Druggability evaluation is one of the core processes in new drug development, yet the inaccuracy and high cost of existing in vitro liver models have been a major technical bottleneck, leading to an increasing demand from the pharmaceutical industry for reliable in vitro liver models to enhance the efficiency of new drug research and development. Traditional animal models and in vitro 2D culture models have their limitations in simulating in vivo physiological and pathological conditions, making it challenging to accurately predict drug efficacy and safety. With the advancement of microfluidic technology, in vitro cell culture, and biosensor technology, liver-on-a-chip (LOC) has garnered increasing attention in the field of new drug development in recent years, and is expected to become a powerful tool for addressing the challenges in druggability evaluation. While introducing the construction technology of LOC, this article mainly summarizes the research and application of existing LOC from the perspectives of disease model construction, drug metabolism research, and drug safety evaluation. Furthermore, it analyzes the role of LOC in druggability evaluation and discusses the current challenges and prospects in this field.

Objective To investigate the factors influencing the efficacy of intravesical Bacille Calmette-Guérin(BCG)instillation after transurethral resection of bladder tumor(TURBT)in patients with intermediate-and high-risk non-muscle invasive bladder cancer(NMIBC),and to construct a prediction model for recurrence after BCG treatment.Methods A retrospective cohort study was conducted on the subjected patients diagnosed with intermediate-and high-risk NMIBC undergoing TURBT followed by standard BCG instillation.The 110 patients treated in Department of Urology of Army Medical Center of PLA from January 2018 to December 2023 were assigned into a training set,while the 52 patients treated at Department of Urology of General Hospital of Central Theater Command from January 2015 to December 2020 were into an external validation set.A total of 17 variables were included and analyzed.Univariate and multivariate Cox regression analyses were performed to identify factors associated with recurrence after BCG instillation,and nomograms were plotted to predict 1-year,3-year,and 5-year recurrence-free survival(RFS).Calibration curve,decision curve analysis(DCA),and receiver operating characteristic(ROC)curve analysis were conducted for internal and external validation to evaluate the predictive performance and clinical utility of the model.Results In the training set,26 patients(23.64%)experienced recurrence during the follow-up period,with a median RFS of 32.00(18.00～50.50)months.Univariate Cox regression analysis suggested that platelet count,eosinophil to lymphocyte ratio(ELR),neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),systemic immune inflammation(SII)index,and neutrophil-monocyte to lymphocyte ratio(NMLR),pathological T1 stage(pT1)tumor and hemoglobin,albumin,lymphocyte,and platelet(HALP)score were potential factors influencing recurrence after BCG instillation.Multivariate Cox regression analysis identified high HALP score(HR=0.185,95%CI:0.046～0.736,P=0.017)as an independent protective factor,while high ELR(HR=3.599,95%CI:1.505～8.608,P=0.004)and pT1 stage(HR=3.240,95%CI:1.191～8.818,P=0.021)were independent risk factors for recurrence.Based on this,a nomogram prediction model was constructed.The calibration curves demonstrated good agreement between predicted and actual 1-,3-,and 5-year recurrence risks.Decision curve analysis indicated clinical utility across a wide threshold probability range.In the training set,the model showed strong predictive performance for 1-(AUC=0.842),3-(AUC=0.847),and 5-year(AUC=0.887)recurrence risks,which was further validated in the external cohort.Conclusion Higher HALP score prior to BCG instillation therapy is a protective factor against tumor recurrence,while higher ELR and pT1 stage are risk factors.Our nomogram prediction model based on HALP score,ELR and pathological T stage,can identify individuals at high risk of recurrence after BCG instillation therapy.

