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*

OBJECTIVES: To investigate the inhibitory effect of Zheng GanDecoction (ZGF) on tumor progression in a rat model of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) and explore the possible mechanism. METHODS: Seventy SD rats were subjected to regular intraperitoneal injections of DEN (50 mg/kg) for 12 weeks to induce HCC tumorigenesis, with another 10 rats receiving saline injections as the normal control. After successful modeling, the rats were randomized into 5 groups (n=10) for daily treatment with distilled water ( model group), Huaier Granules (4 g/kg; positive control group), or ZGF at low, medium, and high doses (2, 4, and 8 g/kg, respectively) via gavage for 17 weeks. Body weight changes of the rats were monitored, and after completion of the treatments, the rats were euthanized for measurement of liver, spleen and thymus indices and morphological and histopathological examinations of the liver tissues using HE staining. The expressions of YAP, p-YAP, MST1, LATS1 and p-LATS1 in the liver tissues were detected using immunohistochemistry and Western blotting. RESULTS: Compared with the normal control rats, the rat models with DEN-induced HCC exhibited much poorer general condition with a significantly reduced survival rate, increased body weight and liver and spleen indices, and a lowered thymus index. ZGF treatment obviously reduced liver and spleen indices, increased the thymus index, and improved pathologies of the liver tissues of the rat models. Immunohistochemistry and Western blotting showed a dose-dependent reduction of YAP expression and an increment of p-YAP expression in ZGF-treated rats, which also exhibited significantly upregulated hepatic expressions of MST1, LATS1 and p-LATS1. CONCLUSIONS ZGF inhibits DEN-induced HCC in rats by activating the Hippo/YAP pathway via upregulating MST1 and LATS1 expression, which promotes YAP phosphorylation and degradation to suppress proliferation and induce apoptosis of the tumor cells.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Diethylnitrosamine ; Rats, Sprague-Dawley ; Rats ; Signal Transduction/drug effects* ; Protein Serine-Threonine Kinases/metabolism* ; Carcinoma, Hepatocellular/drug therapy* ; YAP-Signaling Proteins ; Liver Neoplasms/drug therapy* ; Hippo Signaling Pathway ; Male ; Liver Neoplasms, Experimental/metabolism* ; Transcription Factors/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism*

Widespread utilization of glyphosate has led to environmental residues,posing potential threats to ecological systems and human health.Traditional methods for detection of glyphosate are limited by specialized equipment and operational techniques,resulting in inefficient responses.Therefore,it is urgent to develop a convenient,sensitive and accurate detection method for detection of glyphosate.Herein,a new naphthalenesulfonamide-based"Turn-on"fluorescent probe was synthesized using 2-chloroaniline and dansyl chloride as raw materials through a one-step process,which showed a good linear relationship between the glyphosate concentration in concentration range of 0.003-70 μmol/L and the fluorescence intensity(R2=0.995),with a detection limit of 2.73 nmol/L(S/N=3).Analytical techniques such as nuclear magnetic resonance(NMR)spectroscopy and high-resolution mass spectrometry(HRMS)were used to investigate the interaction mechanism between the fluorescent probe and glyphosate.The results indicated that a nucleophilic substitution reaction occurred between the probe and the secondary amine(—NH—)of glyphosate,inducing a photoinduced electron transfer(PET)effect which enhanced the fluorescence intensity by 11.2 times.The probe showed good anti-interference ability towards coexisting metal ions,anions and pesticides in water.When applied to determination of glyphosate in the samples such as tap water,river water(Xiangxi River Reservoir),soil,soybeans,and corn,the spiking recoveries ranged from 94.7％to 109.9％,demonstrating the high accuracy and broad applicability of this detection method.A portable test strip based on this fluorescent probe was developed for rapid semi-quantitative analysis of glyphosate.The developed method was rapid,sensitive,and portable,providing theoretical and technical support for on-site measurement of environmental contaminants.

