[Chinese multidisciplinary expert consensus on the management of adverse drug reactions associated with savolitinib].

MET gene is a proto-oncogene, which encodes MET protein with tyrosine kinase activity. After binding to its ligand, hepatocyte growth factor, MET protein can induce MET dimerization and activate downstream signaling pathways, which plays a crucial role in tumor formation and metastasis. Savolitinib, as a specific tyrosine kinase inhibitor (TKI) targeting MET, selectively inhibits the phosphorylation of MET kinase with a significant inhibitory effect on tumors with MET abnormalities. Based on its significant efficacy shown in the registration studies, savolitinib was approved for marketing in China on June 22, 2021 for the treatment of advanced non-small cell lung cancer with MET 14 exon skipping mutations. In addition, many studies have shown that MET TKIs are equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression, and relevant registration clinical studies are ongoing. The most common adverse reactions during treatment with savolitinib include nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. Based on two rounds of extensive nationwide investigations to guide clinicians, the consensus is compiled to use savolitinib rationally, prevent and treat various adverse reactions scientifically, and improve the clinical benefits and quality of life of patients. This consensus was prepared under the guidance of multidisciplinary experts, especially including the whole-process participation and valuable suggestions of experts in Traditional Chinese Medicine, thus reflecting the clinical treatment concept of integrated Chinese and western medicines.

[A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors].

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

YiQi ChuTan Recipe Inhibits Epithelial Mesenchymal Transition of A549 Cells under Hypoxia.

This study aims to investigate mechanism of YiQi ChuTan Recipe (YCR) for inhibiting epithelial mesenchymal transition (EMT) of A549 cells under hypoxia. Flow cytometry was used to optimize YCR dosage by measuring A549 apoptosis, which were subjected to different treatments, including normal condition, hypoxia, hypoxia+YCR. Cell morphology and expression of EMT were measured with differential interference contrast microscopy, real-time PCR and western blot. Optimized condition of 4 mg/ml YCR and 2% O2 for 72 h was used to establish hypoxia. Under hypoxic condition, morphology of A549 cells changed from oblate fusi-form to elongated spindle. E-cadherin expression decreased while vimentin and fibronectin increased. EMT-related genes expression were significantly increased in hypoxia group compared to control group (P<0.05). After treatment with YCR, mesenchymal cells obviously decreased and EMT-related genes expression was significantly decreased (P<0.05). Changes of E-cadherin, vimentin and fibronection were significantly attenuated by YCR when compared to hypoxia group. Expression of proteins GRP78, SRC, MAPK, smad2/3 were significantly increased in hypoxia group compared to control group, but was significantly inhibited by YCR treatment. In conclusion, A549 cells underwent EMT under hypoxia while YCR reversed the EMT through GRP78, smad2/3 and SRC/MAPK signal pathway.

Therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats.

The aim of this study was to explore the therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats. Rats were fed high-fat fodder to establish a rat fatty liver model, and were then fed different concentrations of Pleurotus eryngii cellulose for six weeks. Lipitor was used as a positive control. Measured levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and total triglyceride (TG); the activity of malondialdehyde (MDA), superoxide dismutase (SOD), hepatic lipase (HL), and lipoprotein lipase; and liver histopathological changes. Successfully established rat fatty liver model after feeding high-fat fodder for one week. A diet of P. eryngii cellulose for six weeks significantly reduced ALT, AST, TC, and TG levels in rat serum (P < 0.01); TC and AST levels in P. eryngii cellulose high-dose group and Lipitor group were not significantly different from those of the control (P > 0.05). SOD activity increased significantly, while MDA and HL activity decreased (P < 0.05); fatty degeneration and fat accumulation both decreased in hepatic tissue. Hepatic protection of P. eryngii cellulose showed dose-related effect. P. eryngii cellulose can affect lipid metabolism, having therapeutic effects on fatty liver in rats.

[Effect of mandibular third molar tooth germ extraction on mandibular development: a retrospective study].

