Objectives:To explore the antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)—NP@Pt(Ⅳ) in ovarian cancer.Methods:Redox-responsive polymer carriers were synthesized. Polymer carriers and platinum(Ⅳ)—Pt(Ⅳ) can self-assemble into NP@Pt(Ⅳ). Inductively coupled plasma mass spectrometry was performed to detect the platinum release from NP@Pt(Ⅳ) in reducing environment and the platinum content in ovarian cancer cells ES2 treated with cisplatin, Pt(Ⅳ) and NP@Pt(Ⅳ). The proliferation ability of the ovarian cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was assessed by flow cytometry. Collection of primary ovarian cancer tissues from patients with primary high-grade serous ovarian cancer who were surgically treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from October to December 2022. The high-grade serous ovarian cancer patient-derived xenograft (PDX) mice were intravenously injected with Cy7.5 labeled NP@Pt(Ⅳ) followed by in vivo imaging system. Mice were treated with PBS, cisplatin and NP@Pt(Ⅳ). Tumor volume and weight were measured in each group. Necrosis, apoptosis and cell proliferation of tumor tissues were detected by hematoxylin-eosin (HE) staining, TUNEL fluorescence staining and Ki-67 immunohistochemistry staining. Body weight and HE staining of heart, liver, spleen, lung and kidney of mice in each group were measured.Results:The platinum release of NP@Pt(Ⅳ) after 48 hours in reducing environment was 76.29%, which was significantly higher than that of 26.82% in non-reducing environment ( P<0.001). The platinum content in ES2 cells after 4 hours and 7 hours of treatment with NP@Pt(Ⅳ) (308.59, 553.15 ng/million cells) were significantly higher than those of Pt(Ⅳ) (100.21, 180.31 ng/million cells) and cisplatin (43.36, 50.36 ng/million cells, P＜0.05). The half inhibitory concentrations of NP@Pt(Ⅳ) in ovarian cancer cells ES2, A2780, A2780DDP were 1.39, 1.42 and 4.62 μmol/L, respectively, which were lower than those of Pt(IV) (2.89, 7.27, and 16.74 μmol/L) and cisplatin (5.21, 11.85, and 71.98 μmol/L). The apoptosis rate of ES2 cells treated with NP@Pt(Ⅳ) was (33.91±3.80)%, which was significantly higher than that of Pt(Ⅳ) [(16.28±2.41)%] and cisplatin [(15.01±1.17)%, P＜0.05]. In high-grade serous ovarian cancer PDX model, targeted accumulation of Cy7.5 labeled NP@Pt(Ⅳ) at tumor tissue could be observed. After the treatment, the tumor volume of mice in NP@Pt(IV) group was (130±98) mm 3, which was significantly lower than those in control group [(1 349±161) mm 3, P<0.001] and cisplatin group [(715±293) mm 3, P=0.026]. The tumor weight of mice in NP@Pt(IV) group was (0.17±0.09)g, which was significantly lower than those in control group [(1.55±0.11)g, P<0.001] and cisplatin group [(0.82±0.38)g, P=0.029]. The areas of tumor necrosis and apoptosis in mice treated with NP@Pt(Ⅳ) were higher than those in mice treated with cisplatin. Immunohistochemical staining revealed that there were low expressions of Ki-67 at tumor tissues of mice treated with NP@Pt(Ⅳ) compared with cisplatin. The change in body weight of mice in NP@Pt(Ⅳ) group was not significantly different from that of the control group [(18.56±2.04)g vs.(20.87±0.79)g, P=0.063]. Moreover, the major organs of the heart, liver, spleen, lung, and kidney were also normal by HE staining. Conclusion:Redox-responsive NP@Pt(Ⅳ), produced in this study can enhance the accumulation of cisplatin in ovarian cancer cells and improve the efficacy of ovarian cancer chemotherapy.

