Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury. However, its regulatory function in microglial pyroptosis and involvement in SAE remains unclear. In this study, we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury. Furthermore, OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice. Mechanistically, OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation, thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation. In conclusion, this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
Animals ; Microglia/metabolism* ; Pyroptosis/physiology* ; Mice ; Sepsis-Associated Encephalopathy/prevention & control* ; Activating Transcription Factor 2/metabolism* ; N-Acetylglucosaminyltransferases/genetics* ; Mice, Inbred C57BL ; Male ; Mice, Knockout

Objective:To investigate the predictive value of fluid-attenuated inversion recovery (FLAIR) signal strength ratio (SIR) in onset time≤4.5 h in patients with acute ischemic stroke.Methods:A retrospective analysis was performed; 180 acute ischemic stroke patients admitted to Department of Neurology, Nanjing Hospital Affiliated to Nanjing Medical University from January 2020 to June 2023 were chosen. Hypoperfusion intensity ratio (HIR) was used to evaluate the collateral circulation (poor collateral circulation: HIR≤0.4; good collateral circulation: HIR>0.4); clinical data and imaging indexes between poor collateral circulation and good collateral circulation groups were compared. Univariate and multivariate Logistic regressions were used to analyze the influencing factors for onset time≤4.5 h in patients with acute ischemic stroke. Correlation between SIR and onset time was analyzed in patients with acute ischemic stroke. Role of HIR as agency between SIR and onset time was explored. Receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of SIR and diffusion weighted imaging (DWI)-FLAIR mismatch in onset time≤4.5 h in acute ischemic stroke patients.Results:Of the 180 patients, 100 were into the good collateral circulation group and 80 were into the poor collateral circulation group; compared with the good collateral circulation group, the poor collateral circulation group had significantly higher percentage of patients with hyperlipidemia, larger DWI infarction volume before treatment, larger perfusion weighted imaging (PWI)-DWI mismatch volume and higher SIR ( P<0.05). In these 180 patients, 76 had onset time≤4.5 h and 104 had onset time>4.5 h. Univariate Logistic regression analysis showed that hyperlipidemia, DWI infarct volume before treatment, DWI-FLAIR mismatch, HIR and SIR were influencing factors for onset time≤4.5 h in acute ischemic stroke patients ( P<0.05). Multivariate Logistic regression analysis showed that hyperlipidemia ( OR=6.654, 95% CI: 5.751-8.824, P<0.001), HIR ( OR=0.724, 95% CI: 0.521-1.321, P=0.041) and SIR ( OR=739.881, 95% CI: 383.296-14 258.065, P<0.001) were independent influencing factors for onset time≤4.5 h in acute ischemic stroke patients. Pearson correlation analysis showed that SIR was positively correlated to onset time in patients with acute ischemic stroke ( r=0.420, P<0.05), and SIR was positively correlated to onset time in patients from poor collateral circulation group ( r=0.781, P<0.05). ROC curve showed that AUC of SIR in predicting onset time≤4.5 h was 0.917 (95% CI: 0.814-1.000, P<0.001) and that of DWI-FLAIR mismatch in predicting onset time≤4.5 h was 0.530 (95% CI: 0.509-0.757, P=0.075) in poor collateral circulation group, enjoying significant difference in predictive efficacy. Conclusion:Acute ischemic stroke patients with low HIR and SIR have higher odds of onset time≤4.5 h; SIR can more accurately predict the onset time in these patients with poor collateral circulation.

