Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

OBJECTIVES: To investigate the expression of CDKN3 in gastric cancer and its impact on prognosis of gastric cancer patients. METHODS: We analyzed CDKN3 expression in clinical specimens from 114 gastric cancer patients and assessed its association with 5-year postoperative survival of the patients. GO and KEGG enrichment analyses were used to predict the biological function and possible mechanism of CDKN3. The effects of lentivirus-mediated CDKN3 knockdown on biological behaviors of gastric cancer cells were evaluated using Transwell assay, CCK-8 assay, TUNEL staining, flow cytometry, and Western blotting. RESULTS: CDKN3 expression was significantly higher in gastric cancer tissues than in the adjacent tissues with significant correlations with CEA level, CA19-9 level, and T and N staging (P<0.05). High CDKN3 expression was an independent risk factor affecting 5-year postoperative survival of the patients and predictive for long-term prognosis (P<0.01). Enrichment analyses suggested a probable association of CDKN3 with apoptosis. In MGC-803 cells, CDKN3 knockdown significantly lowered migration and invasion capacities of the cells, while CDKN3 overexpression produced the opposite effects. TUNEL staining revealed a significantly lower level of cell apoptosis in gastric cancer tissues than in adjacent tissues (P<0.01). CDKN3 knockdown obviously inhibited proliferation and increased apoptosis of MGC-803 cells. CDKN3 overexpression down-regulated the expressions of p53, p21 and Bax and up-regulated the expressions of p-p65 and Bcl-2. CONCLUSIONS CDKN3 is highly expressed in gastric cancer tissues and affects patient prognosis. CDKN3 overexpression promotes proliferation, invasion and migration and suppressed apoptosis of gastric cancer cells possibly through the p53/NF-κB signaling pathway.
Humans ; Stomach Neoplasms/pathology* ; Apoptosis ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism* ; Cell Movement ; Cell Line, Tumor ; NF-kappa B/metabolism* ; Prognosis ; Cyclin-Dependent Kinase Inhibitor Proteins/metabolism* ; Cell Proliferation ; Neoplasm Invasiveness ; Male ; Female ; Dual-Specificity Phosphatases

Objective To observe resting-state functional connectivity(rs-FC)changes of mirror neuron system(MNS)brain regions in male nicotine addicts,and to explore their correlations with the degree of addiction.Methods Twenty-five male nicotine addicts(addiction group)and 27 healthy males(control group)were prospectively recruited,and resting-statefunctional MR scanning was performed.The general information and rs-FC values were compared between groups,and correlations of rs-FC values with Fagerstr?m test for nicotine dependence(FTND)and heaviness of smoking index(HSI)scale scores in addiction group were analyzed.Results No significant difference of age nor education level was found between groups(both P＞0.05).Compared to control group,rs-FC values between left inferior frontal gyrus(IFG.L)and right middle temporal gyrus(MTG.R)as well as right middle occipital gyrus(MOG.R)increased(GRF corrected,voxel-level P＜0.005,cluster-level P＜0.05),while between right fusiform gyrus(FFG.R)and right dorsal cingulate gyrus(DCG.R),right supplementary motor area(SMA.R),left medial superior frontal gyrus(SFGmed.L)and left supplementary motor area(SMA.L)decreased(GRF corrected,voxel-level P＜0.005,cluster-level P＜0.05).In addiction group,rs-FC value between IFG.L and MTG.R was negatively correlated with HSI scale score(r=-0.457,P=0.022),while that between IFG.L and MOG.R was negatively correlated with HSI scale and FTND scores(r=-0.440,-0.458,P=0.028,0.021).Conclusion There were specific changes of rs-FC patterns of MNS brain regions in male nicotine addicts,which were correlated with the degree of addiction.