Background The mental health problems of employees in administrative organs and public institutions are highly valued.However,there is a lack of understanding regarding the mental health status of employees in provincial and municipal administrative organs and public institutions in Qinghai region.Objective To analyze the anxiety and depression of employees in provincial and municipal administrative organs and public institutions in Qinghai region,so as to provide references for promoting their mental health and intervening in psychological problems.Methods From October 23 to 28,2022,a total of 3 096 employees in provincial and municipal administrative organs and public institutions in Qinghai region were enrolled using stratified cluster sampling technique,and were assessed using Self-rating Anxiety Scale(SAS)and Self-rating Depression Scale(SDS).Results A total of 1797(58.04％)employees in municipal and above administrative organs and public institutions in Qinghai region completed a valid questionnaire survey.Depressive symptoms were noted in 579(32.22％).SDS scores yielded statistical difference among the selected employees of different ethnicities,types of job positions and educational levels(F=9.074,101.488,4.477,P<0.01),and the severity of depressive symptoms also demonstrated statistical difference among the selected employees with different ethnicities,educational levels and types of job positions(H=49.196,17.028,160.848,P<0.01).Anxiety symptoms were detected in 711(39.57％)employees.SAS scores exhibited statistical difference among the employees with different genders,ages,ethnicities,educational levels,marital status and types of job positions(t=-4.571,F=6.648,3.950,5.243,12.008,22.253,P<0.01).Statistical differences were also illustrated in the severity of anxiety symptoms among the selected employees with different ages,genders,ethnicities,educational levels,marital status and types of job positions(H=24.361,-3.788,28.365,24.268,25.976,56.204,P<0.01).Conclusion About one-third of employees in municipal and above administrative organs and public institutions in Qinghai region may have symptoms of depression and anxiety.The depression symptoms are more severe among Tibetan people,those with low education levels and ordinary civil servants.The anxiety symptoms are more severe among employees aged 30 and below,those with low education levels,unmarried and those in technical positions.

Objective To analyze the hotspots and developments in the field of language model-assisted artificial intelli-gence(Al)for antibody design and optimization in order to provide reference for research on development of antibodies.Methods By using CiteSpace software,hotspots of research were analyzed based on literature retrieved from the Web of Science,PubMed,and Scopus databases,focusing on three pivotal areas of research related to antibody design and optimization:the construction of pre-trained language models for antibodies,the generation of antibody sequences,and the prediction of three-dimensional structures of antibodies.In addition,this analysis reviewed the major advances in each of the specified research tasks,focusing on the delineation of similarities and differences across studies and dominating challenges in this field.Results From 2019(10 publications)to 2023(89 publications),the scale of and interest in this field kept increasing.Hotspots involved leveraging language models to assist the design or optimization of humanized,high-affinity,and highly specific antibodies.Within each research,methods were characterized by the diversity of model architectures,consistency of training data,and variations in training strategies.Challenges to the field included sparse antigen data,computational power limitations,and insufficient integration of wet and dry lab experiments.Conclusion Research in language model-assisted Al antibody design and optimization is gaining momentum and proves fruitful.However,researchers should be alert to the inadequate attention to antigen-antibody interactions and insufficient integration of experimental and computational validation,conduct more in-depth research and expand applications.

Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).

Objective:To analyze the relationship between the expression and prognosis of kinesin family member 4A (KIF4A) in renal clear cell carcinoma and explore its potential mechanism.Methods:Information on the KIF4A gene in renal clear cell carcinoma was retrieved from the UALCAN database, including expression levels, survival analysis, and positive and negative correlation gene data, from which the expression levels, prognostic information, and potential mechanisms of KIF4A in renal clear cell carcinoma were derived.Results:KIF4A is highly expressed in renal clear cell carcinoma, and male patients have a higher expression rate than female patients. The higher the tumor grade and the later the N stage, the more expression ( P<0.05). The survival analysis showed that the expression level and prognosis of KIF4A were negatively correlated ( P<0.05). Cyclin B2 (CCNB2), kinesin family member 23 (KIF23), cell division cycle associated 5 (CDCA5), and KIF4A were significantly positively correlated, whereas DHRS12, crumbs protein homolog 3 (CRB3), β-hydroxybutyrate dehydrogenase 2 (BDH2), and KIF4A were significantly negatively correlated. Conclusions:KIF4A plays an important role in the development of renal clear cell carcinoma and can be used as a potential marker and therapeutic target for the diagnosis and prognosis of renal clear cell carcinoma, including in children.

