Objective To explore whether there is a causal relationship between intestinal flora and esophageal cancer. Methods Summary statistics of intestinal flora and esophageal cancer were obtained from the Genome-wide Association Studies (GWAS) database. Five methods, including inverse variance weighted (IVW), weighted median estimation, Mendelian randomization (MR)-Egger regression, single mode, and weighted mode, were used for analysis, with IVW as the main analysis method. Sensitivity analysis was used to evaluate the reliability of MR results. Results In the IVW method, Oxalobacteraceae [OR=1.001, 95%CI (1.000, 1.002), P=0.023], Faecalibacterium [OR=1.001, 95%CI (1.000, 1.002), P=0.028], Senegalimassilia [OR=1.002, 95%CI (1.000, 1.003), P=0.006] and Veillonella [OR=1.001, 95%CI (1.000, 1.002), P=0.018] were positively correlated with esophageal cancer, while Burkholderiales [OR=0.999, 95%CI (0.998, 1.000), P=0.002], Eubacterium oxidoreducens [OR=0.998, 95%CI (0.997, 0.999), P=0.038], Romboutsia [OR=0.999, 95%CI (0.998, 1.000), P=0.048] and Turicibacter [OR=0.998, 95%CI (0.997, 0.999), P=0.013] were negatively correlated with esophageal cancer. Sensitivity analysis showed no evidence of heterogeneity, horizontal pleiotropy and reverse causality. Conclusion Oxalobacteraceae, Faecalibacterium, Senegalimassilia and Veillonella increase the risk of esophageal cancer, while Burkholderiales, Eubacterium oxidoreducens, Romboutsia and Turicibacter decrease the risk of esophageal cancer. Further studies are needed to explore how these bacteria affect the progression of esophageal cancer.

Objective:To investigate the related factors of cognitive impairment in middle-aged and old-aged patients with type 2 diabetes mellitus(T2DM).Methods:A total of 970 patients with T2DM(585 middle-aged group and 385 old-aged group)were selected from residents of a large community in Beijing from September to December 2018.The Mini-Mental State Examination(MMSE)was used to assess the cognitive func-tion.Multivariate logistic regression was used to analyze the related factors.Results:The detection rates of cognitive impairment were 12.0％and 13.5％in middle-aged and old-aged patients with T2DM,respectively.Among mid-dle-aged patients with T2DM,work(OR=0.22,95％CI:0.03-0.77)and education at the junior college or un-dergraduate level and above(OR=0.18,95％CI:0.04-0.55)were protective factors for cognitive impair-ment.Myocardial infarction(OR=4.13,95％CI:1.26-13.63)was a risk factor for cognitive impairment.Among old-aged patients with T2DM,drinking tea 1-2 times a week(OR=0.11,95％CI:0.01-0.58)and education at the junior college or undergraduate level and above(OR=0.19,95％CI:0.05-0.54)were protective factors for cognitive impairment.Stroke(OR=3.64,95％CI:1.55-8.39)and good sleep self-assessment(OR=2.75,95％CI:1.13-7.35)were risk factors for cognitive impairment.Conclusion:Cognitive impairment in middle-aged pa-tients with T2DM is related to work,education level and myocardial infarction,and cognitive impairment in old-aged patients with T2DM is related to lifestyle,education level and stroke.

Objective:To investigate the related factors of cognitive impairment in middle-aged and old-aged patients with type 2 diabetes mellitus(T2DM).Methods:A total of 970 patients with T2DM(585 middle-aged group and 385 old-aged group)were selected from residents of a large community in Beijing from September to December 2018.The Mini-Mental State Examination(MMSE)was used to assess the cognitive func-tion.Multivariate logistic regression was used to analyze the related factors.Results:The detection rates of cognitive impairment were 12.0％and 13.5％in middle-aged and old-aged patients with T2DM,respectively.Among mid-dle-aged patients with T2DM,work(OR=0.22,95％CI:0.03-0.77)and education at the junior college or un-dergraduate level and above(OR=0.18,95％CI:0.04-0.55)were protective factors for cognitive impair-ment.Myocardial infarction(OR=4.13,95％CI:1.26-13.63)was a risk factor for cognitive impairment.Among old-aged patients with T2DM,drinking tea 1-2 times a week(OR=0.11,95％CI:0.01-0.58)and education at the junior college or undergraduate level and above(OR=0.19,95％CI:0.05-0.54)were protective factors for cognitive impairment.Stroke(OR=3.64,95％CI:1.55-8.39)and good sleep self-assessment(OR=2.75,95％CI:1.13-7.35)were risk factors for cognitive impairment.Conclusion:Cognitive impairment in middle-aged pa-tients with T2DM is related to work,education level and myocardial infarction,and cognitive impairment in old-aged patients with T2DM is related to lifestyle,education level and stroke.