Integrated metabolomic and lipidomic profiling,utilizing liquid chromatography coupled with high-resolution mass spectrometry(LC-HRMS),has emerged as a pivotal strategy for biomarker discovery.However,the inherent polarity disparity between metabolites and lipids complicates simultaneous analysis.To address this,a dual-stationary phase polarity-extended liquid chromatography(PELC)system was developed,which surpassed conventional one-dimensional LC(1D-LC)by enabling comprehensive coverage of both polar and non-polar compounds within a single injection.This system enhanced chromatographic resolution,peak capacity,and throughput while minimizing analytical variability.Extracellular vesicles(EVs),lipid bilayer-enclosed nanoparticles ubiquitously present in biofluids,had gained prominence as reservoirs of cancer biomarkers due to their cargo stability and pathophysiological relevance.Herein,the application of PELC-HRMS for concurrent metabolome-lipidome profiling in EVs was pioneered.A total of 193 metabolites were identified using this technique coupled with MS-DIAL software and Human Metabolome Database.Subsequently,this technique was employed to explore potential biomarkers for prostate cancer(PCa).Multivariate analysis identified 17 differentially abundant metabolites in PCa,implicating dysregulated pathways including purine metabolism,starch and sucrose metabolism,galactose metabolism,cysteine and methionine metabolism,and biosynthesis of unsaturated fatty acids.Notably,creatine(AUC=0.92)and DG 42:5(AUC=0.80)demonstrated robust diagnostic efficacy,attributable to their broad polarity ranges and EV-specific enrichment.This study established PELC as a high-fidelity platform for multi-omics integration in complex biospecimens,advancing mechanistic insights into metabolic rewiring and disease pathophysiology.

ObjectiveExisting artificial vision devices can be divided into two types: implanted devices and extracorporeal devices, both of which have some disadvantages. The former requires surgical implantation, which may lead to irreversible trauma, while the latter has some defects such as relatively simple instructions, limited application scenarios and relying too much on the judgment of artificial intelligence (AI) to provide enough security. Here we propose a system that has voice interaction and can convert surrounding environment information into tactile commands on head and neck. Compared with existing extracorporeal devices, our device can provide a larger capacity of information and has advantages such as lower cost, lower risk, suitable for a variety of life and work scenarios. MethodsWith the latest remote wireless communication and chip technologies, microelectronic devices, cameras and sensors worn by the user, as well as the huge database and computing power in the cloud, the backend staff can get a full insight into the scenario, environmental parameters and status of the user remotely (for example, across the city) in real time. In the meanwhile, by comparing the cloud database and in-memory database and with the help of AI-assisted recognition and manual analysis, they can quickly develop the most reasonable action plan and send instructions to the user. In addition, the backend staff can provide humanistic care and emotional sustenance through voice dialogs. ResultsThis study originally proposes the concept of “remote virtual companion” and demonstrates the related hardware and software as well as test results. The system can not only achieve basic guide functions, for example, helping a person with visual impairment to shop in supermarkets, find seats at cafes, walk on the streets, construct complex puzzles, and play cards, but also can meet the demand for fast-paced daily tasks such as cycling. ConclusionExperimental results show that this “remote virtual companion” is applicable for various scenarios and demands. It can help blind people with their travels, shopping and entertainment, or accompany the elderlies with their trips, wilderness explorations, and travels.

Aneurysmal subarachnoid hemorrhage(aSAH),primarily caused by the rupture of intracranial aneurysms with bleeding into the subarachnoid space,is an acute neurological disease associated with high disability and mortality.Brain injury after aSAH results from a combination of injury mechanisms,with early brain injury(EBI)occurring within 72 hours post-onset,laying the foundation for subsequent pathophysiological changes in the brain and poor prognosis of patients.Among them,the brain immunoinflammatory response,involving the interaction of various immune cells and active substances,plays a significant role in post-aSAH EBI,and is related to delayed brain injury and long-term prognosis.Systemic inflammatory response following aSAH can also affect the prognosis and outcome of patients.This review summarizes the role of local and systemic immune inflammatory responses in the occurrence and progression of aSAH,as well as the research progress on related inflammatory biomarkers and therapeutic prospects,aiming to provide a theoretical reference for new treatment for aSAH.

