Objective:Exploring the efficacy and safety of the combination of programmed cell death protein 1 (PD-1) inhibitors with chemotherapy for the treatment of local recurrence at the primary tumor site of esophageal squamous cell carcinoma (ESCC) following definitive chemoradiotherapy.Methods:Seventy-six patients with local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy, who were treated at the Cancer Hospital Affiliated with Nanjing Medical University from January 2019 to January 2024. All patients received treatment with a PD-1 inhibitor combined with chemotherapy, and the short-term efficacy, long-term efficacy, and adverse reactions were observed. Univariate and multivariate Cox regression models were employed to identify the factors influencing overall survival (OS) and after-recurrence survival (ARS).Results:Among the 76 patients, 7 achieved partial response, 35 had stable disease, and 34 experienced progressive disease. The objective response rate was 9.2% (7/76), and the disease control rate was 55.3% (42/76). With a median follow-up time of 23.1 months, 33 out of 76 patients died. The median survival time was 38.5 months (95% CI: 29.6-47.3 months); the 1-year, 2-year, and 3-year OS were 94.5%, 66.6%, and 51.7%, respectively. The median ARS was 14.7 months (95% CI: 10.4-19.1 months); the 6-month, 12-month, and 24-month ARS were 85.8%, 59.6%, and 25.7%, respectively. Univariate analysis showed that the initial radiation dose, the Eastern Cooperative Oncology Group (ECOG) performance status of patients after recurrence, the recurrence-free interval (RFI), and the approach to chemotherapy treatment following local esophageal recurrence were factors affecting OS and ARS ( P＜0.05). Multivariate analysis showed that initial radiotherapy dose ( HR=0.268, 95% CI: 0.100-0.720), the ECOG performance status after recurrence ( HR=4.106, 95% CI: 1.228-13.728), and RFI ( HR=0.248, 95% CI: 0.106-0.582) were independent prognostic factors for OS. Additionally, the initial radiation dose ( HR=0.289, 95% CI: 0.098-0.853) and the ECOG performance status after recurrence ( HR=5.143,95% CI:1.404-18.838) were independent prognostic factors for ARS. The incidence of treatment-related adverse-reactions was 85.5% (65/76). Grade 3 or higher treatment-related adverse reactions primarily included anemia in 4 cases, leukopenia in 8 cases, neutropenia in 9 cases, thrombocytopenia in 2 cases, liver function abnormalities in 4 cases, and elevated troponin T in 2 cases. There were no cases of treatment-related mortality. Conclusions:The combination of PD-1 inhibitors with chemotherapy is safe and effective for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy and can provide survival benefits for patients. This approach can be considered as a therapeutic option for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy.

Objective:To screen the Alzheimer's disease(AD)-related genes and construct its diagnostic model using bioinformatics technology and machine learning(ML)algorithms,to discuss the immunological characteristics of AD patients,and to provide novel biomarkers for AD diagnosis.Methods:The AD-related gene expression dataset GSE125583 was downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were identified through differential analysis.Gene Ontology(GO)functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analyses were performed to explore the biological functions and signaling pathways of DEGs.A protein-protein interaction(PPI)network was constructed,and hub genes were screened using Cytoscape software combined with three ML algorithms:Least Absolute Shrinkage and Selection Operator(LASSO),eXtreme Gradient Boosting(XGBoost),and Random Forest(RF).The screened hub genes were utilized to build an AD diagnostic model via RF,followed by feature importance ranking.The model's efficacy and key genes were evaluated using a test set.Single-sample gene set enrichment analysis(ssGSEA)was used for immune cell infiltration analysis between AD group and control group.Results:Differential analysis identified 1 287 DEGs.The GO functional enrichment analysis results revealed that DEGs were primarily involved in biological functions related to neural signaling,synapses,and vesicles.KEGG signaling pathway enrichment analysis indicated significant enrichment of DEGs in ion transport,neurotransmitter,and ligand-gated channel pathways.Nine overlapping hub genes were screened by the three ML algorithms.In the AD diagnostic model,the top four key genes with highest diagnostic performance were adenylate cyclase-activating polypeptide 1(ADCYAP1),brain-derived neurotrophic factor(BDNF),platelet-derived growth factor receptor β(PDGFRB),and C-X-C motif chemokine receptor 4(CXCR4),with corresponding area under the curve(AUC)values of 0.852,0.795,0.820,and 0.756,respectively.The model achieved an AUC of 0.828,accuracy of 81.25%,sensitivity of 84.40%,and specificity of 71.43%.The immune cell infiltration analysis results demonstrated higher infiltration of macrophages,monocytes,natural killer(NK)cells,and lymphocytes in AD tissue.Among these,NK/natural killer T(NKT)cells and plasmacytoid dendritic cells showed significant correlations with the four key genes(P<0.05).Conclusion:The feature genes screened based on bioinformatics and ML exhibit diagnostic potential for AD.Genes such as ADCYAP1 may serve as potential biomarkers for AD diagnosis,offering significant implications for early prevention and treatment.