Objective:To investigate the efficacy and safety of darolutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.Methods:A retrospective analysis was conducted on 17 cases of prostate cancer patients who received treatment with darolutamide in combination with ADT at our hospital from January to December 2022. The median age was 70 (range: 56 to 92) years old. The median pre-treatment prostate-specific antigen (PSA) level was 63.50 (range: 29.16 to 700.74) ng/ml. Sixteen cases had a Gleason score of 8 or above, and 11 cases were classified as high tumor burden (with four or more bone metastases and/or visceral metastases). The patients were treated with darolutamide in combination with goserelin (10.8 mg, subcutaneous injection, every 12 weeks). The decrease in PSA levels was observed at 2 weeks and at 1, 2, 3, and 6 months post-treatment. The time to achieve a 50% decrease in PSA level (PSA50), a 90% decrease (PSA90), and a PSA level of ≤0.2 ng/ml was recorded.Adverse drug reactions were also documented.Results:All the 17 patients were followed up and continued to receive darolutamide at our center without any loss to follow-up. The median follow-up time was 11.4(8.9, 15.3)months. It showed a median PSA decrease from baseline of 83.33% at 2 weeks, 95.37% at 1 month, 96.71% at 2 months, 97.22% at 3 months, and 99.10% at 6 months. The median time to achieve PSA50, PSA90, and PSA ≤ 0.2 ng/ml were 1.3 (0.9, 1.7)months, 1.7 (1.2, 2.4)months, and 3.6 (2.9, 4.5)months respectively. Six patients with bone metastases experienced relief of metastatic lesions after treatment. Only one patient developed papules on the left upper limb, which were assessed as grade 1 rash, and the rash disappeared after three days treatment of topical application of hydrocortisone cream.Conclusions:Darolutamide could rapidly control and significantly reduce PSA levels in prostate cancer patients, with a favorable safety profile.

Objective:To investigate the efficacy and safety of darolutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.Methods:A retrospective analysis was conducted on 17 cases of prostate cancer patients who received treatment with darolutamide in combination with ADT at our hospital from January to December 2022. The median age was 70 (range: 56 to 92) years old. The median pre-treatment prostate-specific antigen (PSA) level was 63.50 (range: 29.16 to 700.74) ng/ml. Sixteen cases had a Gleason score of 8 or above, and 11 cases were classified as high tumor burden (with four or more bone metastases and/or visceral metastases). The patients were treated with darolutamide in combination with goserelin (10.8 mg, subcutaneous injection, every 12 weeks). The decrease in PSA levels was observed at 2 weeks and at 1, 2, 3, and 6 months post-treatment. The time to achieve a 50% decrease in PSA level (PSA50), a 90% decrease (PSA90), and a PSA level of ≤0.2 ng/ml was recorded.Adverse drug reactions were also documented.Results:All the 17 patients were followed up and continued to receive darolutamide at our center without any loss to follow-up. The median follow-up time was 11.4(8.9, 15.3)months. It showed a median PSA decrease from baseline of 83.33% at 2 weeks, 95.37% at 1 month, 96.71% at 2 months, 97.22% at 3 months, and 99.10% at 6 months. The median time to achieve PSA50, PSA90, and PSA ≤ 0.2 ng/ml were 1.3 (0.9, 1.7)months, 1.7 (1.2, 2.4)months, and 3.6 (2.9, 4.5)months respectively. Six patients with bone metastases experienced relief of metastatic lesions after treatment. Only one patient developed papules on the left upper limb, which were assessed as grade 1 rash, and the rash disappeared after three days treatment of topical application of hydrocortisone cream.Conclusions:Darolutamide could rapidly control and significantly reduce PSA levels in prostate cancer patients, with a favorable safety profile.

Objective To observe the effect of intelligent flexible ankle stretching training on lower extremity spasm in patients with spinal cord injury. Methods From June,2021 to May,2024,28 patients with spinal cord injury were randomly divided into control group(n=14)and experimental group(n=14).Both groups received conventional rehabilitation treatment.On this ba-sis,the control group received manual extension treatment,and the experimental group received intelligent flexi-ble ankle stretching system training,for eight weeks.The modified Ashworth Scale(MAS),ankle dorsiflexion an-gle,Clinical Spasticity Index(CSI),max root mean square(RMSmax)of surface electromyography of gastrocne-mius medial head and vibration perception threshold(VPT)of great toe were compared. Results After treatment,MAS(χ2=10.378,P=0.035),ankle dorsiflexion angle(Z=-3.306,P<0.001),CSI(t=4.101,P=0.001)and RMSmax of gastrocnemius medial head(Z=-3.296,P<0.001)improved in the experimental group,while MAS(χ2=11.418,P=0.022),ankle dorsiflexion angle(Z=-1.986,P=0.047)and RMSmax of gas-trocnemius medial head(Z=-2.297,P=0.021)were better in the experimental group than in the control group.Although VPT was improved after treatment,no significant difference was found within and beteen groups(P>0.05). Conclusion The intelligent flexible ankle stretching training could improve the lower limb muscle spasticity in patients with spinal cord injury,and may be benefit for foot proprioception.