Objective:Persistent proatlantal intersegmental artery (PPIA) is a rare variant of persistent carotid-vertebrobasilar anastomoses and mostly discovered incidentally. To explore the clinical features of PPIA, and enhance the understanding of this rare cerebrovascular variation.Methods:A retrospective analysis was performed. The clinical data of 6 patients with PPIA admitted to Department of Neurointervention, First Affiliated Hospital of Zhengzhou University from June 2018 to June 2024 were analyzed. The imaging features, associated cerebrovascular diseases, treatments and follow-up results were summarized.Results:Among the 6 PPIA patients, 4 were with type I and 2 were with type II; 5 were with left PPIA and 1 patient was with right PPIA; 5 patients had bilateral vertebral artery hypoplasia or absence, and 1 patient had absence of the ipsilateral vertebral artery and normal development of the contralateral vertebral artery. Four PPIA patients were combined with intracranial aneurysms: 2 patients received dual stent-assisted embolization and flow diverter device combined with covered stent implantation, respectively (after 6 months of follow-up, modified Rankin scale score of 0 indicating good prognosis and healed intracranial aneurysms), and the other 2 patients with micro-aneurysms were not treated. One patient was combined with internal carotid artery stenosis and accepted stent placement (good prognosis at 6 months after follow-up). One patient was combined with acute basilar artery tip occlusion and accepted aspiration thrombectomy (died of brain herniation 7 days after thrombectomy).Conclusions:PPIA is often accompanied by vertebral artery developmental abnormalities and prone to have concurrent intracranial aneurysms or ischemic stroke. When performing surgical treatment for cerebrovascular diseases associated with PPIA, PPIA protection to ensure blood supply of the posterior circulation is essential.

Objective To evaluate the efficacy and safety of DSA-guided continuous radiofrequency ablation(CRF)and high-voltage,long-duration pulsed radiofrequency(HL-PRF)of ganglia impar in treating perineal pain in patients with rectal cancer.Methods This study is a single-center,randomized,active-controlled,double-blind trial that included 57 rectal cancer patients with perineal pain.At a 1∶1 ratio,the patients were randomly divided into CRF group(n=28)and HL-PRF group(n=29).The primary outcome indicators were the pain numerical rating scale(NRS)scores determined at the preoperative(T0),postoperative 24 h(T1),one week(T2),one month(T3),3 months(T4)and 6 months(T5)time-points.The secondary outcome indicators included the sitting time at T0,T1,T2,T3,T4 and T5 time-points,the 9-item patient health questionnaire(PHQ-9)score,the pittsburgh sleep quality index(PSQI)score,the postoperative oral morphine dosage,and the incidence of perineal numbness.Results Compared with the value at T0 time-point,in both groups the NRS score,PHQ-9 score and PSQI score at T1-T5 time-points were significantly decreased,while the sitting time become remarkably increased(all P＜0.05).No statistically significant differences in postoperative oral morphine dosage and incidence of perineal numbness existed between the two groups(both P＞0.05).There were no statistically significant differences in NRS score,PHQ-9 score and PSQI score,sitting time and oral morphine dosage at T1,T2,T3 time-points between CRF group and HL-PRF group(all P＞0.05),while at T4 and T5 time-points the NRS score,PHQ-9 score and PSQI score in HL-PRF group were significantly higher than those in CRF group(all P＜0.05),and the sitting time in HL-PRF group was strikingly lower than that in CRF group(P＜0.05).Conclusion Both CRF and HL-PRF of ganglion impar can alleviate perineal pain in patients with advanced rectal cancer and improve the quality of life of patients.CRF is superior to HL-PRF in the long-term efficacy.

Objective To explore the clinical value of mini-incision combined with balloon dilatation under the guidance of miniprobe echoendoscope in the treatment of refractory benign esophageal stenosis.Methods From October 2019 to October 2023,30 cases of esophageal early cancer with esophageal scar stenosis after endoscopic submucosal dissection(ESD)were selected and randomly divided into study group(miniprobe echoendoscope guided small incision+balloon dilatation,15 cases)and control group[esophageal radial incision(ERI),15 cases],EUS in the study group judged the hierarchical structure of esophageal wall before operation,and excluded those with esophageal cancer recurrence and submucosal invasive growth.According to miniprobe echoendoscope,the length of scar segment and the scope of scar ring lumen were defined,and the location and length of pre-incision were defined,and then balloon was used to expand step by step.The short-term postoperative complications,Stooler dysphagia scale score and restenosis rate of the two groups were observed,and the feasibility,safety and efficacy were evaluated.Results The incidence of short-term postoperative complications 6.7％in the study group was significantly lower than that 46.7％in the control group,the difference was statistically significant(P＜0.05),and the Stooler dysphagia scale score were(1.133±0.990)and(1.600±0.737)in the study group at 1 and 2 months after operation with significantly lower than those(2.067±1.033)and(2.467±0.915)in the control group,the differences were statistically significant(P＜0.05).Two months after operation,the restenosis rate was 13.3％,which was significantly lower than that 46.7％of the control group,the difference was statistically significant(P＜0.05),and the scar thickness under miniprobe echoendoscope(2.113±0.887)mm was significantly thinner than that(3.353±1.468)mm of the control group,the difference was statistically significant(P＜0.05).Conclusion Preoperative miniprobe echoendoscope evaluation,can accurately locate lesions,endoscopic mini-incision combined with balloon mechanical expansion are safe and effective,with less pain and fewer postoperative complication.

