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.

BACKGROUND: Generalized pustular psoriasis (GPP), a rare and recurrent autoinflammatory disease, imposes a substantial burden on patients and society. Awareness of GPP in China remains limited. METHODS: This cross-sectional survey, conducted between September 2021 and May 2023 across 14 hospitals in China, included GPP patients of all ages and disease phases. Data collected encompassed demographics, clinical characteristics, economic impact, disease severity, quality of life, and treatment-related complications. Risk factors for GPP recurrence were analyzed. RESULTS: Among 127 patients (female/male ratio = 1.35:1), the mean age of disease onset was 25 years (1st quartile [Q1]-3rd quartile [Q3]: 11-44 years); 29.2% had experienced GPP for more than 10 years. Recurrence occurred in 75.6% of patients, and nearly half reported no identifiable triggers. Younger age at disease onset ( P  = 0.021) and transitioning to plaque psoriasis ( P  = 0.022) were associated with higher recurrence rates. The median diagnostic delay was 8 months (Q1-Q3: 2-41 months), and 32.3% of patients reported misdiagnoses. Comorbidities were present in 53.5% of patients, whereas 51.1% experienced systemic complications during treatment. Depression and anxiety affected 84.5% and 95.6% of patients, respectively. During GPP flares, the median Dermatology Life Quality Index score was 19.0 (Q1-Q3: 13.0-23.5). This score showed significant differences between patients with and without systemic symptoms; it demonstrated correlations with both depression and anxiety scores. Treatment costs caused financial hardship in 55.9% of patients, underscoring the burden associated with GPP. CONCLUSIONS The substantial disease and economic burdens among Chinese GPP patients warrant increased attention. Patients with early onset disease and those transitioning to plaque psoriasis require targeted interventions to mitigate the high recurrence risk.
Humans ; Male ; Female ; Psoriasis/pathology* ; Adult ; Cross-Sectional Studies ; Adolescent ; Child ; Young Adult ; Quality of Life ; Middle Aged ; China/epidemiology* ; Recurrence ; Risk Factors ; Surveys and Questionnaires ; East Asian People

Objective To investigate the role of Dicentrine in regulating lipopolysaccharide(LPS)-induced inflammatory responses in RAW264.7 macrophages and its underlying mechanisms.Methods RAW264.7 macropha-ges were cultured and pretreated with different concentrations of Dicentrine(250,500,1 000 μmol/L).An inflam-matory response model was established using LPS stimulation(model group),with a control group receiving no treatment.Cytotoxicity of Dicentrine was evaluated by MTT assay.Nitric oxide(NO)levels in cell culture supernatants were measured using the Griess method.Fluorescence microscopy was employed to observe in-tracellular reactive oxygen species(ROS)accumulation and apoptosis.Finally,mRNA expression levels of in-flammatory cytokines including IL-1β,IL-6,inducible nitric oxide synthase(iNOS),and tumor necrosis factor-α(TNF-α)were analyzed by qPCR.Results MTT assay results indicated that Dicentrine exhibited no cyto-toxic effects at concentrations below 1 000 μmol/L.Griess method and fluorescence microscopy showed signif-icantly elevated NO and ROS levels in the model group compared to the control group(P<0.05).Compared with the model group,the 250,500,and 1 000 μmol/L Dicentrine groups demonstrated significantly reduced NO and ROS levels(P<0.05).qPCR analysis revealed significantly increased mRNA expression of IL-1β,IL-6,iNOS,and TNF-α in the model group versus the control group(P<0.05).Compared with the model group,the 250,500,and 1 000 μmol/L Dicentrine groups showed significantly decreased mRNA expression of IL-1β,IL-6,iNOS,and TNF-α(P<0.05).Conclusion Dicentrine regulates macrophage apoptosis,thereby ef-fectively inhibiting LPS-induced inflammatory responses in macrophages.

With the increasing abuse of antibiotics,the development of rapid,accurate and sensitive methods for antibiotic detection has become critical.Nucleic acid sensors as new biosensors have shown great potential in the field of antibiotic detection due to their high selectivity,high sensitivity and real-time monitoring ability.This paper reviews the research progress in antibiotic detection based on nucleic acid sensors,including colorimetric,optical and electrochemical nucleic acid sensors,in the hope of providing a reference for the research and development of new types of antibiotic detection technologies based on nucleic acid sensors.