Objective:To explore the characteristics of the brain functional networks in children with spastic cerebral palsy (SCP) while at rest and to correlate them with motor functioning.Methods:Thirty-six children with SCP were enrolled as the SCP group, while thirty-four age-matched healthy children were recruited as the control group (the HC group). Functional near-infrared spectroscopy was used to detect changes in the concentration of oxygenated hemoglobin in the children′s cerebral cortex while at rest. The left prefrontal cortex (LPFC), right prefrontal cortex (RPFC), left motor cortex (LMC), and right motor cortex (RMC) were selected as regions of interest. Phase locking values (PLVs) were used to evaluate the strength of functional connectivity (FC) among these brain regions, and graph theory methods were applied to analyze the topological properties of the brain networks. Motor functioning was assessed using the gross motor function measure (GMFM).Results:The analyses of FC strength revealed that the SCP group had significantly weaker FC among all of the regions of interest while at rest compared to the HC group. Their PLVs for LPFC-RPFC, LPFC-RMC, RPFC-RMC and LMC-RMC connectivity were all significantly smaller. Graph theory analysis showed that the SCP group had significantly lower global efficiency (GE) and smaller clustering coefficients (CCs) and network density (D), while their characteristic path lengths were significantly longer. According to the correlation analysis, the PLVs for LMC-RMC connections in the SCP group were positively correlated with their scores on dimensions D and E of the GMFM ( r=0.496 and r=0.579 respectively). GE ( r=0.587 and r=0.642) and CC ( r=0.318 and r=0.759) showed similar significant positive correlations with GMFM dimensions D and E. Conclusions:At rest, the functional networks in the brains of children with SCP exhibit abnormalities closely associated with their motor dysfunction.

Objective To investigate the predictive value of pre-transfer serum fibroblast growth factor 21(FGF-21),anti-Müllerian hormone(AMH),and neuropilin-1(NRP-1)for early pregnancy loss at 6 weeks following in vitro fertilization-embryo transfer(IVF-ET),and to establish an early predictive model based on serum biochemical markers.Methods This prospective study consecutively enrolled 322 women who achieved clinical pregnancy after IVF-ET at our center between September 2022 and September 2024.Participants were randomly divided into a modeling cohort(n=225)and a validation cohort(n=97)at a 7:3 ratio.According to ultrasound findings at 6 weeks of gestation,patients in the modeling cohort were classified into an early pregnancy loss group(n=59)and an ongoing pregnancy group(n=166).Baseline clinical characteristics and pre-transfer serum levels of FGF-21,AMH,and NRP-1 were collected.Multivariate logistic regression was applied to identify inde-pendent risk factors for early pregnancy loss and to construct a predictive model.Model discrimination,calibra-tion,and stability were evaluated using receiver operating characteristic(ROC)curves,the Hosmer-Lemeshow goodness-of-fit test,and bootstrap resampling in both cohorts.Results Univariate analysis revealed that the FSH/LH ratio,antral follicle count,and number of retrieved oocytes were significantly associated with early pregnancy loss(P<0.001).Compared with the ongoing pregnancy group,women with early loss showed significantly elevated pre-transfer serum FGF-21 levels,whereas AMH and NRP-1 levels were markedly reduced(P<0.001).Multivariate logistic regression demonstrated that an FSH/LH ratio<1.8(OR=1.629,P=0.002)and higher FGF-21 levels(OR=1.338,P=0.002)were independent risk factors,while higher AMH(OR=0.741,P=0.010)and NRP-1 levels(OR=0.874,P=0.007)were protective.Stratified analysis indicated that among patients with FSH/LH≥1.8,FGF-21 levels were significantly higher and AMH and NRP-1 levels significantly lower(all P<0.001).Interaction analysis further suggested that the FSH/LH ratio significantly modified the associations between these biomarkers and pregnancy loss risk(P for interaction<0.05).Specifically,in the higher FSH/LH subgroup,the risk effect of FGF-21 was amplified,while the protective effects of AMH and NRP-1 were more pronounced.The combined predictive model achieved C-indices of 0.869(95%CI:0.826～0.926)in the modeling cohort and 0.835(95%CI:0.811～0.907)in the validation cohort.Its AUC for predicting early pregnancy loss was 0.934 in the modeling co-hort and 0.909 in the validation cohort,both significantly outperforming individual markers(AUCs:FGF-21=0.867,AMH=0.881,NRP-1=0.853;Z=2.024,1.831;P<0.001).Decision curve analysis showed that the model provided consistent net clinical benefit across threshold probabilities of 0.1～0.4,underscoring its clinical utility.Conclusions Elevated pre-transfer serum FGF-21 and reduced AMH and NRP-1 levels are strongly associ-ated with early pregnancy loss at 6 weeks after IVF-ET.The predictive model developed in this study demonstrates robust accuracy and stability,offering substantial clinical application value for early risk stratification.

