Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

Iron is an essential trace element in the human body, crucial in maintaining normal physiological functions. Recent studies have identified iron ions as a significant factor in initiating the ferroptosis process, a novel mode of programmed cell death characterized by iron overload and lipid peroxide accumulation. The iron metabolism pathway is one of the primary mechanisms regulating ferroptosis, as it maintains iron homeostasis within the cell. Numerous studies have demonstrated that abnormalities in iron metabolism can trigger the Fenton reaction, exacerbating oxidative stress, and leading to cell membrane rupture, cellular dysfunction, and damage to tissue structures. Therefore, regulation of iron metabolism represents a key strategy for ameliorating ferroptosis and offers new insights for treating diseases associated with iron metabolism imbalances. This review first summarizes the mechanisms that regulate iron metabolic pathways in ferroptosis and discusses the connections between the pathogenesis of various diseases and iron metabolism. Next, we introduce natural and synthetic small molecule compounds, hormones, proteins, and new nanomaterials that can affect iron metabolism. Finally, we provide an overview of the challenges faced by iron regulators in clinical translation and a summary and outlook on iron metabolism in ferroptosis, aiming to pave the way for future exploration and optimization of iron metabolism regulation strategies.

White-matter tracts play a pivotal role in transmitting sensory and motor information, facilitating interhemispheric communication and integrating different brain regions. Meanwhile, sensorimotor disturbance is a common symptom in patients with major depressive disorder (MDD). However, the role of aberrant sensorimotor white-matter system in MDD remains largely unknown. Herein, we investigated the topological structure alterations of white-matter morphological brain networks in 233 MDD patients versus 257 matched healthy controls (HCs) from the DIRECT consortium. White-matter networks were derived from magnetic resonance imaging (MRI) data by combining voxel-based morphometry (VBM) and three-dimensional discrete wavelet transform (3D-DWT) approaches. Support vector machine (SVM) analysis was performed to discriminate MDD patients from HCs. The results indicated that the network topological changes in node degree, node efficiency, and node betweenness were mainly located in the sensorimotor superficial white-matter system in MDD. Using network nodal topological properties as classification features, the SVM model could effectively distinguish MDD patients from HCs. These findings provide new evidence to highlight the importance of the sensorimotor system in brain mechanisms underlying MDD from a new perspective of white-matter morphological network.
Humans ; Depressive Disorder, Major/pathology* ; White Matter/pathology* ; Male ; Female ; Support Vector Machine ; Adult ; Magnetic Resonance Imaging ; Middle Aged ; Case-Control Studies ; Sensorimotor Cortex ; Brain

Objective To study the therapeutic effect of the type Ⅰ tympanoplasty by the continuous irriga-ting endoscopic ear surgery mode.Methods A total of 50 patients with chronic suppurative otitis media,who pre-pared for the type Ⅰ tympanoplasty in our department,were divided into the traditional operation mode group(20 cases)and the continuous irrigating mode group(30 cases).All patients underwent underlay myringoplasty with tragus cartilage and perichondria limplant.The operation time and postoperative outcome of the two groups were compared and analyzed.Results The mean operation time of the traditional group and the irrigating operation group was 66.10±2.43 minutes and 46.81±5.12 minutes respectively,and there was statistical difference between the two groups(P＜0.05).The tympanic membrane healing rate of the traditional group and the irrigating operation group was 100.00％and 96.67％respectively,and there was no statistical difference between the two groups(P＞0.05).The mean air conduction threshold and the value of air-bone gap were significantly reduced at 2 months after operation compared with that before operation(P＜0.05).There was no significant difference between the two groups in the average pre and post-operative air-bone gaps(P＞0.05).The incidence rates of postoperative compli-cations were 10.00％and 3.33％,respectively,with no statistical significance(P＞0.05).Conclusion The contin-uous irrigating endoscopic ear surgery mode is safe and effective.Under the premise of ensuring clinical efficacy,the operation time is shortened,and it is worth popularizing in middle ear surgery.

