Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Objective To explore the effect of endophytes on Nanyang Mugwort by analyzing the diversity of endophytic flora and its correlation with the content of key secondary metabolites in three compartments of Nanyang Mugwort,and the effect of medicinal material quality.Methods In this study,high-throughput sequencing and high-performance liquid chromatography(HPLC)were carried out to determine the distribution endophytes and key secondary metabolites in three compartments of Nanyang Mugwort respectively.The endophytic communities that were significantly correlated with key secondary metabolites were screened by Pearson correlation analysis.Results We found endophytic diversity and composition showed compartment specificity,and bacterial and fungal alpha diversity values(Chao and Ace)in the root compartment were significantly higher than that of leaf and stem.Linear discriminant analysis efect size(LEfSe)analyses identified some potential microbial biomarkers,such as Rhizobium,Streptomyce,Xanthomonadaceae,and Sordariomycetes.Pearson correlation analysis showed that endophytes(such as Rhizobium,Pseudomonas,Flavobacterium,Streptomyces Aspergillus,and Olpidium)were significantly correlated with contents of some phenylpropanoid and flavonoid metabolites in our study(P<0.05).Conclusion In this study,some endophytic communities with significant correlation between key secondary metabolites of Nanyang Mugwort were identified,which provided valuable information to guide the isolation of endophytic strains related to key secondary metabolites and improve the quality of Nanyang Mugwort.

Objective To characterize the temporal dynamics of endophytic community and key metabolites during the growth developmental stages of Artemisia indica and to explore the effects of endophytes on the medicinal material quality of A.indica from the perspective of microorganism combined with the correlation analysis.Methods In this study,high-throughput sequencing was performed to obtain the temporal dynamics of diversity and composition of endophytic community during the growth stages of A.indica.Key metabolites quantitative analysis were performed using high-performance liquid chromatography and ultraviolet spectrophotometry.Spearman's correlation analysis was further conducted to identify the endophytic communities that were significantly correlated with metabolites.Results There were significant differences in the diversity and composition of endophytic communities during the growth stages of A.indica.Linear discriminant analysis efect size(LEfSe)analyses identified some potential microbial biomarkers,such as Firmicutes,Massilia,Pantoea,Alternaria,Didymella,and Trichomerium.The abundances of some genera were significantly and positively correlated with the content of total polyphenols and total flavonoids(P<0.05),such as Curtobacterium,Pantoea,Tilletiopsis,and Dissoconium.The abundances of Pseudozyma,Ralstonia,and Pleospora were significantly and positively correlated with Chlorogenic acid,Isochlorogenic acid B,Isochlorogenic acid A,and Isochlorogenic acid C(P<0.05).Conclusion This work described the distribution of endophytes and key metabolites during the development stages of A.indica.Some endophytic communities with significant correlation of key metabolites were identified,which provided valuable information to guide the isolation of endophytic strains related to key metabolites and improve the quality of A.indica.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Background: A small shift in high-sensitivity cardiac troponin T (hs-cTnT) assays can lead to different result interpretation and consequent patient management. We explored whether a small bias could be detected using conventional internal quality control (QC) procedures, evaluated the performance of moving average (MA)-based QC procedures, and proposed a new QC procedure based on the moving rate (MR) of positive patient results of hs-cTnT assays. Methods: The ability of conventional QC to detect a 5 ng/L bias was examined using the 1 3s/ 22s/R4s multi-rule procedure as deviation rules.We developed MA and MR procedures for the hs-cTnT assay using eight months of patient data. The performance of different MA or MR procedures was investigated by calculating the median number of patient samples affected until a bias introduced into the dataset was detected (MNPed). After comparing the MNPed across different procedures, we selected an optimal MA or MR procedure for validation. Validation graphs were plotted using the minimum, median, and maximum number of results affected until bias detection. Results: Our conventional QC procedures could not detect a positive bias of 5 ng/L. When a positive bias was introduced, MNPed was much higher using MA than using MR, with cut-off values of 5 ng/L and 14 ng/L, respectively. MR validation charts for optimal procedures provided insight into the MR performance. Conclusions The MR procedure could detect different errors with few false alarms. In the hs-cTnT assay, the MR procedure with a smaller cut-off value outperformed MA and conventional QC procedures for small bias detection.

Objective:To improve the precision and accuracy of gross radioactivity detection in water, and to improve the radiological health and environmental monitoring level of each laboratory, it is necessary to carry out method verification and quality control.Methods:The thick source method for gross α and the thin source method for gross β analysis were used to analyze the actual samples. After multiple tests, the precision of the detection was calculated. Through the spike recovery test and the comparison sample analysis of the national radiological health in 2019, the accuracy analysis of the method was performed.Results:In the precision experiment, the relative standard deviations of the gross α and gross β results were 23% and 13%, respectively. The three spike recoveries were 103.1%, 103.5%, and 105.8%, respectively. The relative errors of gross α and gross β compared with the reference value were 0.92% and 9.4%, respectively. All the result reflected the high accuracy of the method .Conclusions:The relative standard deviations, recoveries, and relative errors in the method validation and quality control were below the limits of the criterion. This work systematically discussed the major factors that may cause errors in the detection, which could further improve the level of radiological health and environmental monitoring.