Objective To observe resting-state functional connectivity(rs-FC)changes of mirror neuron system(MNS)brain regions in male nicotine addicts,and to explore their correlations with the degree of addiction.Methods Twenty-five male nicotine addicts(addiction group)and 27 healthy males(control group)were prospectively recruited,and resting-statefunctional MR scanning was performed.The general information and rs-FC values were compared between groups,and correlations of rs-FC values with Fagerstr?m test for nicotine dependence(FTND)and heaviness of smoking index(HSI)scale scores in addiction group were analyzed.Results No significant difference of age nor education level was found between groups(both P＞0.05).Compared to control group,rs-FC values between left inferior frontal gyrus(IFG.L)and right middle temporal gyrus(MTG.R)as well as right middle occipital gyrus(MOG.R)increased(GRF corrected,voxel-level P＜0.005,cluster-level P＜0.05),while between right fusiform gyrus(FFG.R)and right dorsal cingulate gyrus(DCG.R),right supplementary motor area(SMA.R),left medial superior frontal gyrus(SFGmed.L)and left supplementary motor area(SMA.L)decreased(GRF corrected,voxel-level P＜0.005,cluster-level P＜0.05).In addiction group,rs-FC value between IFG.L and MTG.R was negatively correlated with HSI scale score(r=-0.457,P=0.022),while that between IFG.L and MOG.R was negatively correlated with HSI scale and FTND scores(r=-0.440,-0.458,P=0.028,0.021).Conclusion There were specific changes of rs-FC patterns of MNS brain regions in male nicotine addicts,which were correlated with the degree of addiction.

Objective To explore the clinical value of mini-incision combined with balloon dilatation under the guidance of miniprobe echoendoscope in the treatment of refractory benign esophageal stenosis.Methods From October 2019 to October 2023,30 cases of esophageal early cancer with esophageal scar stenosis after endoscopic submucosal dissection(ESD)were selected and randomly divided into study group(miniprobe echoendoscope guided small incision+balloon dilatation,15 cases)and control group[esophageal radial incision(ERI),15 cases],EUS in the study group judged the hierarchical structure of esophageal wall before operation,and excluded those with esophageal cancer recurrence and submucosal invasive growth.According to miniprobe echoendoscope,the length of scar segment and the scope of scar ring lumen were defined,and the location and length of pre-incision were defined,and then balloon was used to expand step by step.The short-term postoperative complications,Stooler dysphagia scale score and restenosis rate of the two groups were observed,and the feasibility,safety and efficacy were evaluated.Results The incidence of short-term postoperative complications 6.7％in the study group was significantly lower than that 46.7％in the control group,the difference was statistically significant(P＜0.05),and the Stooler dysphagia scale score were(1.133±0.990)and(1.600±0.737)in the study group at 1 and 2 months after operation with significantly lower than those(2.067±1.033)and(2.467±0.915)in the control group,the differences were statistically significant(P＜0.05).Two months after operation,the restenosis rate was 13.3％,which was significantly lower than that 46.7％of the control group,the difference was statistically significant(P＜0.05),and the scar thickness under miniprobe echoendoscope(2.113±0.887)mm was significantly thinner than that(3.353±1.468)mm of the control group,the difference was statistically significant(P＜0.05).Conclusion Preoperative miniprobe echoendoscope evaluation,can accurately locate lesions,endoscopic mini-incision combined with balloon mechanical expansion are safe and effective,with less pain and fewer postoperative complication.