ObjectiveTo investigate the inhibitory effect of Biejiajian Pills （BJJW） on the growth of liver cancer， as well as its potential mechanism in mediating the AMP-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） pathway through mitochondrial energy metabolism. MethodsHuman hepatoma Huh7 cells were used to establish a nude mouse model of subcutaneous xenograft tumor. A total of 18 tumor-bearing nude mice were randomly divided into model group， BJJW group （2.2 g/kg）， and metformin group （250 mg/kg）， and the corresponding drug was given by gavage for 14 consecutive days. Tumor volume and weight were monitored during the experiment； HE staining was used to observe histopathological changes； the levels of reactive oxygen species （ROS） and adenosine triphosphate （ATP） in tumor tissue were measured； immunohistochemistry and Western blotting were used to measure the expression levels of proteins associated with the AMPK/mTOR pathway. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Tukey’s test was used for further comparison between two groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups， and the Dunn’s test was used for further comparison between two groups. ResultsCompared with the model group， the BJJW group had a tumor inhibition rate of 45.73%， with significant reductions in both tumor volume and weight （P<0.01）. Pathological examination showed that compared with the model group， the BJJW group had a significant reduction in the number of tumor cells and the presence of extensive necrosis. Mechanistic studies showed that compared with the model group， the BJJW group had a significant increase in ROS level （P<0.001） and a significant reduction in ATP level （P<0.001）， as well as significant increases in p-AMPK/AMPK ratio （0.81±0.20 vs 0.13±0.04， P<0.01） and p-ULK1/ULK1 ratio （0.69±0.17 vs 0.18±0.13， P<0.01） and a significant reduction in p-mTOR/mTOR ratio （1.34±0.16 vs 3.20±0.62， P<0.01）. ConclusionBJJW may inhibit the growth of liver cancer by inducing mitochondrial energy metabolism dysfunction， increasing the level of ROS， reducing the level of ATP， and activating the AMPK/mTOR signaling pathway.

BACKGROUND: Preclinical studies have indicated that Angong Niuhuang Pills (ANP) reduce cerebral infarct and edema volumes. This study aimed to investigate whether ANP safely reduces cerebral infarct and edema volumes in patients with moderate to severe acute ischemic stroke. METHODS: This randomized, double-blind, placebo-controlled pilot trial included patients with acute ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores ranging from 10 to 20 in 17 centers in China between April 2021 and July 2022. Patients were allocated within 36 h after onset via block randomization to receive ANP or placebo (3 g/day for 5 days). The primary outcomes were changes in cerebral infarct and edema volumes after 14 days of treatment. The primary safety outcome was severe adverse events (SAEs) for 90 days. RESULTS: There were 57 and 60 patients finally included in the ANP and placebo groups, respectively for modified intention-to-treat analysis. The median age was 66.0 years, and the median NIHSS score at baseline was 12.0. The changes in cerebral infarct volume at day 14 were 0.3 mL and 0.4 mL in the ANP and placebo groups, respectively (median difference: -7.1 mL; interquartile range [IQR]: -18.3 to 2.3 mL, P = 0.30). The changes in cerebral edema volume of the ANP and placebo groups on day 14 were 11.4 mL and 4.0 mL, respectively ( median difference: 3.0 mL, IQR: -1.3 to 9.9 mL, P = 0.15). The rates of SAE within 90 days were similar in the ANP (3/57, 5%) and placebo (7/60, 12%) groups ( P = 0.36). Changes in serum mercury and arsenic concentrations were comparable. In patients with large artery atherosclerosis, ANP reduced the cerebral infarct volume at 14 days (median difference: -12.3 mL; IQR: -27.7 to -0.3 mL, P = 0.03). CONCLUSIONS: ANP showed a similar safety profile to placebo and non-significant tendency to reduce cerebral infarct volume in patients with moderate-to-severe stroke. Further studies are warranted to assess the efficacy of ANP in reducing cerebral infarcts and improving clinical prognosis. TRAIL REGISTRATION Clinicaltrials.gov , No. NCT04475328.
Aged ; Female ; Humans ; Male ; Middle Aged ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Ischemic Stroke/drug therapy* ; Pilot Projects ; Stroke/drug therapy* ; Treatment Outcome