Objective To explore the feasibility of inter-laboratory comparison and trueness evaluation among clinical laboratories, and assess the quality of participants′measurement, by measuring the activity of alanine aminotransferase ( ALT ) in patient serum samples.Methods Method comparison study was used.Five patients serum samples, whose target values were assigned by two international candidate reference laboratory with reference method of ALT without pyridoxal phosphate, were measured by 23 routine laboratories.The bias between measurement result of each participant and the mean of reference laboratories was calculated, and then compared to allowable bias 6%.Calculate the mean value and the relative bias.Results Compared with the mean of reference laboratories, the maximum absolute value of bias among the 23 routine laboratories was 31.27%.The rate range which bias was less than the allowable bias was 26.09%-73.91 %.The bias acceptability of 8 participants were more than or equal to 80%;15 participants were less than or equal to 60%; and 3 participants were 0%.Conclusions Using patient serum samples and values assigned by reference method is an effective way to carry out inter-laboratory comparison and trueness evaluation.It can reflect the quality of measurement more truly.

Objective:To investigate the differences of Ego Impairment Index (EII)of Rorschach test be-tween patients with schizophrenia and normal individuals.Methods:Totally 60 patients with schizophrenia (17-53 years old)meeting the criteria of Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition (DSM-IV) and 60 age-and gender-matched normal subjects were involved in this study.The Rorschach ink blots test was used in both patients and normal subjects.The Ego Impairment Index (EII)of all the participants were calculated on the basis of their responses to the Rorschach ink blots test.The EII and the subcomponents of it (including distorted form quality,weighted sum of cognitive processing errors,distorted perceptions of human movement,critical con-tent,good human representation,and poor human representation)of the two samples were compared to explore EII's discrimination to patients and normal individuals.Results:The score of EII [(0.7 ± 1.7 )vs. (-0.9 ± 0.9 )],distorted form quality [(6.2 ± 2.3 )vs. (3.4 ± 2.6 )],weighted sum of cognitive processing errors [(14.0 ±6.5)vs.(7.2 ±4.2)],distorted perceptions of human movement [(0.7 ±1.2)vs.(0.3 ±0.7)], and poor human representation [(3.1 ±2.7)vs.(1.8 ±1.8)]were higher in patients than in normal participants (Ps<0.05 ).No significant differences were found for the score of good human representation and critical content between the two groups (Ps>0.05 ).The result of Diagnostic Test showed that when EII equaling to -0.5 ,the sensitivity,specificity,and Youden Index of it to distinguish patients from normal individuals were 0.9 1 ,0.75 ,and 0.66 respectively.Conclusion:It suggests that the ego functions of patients with schizophrenia have become serious damage compared with normal individuals.The EII of Rorschach test has high sensitivity while relatively low speci-ficity in discriminating patients with schizophrenia,which needs to be further perfected.

Objective To develop a rapid and reliable method for determination of 210Po using large-area grid ionization chamber α spectrometry.Methods Samples were digested using a microwave digestion system.After preparation of sample source,the concentration of 210Po in clam was detected by large-area grid ionization chamber (φ 25 cm).209Po tracer was used to obtain the recovery.Results Large-area grid ionization chamber could achieve better counting and α spectrum resolution when the optimized thickness was 250 μg/cm2.By spiking 209Po tracer in clam,the minimum detectable activity was 9.870 × 10 4 Bq and the recovery of 210Po was 98％.Conclusions Compared with the traditional method,the developed method can avoid separation process,using less quantity of sample (0.2-0.5 g dry) and simplify the measurement process.This method may be has broad application prospects.

Objective To develop the method of analyzing α-radionuclides using large area grid ionization chamber.Methods Ultrasonic dispersion and vacuum drying system was used to prepare sample source,large standard thin source and plutonium plane source were used to optimize the working condition of spectrometer,and calibrate the instrument for analyzing α emitters.The certified reference materials (GBW04127) were used to verify the accuracy of the method.Results The non-linearity of calibration curve for standard thin sources of neptunium,plutonium and americium was less than 0.2％,and the resolution were 112,84 and 106 keV,respectively.The counting efficiency was 31.2％ for the large standard thin source.The values of specific activity measured in this way were in good agreement with those of the certified reference materials.232Th,238U,230Th,234U/226Ra,210Po,222Rn and 218Po were analyzed in a uranium mineral sample,and their specific radioactivity values were 5.3,3.8,35.6,21.4,27.0,19.6 and 11.1 Bq/g,respectively.Conclusions The method can be used to analyze α spectrum quickly in low-level radioactive environmental samples.