An increasing number of studies have shown that there is a close relationship between Alzheimer's disease(AD)and diabetes mellitus(DM).Traditional Chinese medicine holds that"kidney yin deficiency"is the common pathogenesis of these two diseases,while modern medicine believes that their pathogenesis involves abnormal aggregation of amyloid proteins,insulin deficiency and resistance,inflammatory response,oxidative stress,and autophagy,among others.The well-known traditional Chinese medicine formula Liuwei Dihuang Pills plays a significant role in the treatment of these two diseases with the same therapeutic approach.Therefore,this article will explore the connection between Liuwei Dihuang Pills and the treatment of AD and DM from different aspects;analyze the common etiology and pathogenesis of AD and DM,and explain the mechanism of prevention and treatment of Liuwei Dihuang Pills,with the aim of providing new ideas and methods for the integrated traditional and Western medicine prevention and treatment of AD and DM in the future.

Insomnia is often comorbid with anxiety and/or depression.Identifying biomarkers for this comorbidity is crucial for precise diagnosis,elucidating the underlying pathological mechanisms,and developing personalized treatment strategies.Current research has preliminarily revealed a series of potential biomarkers for insomnia comorbid with anxiety and/or depression.Elevated peripheral pro-inflammatory factors(e.g.,interleukin-6),and decreased peripheral brain-derived neurotrophic factor,and monoamine neurotransmitters(e.g.,5-hydroxytryptamine)may indicate the presence of a comorbid state.However,studies focusing on this comorbidity remain relatively limited.In the future,it will be necessary to systematically explore and verify the clinical application value of potential biomarkers through measures such as expanding sample size,strengthening longitudinal design,and expanding the categories of biomarkers.This will provide a more solid theoretical foundation for the early diagnosis and personalized treatment of insomnia comorbid with anxiety and/or depression.

Objective To investigate effects of Cordyceps sinensis(CS)on high glucose(HG)induced podocyte injury by regulating the adenylate activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR)signaling pathway.Methods Mouse podocytes were cultured in vitro and divided into the normal glucose(NG)group,the HG group,the HG+CS group,the HG+CS+autophagy inhibitor(HG+CS+3MA)group and the HG+CS+AMPK inhibitor(HG+CS+Compound C)group.Podocyte viability was detected by CCK-8 method.Western blot assay was used to detect the expression levels of podocyte marker proteins podocin and nephrin,autophagy-related proteins Beclin-1 and P62,and pathway related proteins p-AMPK and p-mTOR.Results Compared with the NG group,the cell viability of podocytes decreased,the expression levels of podocin,nephrin,Beclin-1 and p-AMPK protein were decreased,and the expression levels of P62 and p-mTOR protein were increased in the HG group(P＜0.05).Compared with the HG group,the cell viability of podocytes was increased,the expression levels of podocin,nephrin,Beclin-1 and p-AMPK protein were significantly increased(P＜0.05),and the expression levels of P62 and p-mTOR protein were decreased in the HG+CS group(P＜0.05).Compared with the HG+CS group,the cell viability decreased in the HG+CS+3MA group and the HG+CS+Compound C group(P＜0.05).Compared with the HG+CS group,the HG+CS+3MA group and the HG+CS+Compound C group showed decreased expression levels of podocin,nephrin and Beclin-1 protein,and increased expression of P62 protein(P＜0.05).Compared with the HG+CS group,the expression of p-AMPK protein decreased and the expression of p-mTOR protein increased in the HG+CS+Compound C group(P＜0.05).Conclusion Cordyceps sinensis may play a protective role in diabetic nephropathy by up-regulating AMPK/mTOR signaling pathway to induce podocyte autophagy,alleviate high glucose induced podocyte injury and apoptosis.