Objective:To evaluate the prognostic significance of inflammatory biomarkers,prognostic nutritional index and clinicopathological characteristics in tongue squamous cell carcinoma(TSCC)patients who underwent cervical dissection.Methods:The retrospective cohort study consisted of 297 patients undergoing tumor resection for TSCC between January 2017 and July 2018.The study population was divided into the training set and validation set by 7:3 randomly.The peripheral blood indices of interest were preoperative neutrophil-to-lymphocyte ratio(NLR),lymphocyte-to-monocyte ratio(LMR),platelet-to-lymphocyte ratio(PLR),systemic immune-inflammation index(SII),systemic inflammation score(SIS)and prognostic nutritional index(PNI).Kaplan-Meier survival analysis and multivariable Cox regression analysis were used to evaluate independent prognostic factors for overall survival(OS)and disease-specific survival(DSS).The nomogram's accuracy was internally validated using concordance index,receiver operating characteristic(ROC)curve,area under the curve(AUC),calibration plot and decision curve analysis.Results:According to the univariate Cox regression analysis,clinical TNM stage,clinical T category,clinical N category,differentiation grade,depth of invasion(DOI),tumor size and pre-treatment PNI were the prognostic factors of TSCC.Multivariate Cox regression analysis revealed that pre-treatment PNI,clinical N category,DOI and tumor size were independent prognostic factors for OS or DSS(P＜0.05).Positive neck nodal status(N≥1),PNI≤50.65 and DOI＞2.4 cm were associated with the poorer 5-year OS,while a positive neck nodal status(N≥1),PNI≤50.65 and tumor size＞3.4 cm were associated with poorer 5-year DSS.The concordance index of the nomograms based on independent prognostic factors was 0.708(95％CI,0.625-0.791)for OS and 0.717(95％CI,0.600-0.834)for DSS.The C-indexes for external validation of OS and DSS were 0.659(95％CI,0.550-0.767)and 0.780(95％CI,0.669-0.890),respectively.The 1-,3-and 5-year time-dependent ROC analyses(AUC=0.66,0.71 and 0.72,and AUC=0.68,0.77 and 0.79,respec-tively)of the nomogram for the OS and DSS pronounced robust discriminative ability of the model.The calibration curves showed good agreement between the predicted and actual observations of OS and DSS,while the decision curve confirmed its pronounced application value.Conclusion:Pre-treatment PNI,clinical N category,DOI and tumor size can potentially be used to predict OS and DSS of patients with TSCC.The prognostic nomogram based on these variables exhibited good accurary in predicting OS and DSS in patients with TSCC who underwent cervical dissection.They are effective tools for predicting sur-vival and helps to choose appropriate treatment strategies to improve the prognosis.