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

While multiple step saccades (MSS) are occasionally reported in the healthy population, they are more evident in patients with Parkinson's disease (PD). Therefore, MSS has been suggested as a biological marker for the diagnosis of PD. However, the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic. We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades. Accordingly, brain regions involved in saccadic planning and execution might play a role in the generation of MSS. To test this hypothesis, we explored the role of the prefrontal (PFC) and posterior parietal cortex (PPC) in generating MSS by conducting two experiments: electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task. We found that the PFC and PPC are involved in the generation of MSS.
Humans ; Parietal Lobe/physiology* ; Saccades/physiology* ; Prefrontal Cortex/physiology* ; Male ; Transcranial Magnetic Stimulation ; Female ; Electroencephalography ; Adult ; Young Adult

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*

Objective To assess the exposure levels of heavy metals,including lead,arsenic,mercury,and cadmium,in the local population in Sichuan and Chongqing,China,to compare and analyze the differences in reference intervals(RIs)obtained from direct and indirect sampling methods,and to explore the interchangeability and limitations of these two sampling methods.Methods RIs were obtained by the direct sampling method and the indirect sampling method.In the direct sample method,the levels of blood arsenic,urinary cadmium,urinary mercury,and blood lead levels of 5562 healthy participants aged 22-50 years in Sichuan and Chongqing,China were measured by atomic absorption spectrometry and inductively coupled plasma-mass spectrometry.Using the human biomonitoring(HBM)data,we established RIs for the population by a nonparametric method.On the other hand,in the indirect sampling method,RIs were established via a nonparametric method based on data from the laboratory information system(LIS)of a local hospital after stratifying healthy individuals using a Gaussian mixture model(GMM).Comparative analysis of the RIs derived from the two sampling methods were then conducted.Results The RI for blood arsenic was 0.11-1.3 μmol/L.The RI for urinary cadmium was 0.51-2.80 μmol/mol creatine for adults aged 22 to under 43 years and 0.66-2.96 μmol/mol creatine for adults aged 43-50 years.The RI for urinary mercury was 0.12-1.10 μmol/mol creatine.The RI for blood lead was 14.00-47.00 pg/L for adults aged 22 to under 41 year,16.00-53.38 pg/L for males aged 41-50 year,and 15.00-51.02 pg/L for females aged 41-50 year.Most of the RIs established by the direct sampling method had a narrower range compared to those established by the indirect sampling method,and the RIs established by both sampling methods were partially biased.Conclusions The RIs for blood arsenic,urine cadmium,urine mercury,and blood lead in healthy individuals aged 22-50 years in Sichuan and Chongqing,China were established using both direct and indirect sampling methods,which contributes to a better understanding of environmental exposure to metals in the general population and provides a reference for metal poisoning.For data from the same lab,the GMM-based indirect sampling method demonstrated relatively consistent performance in establishing RIs compared with the direct sampling method.

Objective To explore the relationship between the duration of breastfeeding and re-fractive error in preschool children.Methods A cross-sectional survey was conducted to investigate the visual acuity of 2,915 preschool children aged 3 to 6 years using a questionnaire.Results After adjusting for potential confounding factors such as parental education level,premature birth,birth weight,family structure,only-child status,screen-watching,outdoor activity time,and sleep time u-sing a Logistic regression equation,compared with a breastfeeding duration of less than 6 months,a breastfeeding duration of 6 to 12 months(OR=0.683,95％CI:0.516 to 0.903)and＞12 months(OR=0.628,95％CI:0.451 to 0.874)were found to be protective factors against refractive error.Further stratified analysis revealed that a breastfeeding duration of 6 to 12 months(OR=0.640,95％CI:0.459 to 0.892)and＞12 months(OR=0.519,95％CI:0.347 to 0.777)had a protective effect on the visual acuity of preschool children aged 3 to 4 years.Conclusion The duration of breastfeed-ing is a protective factor against refractive error in preschool children aged 3 to 4 years,and prolonging the duration of breastfeeding is beneficial for reducing the occurrence of refractive error.