Based on the literature study,the thoughts and possible therapeutic mechanism in treating male infertility from the perspective of spleen and kidney by regulating intestinal flora were explored.Disturbance of intestinal flora is one of the important factors leading to the development of male infertility,and the spleen and kidney have certain similarities to intestinal flora in the physiological function and pathological changes.Moreover,tonifying the kidney and strengthening the spleen can regulate the intestinal flora by fostering the growth of beneficial bacteria,inhibiting the reproduction of pathogenic bacteria,and protecting the barrier of the intestinal mucosa.Therefore,the possible therapeutic mechanisms in treating male infertility with the prescriptions for tonifying the kidney and strengthening the spleen to regulate intestinal flora are as follows:inhibiting the expression of inflammatory factors to reduce the inflammatory reaction of testicular tissues;improving the antioxidant capacity to alleviate the damage of spermatozoa caused by oxidative stress,and improving the bad mood to alleviate the impact of psychological stress on the reproductive system.The exploration of the thoughts for treating male infertility from the perspective of spleen and kidney by regulating intestinal flora may provide a new entry point for modern Chinese medicine clinical treatment of male infertility.

Objective To investigate the protective effect of total saponins of Panax japonicus(TSPJ)against CCl4-induced acute liver injury(ALI)in rats and explore the underlying pharmacological mechanisms.Methods Male SD rat models of CCl4-induced ALI were given intraperitoneal injections of distilled water,100 mg/kg biphenyl bisabololol,or 50,100,and 200 mg/kg TSPJ during modeling(n=8).Liver functions(AST,ALT,TBil and ALP)of the rats were assessed and liver pathologies were observed with HE staining.Immunohistochemistry was used to detect the expressions of PI3K/Akt/NF-κB signaling pathway molecules in liver tissue;ELISA was used to determine the levels of T-SOD,GSH-Px,and MDA.Western blotting was performed to detect the expression levels of PI3K-Akt and SIRT6-NF-κB pathways in the liver tissue.Results Network pharmacological analysis indicated that the key pathways including PI3K/Akt mediated the therapeutic effect of TSPJ on ALI.In the rat models of ALI,treatments with biphenyl bisabololol and TSPJ significantly ameliorated CCl4-induced increase of serum levels AST,ALT,ALP,TBil and MDA and decrease of T-SOD and GSH-Px levels(all P<0.01).The rat models of ALI showed significantly increased expression of p-NF-κB(P<0.01),decreased expressions of PI3K,p-Akt and SIRT6 proteins,and elevated expression levels of p-NF-κB,TNF-α and IL-6 proteins in the liver,which were all significantly improved in the treatment groups(P<0.05 or 0.01).Conclusion TSPJ can effectively alleviate CCl4-induced ALI in rats by suppressing inflammatory responses and oxidative stress in the liver viaregulating the PI3K/Akt and SIRT6/NF-κB pathways.

Objective:To evaluate the effect of applying high-fidelity simulation model in the teaching of lower urinary tract injury.Methods:A total of 50 junior medical students majoring in clinical medicine were enrolled. They were randomly assigned to the control group or the experimental group. The students in the control group were taught using the traditional method involving PPT presentation and videos on lower urinary tract anatomy, surgical basis of lower urinary tract injury, and operative methods for lower urinary tract injury. The students in the experimental group were taught using the simulation model for observation and related operation. After four class hours (40 minutes/class hour) of teaching, the students in the two groups were subjected to theoretical assessment and questionnaire survey. The differences between the two groups were compared and analyzed using the t and χ 2 tests in SPSS 26.0. Results:The total scores of theoretical assessment were (36.80±4.00) and (33.12±3.62) in the experimental group and the control group, respectively, and the difference was significant ( P<0.05). The results of the questionnaire showed that the self-evaluation of the experimental group was better than that of the control group in the mastery of theoretical knowledge, clinical operation, early treatment, operation process, and key steps, and the differences were statistically significant ( P<0.05). Conclusions:Compared with the traditional teaching method, the high-fidelity simulation model improves the efficiency of learning anatomy knowledge and operation process, and promotes the mastery of important and difficult knowledge in lower urinary tract injury. This method merits popularization.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.