Objective:To explore the clinical effectiveness of a self-designed robot reduction system for femoral intertrochanteric fractures.Methods:A retrospective study was conducted to analyze the 57 patients with intertrochanteric fracture who had been treated at Department of Orthopedics, The Fourth Affiliated Central Hospital of Tianjin Medical University from June 2022 to February 2023. The patients were divided into a robot group (using the self-designed robot reduction system to assist intramedullary nailing) and a traction bed group (using a traction bed to assist intramedullary nailing) based on their fracture reduction method. The robot group: 31 patients, 11 males and 20 females, with an age of (78.7±9.3) years; 16 left and 15 right sides; 17 cases of type 31-A1, 12 cases of type 31-A2 and 2 cases of type 31-A3 by the AO/OTA classification. The traction bed group: 26 patients, 12 males and 14 females, with an age of (78.7±7.7) years; 13 left and 13 right sides; 16 cases of type 31-A1, 9 cases of type 31-A2 and 1 cases of type 31-A3 by the AO/OTA classification. The 2 groups were compared in terms of reduction and operation time, intraoperative blood loss, fluoroscopy frequency, reduction quality, and VAS and Harris score at preoperation, 1 week and 6 months postoperation.Results:The 2 groups were comparable due to insignificant differences in their preoperative general data ( P>0.05). The robot group was significantly better than the traction bed group in reduction time [(4.4±2.2) min versus (9.4±3.2) min], operation time [(29.0±13.5) min versus (49.3±13.3) min], intraoperative blood loss [(76.5±30.5) mL versus (115.0±38.4) mL], fluoroscopy frequency [(10.2±2.6) times versus (14.8±3.2) times], and good/excellent rate of reduction [80.6% (25/31) versus 50.0% (13/26)] ( P<0.05). All patients were followed up for (6.8±0.3) months. Respectively, the VAS scores at preoperation and 6 months postoperation was (6.2±1.3) and (2.4±0.8) points for the robot group, and (6.3±1.3) and (2.7±0.8) points for the traction bed group, showing no statistically significant differences between the 2 groups ( P>0.05). However, the VAS score was (3.3±1.2) points for the robotic group and (4.8±1.5) points for the traction bed group at 1 week postoperation, showing a statistically significant difference between the 2 groups ( P<0.001). Respectively, the Harris scores at preoperation and 6 months postoperation were (35.3±3.0) and (88.7±3.4) points for the robot group, and (35.6±2.9) and (87.2±3.5) points for the traction bed group, showing no statistically significant differences between the 2 groups ( P>0.05). However, the Harris score was (57.3±3.7) points for the robotic group and (46.7±2.8) points for the traction bed group at 1 week postoperation, showing a statistically significant difference between the 2 groups ( P<0.05). The patient satisfaction rates in the robot and traction bed groups were 96.8% (30/31) and 92.3% (24/26), respectively, showing no statistically significant difference ( P>0.05). Conclusion:Our self-designed robot reduction for femoral intertrochanteric fractures can effectively shorten reduction and operation time, reduce bleeding and fluoroscopy frequency, and enhance anatomical reduction.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

[Objective]This study aimed to improve the existing semen processing methods in the field of reproductive male medicine,particularly focusing on the 300×g 20 min treatment condition in the double-layer density gradient method,to enhance fertilization outcome.[Methods]Semen specimens from 1623 patients undergoing assisted reproductive techniques at the Reproductive Medicine Center of the Sixth Affiliated Hospital of Sun Yat-sen University from July and September 2020 and March and May 2022 were collected for preliminary experiments.Four different double-layer density gradient methods(200×g 10 min,200×g 20 min,300×g 10 min,and 300×g 20 min)were compared for sperm DNA fragmentation rates and recovery rates after processing.Subsequently,the optimal method was selected as the new approach and compared with the current method in use(300×g 20 min double-layer gradient method)to assess any statistical differences in fertilization rates.Further optimization to a single-layer density gradient method was performed based on the new method and compared with the double-layer density gradient method to determine any statistical differences.Experimental conditions were strictly controlled for temperature,centrifugation speed,and duration,with the quantity and processing conditions of each sample recorded.[Results]Among the four double-layer density gradient methods,the sperm DNA fragmentation rate was lower with the 300×g 10 min treatment compared to 300×g 20 min while ensuring sufficient sperm recovery rates.Consequently,the 300×g 10 min method was selected as the new approach for experimentation.Results indicated that the total fertilization rate and 2 pronuclei(2PN)fertilization rate with the new 300×g 10 min method were higher than with the 300×g 20 min method,the difference was statistically significant(P<0.05).Although the cleavage rate with 300×g 10 min was slightly higher than 300×g 20 min,the difference was not statistically significant(P>0.05).The total fertilization rate and 2PN fertilization rate were slightly higher with the single-layer density gradient method compared to the double-layer density gradient method,but the difference was not statistically significant(P>0.05).The cleavage rate with the single-layer density gradient method was higher than the double-layer density gradient method,and the blastocyst formation rate is lower than that of the double-layer density gradient method,and the differences are statistically significant(P<0.05).[Conclusion]The 300×g 10 min double-layer density gradient method successfully improved total fertilization rates,2PN fertilization rates,and cleavage rates compared to the existing 300×g 20 min method,while reducing the time required for semen optimization processing.Although the single-layer density gradient method improves the cleavage rate,and saves reagent costs and operation time,its blastocyst formation rate has decreased.These findings provide valuable guidance and insights for semen processing methods in the field of reproductive andrology.