Objective:Exploring the efficacy and safety of the combination of programmed cell death protein 1 (PD-1) inhibitors with chemotherapy for the treatment of local recurrence at the primary tumor site of esophageal squamous cell carcinoma (ESCC) following definitive chemoradiotherapy.Methods:Seventy-six patients with local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy, who were treated at the Cancer Hospital Affiliated with Nanjing Medical University from January 2019 to January 2024. All patients received treatment with a PD-1 inhibitor combined with chemotherapy, and the short-term efficacy, long-term efficacy, and adverse reactions were observed. Univariate and multivariate Cox regression models were employed to identify the factors influencing overall survival (OS) and after-recurrence survival (ARS).Results:Among the 76 patients, 7 achieved partial response, 35 had stable disease, and 34 experienced progressive disease. The objective response rate was 9.2% (7/76), and the disease control rate was 55.3% (42/76). With a median follow-up time of 23.1 months, 33 out of 76 patients died. The median survival time was 38.5 months (95% CI: 29.6-47.3 months); the 1-year, 2-year, and 3-year OS were 94.5%, 66.6%, and 51.7%, respectively. The median ARS was 14.7 months (95% CI: 10.4-19.1 months); the 6-month, 12-month, and 24-month ARS were 85.8%, 59.6%, and 25.7%, respectively. Univariate analysis showed that the initial radiation dose, the Eastern Cooperative Oncology Group (ECOG) performance status of patients after recurrence, the recurrence-free interval (RFI), and the approach to chemotherapy treatment following local esophageal recurrence were factors affecting OS and ARS ( P＜0.05). Multivariate analysis showed that initial radiotherapy dose ( HR=0.268, 95% CI: 0.100-0.720), the ECOG performance status after recurrence ( HR=4.106, 95% CI: 1.228-13.728), and RFI ( HR=0.248, 95% CI: 0.106-0.582) were independent prognostic factors for OS. Additionally, the initial radiation dose ( HR=0.289, 95% CI: 0.098-0.853) and the ECOG performance status after recurrence ( HR=5.143,95% CI:1.404-18.838) were independent prognostic factors for ARS. The incidence of treatment-related adverse-reactions was 85.5% (65/76). Grade 3 or higher treatment-related adverse reactions primarily included anemia in 4 cases, leukopenia in 8 cases, neutropenia in 9 cases, thrombocytopenia in 2 cases, liver function abnormalities in 4 cases, and elevated troponin T in 2 cases. There were no cases of treatment-related mortality. Conclusions:The combination of PD-1 inhibitors with chemotherapy is safe and effective for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy and can provide survival benefits for patients. This approach can be considered as a therapeutic option for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy.

