Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; alpha-Synuclein/metabolism* ; Male ; Prefrontal Cortex/drug effects* ; Rats, Sprague-Dawley ; Depression/metabolism* ; MAP Kinase Signaling System/drug effects* ; Rats ; Parkinson Disease/metabolism* ; Receptor, trkB/metabolism* ; Phosphorylation ; Disease Models, Animal ; Signal Transduction

Objective To evaluate the relationship between anxiety levels and clinicopathological characteristics in patients with papillary thyroid carcinoma (PTC). Methods Among the patients who underwent surgical treatment in our center from July 2022 to September 2023, 304 patients completed the Hamilton anxiety rating scale (HAM-A) questionnaire. The clinical and pathological characteristics of these patients and their association with anxiety levels were investigated. Results Among the 304 patients, 271 were pathologically confirmed to have PTC. Of the 271 patients, 75 had higher levels of anxiety (according to HAM-A scoring system, a score ≥14 indicates clinically significant anxiety) and were assigned to the anxiety group. Univariate statistical analysis showed that the proportion of patients with elevated thyroid peroxidase antibody (TPOAb) in the anxiety group was higher than that in the non-anxiety group (34.7% vs. 16.8%, P=0.002 4). Moreover, the proportion of patients with multifocal tumors in the anxiety group was also higher than that in the non-anxiety group (33.3% vs. 16.7%, P=0.004 4). Multivariate Logistic regression confirmed that anxiety levels were associated with elevated TPOAb (P=0.005 6) and tumor multifocality (P=0.001 9). Conclusions Anxiety levels may be related to elevated TPOAb and tumor multifocality in PTC patients.

Objective:To study the inhibitory effects and mechanism of Armeniacae Semen Amarum alcohol extract in melanogenesis in zebrafish embryos.Methods:48 HPF healthy zebrafish embryos were randomly divided into blank control group, arbutin group, high-, medium- and low-dosage groups. The blank control group was added with 6 ml embryo culture medium, the arbutin group was added with 8 000 μg/ml arbutin solution 6 ml, and the high-, medium- and low-dosage groups were added with 2 925, 1 950 and 1 300 μg/ml Armeniacae Semen Amarum alcohol extract, respectively. After 24 hours of intervention, the melanin area of zebrafish embryos was observed by stereomicroscope, and the inhibition rate of ethanol extract of bitter almond on tyrosinase (TYR) activity and melanin content in zebrafish embryos were detected by spectrophotometry; the antioxidant activity was evaluated by DPPH radical scavenging capacity, ABTS radical scavenging capacity and CAT activity. RT-qPCR was used to detect the mRNA levels of MITF, Tyr and TYRP2 in zebrafish embryos.Results:Compared with the arbutin group, the low-, medium-, and high-dosage groups showed an increase in melanin area ( P<0.01 or P<0.05), a decrease in TYR activity and melanin content inhibition rate ( P<0.01), and IC50 values for DPPH and ABTS free radical scavenging rates of 23.636 and 3.195 mg/ml, respectively. The CAT activity increased in the medium- and high-dosage groups ( P<0.05 or P<0.01), while the mRNA levels of TYR and MITF decreased in the low-, medium-, and high-dosage groups ( P<0.01). Conclusion:Armeniacae Semen Amarum alcohol extract can effectively inhibit the production of melanin in zebrafish embryos, and its mechanism may be closely related to TYR activity and MITF related signaling pathway.

Objective To analyze the auxiliary diagnostic effect of oral cone beam computed tomography(CBCT)in root canal treatment of flight personnel.Methods Eighty flight personnel who underwent root canal treatment in Qingdao Special Service Rehabilitation Center of the Navy from February 2020 to February 2022 were enrolled in this study.All the patients received X-ray examination and oral CBCT.The number of detected root canals,root canal localization,and root canal treatment were analyzed.Results There were 235 root canals in the 80 patients.The detection rate of oral CBCT was significantly higher than that of X-ray examination(94.47%vs 87.66%,P<0.05).A total of 206 root canals were detected by both detection methods,and the Kappa value for consistency in the number of root canals detected was 0.643(P<0.05).The successful rate of root canal negotiation assisted by oral CBCT was significantly higher than that of X-ray examination(90.64%vs 82.98%,P<0.05).Conclusion Oral CBCT can effectively assist in the detection of complex root canals,increase the number of detected root canals and assist in the location of the root canals,check the calcification of root canals,and guide root canal negotiation,which provide a guarantee for complex root canal treatment of flight personnel.

