Objective: To investigate the relationship between 24 hour activity behaviors and fine motor development in preschool children, and to simulate the effects of reallocating time among different activity behaviors on fine motor development using isotemporal substitution analysis. Methods: From March to July 2022, a stratified cluster random sampling method was used to recruit 447 preschool children aged 3-6 years (254 boys and 193 girls) from Pingxiang City, Jiangxi Province. The 24 hour activity behaviors in preschool children were measured using ActiGraph wGT3-BT accelerometers and subjective sleep reports. Fine motor development was assessed using the Gesell Developmental Schedules. A component linear regression model was employed to analyze the impact of 24 hour activity behaviors on the development of fine motor activities, and the potential effects of adjusting activity behaviors were simulated through an isochoric substitution model. Results: The daily durations of sedentary behavior (SB) was ( 572.92 ±102.96) min (accounting for 39.79% of 24 h), the duration of light physical activity (LPA) was (131.21± 38.11 ) min ( 9.11% ), the duration of moderate to vigorous physical activity (MVPA) was (65.61±22.21) min (4.56%), and sleep duration was (670.65±57.58) min (46.82%). Sleep composition was positively associated with fine motor development ( β =2.74), while MVPA ( β =-0.84) and SB ( β =-1.93) compositions were negatively associated with fine motor development (all P <0.01). Isochoric substitution analysis showed that sleep had positive effects on the development of fine motor skills when replacing other activity behaviors (all P < 0.05), with the substitution effect for MVPA being the most significant and gradually increasing with the duration of substitution (60 min: β =28.66); sleep replacement of SB and LPA also showed positive effects (60 min: β =4.25, 2.00) (all P < 0.05). On the contrary, the substitution of sleep with MVPA showed negative effects (60 min: β =-7.86), and the substitution of LPA and SB with MVPA also showed negative effects (60 min: β =-5.65, -3.40) (all P <0.05). Conclusions The overall composition of 24 hour activity behaviors is associated with fine motor development in preschool children, with sleep playing a crucial role. Ensuring adequate sleep and optimizing the structure of activity behaviors may effectively promote the development of fine motor skills in preschool children.

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

OBJECTIVE To explore the potential mechanisms of forkhead box protein A1(FOXA1)in benzo[a]pyrene(BaP)-induced carcinogenesis by investigating the effect of FOXA1 by knockout on microRNA(miRNA)expression profiles in BaP malignant transformed cells THBEc1 and establishing regulatory networks between FOXA1,miRNA and their target genes.METHODS FOXA1 knockout THBEc1 cells THBEc1-ΔFOXA1-c34 and control cells THBEc1-ctrl were used as study models.Western blotting was employed to determine FOXA1 protein expression levels.Next-generation sequencing(NGS)tech-nology was used to identify differentially expressed miRNAs between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells,with subsequent validation by RT-qPCR.Five databases(ENCORI,miRDB,mirDIP,miRWalk and TargetScan 8.0)were used in conjunction with NGS results of mRNA between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl to predict different expressed genes(DEGs)regulated by the identified differentially expressed miRNAs.GO and KEGG enrichment analyses were conducted on the DEGs using the DAVID database.Interaction network analysis of the proteins encoded by the DEGs was performed using STRING 12.0 and Cytoscape 3.10.2 software.RESULTS No FOXA1 expression was detected in THBEc1-ΔFOXA1-c34 cells.A differential analysis of miRNA expressions revealed 33 miRNAs with a fold change of＞2 or＜0.5 and a false discovery rate of＜0.05 between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells,13 of which were down-regulated and 20 were up-regulated in THBEc1-ΔFOXA1-c34 cells.A regulatory network was formed by 11 down-regulated miRNAs and 32 up-regulated mRNAs,while a second network included 16 up-regulated miRNAs and 56 down-regulated mRNAs.The 27 differentially expressed miRNAs participated in various biological processes through the regulation of 88 DEGs,primarily associated with cell growth,proliferation,migration,apoptosis,angiogenesis,epithe-lial-mesenchymal transition,and signal transduction(TGF-β,Hippo,NF-kappa B and MAPK pathways).CONCLUSION The miRNA expression profile in BaP-malignant transformed THBEc1 cells is altered following FOXA1 knockout that may disrupt TGF-β and MAPK signaling pathways by changing miRNA expression levels,thereby inhibiting cell proliferation and migration.