Objective To investigate the role and mechanism of milk fat globule-EGF factor 8(MFG-E8)in neuroprotection in glaucoma rats.Methods A glaucoma rat model was constructed,and MFG-E8 or D89E was injected into the vitreous cavity of the rats.The intraoc-ular pressure of the rats was measured.HE staining,TUNEL staining and immunofluorescence staining were used to detect the patholog-ical injury,apoptosis and microglia activation of the retina.The protein expressions of cleaved caspase-3,caspase-3,cleaved caspase-9,caspase-9 and Bax were detected by Western blotting,and the expression levels of IL-10,TGF-βand NGFwere detected by ELISA and RT-qPCR.Results Compared with the control group,the intraocular pressure of glaucoma rats significantly increased,the retinal GCC layer became thinner,the apoptotic cells increased,the levels of cleaved caspase-3/caspase-3,cleaved caspase-9/caspase-9 and Bax increased,and the number of IBA1 positive cells increased,after treatment with MFG-E8,retinal GCC layer thickness increased,and the levels of cleaved caspase-3/caspase-3,cleaved caspase-9/caspase-9,Bax decreased,the number of IBA1 positive cells and the levels of IL-10,TGF-β,NGFincreased,but the progression of glaucoma was aggravated after the treatment of MFG-E8 inactivated isomer D89E.Conclusion MFG-E8 can mediate microglia activation,inhibit apoptosis of ganglion cells,and slow down the progression of glaucoma in rats.

Purpose: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. Results: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. Conclusion EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Objective To investigate changes in the intraocular pressure(IOP) and anterior chamber angle in patients with chronic renal failure before and after hemodialysis. Methods Fifty?eight patients(116 eyes) with chronic renal failure were measured with Goldmann applanation tonometer and anterior segment optical coherence tomograph. The patients were divided into three groups based on gonioscopy results:the narrow angle group(22 eyes),the Iris neovascular group(3 eyes)and the open angle group(91 eyes). IOP was measured by Goldmann applanation tonometer in patients in the three groups before and after hemodialysis. Anterior chamber angle opening distance (AOD) was detected by anterior segment optical coherence tomograph before and after hemodialysis. The blood urea nitrogen,creatinine,albumin were also determined before and after hemodialysis. All changes in the parameters were analyzed with a paired t test. Results The IOP in narrow angle eyes and in neovascular eyes increased significantly after hemodialysis ,while the IOP in open angle eyes showed no significant changes. The AOD decreased significantly after hemodialysis. The blood urea nitrogen and creatinine decreased significantly in 58 patients,while albumin increased after hemodialysis. Conclusion The IOP in narrow angle eyes and in neovascular eyes increased after hemodialysis ,correlating with the resistance increase of aqueous outflow pathway and the change of plasma osmotic pressure. As a result ,it is recommended that the condition of eye of patients with chronic renal failure should be checked ,and patients should receive appropriate controlling measure or treatment before hemodialysis.

Objective To investigate the clinical effect of a new type of disposable heparin freedialysis tube in uremic patients without heparin dialysis. Methods A total of 110 patients withoutheparin dialysis were divided into control group and observation group by random digits table method with55 cases each. Based on the same pre dialysis and dialysis for heparin saline flushing of discontinuoussaline on the control group using the traditional dialysis pipe for hemodialysis without heparin, theobservation group used disposable non heparin dialysis pipe for hemodialysis without heparin. The numberof patients with venous catheter blockage, blood loss and completion of dialysis time in two groups wasrecorded. Results The number of patients with venous catheter blockage, blood loss and completion ofdialysis time was 6, 6, 47 cases in control group and 0, 0, 54 cases in observation group. The differences were statistically significant (χ2=4.407, 4.407, 4.356, P<0.05). Conclusions The new disposableheparin free dialysis tube can reduce the loss of blood and prolong the treatment time, and the operation issimple, safe and effective, and has good application value and application prospect.

