BACKGROUND: Durvalumab after chemoradiotherapy (CRT) failed to bring survival benefits to patients with epidermal growth factor receptor ( EGFR ) mutations in PACIFIC study (evaluating durvalumab in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy). We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors (TKIs) and the optimal treatment regimen. METHODS: We searched the PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from inception to December 31, 2022 and performed a meta-analysis based on a Bayesian framework, with progression-free survival (PFS) and overall survival (OS) as the primary endpoints. RESULTS: A total of 1156 patients were identified in 16 studies that included 6 treatment measures, including CRT, CRT followed by durvalumab (CRT-Durva), TKI monotherapy, radiotherapy combined with TKI (RT-TKI), CRT combined with TKI (CRT-TKI), and TKI combined with durvalumab (TKI-Durva). The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens (hazard ratio [HR] = 0.37, 95% confidence interval [CI], 0.20-0.66). The PFS of TKI monotherapy was significantly longer than that of CRT (HR = 0.66, 95% CI, 0.50-0.87) but shorter than RT-TKI (HR = 1.78, 95% CI, 1.17-2.67). Furthermore, the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva. RT-TKI ranked first in the Bayesian ranking, with the longest OS (60.8 months, 95% CI = 37.2-84.3 months) and the longest PFS (21.5 months, 95% CI, 15.4-27.5 months) in integrated analysis. CONCLUSIONS: For unresectable stage III EGFR mutant NSCLC, RT and TKI are both essential. Based on the current evidence, RT-TKI brings a superior survival advantage, while CRT-TKI needs further estimation. Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI, radiotherapy, and chemotherapy. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022298490.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; ErbB Receptors/genetics* ; Lung Neoplasms/drug therapy* ; Mutation/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Chemoradiotherapy ; Antibodies, Monoclonal/therapeutic use*

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

Intentional tooth replantation (ITR) is an advanced treatment modality and the procedure of last resort for preserving teeth with inaccessible endodontic or resorptive lesions. ITR is defined as the deliberate extraction of a tooth; evaluation of the root surface, endodontic manipulation, and repair; and placement of the tooth back into its original socket. Case reports, case series, cohort studies, and randomized controlled trials have demonstrated the efficacy of ITR in the retention of natural teeth that are untreatable or difficult to manage with root canal treatment or endodontic microsurgery. However, variations in clinical protocols for ITR exist due to the empirical nature of the original protocols and rapid advancements in the field of oral biology and dental materials. This heterogeneity in protocols may cause confusion among dental practitioners; therefore, guidelines and considerations for ITR should be explicated. This expert consensus discusses the biological foundation of ITR, the available clinical protocols and current status of ITR in treating teeth with refractory apical periodontitis or anatomical aberration, and the main complications of this treatment, aiming to refine the clinical management of ITR in accordance with the progress of basic research and clinical studies; the findings suggest that ITR may become a more consistent evidence-based option in dental treatment.
Humans ; Tooth Replantation/methods* ; Consensus ; Periapical Periodontitis/surgery*

