Gastric cancer(GC)is one of the most prevalent malignant tumors worldwide.Although the incidence of GC has significantly de-creased over the past decade owing to advancements in early stage diagnostic techniques,its mortality rate remains high.Immune check-point inhibitors(ICIs),such as programmed cell death protein-1(PD-1)inhibitors,have become a promising treatment option for patients with GC.However,only a minority of patients with GC exhibit durable responses to PD-1 inhibitor therapy.Moreover,the overall efficacy of these treatments is limited.Existing studies have indicated that immunotherapeutic failure is closely associated with the development of res-istance to PD-1 inhibitors;however,the mechanisms underlying this resistance are not fully understood.Therefore,this review aimed to ex-plore the potential molecular mechanisms contributing to the resistance to PD-1 inhibitors in the treatment of GC and provide a new re-search perspective on the clinical responses to this resistance.

Objective To explore the factors affecting the prognosis of patients with symptomatic severe intracranial artery stenosis after interventional therapy,and to construct a nomogram prediction model accordingly.Methods The clinical data of 121 patients with symptomatic severe intracranial artery stenosis,who received interventional treatment at the First People's Hospital of Zhengzhou from June 1,2021 to October 31,2024,were retrospectively analyzed.The general data,characteristics of vascular lesions,treatment-related factors and prognosis of patients were collected.According to the modified Rankin scale(mRS)score,the patients were divided into good prognosis group(mRS score ≤2 points)and poor prognosis group(mRS score＞2 points).The clinical data were compared between the two groups.Multivariate logistic regression analysis was used to identify and determine independent factors affecting patient's outcomes,to construct a nomogram prediction model and to validate this model.Results Among the 121 patients,31(25.61％)had poor prognosis and 90(74.38％)had good prognosis.The postoperative 3-month mRS score was lower than preoperative mRS score value(P＞0.05).There were significant differences in hypertension history,stenosis site,stenosis degree,collateral circulation state,interventional therapeutic mode,cholesterol level,platelet count,lesion length and preoperative NIHSS score(P＜0.05)between the poor prognosis group and the good prognosis group.Multivariate analysis showed that hypertension history,stenosis degree,collateral circulation status,cholesterol level,platelet count,lesion's length and preoperative NIHSS score were the independent influencing factors for the prognosis of patients with symptomatic severe intracranial artery stenosis.The predicted AUC of the nomogram model was 0.931(95％ CI=0.873-0.989),and the calibration curve showed that the predicted value was in good agreement with the actual value.Conclusion Hypertension history,stenosis degree,collateral circulation status,cholesterol level,platelet count,lesion length and preoperative NIHSS score are the important influencing factors for the prognosis of patients with symptomatic severe intracranial artery stenosis.The nomogram prediction model constructed in this study shows a high accuracy in predicting the prognosis of patients,and it can provide important reference for clinical decision-making.

Objective:To explore the impact of various fixatives on the nuclear-cytoplasmic localization of Yes-associated protein (YAP) in human corneal epithelial cells under hyperosmotic stress condition.Methods:Immortalized human corneal epithelial cells were divided into control group and hypertonic group.After 1 day of normal culture, cells of the hypertonic group were exposed to hyperosmotic medium at 450 mOsM by adding sodium chloride for 1 hour.No special treatment was given to the control group.Both groups of cells were fixed with four different fixatives, including 4% paraformaldehyde (PFA), -20 ℃ precooled absolute ethanol, -20 ℃ precooled methanol-acetone 1∶1 mixture, and Zamboni fixative solution for 20 minutes.Subsequent to fixation, immunofluorescent staining procedures were performed to identify the intracellular localization of YAP in the two groups.Results:After fixation with 4% PFA, human corneal epithelial cells showed normal morphology with YAP mainly in the nucleus in both groups, and there was no significant difference in the mean nuclear YAP fluorescence intensity between the two groups ( t=1.803, P=0.121).After fixation with absolute ethanol, cells showed some degree of shrinkage and deformation, diffuse YAP fluorescence staining with YAP-positive signals mainly localized in the cytoplasm in both groups, and the mean nuclear YAP fluorescence intensity was slightly decreased in the hypertonic group compared with the control group, but the difference was not statistically significant ( t=0.803, P=0.453).After fixation with methanol-acetone 1∶1 mixture, cells were crenulated with YAP mainly in the cytoplasm, and the mean nuclear YAP fluorescence intensity in the hypertonic group was slightly decreased compared with the control group, but the difference was not statistically significant ( t=1.067, P=0.327).After fixation with Zamboni solution, the cell structure was complete and clearly outlined, and the YAP nucleoplasmic translocation phenomenon could be clearly observed in cells in different states.The mean nuclear YAP fluorescence intensity in the hypertonic group was 197.5±34.5, which was significantly higher than 62.2±10.0 in the control group ( t=7.530, P<0.001). Conclusions:In the immunofluorescence staining experiment, the nucleoplasmic localization of YAP in corneal epithelial cells is affected by different fixative treatments.Zamboni fixative is better than 4% PFA, absolute ethanol, and methanol-acetone 1∶1 mixture in observing nuclear translocation of YAP after hypertonic stimulation.