OBJECTIVE To establish an in vitro simulated one compartment extravascular adminis-tration model with lanthanum nitrate as the test substance,and explore the differences between this model and the classic in vitro administration model in lanthanum nitrate induced HepG2 cell death.METHODS An in vitro administration device was designed based on compartment model theories which consisted of four functional chambers:the liquid storage chamber,mixing chamber,toxicant exposure chamber,and waste liquid receiving chamber.The four chambers were connected by peristaltic pump hoses.The peristaltic pumps were employed to ensure unidirectional and constant speed trans-mission of liquid between these chambers.According to the preset toxicokinetic parameters such as T1/2a and T1/2,an in vitro simulated one compartment extravascular administration model of lanthanum nitrate was constructed using the device.The content of lanthanum nitrate in the toxicant exposure chamber at different time points was measured using inductively coupled plasma mass spectrometry.The concentration-time curves of lanthanum nitrate were analyzed using PKsolver and GraphPad Prism 8.0 software.The constructed in vitro simulated one compartment extravascular administration model was evaluated by comparing the measured and theoretical values of toxicokinetic parameters.HepG2 cells were treated with lanthanum nitrate in the in vitro simulated one compartment extravascular administration model and classic in vitro administration model,respectively,and cell death was measured using the Hoechst 33342/propidium iodide staining method.RESULTS Within the Cmax range of 3.91-1 000.00 μmol·L-1,the measured concentration-time curves of lanthanum nitrate in the toxicant expo-sure chamber almost conformed with the corresponding calculated theoretical curves(the correlation coefficients were all>0.998 0).The measured values of toxicokinetic parameters,including Ke,T1/2,Ka,T1/2a,Tmax,Cmax,CL and AUC0-∞,were close to the corresponding theoretical values.The fitting coeffi-cients(R2)of the concentration-time curves for each experimental group were all>0.990 0,which was consistent with one compartment model for extravascular administration.In the simulated one compart-ment extravascular administration model,no significant death of HepG2 cells was observed in any lanthanum nitrate dose group.In the classic in vitro administration model,the cell death rate of the 0.500 mmol·L-1 lanthanum nitrate group was higher than that of the solvent control group,but no significant cell death was observed in the 0.119 mmol·L-1 group or 0.243 mmol·L-1 group.When Cmax or Cadministration was 0.500 mmol·L-1,classic in vitro administration induced a higher cell death rate than simulated one compart-ment extravascular administration.However,there was no statistically significant difference in lanthanum nitrate induced HepG2 cell death between the two administration models when the AUC was equal.CONCLUSION The device designed in this study can be used to in vitro simulate one compartment extravascular administration,making in vitro toxicity testing more similar to in vivo scenarios,and providing data for optimizing administration methods of in vitro toxicity testing.There are differences in lanthanum nitrate induced HepG2 cell death between simulated one compartment extravascular administration and classic in vitro administration,indicating that different in vitro exposure modes can affect toxicity.