AIM To study the chemical constituents from the leaves of Cyanocarya paliurus(Batalin)Iljinskaja and their α-glucosidase inhibitory activities.METHODS The 95%ethanol extract from the leaves of C.paliurus was isolated and purified by macroporous resin,silica gel,Sephadex LH-20,polyamide,C18 reversed-phase silica gel and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their α-glucosidase inhibitory activities were evaluated by PNPG.RESULTS Fifteen compounds were isolated and identified as cyclopaloside C(1),cyclopaloside A(2),juglanosides E(3),vaccinin A(4),ent-murin A(5),kaempferol 3-O-α-L-rhamnopyranoside(6),kaempferol-3-O-β-D-glucopyranoside(7),kaempferol-3-O-β-D-glucuronide methyl ester(8),kaempferol-3-O-β-D-glucuronide ethyl ester(9),kaempferol-3-O-β-D-glucuronide butyl ester(10),quercetin-3-O-α-L-rhamnopyranoside(11)quercetin-3-O-β-D-glucopyranoside(12),quercetin-3-O-β-D-galactopyranoside(13),quercetin-3-O-β-D-glucuronide butyl ester(14),dihydrokaempferol(15).The IC50 value of total extracts ihibited α-glucosidase was(1.83±0.04)μg/mL,and the IC50 values of compounds 1,4-5 were(29.48±1.86),(0.50±0.07),(0.71±0.07)μmol/L,respectively.CONCLUSION Compound 1 is a new tetrahydronaphthalene glycoside.Compounds 4-5,8-10 and 14 are isolated from the leaves of C.paliurus for the first time.Compounds 4-5 are relatively rare flavonoid lignans with potential inhibitory activities against α-glucosidase.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To investigate the relationship between the expression of microRNA(miR)-23a-3p and miR-361-5p and the signaling pathway of phosphatidylinositol 3 kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)and prognosis in gastric cancer tissue.Methods The expressions of miR-23a-3p,miR-361-5p,PI3K mRNA,AKT mRNA and mTOR mRNA in gastric cancer tissue and adjacent tissue of 120 patients with gastric cancer were detected by real-time fluorescence quantitative polymerase chain reaction.The correlation between the expressions of miR-23a-3p and miR-361-5p and the expressions of PI3K mRNA,AKT mRNA and mTOR mRNA in gastric cancer tissue was analyzed by Pearson correlation analysis,as well as the relationship between the expressions of miR-23a-3p and miR-361-5p and the clinicopathological characteristics of patients with gastric cancer.Kaplan-Meier survival analysis of different expressions of miR-23a-3p and miR-361-5p in gastric cancer tissue and the relationship between survival and prognosis of patients with gastric cancer.Univariate and multivariate COX regression analysis of factors affecting survival and prog-nosis of patients with gastric cancer.Results Compared with paracancerous tissue,the expressions of miR-23a-3p and miR-361-5p in gastric cancer tissue were significantly lower,while the expressions of PI3K mR-NA,AKT mRNA and mTOR mRNA were significantly higher,with statistical significance(all P＜0.05).The results of Pearson correlation analysis showed that the expressions of miR-23a-3p and miR-361-5p in gas-tric cancer tissue were negatively correlated with the mRNA expressions of PI3K,AKT and mTOR(all P＜0.05).There were statistically significant differences in the expression of miR-23a-3p and miR-361-5p in gas-tric cancer tissue of patients with different tumor TNM stages,tumor differentiation degrees,postoperative adjuvant chemotherapy and lymph node metastasis(all P＜0.05).The 3-year overall survival rate of gastric cancer patients with low miR-23a-3p expression was 46.77％(29/62),which was lower than that of gastric cancer patients with high miR-23a-3p expression[81.03％(47/58)],and the difference was statistically sig-nificant(Log-Rank X2=30.243,P＜0.001).The 3-year overall survival rate of gastric cancer patients with low miR-361-5p expression was 50.79％(32/63),which was lower than that of gastric cancer patients with high miR-361-5p expression[77.19％(44/57)],and the difference was statistically significant(Log-Rank x2=24.932,P＜0.001).Univariate and multivariate Cox regression analysis showed that TNM stage m,lymph node metastasis,no postoperative adjuvant chemotherapy,low expression of miR-23a-3p,and low ex-pression of miR-361-5p were independent risk factors for adverse prognosis in gastric cancer patients(P＜0.05).Conclusion The expression of miR-23a-3p and miR-361-5p in gastric cancer tissue of patients with gastric cancer is decreased,which is related to the PI3K/AKT/mTOR signaling pathway,and is a potential prognostic tumor marker of gastric cancer.