Objective To explore the function of 5-Aza-CdR in B-cell acute lymphocytic leukemia cell line NALM-6 and its influence on the expression of microRNA (miRNA) in the cells. Methods NALM-6 was treated with different concentrations of 5-Aza-CdR. Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) test, and DNA methyltransferase (DNMT) mRNA expression level was detected by reverse transcription PCR (RT-PCR). The expression changes of miRNA were detected by miScript miRNA PCR Array chip in cells after methylation. Results NALM-6 cell growth was inhibited by different concentrations of 5-Aza-CdR processing time, reaching to the maximum inhibitory rate was (74.163 ±0.381) %. 5-Aza-CdR affected concentrations was inversely proportional with expression level of DNMT mRNA. After 1 000 μmol/L of 5-Aza-CdR was dealed with cell 72 h, the relative expression of DNMT-1 was reduced to 0.453 ±0.021, DNMT-3L was 0.003±0.001, DNMT-3B was 0.395±0.019. MiScript miRNA PCR array sieved out 3 miRNA (miR-184, miR-23a-3p, miR-34a-5p) associated with DNA methylation. Conclusions 5-Aza-CdR down regulates the expression of DNMT gene in NALM-6 cells, and inhibits the proliferation of cells. MiR-184, miR-23a-3p and miR-34a-5p are related to DNA methylation in the occurrence and development of B-cell acute lymphocytic leukemia.

Objective To evaluate the recent safety and long-term curative effect of double-pool shaping trabeculectomy with adjustable sutures in glaucoma. Methods A hundred and twenty patients with glaucoma were randomly divided into two groups, in which the control group in 62 patients underwent traditional trabeculectomy and the experimental group in 58 patients underwent double-pool shaping trabeculectomy with adjustable sutures. All patients were followed up for one year. Postoprative intraocular pressure, anterior chamber depth and filtering bleb were observed. Results In the experimental group, after the demolition of adjustable sutures, 3 eyes(5.17%) suffered from I degree shallow anterior chamber. By contrast, 8 eyes suffered from I degree shallow anterior chamber, and 1 eye (total 14.52%) suffered from Ⅱ degree shallow anterior chamber in the control group (P < 0.05). Following up in one year, the functional filtering bleb and intraocular pressure got better in the experimental group than in the control group (P < 0.05). Conclusion Double-pool shaping trabeculectomy with adjustable sutures is a safe and feasible method for glaucoma, in which it can effectively reduce intraocular pressure without complications.

This study was aimed to optimize the uniform design for effective constituents in water-soluble extractives D, E, F of traditional Chinese medicine (TCM) in Qi-Xue Bing-Zhi Fang (QXBZF) for the further validation of the ratio of different compatibility. A total of 100 SD rats were used in the study. Among them, 90 rats were given high fat feeding for 7 days. Then, stratified randomization was used. The rats were divided into the all-party group; D, E original prescription group; D, E optimized compatible group; D, E between optimized and original group; D, E optimized but anti-compatibility group; all-party group adding F; optimized compatible group adding F; QXBZF with mainly paeoniflorin accounted for 49.12% as component D, total flavonoids accounted for 30.0% as component E, total acids accounted for 32.07% in component F; the positive drug control group (Xue-Zhi-Kang, 0.108 g/kg); and the high fat model group. In addition, a blank control group (with normal diet) was set. Each group was treated with gastric perfusion according to drug compatibility proportion for 14 days. Rats were sacrificed to take blood samples for the detection of serum lipid, platelet aggregation, vasoactive substance, and inflammation level. The results showed that compared with the model group, the QXBZF D, E original prescription group and D, E optimized compatible group had significant decreasing effects on TC (P< 0.05). The lowest level of TC decreased by optimized compatible group was (3.49 ± 0.86) mmol/L. The all-party group, D, E original prescription group and optimized compatible group can inhibit the platelet with maximum aggregation rate effectively(P< 0.05, P< 0.01); while the D, E optimized but anti-compatibility group (with D, E inverse proportion) had no effect on it. All-party group and the D, E original group adding F had significant inhibition on IL-6 and IL-8 (P < 0.05, P < 0.01). The D, E original prescription group, D, E optimized compatible group and D, E between optimized and original group can ascend 6-Keto-PGF1α significantly (P< 0.05). ET-1 was decreased in the D, E optimized compatible group (P< 0.05). Other groups had no obvious effect on vascular active substances. It was concluded that different effects between the QXBZF D, E original prescription group and the D, E optimized compatible group were observed in action segment and strength. When F parts added, inhibitions of inflammation levels were enhanced at certain level.