Objective:To analyze the clinical characteristics of acute leukemia complicated with arterial ischemic stroke (AIS) in children, and to provide a reference for its diagnosis, treatment, and prognosis.Methods:Case summary.This report presents three children with acute leukemia complicated with AIS admitted to the First Affiliated Hospital of Zhengzhou University from April 2015 to August 2024, and reviews the relevant literature at home and abroad to analyze the clinical characteristics, pathogenesis, and treatment of the disease.Results:All three cases were female, aged 4-14 years; two had acute lymphoblastic leukemia (ALL) and one had acute myeloid leukemia (AML). Hemiparesis was the main presenting symptom in all cases, occurring during induction therapy.Symptoms resolved completely after anticoagulant and symptomatic treatment, with no sequelae and good prognoses.A literature search identified 8 reported cases of pediatric acute leukemia complicated with AIS.Combining these with our 3 cases yielded a total of 11 cases: 5 males and 6 females; median age 7 years (range 2-15 years); 8 with ALL and 3 with AML.Clinically, all presented with hemiparesis.Vascular imaging in 6 patients showed involvement of the middle cerebral artery.In 8 cases of ALL complicated with AIS, the event occurred during induction therapy, which was considered associated with the use of Asparaginase and intrathecal Cytarabine.Anticoagulation was the main treatment.Symptoms resolved in 10 cases, 3 had neurologic sequelae, and 1 died.Conclusions:AIS complicating acute leukemia in children is often the first clinical manifestation of hemiparesis, which mainly occurs in the process of induction therapy, and may be related to the adverse reactions of chemotherapy drugs such as hypercoagulable state of the blood caused by mendonuclease and insufficient cerebral perfusion caused by intrathecal injection of Cytarabine, etc.; once hemiplegic neurological symptoms appear in the process of induction therapy of children′s acute leukemia, it is highly suspicious of the concomitant AIS, and earlycranial magnetic resonance examination can help to clarify the diagnosis.Although most symptoms resolve with treatment, some patients may develop neurological sequelae.

OBJECTIVE To explore the potential mechanisms of forkhead box protein A1(FOXA1)in benzo[a]pyrene(BaP)-induced carcinogenesis by investigating the effect of FOXA1 by knockout on microRNA(miRNA)expression profiles in BaP malignant transformed cells THBEc1 and establishing regulatory networks between FOXA1,miRNA and their target genes.METHODS FOXA1 knockout THBEc1 cells THBEc1-ΔFOXA1-c34 and control cells THBEc1-ctrl were used as study models.Western blotting was employed to determine FOXA1 protein expression levels.Next-generation sequencing(NGS)tech-nology was used to identify differentially expressed miRNAs between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells,with subsequent validation by RT-qPCR.Five databases(ENCORI,miRDB,mirDIP,miRWalk and TargetScan 8.0)were used in conjunction with NGS results of mRNA between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl to predict different expressed genes(DEGs)regulated by the identified differentially expressed miRNAs.GO and KEGG enrichment analyses were conducted on the DEGs using the DAVID database.Interaction network analysis of the proteins encoded by the DEGs was performed using STRING 12.0 and Cytoscape 3.10.2 software.RESULTS No FOXA1 expression was detected in THBEc1-ΔFOXA1-c34 cells.A differential analysis of miRNA expressions revealed 33 miRNAs with a fold change of＞2 or＜0.5 and a false discovery rate of＜0.05 between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells,13 of which were down-regulated and 20 were up-regulated in THBEc1-ΔFOXA1-c34 cells.A regulatory network was formed by 11 down-regulated miRNAs and 32 up-regulated mRNAs,while a second network included 16 up-regulated miRNAs and 56 down-regulated mRNAs.The 27 differentially expressed miRNAs participated in various biological processes through the regulation of 88 DEGs,primarily associated with cell growth,proliferation,migration,apoptosis,angiogenesis,epithe-lial-mesenchymal transition,and signal transduction(TGF-β,Hippo,NF-kappa B and MAPK pathways).CONCLUSION The miRNA expression profile in BaP-malignant transformed THBEc1 cells is altered following FOXA1 knockout that may disrupt TGF-β and MAPK signaling pathways by changing miRNA expression levels,thereby inhibiting cell proliferation and migration.