Objective:To explore the impact of various fixatives on the nuclear-cytoplasmic localization of Yes-associated protein (YAP) in human corneal epithelial cells under hyperosmotic stress condition.Methods:Immortalized human corneal epithelial cells were divided into control group and hypertonic group.After 1 day of normal culture, cells of the hypertonic group were exposed to hyperosmotic medium at 450 mOsM by adding sodium chloride for 1 hour.No special treatment was given to the control group.Both groups of cells were fixed with four different fixatives, including 4% paraformaldehyde (PFA), -20 ℃ precooled absolute ethanol, -20 ℃ precooled methanol-acetone 1∶1 mixture, and Zamboni fixative solution for 20 minutes.Subsequent to fixation, immunofluorescent staining procedures were performed to identify the intracellular localization of YAP in the two groups.Results:After fixation with 4% PFA, human corneal epithelial cells showed normal morphology with YAP mainly in the nucleus in both groups, and there was no significant difference in the mean nuclear YAP fluorescence intensity between the two groups ( t=1.803, P=0.121).After fixation with absolute ethanol, cells showed some degree of shrinkage and deformation, diffuse YAP fluorescence staining with YAP-positive signals mainly localized in the cytoplasm in both groups, and the mean nuclear YAP fluorescence intensity was slightly decreased in the hypertonic group compared with the control group, but the difference was not statistically significant ( t=0.803, P=0.453).After fixation with methanol-acetone 1∶1 mixture, cells were crenulated with YAP mainly in the cytoplasm, and the mean nuclear YAP fluorescence intensity in the hypertonic group was slightly decreased compared with the control group, but the difference was not statistically significant ( t=1.067, P=0.327).After fixation with Zamboni solution, the cell structure was complete and clearly outlined, and the YAP nucleoplasmic translocation phenomenon could be clearly observed in cells in different states.The mean nuclear YAP fluorescence intensity in the hypertonic group was 197.5±34.5, which was significantly higher than 62.2±10.0 in the control group ( t=7.530, P<0.001). Conclusions:In the immunofluorescence staining experiment, the nucleoplasmic localization of YAP in corneal epithelial cells is affected by different fixative treatments.Zamboni fixative is better than 4% PFA, absolute ethanol, and methanol-acetone 1∶1 mixture in observing nuclear translocation of YAP after hypertonic stimulation.

Gastric cancer(GC)is one of the most prevalent malignant tumors worldwide.Although the incidence of GC has significantly de-creased over the past decade owing to advancements in early stage diagnostic techniques,its mortality rate remains high.Immune check-point inhibitors(ICIs),such as programmed cell death protein-1(PD-1)inhibitors,have become a promising treatment option for patients with GC.However,only a minority of patients with GC exhibit durable responses to PD-1 inhibitor therapy.Moreover,the overall efficacy of these treatments is limited.Existing studies have indicated that immunotherapeutic failure is closely associated with the development of res-istance to PD-1 inhibitors;however,the mechanisms underlying this resistance are not fully understood.Therefore,this review aimed to ex-plore the potential molecular mechanisms contributing to the resistance to PD-1 inhibitors in the treatment of GC and provide a new re-search perspective on the clinical responses to this resistance.