Objective:To investigate the value of plasma Epstein-Barr virus (EBV) DNA detection in the screening of nasopharyngeal carcinoma (NPC) and its clinical application in non-high-risk areas.Methods:Plasma EBV DNA results in 1 153 newly diagnosed nasopharyngeal carcinoma patients who were treated in Sichuan Cancer Hospital from 2015 to 2020 and 244 healthy control cases with matched sex and age were retrospectively analyzed. EBV DNA were detected by quantitative real-time PCR. Positive rate of EBV DNA was determined by the cutoff value of 400 (≥400 copies/ml as positive) and optimization threshold method (presence of S amplification curve as positive). Further analyses were conducted to compare EBV DNA load in different clinical stage, TNM stage and regions distribution characteristics. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of the cutoff value of 400 and optimization threshold method for NPC.Results:Compared with healthy controls, EBV DNA increased significantly in newly diagnosed NPC patients ( P<0.001). Both evaluation methods revealed that the EBV DNA positive percentage increased with TNM and clinical stage ( P<0.001). With 400 copies/ml as cutoff value, the diagnostic sensitivity and specificity were 40.85% and 100%, respectively. The area under the curve was 0.704 (95% CI 0.676-0.733, P<0.001). Evaluated by the optimization threshold method, the sensitivity and specificity could improve to 82.0% and 99.2%, respectively, and the area under the curve reached 0.910 (95% CI 0.894-0.924, P<0.001). Conclusions:In the low prevalence area of nasopharyngeal carcinoma, the sensitivity for diagnosis of nasopharyngeal carcinoma is only 40.9% by the 400 copies/ml cutoff value method. The optimization threshold method is a better choice to improve the diagnostic sensitivity without lowering the diagnostic specificity.

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

Objective:To investigate the risk factors for axial deviation in the treatment of tibial defect susing Orthofix unilateral external fixator and proximal tibial osteotomy for bone transport.Methods:A retrospective study was performed to analyze the clinical data of 90 patients who had been treated for tibial bone defects by the Orthofix unilateral external fixator at Department of Microrepair and Reconstruction, The First Hospital Affiliated to Xinjiang Medical University from May 2012 to June 2019. There were 77 males and 13 females with a mean age of 41.2 years (from 17 to 63 years).The bone defects ranged from 4 to 13 cm in length. According to the Paley criteria for axial deviation, the 90 patients were divided into 2 groups: a deviation-free group with no axial deviation or an axial deviation ≤5° and a deviation group with an axial deviation>5°. The 2 groups were compared in terms of age, number of prior surgery, defect length, placement angle of Schanz screws, external fixation time, external fixation index and bending degree of Schanz screws at the last follow-up.The factors with P<0.05 were analyzed by multivariate logistic regression to find the risk factors for coronal axial deviation. Results:The 90 patients were followed up for an average of 23 months (from 12 to 40 months). The incidence of axial deviation in this cohort was 36.7% (33/90).The deviation group had a significantly larger number of prior surgery [5 (3, 6) times], a significantly longer defect length [8 (8, 9) cm], a significantly longer external fixation time [400.0 (341.8, 426.3) d], and a significantly greater bending degree of Schanz screws at the last follow-up [1.2° (0.4°, 3.5°)] than the deviation-free group [3 (2, 3) times, 6 (5, 8) cm, 340.8 (226.5, 422.8) d, and 0.8° (0.2°, 3.7°)] (all P<0.05). Multivariate logistic regression analysis showed that the number of prior surgery ( OR=2.581, 95% CI: 1.496-4.450, P=0.001) and the defect length ( OR=5.310, 95% CI: 1.952-14.442, P=0.001) were the risk factors for the axial deviation. Conclusion:In the treatment of tibial defect susing Orthofix unilateral external fixator and proximal tibial osteotomy for bone transport, the more prior surgeries and the longer a bone defect, the higher the risk for axial deviation.