To prepare a lipid nanoparticle (LNP)-based subunit vaccine of Mycobacterium tuberculosis (Mtb) antigen EsxV and study its immunological characteristics, the LNP containing EsxV and c-di-AMP (EsxV: C: L) was prepared by thin film dispersion method, and its encapsulation rate, LNP morphology, particle size, surface charge and polyphase dispersion index were measured. BALB/c mice were immunized with EsxV: C: L by nasal drops. The levels of serum and mucosal antibodies, transcription and secretion of cytokines in lung and spleen, and the proportion of T cell subsets were detected after immunization. EsxV: C: L LNPs were obtained with uniform size and they were spherical and negatively charged. Compared with EsxV: C immunization, EsxV: C: L mucosal inoculation induced increased sIgA level in respiratory tract mucosa. Levels of IL-2 secreted from spleen and ratios of memory T cells and tissue-resident T cells in mice were also elevated. In conclusion, EsxV: C: L could induce stronger mucosal immunity and memory T cell immune responses, which may provide better protection against Mtb infection.
Animals ; Mice ; Mycobacterium tuberculosis ; Antigens, Bacterial ; Immunization ; Nanoparticles ; Vaccines, Subunit ; Mice, Inbred BALB C

ObjectiveTo establish a model of inflammasome activation induced by psoralidin based on bone marrow-derived macrophages （BMDM） in mice， and to explore the immunomodulatory effects of psoralidin combined with echinatin. MethodLipopolysaccharide （LPS） and psoralidin were used to activate inflammasomes， and after 4 h LPS stimulation， echinatin （40 μmol·L^-1） was administered for pre-protection for 1 h， followed by stimulation with psoralidin （10， 20， 40 μmol·L^-1） for 4 h. The protein expression of Caspase-1 p20 in cell supernatant and precursor （pro）-Caspase-1 and pro-interleukin（IL）-1β in cell lysate were simultaneously detected by Western blot. Enzyme-linked immunosorbent assay （ELISA） was adopted to determine the content of IL-β and TNF-α in the supernatant of BMDM. ResultWestern blot revealed that compared with the conditions in the control group， the maturation of psoralidin-induced pro-Caspase-1 and the secretion of IL-1β was inhibited by echinatin （P<0.05，P<0.01）. ELISA showed that the production of IL-1β and TNF-α was enhanced by psoralidin of different concentrations （P<0.05，P<0.01） compared with the condition in the control group. In addition， compared with the psoralidin group， the psoralidin combined with echinatin group reduced the secretion of IL-1β and TNF-α （P<0.01）. ConclusionEchinatin could significantly inhibited the excessive immune-inflammatory response mediated by psoralidin， and thus achieve the effect of toxicity reduction. The present study explored the toxicity-reducing effect of psoralidin combined with echiantin， providing a basis for safe clinical application.

Objective:To improve the accuracy of cone-beam CT (CBCT) image registration by using a dose-guided registration algorithm based on multi-objective optimization.Methods:A total of 28 sets of CBCT images of 6 patients with lung cancer and 5 patients with cervical cancer admitted to Harbin Medical University Cancer Hospital in 2022 were retrospectively analyzed. Using the results of bone-based registration as the starting points for dose registration algorithm, the dose fluence weighted mean square errors of each displacement point in surrounding three-dimensional space were calculated, and the candidate displacement points were selected by unsupervised k-means clustering method. The three-dimensional dose distribution of each candidate displacement point was calculated by using the limited size pencil beam algorithm, and the dose histogram indexes were extracted as the optimization variables of the multi-objective optimization algorithm. After the Pareto optimal solution set obtained using multi-objective genetic algorithm, the optimal unique solution was then determined based on the predetermined objective weight scheme.Results:After dose optimization registration, the values of D 90%, D 95%, D 98%, D mean and conformity index (CI) of planning target volume (PTV) of lung cancer patients were increased by 0.23 Gy, 0.49 Gy, 1.05 Gy, 0.15 Gy, 0.03 compared with conventional registration, respectively, and no significant difference was found for the organs at risk (OAR). For cervical cancer cases, the values of D 90%, D 95%, D 98%, D mean and CI of PTV were increased by 0.72 Gy, 1.15 Gy, 2.53 Gy, 0.24 Gy, 0.05 compared with conventional registration, respectively, whereas the evaluation indexes of partial OAR were decreased by 1.06-1.81 Gy. Conclusion:The proposed dose-guided registration algorithm can improve the dose coverage for the target area, decrease the dose for OAR and reduce residual error of rigid registration algorithm, which can be implemented as part of online adaptive radiotherapy.