Objective: To investigatethe effect of extraction of mandibular third molar (M3) tooth germon the development of the mandible in orthodontic patients, with a view to providing a reference for clinical M3 tooth germ extraction. Methods: One hundred and twenty-nine Angel class Ⅰ patients aged 10-16 years who attended the Department of Orthodontics Division 1, School & Hospital of Stomatology, Wuhan University from 1 January 2013 to 30 December 2021 and fulfilled the criteria for nativity were included. Those who had their M3 extracted in the Department of Oral and Maxillofacial Surgery were included in the study group, with a total of 66 cases; and those who did not have their M3 extracted were included in the control group, with a total of 63 cases. The average annual growth was calculated by tracing point measurements on cephalometric films before and after orthodontic treatment according to the Jarabak and McNamara methods, with measurements of the mandibular ramus height (Ar-Go'), mandibular body length (Go'-Me), and overall mandibular length (Co-Gn) values, respectively. The average annual growth of Ar-Go', Go'-Me, and Co-Gn were compared between the two groups for the overall sample of patients, patients of the same sex (male/female), patients of the same age group (A, B, and C), and patients of the same cervical vertebral maturation stage (stages Ⅱ, Ⅲ, and Ⅳ), respectively, to see if there was any difference in the average annual growth of Ar-Go', Go'-Me, and Co-Gn. Results: There was no statistically significant difference in the average annual growth of Ar-Go', Go'-Me, and Co-Gn between the study group [0.88 (0.40, 1.80), 0.67 (0.15, 1.18), and 0.86 (0.40, 1.90) mm, respectively] and the control group [1.08 (0.45, 1.60), 0.53 (0.25, 1.13), and 1.20 (0.46, 2.28) mm, respectively] (P>0.05). In addition, there was no significant difference in the average annual growth in the Ar-Go', Go'-Me, and Co-Gn between the groups for patients of the same sex group (male/female), patients of the same age group (A, B, and C), and patients of the same cervical vertebral maturation stage group (stages Ⅱ, Ⅲ, and Ⅳ) (P>0.05). Conclusions: Extraction of the mandibular third molar tooth germ has no significant effect on the development of the mandible in Angle class Ⅰ orthodontic patients.

[Risk factors for recurrence and survival analysis in locally advanced T4a papillary thyroid carcinoma after R0 resection].

Objective: To investigate the treatment outcomes and risk factors of postoperative recurrence in T4a papillary thyroid carcinoma (PTC). Methods: A total of 185 patients with locally advanced T4a PTC treated in Beijing Tongren Hospital, Capital Medical University from January 2006 to December 2019 were retrospectively analyzed, including 127 females and 58 males, aged between 18 and 80 years, with 74 patients aged over 55 years. According to AJCC thyroid tumor staging, 111 cases were stage I (T4aN0M0 26 cases, T4aN1aM0 35 cases, and T4aN1bM0 50 cases) and 74 cases were stage Ⅲ (T4aN0M0 29 cases, T4aN1aM0 19 cases, and T4aN1bM0 26 cases). Kaplan-Meier method was used to calculate the overall survival and the recurrence-free rate, and univariate and multivariate logistic regression analyses on the clinical data were performed. Results: Recurrent laryngeal nerve invasion was observed in 150 cases, trachea invasion in 61 cases, esophagus invasion in 30 cases, and laryngeal structure invasion in 10 cases. Postoperative follow-up periods were 24-144 months, with an average of 68.29 months. Of the 185 patients, 18 (9.73%) had recurrences or metastases, including 9 cases (4.86%) died of recurrences or metastases. The 5-year and 10-year overall survival rates were respectively 95.21% and 93.10%. The 5-year and 10-year disease-free survival rates were respectively 89.65% and 86.85%. Univariate analysis showed that age of onset, tumor diameter, preoperative recurrent laryngeal nerve palsy, esophageal invasion and cervical lymph node metastasis were the risk factors for postoperative recurrence of T4a PTC(all P<0.05). Multivariate analysis showed that preoperative recurrent laryngeal nerve palsy (OR=3.27, 95%CI: 1.11-9.61, P=0.032) and lateral cervical lymph node metastasis (OR=4.71, 95%CI: 1.19-18.71, P=0.027) were independent risk factors for T4a PTC recurrence. Survival rate of patients with T4a PTC involving only the recurrent laryngeal nerve or the outer tracheal membrane was significantly better than that of patients with tracheal invasion (P<0.05). Conclusions: T4a PTC patients with R0 resection can still achieve good efficacy. Preoperative recurrent laryngeal nerve palsy and lateral cervical lymph node metastasis are independent risk factor for postoperative recurrence in the patients.