Objective:To quantitatively evaluate the accuracy of data obtained from liquid-interference surfaces using an intraoral 3D scanner(IOS)integrated with a compressed airflow system,so as to pro-vide clinical proof of accuracy for the application of the compressed airflow system-based scanning head in improving data quality on liquid-interference surfaces.Methods:The study selected a standard model as the scanning object,adhering to the"YY/T 1818-2022 Dental Science Intraoral Digital Impression Scanner"guidelines,a standard that defined parameters for intraoral scanning.To establish a baseline for accuracy,the ATOS Q 12M scanner,known for its high precision,was used to generate true reference values.These true values served as the benchmark for evaluating the IOS performance.Building on the design of an existing scanner,a new scanning head was developed to integrate with a compressed airflow system.This new design aimed to help the IOS capture high-precision data on sur-faces where liquid-interference,such as saliva,might otherwise degrade scanning accuracy.The tradi-tional scanning method,without airflow assistance,was employed as a control group for comparison.The study included five groups in total,one control group and four experimental groups,to investigate the effects of scanning lens obstruction,airflow presence,liquid media,and the use of the new scan-ning head on scanning process and accuracy.Each group underwent 15 scans,generating ample data for a robust statistical comparison.By evaluating trueness and precision in each group,the study as-sessed the impact of the compressed airflow system on the accuracy of IOS data collected from liquid-interference surfaces.Additionally,we selected Elite and Primescan scanners as references for numeri-cal accuracy values.Results:The scanning accuracy on liquid-interference surfaces was significantly reduced in terms of both trueness and precision[Trueness:18.5(6.5)vs.38.0(6.7),P＜0.05;Preci-sion:19.1(8.5)vs.31.7(15.0),P＜0.05].The use of the new scanning head assisted by the com-pressed airflow system significantly improved the scanning accuracy[Trueness:22.3(7.6)vs.38.0(6.7),P＜0.05;Precision:25.8(9.6)vs.31.7(15.0),P＜0.05].Conclusion:The scanning head based on the compressed airflow system can assist in improving the accuracy of data obtained from liquid-inter-ference surfaces by the IOS.

AIM: To investigate the efficacy and safety of ZKY001 eye drops with different concentrations in the treatment of corneal epithelial defects(CED)after primary pterygium excision.METHODS: This was a multicenter, randomized, double-blinded, placebo-controlled phase II clinical trial. From March 15, 2022 to November 14, 2022, patients with primary pterygium who had undergone surgery were recruited from 12 tertiary hospitals across China. Using block randomization, 178 patients(178 eyes)were randomly assigned to 3 groups in a 1:1:1 ratio: 0.002% ZKY001 group(n=59), 0.004% ZKY001 group(n=59), and placebo group(n=60, receiving ZKY001 sham eye drops). Subjects in each group received 1 drop of the study drug 4 times per day for 4 d. The percentage of CED area recovery from baseline, the first complete healing time of CED area, the number of first complete healing cases of CED, and changes in visual analogue scale(VAS)scores for eye discomfort including eye pain, foreign body sensation, tearing and photophobia were observed.RESULTS: In terms of improvement in CED, there were no statistically significant differences among the three groups including the first healing time of CED, the percentage improvement in CED area compared to baseline, and the percentage of first healing cases at different follow-up visits(all P>0.05). Numerically, the first healing time of CED was shorter in the test groups compared to the placebo group(67.87±21.688 h for the 0.002% ZKY001 group, 61.48±22.091 h for the 0.004% ZKY001 group, and 68.85±20.851 h for the placebo group). On D1 morning, the percentage improvement in CED area compared to baseline was maximally different from the placebo group, and the numerical difference advantage was maintained at subsequent follow-up visits. The number of first healing cases in the CED area at different follow-up visits was higher in the test groups than the placebo group. In terms of improvement in ocular discomfort, the total VAS scores were lower in the test groups compared to the placebo group, mainly due to reductions in foreign body sensation and pain scores. At D3, the 0.004% ZKY001 group showed statistically significant improvement in foreign body sensation(P<0.017). In terms of safety, the overall incidence of adverse events was low(9.0%)and similar among groups.CONCLUSION: The use of ZKY001 eyedrops after primary pterygium surgery can safely improve the CED repair, and alleviate postoperative symptoms caused by CED.