BackgroundPrevention and intervention of procrastination in college students are of great practical significance， and studies have illustrated a pairwise correlation among mindfulness， self-control， insecure attachment and procrastination， whereas the mechanism by which insecure attachment leads to procrastination remains unclear， and the related mediation path is quite understudied. ObjectiveTo investigate the effect of insecure attachment on procrastination among college students and the pathway of mindfulness and self-control， so as to inform the design of interventions for procrastination among college students. MethodsRandom and cluster sampling method were utilized to enroll 514 college students from 4 colleges in Guangdong Province From February to April 2023. Subjects were assessed using Irrational Procrastination Scale （IPS）， Adult Attachment Scale （AAS）， Mindful Attention Awareness Scale （MAAS） and Brief Self-Control Scale （BSCS）. Pearson correlation analysis were adopted to identify the correlation among above scales， and the mediation effect was examined via Bootstrap procedure. ResultsAAS score was positively correlated with IPS score （r=0.382， P<0.01）， and negatively correlated with MAAS and BSCS scores （r=-0.242， -0.353， P<0.01）. IPS score was negatively correlated with MAAS and BSCS scores （r=-0.314， -0.682， P<0.01）. MAAS score was positively correlated with BSCS score （r=0.439， P<0.01）. Insecure attachment positively predicted procrastination （β=0.377， P<0.01）， and the prediction of procrastination by insecure attachment was mediated by self-control， with an indirect effect value of 0.163 （95% CI： 0.105~0.223）， accounting for 43.24% of the total effect value. The mindfulness and self-control exerted a chained mediation effect on the relationship between insecure attachment and procrastination， and the indirect effect value was 0.056 （95% CI： 0.028~0.089）， accounting for 14.85% of the total effect value. ConclusionInsecure attachment can influence procrastination among college students both directly and indirectly through the single mediation of self-control or the chained mediation of mindfulness and self-control. ［Funded by 2023 National College Student Innovation and Entrepreneurship Training Program （number， 202310570023）］

BACKGROUND:The combination of good biomechanical properties,controlled drug release and multi-functionality of core-shell structured nanofibers is receiving more and more attention,which also makes them promising for a wide range of applications in the field of oral tissue regeneration. OBJECTIVE:To summarize the preparation,drug loading and release mechanisms of core-shell structured nanofibers and their application in the regenerative repair of oral tissues. METHODS:A computer search of the literature collected in CNKI and PubMed from January 2000 to November 2022 was applied,and the search terms in English and Chinese were"electrospinning,core-shell structures,drug delivery systems,jaw bone regeneration,cartilage regeneration,periodontal tissue regeneration". RESULTS AND CONCLUSION:(1)There are various methods for the preparation of core-shell structured nanofibers,but the coaxial and emulsion methods of electrostatic spinning have unique advantages such as simple operation,diverse material selection and good biocompatibility.(2)Core-shell structured nanofibers can be used as bacteriostatic agents,carriers of different types of drugs,and scaffolds for cell adhesion,providing new therapeutic options for oral tissue regeneration.(3)Controlled degradation and drug release rate of core-shell structured nanofibers can better adapt to the healing process of oral tissue defect repair and achieve ideal tissue regeneration.