De-O-ethylsalvonitin and salprionin, two further diterpenoids from Salvia prionitis.

From Salvia prionitis two new diterpenoids, de-O-ethylsalvonitin and salprionin, were isolated, and their structures and NMR data were assigned by spectral analysis and computer modelling calculations.

Triterpene saponins from Aster yunnanensis.

Four new triterpene saponins, asteryunnanosides A, B, C and D, have been isolated from Aster yunnanensis and their structures deduced as 2 alpha,3 beta,23-trihydroxyolean-12-en-28-oic acid-28-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside, 2 alpha,3 beta,23-trihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, 2 alpha,3 beta-dihydroxyolean-12-en-28-oic acid-28-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside and 2 alpha,3 beta-dihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside, respectively, by means of spectral and chemical data.

Triterpenoid saponins from Aster batangensis.

Four novel triterpenoid saponins named asterbatanoside F, G, H and I were isolated from the roots of Aster batangensis and their structures elucidated as 3-O-beta-D-glucopyranosyl-23-O-acetyl-bayogenin-28-O-beta-D-glu cop yranosyl- (1-->6)-[alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-glucopyranoside, 3-O-beta-D-glucopyranosyl-bayogenin-28-O-beta-D-glucopyranosyl-(1- ->6)-[alpha-f1p4amnopyranosyl-(1-->2)]-beta-D-glucopyranoside, 3-O-beta-D-glucopyranosyl- (1-->3)-beta-D-glucopyranosyl-bayogenin-28-O-beta-D-glucopyranosyl -(1-->6)-beta-D-glucopyranoside, and 3-O-beta-D-glucopyranosyl-(1-->3)-beta-D- glucopyranosyl-23-O-acetyl-bayogenin-28-O-beta-D-glucopyranosyl-(1 -->6)-beta-D- glucopyranoside by means of spectral data, especially NMR including COSY, HETCOR, COLOC, HOHAHA, ROESY and selective INEPT techniques, and chemical evidence.

Saikosaponin derivatives from Bupleurum wenchuanense.

From the roots of Bupleurum wenchuanense 14 derivatives of saikosaponin were isolated and identified as 2"-O-beta-D-xylopyranosylsaikosaponin b2, 3",6"-O O-diacetylsaikosaponin b2, 2"-O-beta-D-glucopyranosylsaikosaponin b2, saikosaponin b2, 6"-O-acetylsaikosaponin b2, saikosaponin d, 2"-O-acetylsaikosaponin d, 3"-O-acetylsaikosaponin d,6"-O-acetylsaikosaponin d, 16-epichikusaikoside, prosaikogenin G, saikosaponin a,2"-O-acetylsaikosaponin a and 3"-O-acetylsaikosaponin a. The first two compounds are new derivatives of saikosaponin and this is the first isolation of prosaikogenin G from a plant. Their complete 1H and 13C NMR assignments were made by using a combination of 2D NMR techniques (DQF-COSY, HOHAHA, ROESY, HETCOR, HMQC and HMBC). Some of the compounds showed cytotoxic activity against the P-388 cell line.

3-hydroxycoumarin glycosides from Alyxia reinwardti var. Lucida.

Investigation of the inner bark of Alyxia reinwardti var. lucida led to the isolation of two new coumarin glycosides, 1 and 2, whose structures were determined by interpretation of their spectroscopic data, particularly NMR spectroscopy.

Glycosides from Aster yunnanensis.

