CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.

Problems and countermeasures in clinical studies on acupuncture and moxibustion in course of developing / 中国针灸

To explore the problems and countermeasures existing in acupuncture and moxibustion clinical studies, in the perspective of the key steps of

Expression of plasma Dickkopf-1 in patients with rheumatoid arthritis and its correlation with peripheral blood T cell subsets / 北京大学学报(医学版)

OBJECTIVE@#To detect the levels of Dickkopf-1 (DKK-1) in the plasma of patients with rheumatoid arthritis (RA), and to analyze their correlation with peripheral blood T cell subsets and clinical indicators.@*METHODS@#Enzyme-linked immunosorbent assay (ELISA) was used to detect plasma DKK-1 levels in 32 RA patients and 20 healthy controls, and to record the various clinical manifestations and laboratory indicators of the RA patients, and flow cytometry to detect peripheral blood T cell subsets in the RA patients (Including Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4+CD161+T, CD8+T, CD8+CD161+T cells). The plasma DKK-1 levels between the two groups were ompared, and its correlation with peripheral blood T cell subsets and clinical indicators analyzed.@*RESULTS@#(1) The plasma DKK-1 concentration of the RA patients was (124.97±64.98) ng/L. The plasma DKK-1 concentration of the healthy control group was (84.95±13.74) ng/L. The plasma DKK-1 level of the RA patients was significantly higher than that of the healthy control group (P < 0.05), and the percentage of CD8+CD161+T cells in the peripheral blood of the RA patients was significantly higher than that of the healthy control group (P < 0.05). (2) The plasma DKK-1 level was positively correlated with erythrocyte sedimentation rate (r=0.406, P=0.021), DAS28 score (r=0.372, P=0.036), immunoglobulin G(r=0.362, P=0.042), immunoglobulin A(r=0.377, P=0.033); it had no correlation with age, course of disease, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptide antibody, immunoglobulin M, complement C3, complement C4, white blood cell, neutrophil ratio. (3) The plasma DKK-1 level in the RA patients was positively correlated with the percentage of peripheral blood CD161+CD8+T cells (r=0.413, P=0.019);it had no correlation with Treg, nTreg, aTreg, sTreg, Teff, Tfh, CD4+CD161+T, CD8+T cells. (4) The percentage of CD161+CD8+T cells was negatively correlated with erythrocyte sedimentation rate (r=-0.415, P=0.004), C-reactive protein (r=-0.393, P=0.007), DAS28 score(r=-0.392, P=0.007), rheumatoid factor (r=-0.535, P < 0.001), anti-citrullinated protein antibody (r=-0.589, P < 0.001), immunoglobulin G(r=-0.368, P=0.012) immunoglobulin M (r=-0.311, P=0.035); it had no correlation with age, disease course, immunoglobulin A, complement C3, complement C4, white blood cell, and neutrophil ratio.@*CONCLUSION@#RA patients' plasma DKK-1 levels and the percentage of CD8+CD161+T cells in T cell subsets in peripheral blood increase, which may be related to the secretion of proinflammatory cytokines in patients; DKK-1 is involved in the regulation of bone homeostasis and can be used as a marker of bone destruction in RA.

[Quality assessment and classification of persicae semen based on HPLC-UV fingerprint].

Persicae Semen (PS), a traditional Chinese medicine, has been widely used for the syndrome of blood stasis in China since the Eastern Han Dynasty. In the present study, we developed an HPLC-UV fingerprint analysis method for the quality control of PS. The HPLC fingerprint was performed on Shimadzu Inertsil C18 column (4.6 mm x 250 mm, 5 microm) at 35 degrees C. The mobile phases were composed of acetonitrile and water using a gradient elution. The flow rate was 1.0 mL x min(-1), and the detection wavelength was set at 210 nm. The fingerprint method was validated according to the Guidelines for Traditional Chinese Medicine Injection Fingerprint, and applied to determine 41 batches representative herbs collected from Xinjiang of China. The chromatographic peaks were characterized by UPLC-Q-TOF-MS, and nine of them were identified by comparison with the literature and/or reference standards. In order to classify and assess the samples, hierarchical clustering analysis and partial least square discriminant analysis were performed based on the common chromatographic peaks, and the samples were geographically classified into two classes, with six chemical compounds as classification markers which were significantly different between the two classes (P < 0.05).

Developmental toxicity and neurotoxicity of two matrine-type alkaloids, matrine and sophocarpine, in zebrafish (Danio rerio) embryos/larvae.

Matrine and sophocarpine are two major matrine-type alkaloids included in the traditional Chinese medicine (TCM) Kushen (the root of Sophora flavescens Ait.). They have been widely used clinically in China, however with few reports concerning their potential toxicities. This study investigated the developmental toxicity and neurotoxicity of matrine and sophocarpine on zebrafish embryos/larvae from 0 to 96/120h post fertilization (hpf). Both drugs displayed teratogenic and lethal effects with the EC50 and LC50 values at 145 and 240mg/L for matrine and 87.1 and 166mg/L for sophocarpine, respectively. Exposure of matrine and sophocarpine significantly altered spontaneous movement and inhibited swimming performance at concentrations below those causing lethality and malformations, indicating a neurotoxic potential of both drugs. The results are in agreement with most mammalian studies and clinical observations.

In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier.

In order to improve the dissolution and absorption of the water insoluble drug repaglinide, a solid dispersion was developed by solvent method using polyvinylpyrrolidone K30 (PVP K30) as the hydrophilic carrier for the first time. Studies indicated that both solubility and the dissolution rate of repaglinide were significantly increased in the solid dispersion system compared with that of repaglinide raw material or physical mixtures. The repaglinide solid dispersions with PVP K30 solid state was characterized by polarizing microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). DSC and XRD studies indicated that repaglinide existed in an amorphous form in the solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PVP K30 in the solid dispersion. In the in situ gastrointestinal perfusion experiment, solid dispersion was shown to remarkably enhance the absorption of repaglinide in stomach and all segments of intestine. In vivo pharmacokinetic study in rats showed that immediate and complete release of repaglinide from the solid dispersion resulted in rapid absorption that significantly increased the bioavailability and the maximum plasma concentration over repaglinide raw material. These results demonstrated PVP K30 was an appropriate carrier for solid dispersion of repaglinide, with increased dissolution and oral absorption.

[Determination of twelve elements in ephedrine extraction by microwave digestion-AAS].

The sample digested by microwave are of some merits: simple, rapid, saving agents, nonpollution and being easily digested. Microwave-digested sample with HNO3-H2O2 and AAS method were established for the determination of Fe, Ca, Mg, Zn, Mn, Cu, Na, K, Ni, Cd, Pb and Cr in ephedrine extraction. In this paper, the selection of digestion conditions, including pressure, power, acids and time of digestion was evaluated. According to standard sample GBW08501 Tea-leaves, we checked the method accuracy and precision. The accuracy values are in the range of 91.1%-105%. The RSDs of flame atomic spectrometry and graphite furnace atomic spectrometry are in the range of 0.2%-2.3% and less than 7%, respectively. The results are very consistent with the the reference values. It proved that the method has satisfactory precision and accuracy. The proposed method is simple, rapid, of nonpollution and safe. It was has been applied to the determination of trace elements in ephedrine extraction and provided useful data for production in factory.