OBJECTIVE To analyze clinical switching patterns and reasons between bevacizumab biosimilar and originator drugs. METHODS The data were collected from 1 175 cancer patients treated with bevacizumab at Ruijin Hospital， Shanghai Jiao Tong University School of Medicine from January 1， 2018， to December 31， 2023. The patients were divided into originator group （n＝250） and biosimilar group （n＝925）. The switching rate， switching type and reasons of the two groups were compared. RESULTS There were no statistically significant differences in the switching rate， switching types， and the number of switches between the two groups （P＞0.05）. Single， one-way switches were the switching type in both groups. The proportion of patients in the biosimilar group who switched due to adverse events was significantly higher than originator group， while the proportion of patients who switched due to treatment costs was significantly lower than originator group （P＜0.05）. There were no statistically significant differences in the proportions of patients who switched due to efficacy and drug accessibility between the two groups （P＞0.05）. CONCLUSIONS The switching between bevacizumab biosimilar and the originator drugs mainly involves single， one- way switches. Treatment costs and drug accessibility are the main factors for the switches among users of originator drugs， while drug accessibility and adverse events are the main factors for the switches among users of biosimilar.

Objective To investigate the predictive value of pre-treatment prognostic nutritional index (PNI) and nutrition-related indicators on the prognosis of patients with brain glioma. Methods The clinical data of 210 patients with brain glioma admitted to two hospitals in Yibin City from January 2015 to December 2020 were retrospectively collected, with the follow-up deadline on December 30, 2022. The receiver operating characteristic (ROC) curve was plotted to calculate the area under the curve (AUC) and the optimal cut-off value of each indicator for predicting patients′prognosis. The Kaplan-Meier method was used to plot the survival curve, and the influencing factors of prognosis of patients were explored through Log-rank test and multivariate Cox regression analysis. Results The average overall survival time of 210 patients was 21.8 months, and 140 patients (66.7%) died during the follow-up period, with a 1-year survival rate of 54.6%. ROC curve analysis results showed that the AUCs of albumin, prealbumin, lymphocytes, PNI, and body mass index for predicting the prognosis of patients with brain glioma were 0.856, 0.689, 0.833, 0.927, and 0.647, with the optimal cut-off values of 36.0 g/L, 205.0 mg/L, 1.85×10⁹/L, 46.5, and 21.0 kg/m², respectively. The results of multivariate Cox regression analysis showed that PNI, albumin, and World Health Organization (WHO) grading were all influencing factors for the prognosis of patients with brain glioma (P < 0.05). The survival curve analysis results showed that the 1-year survival rates of patients with PNI < 46.5 and PNI≥46.5 were 35.1% and 84.2%, respectively, were 35.8% and 74.3%, respectively in patients with albumin < 36.0 g/L and albumin ≥ 36.0 g/L, and were 90.2%, 55.2%, and 16.3%, respectively in patients with WHO grades of Ⅱ, Ⅲ, and Ⅳ. Conclusion The prognosis of patients with brain glioma is related to PNI, albumin, and WHO grading, and PNI has a high predictive value for the prognosis of patients with brain glioma.

Objective:To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods:The prospective multicenter study was conducted in Zhejiang, China from May 1 st, 2019 to January 31 st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results:A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95% CI 0.593-0.771, P<0.01). Conclusion:In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

Danshen, the dried roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza), is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tanshinones, the bioactive compounds from Danshen, exhibit a wide spectrum of pharmacological properties, suggesting their potential for future therapeutic applications. Tanshinone biosynthesis is a complex process involving at least six P450 enzymes that have been identified and characterized, most of which belong to the CYP76 and CYP71 families. In this study, CYP81C16, a member of the CYP71 clan, was identified in S. miltiorrhiza. An in vitro assay revealed that it could catalyze the hydroxylation of four para-quinone-type tanshinones, namely neocryptotanshinone, deoxyneocryptotanshinone, and danshenxinkuns A and B. SmCYP81C16 emerged as a potential broad-spectrum oxidase targeting the C-18 position of para-quinone-type tanshinones with an impressive relative conversion rate exceeding 90%. Kinetic evaluations andin vivo assays underscored its highest affinity towards neocryptotanshinone among the tested substrates. The overexpression of SmCYP81C16 promoted the accumulation of (iso)tanshinone in hairy root lines. The characterization of SmCYP81C16 in this study accentuates its potential as a pivotal tool in the biotechnological production of tanshinones, either through microbial or plant metabolic engineering.
Humans ; Salvia miltiorrhiza/metabolism* ; Biosynthetic Pathways ; Quinones/metabolism* ; Plant Roots/metabolism* ; Gene Expression Regulation, Plant

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.