Objective To investigate the association between the TyG index,its modified variants,and the risk of developing colorectal cancer(CRC).Methods This study included a total of 93,177 participants from the 2006 Kailuan Group health examination cohort.Participants were categorized into four quartiles(Q1-Q4)according to their TyG and modified TyG indices.Follow-up began at the baseline examination,with incident CRC as the primary outcome.Participants were censored at the time of CRC diagnosis,death,or the end of the study,whichever occurred first.The dose-response relationship between TyG and its modified indices and the risk of CRC was evalu-ated using restricted cubic splines(RCS)in conjunction with Cox proportional hazards regression models,yielding hazard ratios(HRs)and 95%confidence intervals(CIs).To compare the strength of associations between TyG and its modified versions(TyG-BMI,TyG-WC,TyG-WHR,TyG-WHtR,TyG-WWI)and CRC risk,HRs for CRC per one standard deviation increase in each index were calculated and compared.Results Both the TyG index and its modified variants demonstrated a significant dose-response relationship with the risk of CRC incidence.Specifically,for the TyG index,each 1-standard deviation(SD)increase was associated with a 1.17-fold(95%CI:1.09～1.27)higher risk of CRC.Compared with the first quartile(Q1),the third quartile(Q3)and fourth quartile(Q4)exhibited a 1.25-fold(95%CI:1.01～1.55)and 1.26-fold(95%CI:1.01～1.57)increased risk,respectively.For TyG-BMI,each 1-SD increase was linked to a 1.20-fold(95%CI:1.07～1.35)elevated CRC risk.Compared with Q1,Q3 and Q4 showed a 1.32-fold(95%CI:1.06～1.64)and 1.51-fold(95%CI:1.21～1.88)increase,respectively.Regarding TyG-WC,each 1-SD increment was associated with a 1.22-fold(95%CI:1.13～1.32)higher CRC risk,with Q3 and Q4 showing a 1.35-fold(95%CI:1.08～1.70)and 1.56-fold(95%CI:1.24～1.96)increased risk compared to Q1.For TyG-WHtR,each 1-SD increase was associated with a 1.24-fold(95%CI:1.08-1.42)higher CRC risk.Compared with Q1,Q2,Q3,and Q4 demonstrated a 1.31-fold(95%CI:1.03～1.66),1.55-fold(95%CI:1.23～1.95),and 1.60-fold(95%CI:1.27～2.02)increase,respectively.In the case of TyG-WHR,each 1-SD increase was associated with a 1.19-fold(95%CI:1.10～1.29)higher CRC risk,with Q4 showing a 1.42-fold(95%CI:1.14～1.77)increased risk compared to Q1.Finally,for TyG-WWI,each 1-SD increase was associated with a 1.22-fold(95%CI:1.13～1.32)elevated CRC risk,with both Q3 and Q4 showing a 1.58-fold increase(Q3:95%CI:1.26～1.98;Q4:95%CI:1.25～1.99).Stratified analyses by sex and age consistently revealed significant associations between the TyG index and its modified variants and CRC risk.Furthermore,these indices were independently associated with the incidence of both colon cancer and rectal cancer.Conclusions(1)Elevated levels of the TyG index and its modified variants are independent risk factors for CRC.(2)Both the TyG index and its modified forms demonstrate a significant dose-response association with the incidence of CRC.(3)Among the modified TyG indices,TyG-WWI,TyG-WHtR,TyG-BMI,TyG-WC,and TyG-WHR showed stronger correlations with CRC risk compared to the original TyG index.

Objective To investigate the expression of NOP16 nucleolar protein(HSPC111)and triple do-main protein 2(TRIM2)in colorectal cancer(CRC),as well as their clinicopathological characteristics and prognostic evaluation value.Methods A total of 110 CRC patients admitted to SUN Simiao Hospital,Beijing University of Traditional Chinese Medicine from February 2018 to February 2019 were selected as the research subjects.The expressions of HSPC111 and TRIM2 in tissues were detected by immunohistochemistry.The survival curves of the HSPC111 and TRIM2 positive and negative groups were plotted by Kaplan-Meier sur-vival analysis.The COX regression model was used to analyze the risk factors influencing the prognosis of CRC patients.A nomogram model for the prognosis of CRC was constructed,and the accuracy of the model was analyzed using the prognostic calibration curve.Results The positive rates of HSPC111 and TRIM2 in CRC cancer tissues were higher than those in the adjacent groups,and the differences were statistically signifi-cant(P＜0.001).The positive rates of HSPC111 and TRIM2 in CRC cancer tissues with TNM stage Ⅲ and lymph node metastasis increased,and the difference was statistically significant(P＜0.001).The 5-year sur-vival rate of CRC patients in the HSPC111 positive group was lower than that in the negative group(Log-rank x2=10.121,P=0.001).The 5-year survival rate of CRC patients TRIM2 positive group was lower than that in the negative group(Log-rank x2=13.620,P＜0.001).Positive HSPC111,positive TRIM2,TNM stage Ⅲand lymph node metastasis were risk factors affecting the prognosis of CRC patients.The consistency index of the Nomogram prediction model based on HSPC111,TRIM2,TNM staging and lymph node metastasis was 0.846(95％CI:0.822-0.870)and the predicted value was close to the actual value,with good discrimination.Conclusion The increased expression of HSPC111 and TRIM2 in CRC is involved in promoting the progres-sion of CRC.Nomogram prediction models based on HSPC111,TRIM2,TNM staging and lymph node metas-tasis are helpful for evaluating the prognosis of CRC.