Objective:To compare the application effect among Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scale, Medical Outcomes Study 36-item Short Form (SF-36) scale and "Assessment for Therapeutic Efficacy on Kashin-Beck Disease" (WS/T 79-2011) standard in the evaluation of therapeutic effect of patients with Kashin-Beck disease, which could provide basis for the treatment evaluation of patients with Kashin-Beck disease.Methods:A total of 213 patients with Kashin-Beck disease in Gansu Province were investigated. WOMAC scale, SF-36 scale and standard of WS/T 79-2011 were used to analyze the quality of life of patients before and after treatment. The reliability, construct validity, content validity, discriminant validity of WOMAC and SF-36 scales were compared. Correlation between WOMAC, SF-36 scales and standard of WS/T 79-2011 were evaluated.Results:Both WOMAC and SF-36 scales had good construct validity and content validity (construct validity showed WOMAC and SF-36 scales contained 1 and 2 common factors, respectively; content validity showed WOMAC and SF-36 scales contained 3 and 8 common factors, respectively). The reliability and discriminant validity of WOMAC scale were better than those of SF-36 seale (reliability showed WOMAC reliability coefficient ≥0.934, the reliability coefficient of SF-36 scale was ranged from 0.386 to 0.999. Discriminant validity showed there were differences in 3 dimensions of the WOMAC scale before and after treatment, while there were differences in 6 out of 8 dimensions of the SF-36 scale). The correlation coefficients between WOMAC scale and standard of WS/T 79-2011 ranged from 0.175 to 0.437, the correlation coefficients between SF-36 scale and standard of WS/T 79-2011 ranged from - 0.434 to - 0.099 ( P < 0.05). Conclusion:The reliability, discriminant validity and correlation with the standard of WS/T 79-2011 of WOMAC scale are better than those of SF-36 scale in efficacy evaluation of patients with Kashin-Beck disease.

Objective: To investigate the prevalence and influencing factors of electronic cigarette (e-cigarette) use among adolescents in Haidian District, Beijing, so as to provide insights into tobacco control among adolescents. Methods: The students in junior high school, high school and vocational high school were recruited from Haidian District using the stratified cluster random sampling method in October of 2019, and subjects' demographic features and use of e-cigarettes were collected using the Questionnaire for Survey on Tobacco Prevalence among Adolescents in China in 2019. The factors affecting e-cigarette use were identified among adolescents using the multivariable logistic regression analysis. Results: A total of 658 adolescents were investigated, including 315 junior high school students ( 47.87% ), 221 high school students ( 33.59% ), and 122 vocational high school students ( 18.54% ), and there were 261 boys ( 39.66% ), and 397 girls ( 60.34% ). There were 605 students that had heard of electronic cigarettes ( 91.95% ), 63 students that had used e-cigarettes (9.57%), and 23 students with current use of e-cigarettes ( 3.50% ), and there were 39 students that had never used electronic cigarettes but had a tendency of use in the future ( 6.55% ). Multivariable logistic regression analysis identified parental smoking ( OR=2.408, 95%CI: 1.179-4.916 ), close friends' smoking ( OR=3.597, 95%CI: 1.715-7.544 ) and cigarette smoking ( OR=23.029, 95%CI: 11.092-47.812 ) as factors affecting e-cigarette use among adolescents. Conclusions The prevalence of electronic cigarette uses is 9.57% among adolescents in Haidian District, Beijing. Parental smoking, peer smoking and use of cigarettes may facilitate the use of e-cigarettes among adolescents.