Objective:To investigate the impacts and mechanisms of the GCH1-S81A mutants of the rate-limiting enzyme GTP cyclohydrolase 1 (GCH1) at key phosphorylation sites on the radiosensitivity of esophageal cancers during the de novo synthesis of tetrahydrobiopterin (BH4). Methods:The KYSE-150 cell lines of esophageal squamous cell carcinoma with stable GCH1 overexpression at different phosphorylation levels were constructed in this study. Based on GCH1′s phosphorylation levels and radiation doses, the experimental groups were divided into the blank control group, the empty virus group, the empty virus + irradiation group, the wild-type GCH1 group, the GCH1 phosphorylation group, the GCH1 dephosphorylation group, the GCH1 dephosphorylation + irradiation group, the validation group, and the validation + irradiation group. The Western blot and the CCK-8 assay were employed to detect the infection efficiency and the survival rates of tumor cells in various groups, respectively. The flow cytometry was applied to detect the changes in the apoptosis rate, reactive oxygen species (ROS) level, and lipid peroxide level of tumor cells in various groups. The colony formation assay was used to detect the changes in the radiosensitivity of tumor cells. Besides, the Western blot was performed to detect the changes in the expression of ferroptosis-related proteins.Results:The GCH1 dephosphorylation group showed a significantly decreased expression level of phosphorylated GCH1-S81 protein in the cells at 48 h after infection ( t=9.35, 16.57, P<0.05). Compared to the empty virus + irradiation group, the GCH1 dephosphorylation + irradiation group exhibited a significantly decreased cell survival rate 24 h after 10 Gy X-ray irradiation ( t=26.97, P<0.05). The ROS levels in KYSE-150 cells at 8 h after 10 Gy X-ray irradiation, and the apoptosis rates and lipid peroxide levels at 48 h after irradiation, all showed a significant increase ( t=17.89-131.1, P<0.05), which was further aggravated following the addition of GCH1-S81A mutants ( t=157.06-97.81, P<0.05). This phenomenon could be inhibited by complementing wild-type GCH1 ( t=66.38-23.08, P<0.05). Compared to the empty virus + irradiation group, the GCH1 dephosphorylation + irradiation group manifested decreased colony formation capacity under various X-ray doses (2, 4, 6 and 8 Gy, t=7.31-8.16, P<0.05). The GCH1-S81A mutation reduced the expression level of the ferroptosis-related protein GPX4 ( t=4.55, P<0.05), which was further decreased after 10 Gy X-ray irradiation ( t=12.98, P<0.05). Conclusions:The GCH1-S81A dephosphorylated mutants can inhibit the growth of esophageal carcinoma cells KYSE-150 and enhance their radiosensitivity, which may hold promise as a novel approach to improve the efficacy of radiotherapy for esophageal cancers.

Background:Esophageal neuroendocrine neoplasms(E-NENs)are rare and highly aggressive malignancies.Although endoscopic resection(ER)has demonstrated efficacy in managing gastrointestinal neuroendocrine tumors,ER for E-NENs lacks systematic evidence.Aims:To evaluate the feasibility and safety of ER in E-NENs,establish risk-stratified follow-up strategies based on tumor grade,invasion depth,and margin status,and define indications for ER.Methods:A retrospective analysis was conducted for 8 E-NEN patients treated with ER at the Endoscopy Center,Zhongshan Hospital,Fudan University from November 2017 to July 2021.The clinicopathological data,procedural parameters,adverse events,and follow-up outcomes were collected to summarize the diagnostic and therapeutic insights.Results:The cohort included 8 patients,with male-to-female ratio of 1:1;the mean age was(71.4±8.5)years.Half of the cases were incidentally detected during asymptomatic endoscopic screening.All tumors were confined to the submucosa:4 were small cell neuroendocrine carcinomas(SCNECs),and 4 were mixed neuroendocrine-non-neuroendocrine neoplasms(MiNENs).Endoscopic submucosal dissection(ESD)was performed in 6 cases and submucosal tunneling endoscopic resection(STER)in 2 cases.Self-limiting fever was reported in one case.One cases required additional surgery due to horizontal margin involving(no recurrence over 67 months follow-up).The median hospitalization was 4.5 days.With a median follow-up of 66 months,the recurrence and all-cause mortality rates were both 25.0%(2/8).Conclusions:MiNENs≤2.5 cm with complete ER exhibit favorable prognoses,whereas SCNECs with high mitotic indices or elevated Ki-67 proliferation indices correlate with poorer outcomes.Post-ER surveillance for E-NENs should meet or exceed esophageal squamous cell carcinoma standards.As the largest single-center ER cohort for E-NENs,this study provides critical evidence for minimally invasive management,though multicenter validation is needed.