The rapid spread of carbapenemase-producing Klebsiella pneumoniae(cpKP)poses seri-ous threats to public health;however,the underlying genetic basis for its dissemination is still unknown.We conducted a comprehensive genomic epidemiology analysis on 420 cpKP isolates col-lected from 70 hospitals in 24 provinces/autonomous regions/municipalities of China during 2009-2017 by short-/long-read sequencing.The results showed that most cpKP isolates were categorized into clonal group 258(CG258),in which ST11 was the dominant clone.Phylogenetic analysis revealed three major clades including the top one of Clade 3 for CG258 cpKP isolates.Additionally,carbapenemase gene analysis indicated that blaKPC was dominant in the cpKP isolates,and most blaKPC genes were located in five major incompatibility(Inc)groups of blaKPC-harboring plasmids.Importantly,three advantageous combinations of host-blaKPC-carrying plasmid(Clade 3.1+3.2-IncFⅡpHN7A8,Clade 3.1+3.2-IncFⅡpHN7A8:IncR,and Clade 3.3-IncFⅡpHN7A8:InCpA1763-KPC)were identified to confer cpKP isolates the advantages in both genotypes(strong correlation/coevolution)and phenotypes(resistance/growth/competition)to facilitate the nationwide spread of ST11/CG258 cpKP.Intriguingly,Bayesian skyline analysis illustrated that the three advanta-geous combinations might be directly associated with the strong population expansion during 2007-2008 and subsequent maintenance of the population of ST11/CG258 cpKP after 2008.We then examined drug resistance profiles of these cpKP isolates and proposed combination treatment regimens for CG258/non-CG258 cpKP infections.Thus,the findings of our systematical analysis shed light on the molecular epidemiology and genetic basis for the dissemination of ST11/CG258 cpKP in China,and much emphasis should be given to the close monitoring of advantageous cpKP-plasmid combinations.

Objective: To study the effect of comprehensive treatment in stroke unit on the cognition and life quality of patients with vascular cognitive impairment (VCI) and also its effects on the mental state of their caregivers. Methods: Ninety-three persons with VCI were randomly divided into a control group (n=44) and a comprehensive treatment group (n=49) after being admitted into the stroke unit. Both groups took routine basic drugs (such as anti-platelet drugs, lipid lowering drugs, anti-hypertension drugs, huperzine-A tablets and Nicergoline tablets). The treatment group was additionally provided with limb movement rehabilitation training, social practice, cognitive training and health education. During the treatment, the treatment group′s caregivers were also given health education about VCI and stroke, systematic rehabilitation knowledge and skills training and appropriate anti-depressant and anxiety medication if need. Before the treatment, as well as 3 and 6 months after the treatment, the patients of both groups were evaluated using the mini-mental state examination (MMSE), the Montreal cognitive assessment (MoCA), their ability in the activities of daily living (ADL) was rated and Spitzer quality of life (QLI) values were assigned. The caregivers were evaluated using the Hamilton depression scale (HAMD) and the Hamilton anxiety scale (HAMA). Results: After 3 and 6 months of treatment, the average MMSE, MoCA, ADL and QLI scores of the treatment group had improved significantly and were then significantly better than those of the control group at the same time points. The average HAMD score of the treatment group was also significantly better. Conclusion Comprehensive stroke unit therapy can improve the cognition and life quality of patients with vascular cognitive impairment. It can also improve the mental state of their caregivers.