Background A large amount of iron deposition in the brain can cause neuronal damage by inducing oxidative stress, neuroinflammation, and abnormal mitochondrial function. In addition, iron deposition is also reported to be closely related to the pathogenesis of Alzheimer's disease (AD). The neurofibrillary tangles aggregated by tau hyperphosphorylation are one of the important pathological features of AD. Objective To investigate potential effect of exogenous trivalent iron ions on neuronal activity in human neuroblastoma (SH-SY5Y) cells and tau hyperphosphorylation and aggregation. Methods SH-SY5Y cells were treated with ferric chloride (FeCl₃) at four concentrations (10, 100, 200, and 400 mg·L⁻¹). Cell survival rate was then detected by CCK8 assay. Intracellular iron content was determined prussian blue (Perl's) by iron staining after 24 h exposure to FeCl₃ at 10 or 200 mg·L⁻¹. Transfection of tau-P301L plasmid was conducted to construct an AD-like cell model for tau overexpression. The differences in the expression of the phosphorylated tau (p-tau) protein in SH-SY5Y cells and SH-SY5Y cells with tau overexpression were detected by Western blotting after 24 h exposure to FeCl₃ at 10 and 200 mg·L⁻¹. After dilution with phosphate buffered saline (PBS), FeCl₃, human tauR3, and FeCl₃ + tauR3 were incubated at 37℃, and the fluorescence intensity reflecting tau aggregation level was measured by thioflavin T(ThT) method at 12, 24, 36, 48, 60, 72, 84, and 96 h, respectively. Meanwhile, after 96 h coincubation of FeCl₃ and tauR3, the fibers formed by tau aggregation were observed under a transmission electron microscope (TEM). Results After 24 h of FeCl₃ exposure, the cell survival rate of SH-SY5Y cells among all groups was statistically different (F=8.63, P<0.01). The cell survival rates in the 200 and 400 mg·L⁻¹ groups were 80.1% and 68.7% of the control group, respectively (P<0.05). Compared with the control group, the nuclei of the 200 mg·L⁻¹ FeCl₃ group were mainly yellowish-brown after iron staining and the positive cell rate was up-regulated by 12.9% (P<0.01). After 24 h of FeCl₃ exposure , the p-tau (Ser396) protein expression was statistically different among all groups (F=11.6, P<0.01). Compared with the control group, the p-tau protein expression level of SH-SY5Y cells in the 200 mg·L⁻¹ group was up-regulated by 72.7% (P<0.01). After FeCl₃-treated SH-SY5Y cells with tau overexpression for 24 h, the p-tau (Ser396) protein expression was statistically different among all groups (F=27.8, P<0.01). Compared with the tau group, the p-tau (Ser396) protein expression level of SH-SY5Y cells in the tau + 200 mg·L⁻¹ group was up-regulated by 44.6% (P<0.05). Compared with the tauR3 group, the fluorescence intensities in the 84 and 96 h tauR3 + FeCl₃ groups were up-regulated by 49.9% and 53.7% (P<0.01) respectively. After 96 h of coincubation, compared with the tauR3 group, FeCl₃ + tauR3 aggravated tau aggregation and formed fiber deposition under TEM. Conclusion Exogenous trivalent iron ions may inhibit SH-SY5Y cell viability, promote the phosphorylation of tau in SH-SY5Y cells transfected with tau-P301L plasmid, and aggravate tauR3 aggregation and fiber production.