Objective To explore the role of an artificial intelligence(AI)model based on real-time object detection network in fetal facial ultrasound examination.Methods With the normal fetal facial ultrasound standard plane(FFUSP)at 20-24 weeks of gestation as the research object,a FFUSP recognition model based on real-time object detection network was constructed.The recognition accuracy of the model for FFUSP and the anatomical structures were analyzed,and the clinical value was evaluated by analyzing its performance in identifying FFUSP in 119 cases of fetal ultrasound images.Results The overall precision,recall rate,mAP@.5 and mAP@.5:.95 of the AI model were 97.8%,98.5%,98.1%and 61.0%,respectively.The clinical validation showed that the AI model had a sensitivity,specificity,positive predictive value,negative predictive value and accuracy of 100.0%,98.5%,87.4%,100.0%and 98.7%for facial anatomy recognition,and the results were highly consistent with the classification of fetal ultrasound experts(k=0.925,P<0.001).The recognition accuracy of the model for 3 types of standard planes reached 100%;and the average speed of dynamic video detection was 33.93 frames per second.Conclusion The FFUSP recognition model based on real-time object detection network exhibits excellent performance,and it can be applied to real-time ultrasound diagnosis,teaching and intelligent quality evaluation.

Objective To investigate the effects of a disintegrin and metalloprotease domain 10(ADAM10)inhibitor on synaptic structure and blood-brain barrier(BBB)permeability in rats with autism-like behavior.Methods A total of 50 male offspring rats with prenatal exposure to valproic acid(VPA)to induce autism-like behavior were randomly divided into VPA group and ADAM 10 inhibitor,TAT-Pro-ADAM10(709-729)group(TAT-Pro group),with 25 rats in each group.And another 25 offspring male rats induced by normal saline during pregnancy served as control group(CON group).The TAT-Pro group was given intraperitoneal injection on postnatal day 20 with 3 nmol/g TAT-Pro-ADAM10(709-729),and equal volumes of normal saline were given to the CON and VPA groups.The changes of body mass and tail length of offspring rats were measured and recorded during modeling.Western blotting was performed to detect the protein levels of ADAM10,vascular endothelial cadherin(VE-Cad),Occludin,zonula occludens-1(ZO-1),post-synaptic density protein-95(PSD95),and synaptophysin(SYN)in the hippocampal tissue of the offspring rats in 24 h after administration.The expression of ZO-1 protein was further verified by immunofluorescence assay.Behavioral tests were conducted from postnatal day 24,including open field,grooming,three-chamber social interaction,and water maze tests.The density of dendritic spines in hippocampal tissue in the offspring rats on postnatal day 28 was detected by Golgi staining.Results Compared with the VPA group,the TAT-Pro group showed no significant changes in body weight and tail length,but significantly improved repetitive stereotyped behaviors,social skills and learning memory ability(P＜0.05),reduced protein levels of ADAM10 and PSD95 in hippocampal tissues(P＜0.05),and elevated levels of VE-cad and Occludin(P＜0.05).The density of dendritic spines was significantly reduced(P＜0.05),and the number of immature dendritic spines also decreased in the TAT-Pro group than the VPA group.Conclusion Inhibition of ADAM10 overexpression during the critical period of synaptic development can alleviate learning and memory dysfunctions in VPA-induced rats with autism-like behavior,and has a certain restorative effect on abnormal synaptic structures and blood-brain barrier permeability.