Objective:To investigate the effect of different incubation time of aminolevulinic acid (ALA) on photodynamic inhibition of Propionibacterium acnes biofilms. Methods:Propionibacterium acnes biofilms were formed in 24-well plates with pre-placed cell slides and 96-well plates. The formation of the biofilm structure was observed by confocal laser scanning microscopy (CLSM) , and the growth activity of the biofilm was assessed by the tetrazolium salt XTT assay. The in vitro successfully constructed biofilm models were divided into 6 groups: negative control group receiving neither ALA treatment nor LED radiation, ALA group incubated with ALA alone for 30 minutes, LED group receiving LED radiation alone, ALA-PDT1 group, ALA-PDT2 group and ALA-PDT3 group incubated with ALA for 15, 30 and 60 minutes respectively followed by LED radiation. After the treatment, CLSM was performed to observe the biofilm structure, as well as to determine the dead/living bacteria ratio, and XTT assay to assess the growth activity of the biofilm. Differences among groups were analyzed using one-way analysis of variance and least significant difference- t test. Results:CLSM showed that the Propionibacterium acnes biofilm model was successfully constructed in vitro. The dead/living bacteria ratios were 0.90 ± 0.16, 1.75 ± 0.19, and 2.57 ± 0.32 in the ALA-PDT1 group, ALA-PDT2 group and ALA-PDT3 group respectively, which were significantly higher than the dead/living bacteria ratio in the negative control group (0.31 ± 0.01; t= 55.56, 138.62, 74.64, respectively, all P<0.001) ; the biofilm viability value was significantly lower in the ALA-PDT1 group, ALA-PDT2 group and ALA-PDT3 group (0.35 ± 0.02, 0.26 ± 0.02, 0.18 ± 0.01, respectively) than in the negative control group (0.43 ± 0.00; t= 35.66, 2.64, 110.96, respectively, all P < 0.001) . CLSM showed that the structure of the Propionibacterium acnes biofilm was destroyed under the action of ALA-PDT, and the destruction was aggravated with the prolongation of incubation time of ALA. Conclusion:The prolongation of incubation time of ALA can enhance the inhibitory effect of ALA-PDT on Propionibacterium acnes biofilms.

Cell Line, Tumor ; Cell Proliferation ; Glutaminase

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

OBJECTIVE To establish the method for the content determination of ephedrine hydrochloride and pseudoephedrine hydrochloride in Shexiang zhuanggu plaster ，and to evaluate the quality of 222 batches of Shexiang zhuanggu plaster from 41 manufacturers. METHODS HPLC method was established. The determination was performed on Shimadzu Shim-pack GIS-C 18 column with mobile phase consisted of acetonitrile- 0.1％ phosphoric acid （3∶97，V/V）at the flow rate of 0.9 mL/min. The column temperature was set at 30 ℃，the detection wavelength was 210 nm，the sample size was 10 μL. Taking the content data of 222 batches of samples as index ，the cluster heatmap was drawn by Hiplot biomedical data visualization and analysis platform. RESULTS The results of the methodological investigation were in line with the requirements of the general principles stated in 2020 edition of Chinese Pharmacopoeia （part Ⅳ ）. The total contents of ephedrine hydrochloride and pseudoephedrine hydrochloride in 222 batches of samples from 41 manufacturers were 0.646-6.325 μg/cm2. Results of cluster heatmap analysis showed that these samples of 41 manufacturers could be divided into 3 categories. The contents of components in samples from different manufacturers varied greatly ，and the contents of components in different batches of samples from the same manufacturers also varied greatly. If the proposed limit of this product was that the total amount of ephedrine hydrochloride and pseudoephedrine hydrochloride per 1 cm2 would not be less than 1.00 μg，23 of the 222 batches of samples were unqualified. CONCLUSIONS The established method for the content determination of ephedrine hydrochloride and pseudoephedrine hydrochloride in Shexiang zhuanggu plaster is accurate and precise ，and can be used for the quality control. Some manufacturers should pay attention to optimizing production process and strengthening quality control.

With the boom of China's innovative pharmaceutical industry, licensing-in model has gradually become an important research and development model for innovative pharmaceutical companies. The in-licensed drugs at different stages need different research and development (R&D) strategy in China. The pharmaceutical companies take the responsibility to comprehensively collate the oversea clinical data and conduct a detailed analysis of clinical pharmacology, safety, efficacy and ethnic sensitivity. Clinical R&D strategy should be made based on the results of the above data and analysis. We encourage high-quality drugs which fill unmet clinical needs licensed in, and as early as possible, so as to conduct multi-regional clinical trials (MRCTs). The clinical R&D strategy in China is particularly important for the drug's approval. Guidelines published by the National Medical Products Administration (NMPA) and clinical associations should be followed. Communications about clinical R&D strategy with Center of Drug Evaluation (CDE) are encouraged.
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Antineoplastic Agents/therapeutic use* ; China ; Drug Industry ; Humans ; Lung Neoplasms/drug therapy* ; Pharmaceutical Preparations