Objective:To analyze the clinical characteristics of acute leukemia complicated with arterial ischemic stroke (AIS) in children, and to provide a reference for its diagnosis, treatment, and prognosis.Methods:Case summary.This report presents three children with acute leukemia complicated with AIS admitted to the First Affiliated Hospital of Zhengzhou University from April 2015 to August 2024, and reviews the relevant literature at home and abroad to analyze the clinical characteristics, pathogenesis, and treatment of the disease.Results:All three cases were female, aged 4-14 years; two had acute lymphoblastic leukemia (ALL) and one had acute myeloid leukemia (AML). Hemiparesis was the main presenting symptom in all cases, occurring during induction therapy.Symptoms resolved completely after anticoagulant and symptomatic treatment, with no sequelae and good prognoses.A literature search identified 8 reported cases of pediatric acute leukemia complicated with AIS.Combining these with our 3 cases yielded a total of 11 cases: 5 males and 6 females; median age 7 years (range 2-15 years); 8 with ALL and 3 with AML.Clinically, all presented with hemiparesis.Vascular imaging in 6 patients showed involvement of the middle cerebral artery.In 8 cases of ALL complicated with AIS, the event occurred during induction therapy, which was considered associated with the use of Asparaginase and intrathecal Cytarabine.Anticoagulation was the main treatment.Symptoms resolved in 10 cases, 3 had neurologic sequelae, and 1 died.Conclusions:AIS complicating acute leukemia in children is often the first clinical manifestation of hemiparesis, which mainly occurs in the process of induction therapy, and may be related to the adverse reactions of chemotherapy drugs such as hypercoagulable state of the blood caused by mendonuclease and insufficient cerebral perfusion caused by intrathecal injection of Cytarabine, etc.; once hemiplegic neurological symptoms appear in the process of induction therapy of children′s acute leukemia, it is highly suspicious of the concomitant AIS, and earlycranial magnetic resonance examination can help to clarify the diagnosis.Although most symptoms resolve with treatment, some patients may develop neurological sequelae.

OBJECTIVE To establish an in vitro simulated one compartment extravascular adminis-tration model with lanthanum nitrate as the test substance,and explore the differences between this model and the classic in vitro administration model in lanthanum nitrate induced HepG2 cell death.METHODS An in vitro administration device was designed based on compartment model theories which consisted of four functional chambers:the liquid storage chamber,mixing chamber,toxicant exposure chamber,and waste liquid receiving chamber.The four chambers were connected by peristaltic pump hoses.The peristaltic pumps were employed to ensure unidirectional and constant speed trans-mission of liquid between these chambers.According to the preset toxicokinetic parameters such as T1/2a and T1/2,an in vitro simulated one compartment extravascular administration model of lanthanum nitrate was constructed using the device.The content of lanthanum nitrate in the toxicant exposure chamber at different time points was measured using inductively coupled plasma mass spectrometry.The concentration-time curves of lanthanum nitrate were analyzed using PKsolver and GraphPad Prism 8.0 software.The constructed in vitro simulated one compartment extravascular administration model was evaluated by comparing the measured and theoretical values of toxicokinetic parameters.HepG2 cells were treated with lanthanum nitrate in the in vitro simulated one compartment extravascular administration model and classic in vitro administration model,respectively,and cell death was measured using the Hoechst 33342/propidium iodide staining method.RESULTS Within the Cmax range of 3.91-1 000.00 μmol·L-1,the measured concentration-time curves of lanthanum nitrate in the toxicant expo-sure chamber almost conformed with the corresponding calculated theoretical curves(the correlation coefficients were all>0.998 0).The measured values of toxicokinetic parameters,including Ke,T1/2,Ka,T1/2a,Tmax,Cmax,CL and AUC0-∞,were close to the corresponding theoretical values.The fitting coeffi-cients(R2)of the concentration-time curves for each experimental group were all>0.990 0,which was consistent with one compartment model for extravascular administration.In the simulated one compart-ment extravascular administration model,no significant death of HepG2 cells was observed in any lanthanum nitrate dose group.In the classic in vitro administration model,the cell death rate of the 0.500 mmol·L-1 lanthanum nitrate group was higher than that of the solvent control group,but no significant cell death was observed in the 0.119 mmol·L-1 group or 0.243 mmol·L-1 group.When Cmax or Cadministration was 0.500 mmol·L-1,classic in vitro administration induced a higher cell death rate than simulated one compart-ment extravascular administration.However,there was no statistically significant difference in lanthanum nitrate induced HepG2 cell death between the two administration models when the AUC was equal.CONCLUSION The device designed in this study can be used to in vitro simulate one compartment extravascular administration,making in vitro toxicity testing more similar to in vivo scenarios,and providing data for optimizing administration methods of in vitro toxicity testing.There are differences in lanthanum nitrate induced HepG2 cell death between simulated one compartment extravascular administration and classic in vitro administration,indicating that different in vitro exposure modes can affect toxicity.