Objective To investigate the value of HALP score in evaluating the prognosis of patients with hepatocellular carcinoma (HCC) after hepatectomy and whether the nomogram based on HALP score could effectively predict the postoperative survival of patients. Methods A retrospective study was performed for the clinical data of 253 HCC patients who underwent surgical treatment in Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, from July 2013 to March 2020. The receiver operating characteristic (ROC) curve was plotted to calculate the optimal cut-off values of HALP score and other related indicators; the chi-square test was used to investigate the association between HALP score and clinicopathological features; the Kaplan-Meier method was used to plot survival curves, and the Log-rank test method was used for comparison. The univariate and multivariate Cox regression analyses were used to investigate the association of HALP score and other clinical parameters with the prognosis of patients. R3.6 was used to establish a nomogram; C-index and calibration curve were used to evaluate the predictive ability of the nomogram, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to compare predictive ability between the nomogram model and the conventional model. Results The Kaplan-Meier analysis showed that the high HALP group had significantly better overall survival (OS) and recurrence-free survival (RFS) than the low HALP group ( P < 0.001). The univariate Cox regression analysis showed that white blood cell count, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), alpha-fetoprotein (AFP), surgical approach, microvascular invasion, TNM stage, degree of tumor differentiation, HALP, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) were significantly associated with OS (all P < 0.05). The variables with statistical significance in the univariate Cox regression analysis were included in the multivariate Cox regression analysis, and the results showed that ALP, AST/ALT ratio, ALP, AFP, degree of tumor differentiation, and TNM stage were independent influencing factors for OS after surgery in HCC patients (all P < 0.05). The univariate Cox regression analysis showed that GGT, ALP, AFP, microvascular invasion, TNM stage, degree of tumor differentiation, HALP, AST/ALT ratio, NLR, and MLR were significantly associated with RFS (all P < 0.05), and the multivariate Cox regression analysis showed that HALP, AST/ALT ratio, NLR, ALP, AFP, and TNM stage were independent influencing factors for RFS after surgery in HCC patients (all P < 0.05). The nomograms for OS and RFS of HCC patients were established based on the multivariate analysis. The nomogram for OS had a C-index of 0.732 (95% confidence interval [ CI ]: 0.691-0.774) and an area under the ROC curve of 0.795, 0.791, and 0.775, respectively, in predicting 1-, 3-, and 5-year survival rates, and the nomogram for RFS had a C-index of 0.677 (95% CI : 0.637-0.717) and an area under the ROC curve of 0.742, 0.733, and 0.716, respectively, in predicting 1-, 3-, and 5-year survival rates. The calibration curves of 1-, 3-, and 5-year OS were well fitted to those of 1-, 3-, and 5-year RFS. Conclusion A low level of HALP before surgery is a predictive factor for poor long-term prognosis in HCC patients undergoing surgical treatment, and the nomogram model based on HALP score is superior to the BCLC staging model and can better predict the prognosis of HCC.

Objective:To evaluate the efficacy and safety of hippocampal avoidance whole-brain irradiation with simultaneous integrated boost in the treatment of brain metastases of lung cancer.Methods:Forty lung cancer patients with brain metastases who received whole-brain radiotherapy with simultaneous integrated boost and hippocampal avoidance in Cancer Hospital, Chinese Academy of Medical Sciences from 2014 to 2020 were enrolled in this study. Brain MRI, survival follow-up and evaluation of side effects were performed before radiotherapy and at 1, 3, 6 and 12 months after radiotherapy, respectively. Overall survival (OS), progression-free survival (PFS) and changes in cognitive function were analyzed. Continuous data were described as Mean ± SD. Categorical data were described by frequency and composition ratio or percentage. Survival analysis was conducted by Kaplan-Meier method. Influencing factors of survival were identified by univariate and multivariate Cox's regression analyses.Results:A total of 40 patients were enrolled in the study. The median follow-up time was 14.2 months and the median OS, PFS and intracranial PFS of all patients were 14.8 months, 6.7 months and 14.8 months, respectively. Multivariate analysis showed that male gender and newly diagnosed stage Ⅳ disease were associated with worse OS and PFS, respectively. The Hopkins verbal learning test-revised (HVLT-R) scores at baseline and 1, 3 and 6 months after radiotherapy were 21.94±2.99, 20.88±3.12, 20.03±3.14, and 19.78±2.98, respectively. The HVLT-R score at 6 months after radiotherapy was decreased by approximately 9.8% compared with the baseline. No grade 3 or above toxic and side effect occurred in the entire cohort.Conclusion:Hippocampal avoidance whole-brain irradiation with simultaneous integrated boost is a safe and effective treatment for brain metastases of lung cancer, which is expected to reduce the impact of radiotherapy on cognitive function.