Objective:To analyze the distribution of clopidogrel metabolism-related gene variability in Kawasaki disease (KD) children with coronary artery lesions (CAL) across different age groups and the impact of genetic variability on the efficacy of clopidogrel antiplatelet therapy.Methods:A retrospective cohort study was conducted. Clinical data were collected from 46 KD children with CAL who were hospitalized in the Cardiovascular Center of Children′s Hospital of Fudan University between January 2021 and August 2022 and were treated with clopidogrel, including gender, age, body mass index, course of KD, CAL severity grade, and baseline platelet count. According to their age, the children were divided into ≥2-year-old group and <2-year-old group. Their platelet responsiveness was assessed by adenosine diphosphate-induced platelet inhibition rate (ADPi) calculated via thromboelastography, and children were categorized into high on-treatment platelet reactivity (HTPR) and normal on-treatment platelet reactivity (NTPR) groups. Genotypes of CYP2C19, PON1 and ABCB1 were detected. The t test, one-way analysis of variance and Chi-square test were used for intergroup comparison. Results:Among the 46 KD children with CAL, 34 were male and 12 were female; 37 were ≥2-year-old and 9 were <2-year-old; 25 cases were in the HTPR group and 21 cases were in the NTPR group, with 19 HTPR and 18 NTPR in the ≥2-year-old group, and 6 HTPR and 3 NTPR in the <2-year-old group. Genetic analysis showed that 92 alleles among the 46 children, with frequencies of CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*17, PON1 192Q, PON1 192R, ABCB1 3435C, ABCB1 3435T at 59% (54/92), 32% (29/92), 9% (8/92), 1% (1/92), 36% (36/92), 64% (59/92), 63% (58/92) and 37% (34/92), respectively. Analysis of the impact of genotype on ADPi revealed that in children aged ≥2 years, those with CYP2C19*1/*3 genotype had significantly lower ADPi than those with CYP2C19*1/*1 genotype ((34±15)% vs. (61±29)%, t=2.18, P=0.036). There were also no significant difference in ADPi among children with PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes ((40±22)% vs. (52±33)% vs. (65±27)%, F=2.17, P=0.130), or among those with ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((55±34)% vs. (60±27)% vs. (49±24)%, F=0.33, P=0.719). In <2-year-old group, there were no significant differences in ADPi across CYP2C19*1/*1, CYP2C19*1/*2 and CYP2C19*2*2 genotypes ((40±20)% vs. (53±37)% vs. (34±16)%, F=0.37, P>0.05). There were no significant differences in ADPi across CYP2C19*1/*1 and CYP2C19*1/*3 genotypes ((44±27)% vs. (42±20)%, t=0.08, P>0.05). There were no significant differences in ADPi across PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes (45% vs. (55±27)% vs. (24±5)%, F=1.83, P>0.05). There were no significant differences in ADPi across ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((36±16)% vs. (50±35)% vs. 45%, F=0.29, P>0.05). The risk analysis of HTPR in different genotypes revealed that in children aged ≥2 years, carrying at least 1 or 2 loss-of-function alleles of CYP2C19 was a risk factor for HTPR ( OR=4.69, 10.00, 95% CI 1.11-19.83, 0.84-119.32, P=0.033, 0.046, respectively), and PON1 192R homozygosity and carrying at least one PON1 192R allele were protective factors against HTPR ( OR=0.08, 0.13, 95% CI 0.01-0.86, 0.01-1.19, P=0.019, 0.043, respectively). Conclusion:KD children aged ≥2 years carrying CYP2C19 loss-of-function alleles and PON1 192Q are more likely to develop HTPR.

The structures and activities of enzymes are influenced by pH of the environment. Understanding and distinguishing the adaptation mechanisms of enzymes to extreme pH values is of great significance for elucidating the molecular mechanisms and promoting the industrial applications of enzymes. In this study, the ESM-2 protein language model was used to encode the secreted microbial proteins with the optimal performance above pH 9 and below pH 5, which yielded 47 725 high-pH protein sequences and 66 079 low-pH protein sequences, respectively. A deep learning model was constructed to identify protein acid-base tolerance based on amino acid sequences. The model showcased significantly higher accuracy than other methods, with the overall accuracy of 94.8%, precision of 91.8%, and a recall rate of 93.4% on the test set. Furthermore, we built a website (https://enzymepred.biodesign.ac.cn), which enabled users to predict the acid-base tolerance by submitting the protein sequences of enzymes. This study has accelerated the application of enzymes in various fields, including biotechnology, pharmaceuticals, and chemicals. It provides a powerful tool for the rapid screening and optimization of industrial enzymes.
Deep Learning ; Hydrogen-Ion Concentration ; Amino Acid Sequence ; Enzymes/metabolism* ; Sequence Analysis, Protein ; Proteins/metabolism* ; Bacterial Proteins/metabolism*

Background: and Purpose The relationships among interleukin (IL)-10 levels, anxiety, and cognitive status after stroke remain controversial. We aimed to determine the associations of serum IL-10 levels with poststroke anxiety (PSA) and poststroke cognitive impairment (PSCI). Methods: We recruited 350 patients with stroke, of whom only 151 completed a 1-month follow-up assessment. The Mini Mental State Examination (MMSE) and Hamilton Anxiety Scale (HAMA) were used to assess the cognitive status and anxiety, respectively. Serum IL-10 levels were measured within 24 hours of admission. Results: IL-10 levels were significantly lower in the PSA group than in the non-PSA group, and they were negatively associated with HAMA scores (r=-0.371, p<0.001). After adjusting for all potential confounders, IL-10 levels remained an independent predictor of PSA (odds ratio=0.471, 95% confidence interval=0.237–0.936, p=0.032). IL-10 levels were strongly correlated with behavior during interviews, psychic anxiety, and somatic anxiety. Patients without PSCI had higher IL-10 levels were higher in non-PSCI patients than in PSCI patients, and they were positively associated with MMSE scores in the bivariate correlation analysis (r=0.169, p=0.038), and also with memory capacity, naming ability, and copying capacity.However, IL-10 did not predict PSCI in the univariable or multivariable logistic regression. Conclusions Low IL-10 levels were associated with increased risks of PSA and PSCI at a 1-month follow-up after stroke. Serum IL-10 levels may therefore be helpful in predicting PSA.