Cetuximab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) for the treatment of metastat-ic colorectal cancer (mCRC). However,most patients treated with cetuximab experience disease progression due to the development of sec-ondary drug resistance,presenting a significant challenge in managing cetuximab therapy. Existing studies have found that cetuximab resist-ance mechanisms are not only linked to the RAS/RAF/PIK3CA genetic mutations but also closely associated with the abnormal activation of PI3K/AKT/mTOR,Wnt/β-catenin,c-MET/HGF,and RAS-MAPK signaling pathways. Additionally,HER2 and MET amplification,microsatellite instability,changes in tumor metabolism,and alterations in the tumor microenvironment may also contribute to cetuximab resistance in pa-tients. This review focuses on the potential molecular mechanisms of cetuximab resistance in the treatment of mCRC,and provides new ideas for overcoming cetuximab resistance in clinic.

Cetuximab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) for the treatment of metastat-ic colorectal cancer (mCRC). However,most patients treated with cetuximab experience disease progression due to the development of sec-ondary drug resistance,presenting a significant challenge in managing cetuximab therapy. Existing studies have found that cetuximab resist-ance mechanisms are not only linked to the RAS/RAF/PIK3CA genetic mutations but also closely associated with the abnormal activation of PI3K/AKT/mTOR,Wnt/β-catenin,c-MET/HGF,and RAS-MAPK signaling pathways. Additionally,HER2 and MET amplification,microsatellite instability,changes in tumor metabolism,and alterations in the tumor microenvironment may also contribute to cetuximab resistance in pa-tients. This review focuses on the potential molecular mechanisms of cetuximab resistance in the treatment of mCRC,and provides new ideas for overcoming cetuximab resistance in clinic.

Objective:To evaluate the efficacy and safety of a China original liquid pulsation system for the treatment of meibomian gland dysfunction (MGD).Methods:A non-randomized controlled clinical trial was conducted.Twenty-two patients (44 eyes) diagnosed with MGD in Eye and ENT Hospital of Fudan University from February to August 2022 were enrolled.The patients were assigned into two groups according to their willingness.Of the 22 patients (44 eyes), 10 patients (20 eyes) in single liquid pulsation system group were treated with single liquid pulsation system for 12 minutes, and 12 patients (24 eyes) in intense pulsed light (IPL) group were treated with a course (4 times) of IPL, warm compresses and meibomian gland massage at three-week intervals.There was no difference in age and other baseline clinical indexes between the two groups (all at P<0.05). The meibum grading, quality grading of tear film lipid layer, Symptom Assessment Questionnaire in Dry Eye (SANDE) questionnaire score, first and average tear breakup time (BUT), corneal fluorescein sodium staining (CFS) score, tear meniscus height (TMH), and the area of meibomian gland loss were determined at baseline, 1 and 3 months after treatment.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Eye and ENT Hospital of Fudan University (No.2021069). Written informed consent was obtained from each patient before any medical examination. Results:Statistically significant group effects and time effects were found in the quality of tear film lipid layer ( Hgroup=4.39, P=0.036, Htime=6.30, P=0.043) and average BUT ( Fgroup=4.41, P=0.038; Ftime=4.08, P=0.049) in the two groups.The meibum grading, first BUT and TMH 1 and 3 months after treatment were significantly better than before treatment in single liquid pulsation system group (all at P<0.05). Compared with before treatment, there was no significant improvement in the meibum grading, distribution of tear film lipid, first BUT and TMH at 1 and 3 months after treatment in IPL group (all at P>0.05). In both groups, the SANDE and CFS scores 1 and 3 months after treatment were better than those before treatment, showing statistically significance (all at P<0.05). In terms of safety, neither instrument-related adverse events nor extra complaints of discomfort were reported in the single liquid pulsation system group.In both groups, the number of patients with positive CFS staining significantly decreased, and no new cases with positive CFS appeared after treatment. Conclusions:This China original liquid pulsation system is a safe and effective physical therapy in improving tear film dysfunction and ocular surface symptoms of MGD patients within 3 months after treatment.