AIM:To investigate the potential of resveratrol(Res)to alleviate cerebral ischemia-re-perfusion injury(CIRI)by activating autophagy.METHODS:One hundred SD rats were purchased and subjected to middle cerebral artery occlusion/reperfusion(MCAO/R)using the suture method.Rats with failed surgeries were excluded,and they were randomly divided into seven groups:Sham(S)group,Model(M)group,Resveratrol pretreatment(Res)group,3-methyladenine(3-MA)group,Resve-ratrol+3-methyladenine(Res+3-MA)group,Z-YVAD group,and Res+Z-YVAD group,with 12 rats in each group.Neurological deficits and brain dam-age were assessed using Longa scoring,TTC stain-ing,and measurement of infarct volume.Immuno-histochemistry,immunofluorescence,and immu-noblotting were employed to detect the expression of autophagy-related proteins Beclin-1,LC3-Ⅱ,P62,and pyroptosis-related proteins NLRP3,caspase-1,GSDMD,IL-1β.RESULTS:Resveratrol pretreatment improved neurological deficits and reduced infarct volume in rats.It upregulated autophagy-related proteins Beclin-1,LC3-Ⅱ,downregulated P62,and pyroptosis-related proteins NLRP3,caspase-1,GSD-MD,IL-1β expression.The autophagy inhibitor 3-MA completely reversed the above effects of Res.After adding the pyroptosis inhibitor Z-YVAD,the changes in autophagy-related proteins Beclin-1,LC3-Ⅱ,and P62 were not significant,while the ex-pression of NLRP3,caspase-1,GSDMD,IL-1β signifi-cantly decreased.Neurological deficits worsened,and infarct volume increased in rats.CONCLUSION:Res attenuates cerebral ischemia-reperfusion injury by activating autophagy and inhibiting pyroptosis,possibly through the regulation of the P62.

Objective:To explore the mechanism of pterostilbene(PTE)in preventing and treating neuroinflamma-tion after cerebral ischemia-reperfusion injury(CIRI)in rats.Methods:Ninety male SD rats were randomly divided in-to a sham group,a model group(MCAO/R),a low-dose PTE group(PTE-L),a medium-dose PTE group(PTE-M),and a high-dose PTE group(PTE-H).CIRI model was prepared by middle cerebral artery occlusion reperfusion(MCAO/R)in rats.The neurological deficit in rats was evaluated by Zea Longa score.The volume of cerebral infarc-tion was detected by TTC staining.The morphological changes of ischemic cortex was observed HE staining.The ex-pressions of cyclooxygenase-2(COX-2),prostaglandin D2 receptor(DP2)and prostaglandin D1 receptor(DP1)were detected by RT-qPCR and Western Blot.The expressions of prostaglandin D2(PGD2),interleukin-1 β(IL-1β)and tumor necrosis factor-α(TNF-α)were detected by ELISA.Results:Compared with the sham group,the MCAO/R group showed a significant increase in neurological scores(P＜0.05),a significant increase in cerebral infarction vol-ume(P＜0.05),and aggravated cortical damage in the ischemic area.Additionally,there were significant increase in the expressions of COX-2,DP2 mRNA and protein(P＜0.05),along with increased expressions of PGD2,IL-1β and TNF-α(P＜0.05).Compared with the MCAO/R group,the PTE-L,PTE-M,and PTE-H groups showed a significant decrease in neurological scores(P＜0.05),a significant decrease in cerebral infarction volume(P＜0.05),and markedly alleviated cortical damage in the ischemic region.Additionally,there were significant decrease in the expres-sions of COX-2,DP2 mRNA and protein(P＜0.05),along with decreased expressions of PGD2,IL-1β and TNF-α(P＜0.05).Furthermore,a dose-effect relationship was observed for the neuroprotective effects of PTE on brain tissue(P＜0.05).However,there were no significant differences in the expressions of DP,mRNA and protein among all groups(P＞0.05).Conclusion:PTE can attenuate the neuroinflammation of CIRI in rats by inhibiting COX-2/PGD2/DP2 signaling pathway.