A new oleanane-type triterpene saponin named asteryunnanoside E and a new acetylene glycoside named asteryunnanoside I have been isolated from the roots of Aster yunnanensis, and their structures elucidated as 3-O-beta-D-glucopyranosyl-bayogenin-28-O-beta-D- glucopyranosyl-(1-->2)-beta-D-glucopyranoside and 2Z,8E-decadiene-4,6-diyn-1-O-beta-D-glucopyranos yl-(1-->2)-beta-D- glucopyranoside by means of 1D and 2D NMR techniques (COSY, HETCOR, COLOC, HOHAHA and ROESY) and chemical transformations.

Further polyoxypregnanes from Marsdenia tenacissima.

Two new polyoxypregnanes, designated marstenacigenins A and B, along with a known compound, dresgenin, were isolated from the mild acid hydrolysate of the ethanol extract of the stems of Marsdenia tenacissima. Their structures were deduced by a combination of 1D and 2D NMR spectroscopic techniques as 12 beta-cinnamoyl-dihydrosarcostin and 12 beta,20-dibenzoyldihydrosarcostin, respectively.

Aleppicatines A and B from Euphorbia aleppica.

Two new pentacyclic diterpene polyesters, aleppicatine A and B, have been isolated from the acetone extract of the whole plant of Euphorbia aleppica, in addition to five known cycloartane-type triterpenes (24-methylenecycloartanol, cyclolaudenol cycloart-25-en-3 beta-ol-24-one, cycloart-22-en-3 beta,25-diol and cycloart-25-en-3 beta,24-diol), scopoletin, kaempferol and 4-hydroxybenzoic acid and its methyl ether. The structures of the new compounds and their hydrolysis products have been extensively characterized by high-field NMR spectroscopic methods, including 2D NMR techniques.

Cytotoxic ent-kaurene diterpenoids from Isodon gesneroides.

From Isodon gesneroides, three new cytotoxic diterpenoids, gesneroidins A, B and C, together with one known diterpenoid, dawoensin A, were isolated, and the structure determination and unambiguous assignment of their stereochemistry and NMR spectral data were made by a combination of one-and two-dimensional NMR techniques, computer modelling calculations and X-ray analysis.

Diterpenoids from Isodon eriocalyx var. laxiflora.

Three new, seco-ent-kaurane diterpenoids, laxiflorins A, B and C, together with four known diterpenoids eriocalyxin B, oriodonin, and maeocrystals A and B, were isolated from the leaves of Isodon eriocalyx var. laxiflora. Their structures were assigned by a combination of one- and two-dimensional NMR techniques and computer modeling calculations. Laxiflorin C displayed weak cytotoxic activity.

Cytotoxic ent-kaurene diterpenoids from three Isodon species.

From Isodon loxothyrsa, one new diterpenoid, loxothyrin A, together with one known diterpenoid, adenolin B, from I.pleiophyllus, three known diterpenoids, coetsoidins A, B and G, and from I. adenoloma, one known diterpenoid, longikaurin F, were isolated. The structure determination of loxothyrin A, and the unambiguous NMR spectral assignments of the known compounds were made by a combination of 1D and 2D NMR techniques and computer modelling calculations. The isolates showed potent cytotoxic activities.

Lycorine alkaloids from Hymenocallis littoralis.

From Hymenocallis littoralis, one new alkaloid, named littoraline, together with 13 known lycorine alkaloids and one lignan, were isolated. The structure and NMR assignments of this new alkaloid were determined by 1D and 2D NMR techniques. Littoraline showed inhibitory activity of HIV reverse transcriptase, and lycorine and haemanthamine showed potent in vitro cytotoxicity.

Phenolic aporphine-benzylisoquinoline alkaloids from Thalictrum faberi.

From the roots of Thalictrum faberi, six new phenolic aporphine-benzylisoquinoline alkaloids, 3-hydroxy-6'-desmethyl-9-O-methylthalifaboramine (1), 3-hydroxythalifaboramine (2), 6'-desmethylthalifaboramine (3); 3,5'-dihydroxythalifaboramine (4), 5'-hydroxythalifaboramine (5) and 3-hydroxy-6'-desmethylthalifaboramine (6) were isolated. Their structures were established through the use of one- and two-dimensional NMR techniques. All of the tested alkaloids showed potent cytotoxic and antimalarial activities.