Objective:To investigate the safety and short-term efficacy of yttrium-90 [ 90Y] resin microspheres transarterial radioembolization (TARE) for the treatment of initial unresectable malignant hepatic tumor. Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 10 patients with initial unresectable malignant hepatic tumor who were admitted to The First Affiliated Hospital of Army Medical University from June 2022 to June 2023 were collected. All patients were males, aged (57±4)years. Measurement data with normal distribution were represented as Mean± SD, and comparison before and after treatment within the group was conducted using the paired t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and comparison before and after treatment within the group was conducted using the paired rank sum test. Count data were described as absolute numbers or proportions. Results:(1) Pre-treatment assessment. All 10 patients completed pre-treatment assessment, with 8 cases undergoing once of technetium 99-polymerised protein perfusion test and 2 cases under-going ≥ twice of technetium 99-polymerised protein perfusion test. The ratio of uptake of techne-tium 99-polymerised protein in tumor tissue to normal tissue, the hepatopulmonary shunting ratio and the therapeutic requirement of 90Y resin microspheres in 10 patients were 5.8±1.2, 4.8%±0.8% and (1.10±0.20)GBq, respectively. (2) Treatment strategy of 90Y resin microspheres TARE. Of the 10 patients, cases treated with whole tumor radioembolisation, radioembolisation of the main target lesion+non-target lesion radiofrequency ablation, radioembolisation of the main target lesion+non-target lesion iodine-125 particles implantation, radioembolisation of the liver lobe or liver segment were 6, 2, 1, 1, respectively. During the treatment period, one elderly case did not receive target therapy combined with immunotherapy due to intolerance, and the remaining 9 cases received target therapy combined with immunotherapy. Of the 10 patients, there were 7 cases receiving once of 90Y resin microspheres TARE, and 3 cases receiving twice of 90Y resin microspheres TARE. (3) Follow-up. All 10 patients were followed up for 4.5(range, 3.0-12.0)months. During the follow-up, none of patient had adverse event associated with 90Y resin microspheres TARE. The tumor diameter, alpha-fetoprotein (AFP), abnormal prothrombin, alanine aminotransferase (ALT), aspartate amino-transferase (AST), albumin (Alb), total bilirubin (TBiL), glutamyltransferase (GGT) of the 10 patients were 96(72,135)mm, 26(6,833)μg/L, 290(56,2 997)Au/L, (36±13)IU/L, (41+16)IU/L, (40±4)g/L, (15.3±4.1)μmol/L, (99±68)IU/L before receiving 90Y microspheres TARE. The above indicators of the 10 patients were 63(43,97)mm, 4(3,357)μg/L, 38(25, 142) Au/L, (40±16)IU/L, (51±28)IU/L, (39±4)g/L, (14.4±1.2) μmol/L, (134±93)IU/L after 90 days of receiving 90Y microspheres TARE. There were significant differences in tumor diameter and abnormal prothrombin ( Z=-2.08, -2.24, P<0.05) and there was no significant difference in AFP, ALT, AST, Alb, TBil, GGT ( Z=-1.27, t=0.63, 1.69, 1.73, 0.67, 1.30, P>0.05). During the follow-up period, 5 cases achieved clinical complete response, 4 cases achieved clinical partial remission, and 1 case experienced non-target lesion progression within 30 days after receiving 90Y resin microspheres TARE. The disease remission rate and disease control rate of the 10 patients were 9/10 and 9/10, respectively. None of patient died during follow-up period. Conclusion:90Y resin microspheres TARE for the treatment of initial unresectable malignant hepatic tumor is safe and feasible, and can achieve satisfactory short-term efficacy when combined with other treatment methods.

Primary hepatic cancer is one of the major problems that need to be solved urgently in the field of public health, seriously endangering the life and health of Chinese people. Its treatment mode is multidisciplinary participation and synergy of multiple therapeutic methods. Even though there are many common clinical treatments for liver cancer in China, its therapeutic outcome is still unsatisfactory. yttrium-90 has been applied for more than 20 years, and a large amount of foreign clinical data have been accumulated. Combining the latest literature and clinical practice, the authors describe the clinical application and research progress of yttrium-90 micro-sphere selective internal radiation therapy in primary liver cancer.