whether IL-6 production by LPS is affected by addition of each sample. The IL-6 production in medium was determined by ELISA and the inhibitory activity of each sample was analyzed. In addition, the fingerprints of these 64 samples were also established by ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-MS). We used the PLS, a simplified method, to evaluate the results from IL-6 production and fingerprints. RESULTS: Each of 64 samples markedly suppressed LPS-induced IL-6 production in RAW cells. The fingerprints by UPLC-MS clearly revealed variations among 64 samples produced in different extract conditions. The PLS analysis with IL-6 production and fingerprints by UPLC-MS suggested that the peaks 71, 93, 150, 157, 168 have more influence on the inhibitory activity of Caesalpinia sappan L. extracts. The peaks 71, 93, 150 are likely representing sappanone A, protosappanin E and neoprotosappanin, respectively. The peaks 157 and 168 are still at large. CONCLUSION: This is the first report that sappanone A, protosappanin E, neoprotosappanin and two unidentified compounds can be considered as possible active compounds that might inhibit IL-6 production. Further studies are needed to confirm the effectiveness of these five compounds on IL-6 production and possible mechanism.

[Study on the method of nanometer-size zirconium dioxide enrichment separation and inductively coupled plasma mass spectrometry determination of trace barium(II) in water].

Monoclinic fusiform zirconium dioxide (ZrO2) nanoparticles were synthesized by hydrothermal method, a method was established based on monoclinic fusiform nanometer-sized ZrO2 enrichment separation, and trace barium in water was determined by inductively coupled plasma mass spectrometry (ICP-MS). The detection limit for Ba(II) was 0.007 ng x mL(-1), and the relative standard deviation was 0.13% (n = 11). The optimal enrichment separation conditions of nanometer-sized ZrO2 for Ba(II) were studied in detail, it was found that the percentage of adsorbed Ba(II) was more than 99% under pH 10.0 and 2 mL 0.5 mol x L(-1) HCl was sufficient for elution of Ba(II) by more than 98%. The static adsorption capacity of ZrO2 to Ba(II) was 196.6 microg x g(-1) and enrichment factor was 250. Properties of nanometer-sized ZrO2 were discussed through regeneration experiment and effects of co-existing ions and contrast experiment to ordinary ZrO2, adsorption properties of nanometer-sized ZrO2 were applied to real samples in the analysis of Ba(II) and the determination was carried out by ICP-MS with satisfactory results.

[Method study on calcium and phosphorus simultaneous determination by microwave-digestion and ICP-MS].

As a pre-digestion method of breast milk microwave-digestion was adopted in this method, and the contents of calcium and phosphorus were determined by ICP-MS at the same time. By optimizing conditions of digestion and ICP-MS, appropriate internal elements and the isotope mass number and EPA200.8 interference calibration equation were chosen. The accuracy and reliability of method were verified through the recovery and milk powder analysis of national standard substances (GBW10017). Determination results are in the permissible range. The relative deviation (RSD) is less than 2.40%, while the recovery is between 102.8% and 104.0%. ICP-MS method has wide dynamic range, and doesn't need to dilute samples. It is suitable for lots of samples and multi-element analyzed at the same time, and making up default of different method and different element determined respectively in national standard. It is a determination method for calcium and phosphorus supply of breast milk.

[Study on determining cadmium and arsenic in rice and flour by different digestion manner].

Cadmium and arsenic in rice and flour was determined by microware digestion and direct digestion with electrothermal board. Mastering the characters of the pre-disposal mode for these samples, and depending on the phenomena during the experiment and the results determined by the machine, the authors can analyse the merit and disadvantage of the different digestion mode to find out the most excellent conditions and methods for experiment, then give out reasonable and applicable method based on unsuccessful experiments, analyse the reasons for unsuccessful experiments, and perfect two digestion methods which the authors used to determine cadmium and arsenic.