This paper summarized Professor PENG Peichu's experience in the differentiation and treatment of prostate cancer in three phases and four stages. It is considered that prostatic cancer is categorized into root deficiency and branch excess， with depletion of healthy qi as the root， and the accumulation of cancer toxin as the minifestation. Clinical diagnosis and treatment of prostatic cancer can be divided into three phases and four stages according to the exuberance and decline of pathogenic and healthy qi and the changes of deficiency and excess of yin and yang. In the initial accumulation phase of cancer toxin （yang excess stage）， the key pathogenesis is the accumulation of dampness， heat and static blood， and internal generation of cancer toxin， and the treatment should be resolving toxins， fighting cancer and dispelling yang excess. In the phase of healthy qi deficiency and toxin accumulation （yin deficiency stage）， with the lung and kidney yin deficiency， dampness， heat and static toxin accumulation as the key pathogenesis， the treatment should be centered on mutual generation between metal and water to nourish kidney yin， supplemented with the method of clearing heat and draining dampness， activating blood and resolving toxins， for which self-made Nanbei Formula（南北方）is usually used. In the phase of yang deficiency and cold stagnation （yang deficiency stage and yin excess stage）， with the spleen and kidney yang deficiency， cold dampness stagnation， static heat and toxin accumulation as the key pathogenesis， the treatment should be warming and tonifying spleen and kidney to dissipate cold accumulation； for deficiency of both yin and yang， and excess pathogen obstruction， modified Yanghe Decoction（阳和汤） is recommended， while for yang deficiency， cold congealing and blood stasis， self-made Wenshen Sanjie Formula（温肾散结方） can be used， and for cold dampness binding with cancer toxin， and cold complex with heat， self-made Quanan Formula （泉安方） is advised.

Objective To develop an automatic segmentation model of acute stroke lesions based on DWI images,and build a 1-year recurrence prediction model of acute stroke based on this model and machine learning technology.Methods The patients with acute ischemic stroke who received intravascular therapy in Nanjing First Hospital from January 2019 to September 2021 were retrospectively included.The patients were divided into recurrence group and non-recurrence group according to clinical and imaging data within 1 year.The developed EfficientNet-B0 network was applied to segment acute stroke lesions on DWI images and its segmentation efficiency was evaluated.Based on automatic segmentation and manual delineation of tags respectively,the radiomics were extracted and the support vector machine classifier was used to construct the prediction model of acute stroke recurrence.Delong test was used to compare the differences between the two models.Results A total of 268 patients were included in the study,161 in the non-recurrence group and 107 in the recurrence group.The sensitivity,specificity,accuracy and Dice similarity coefficient of DWI automatic lesion segmentation model was 0.791,0.999,0.817 and 0.803,respectively.The area under the curve(AUC)of the prediction model of acute stroke recurrence based on the radiomics of the automatic segmentation lesions was 0.878(95%CI:0.834-0.923)(sensitivity:0.879,specificity:0.851).The AUC of the prediction model of acute stroke recurrence based on the radiomics of of manually outlined tags was 0.865(95%CI:0.819-0.911)(sensitivity:0.860,specificity:0.832).There was no significant statistical difference between the two models(Z=0.526,P=0.599).Conclusion The network proposed in this study can well segment acute stroke lesions on DWI,and the prediction model based on the radiomics of this model can predict the recurrence of acute stroke very well.

Objective To investigate the safety and short-term efficacy of π-shaped anastomosis and circular anastomosis(reverse puncture device)in reconstruction of esophagojejunostomy after laparoscopic total gastrectomy.Methods A retrospective study was used to collect the clinical and pathological data of 75 cases of gastric cancer from January 2019 to March 2021.According to the different reconstruction methods of esophagojejunal anastomosis,the patients were divided into a linear cutting obturator group(π-shaped anastomosis group,n = 27)and a circular anastomat anastomosis group(reverse puncture device group,n = 48).The general information of the two groups,operation time,esophagojejunostomy time,intraoperative bleeding volume,number of intraoperative lymph node dissection,intraoperative complications,and postoperative complications were compared and analyzed.Results The operation time and esophagojejunostomy time in the π-shaped anastomosis group were(221.5±8.8)and(34.7±3.7)min,and the reverse puncture device group were and(246.9±5.6)and(47.2±4.6)min,respectively,the differences were statistically significant(t = 15.19,t = 11.81,P＜0.05).There were no statistical significance in the comparison of intraoperative bleeding volume and number of intraoperative lymph node dissection between the two groups(P＞0.05).In the reverse puncture device group,there were two intraoperative complications,including one case of esophageal jejunal anastomosis atresia and one case of anastomosis tear,postoperative complications occurred in 3 cases,postoperative anastomotic stenosis occurred in 2 case,and anastomotic bleeding occurred in 1 case.Conclusion Laparoscopic total esophagojejunostomy with π-shaped anastomosis and reverse puncture device are safe and feasible.In terms of esophagojejunostomy time,π-shaped anastomosis reconstruction time is shorter.When the small intestine diameter is relatively small and it is difficult to extend into the 25 mm stapler,the advantage of π-shaped anastomosis is more obvious.When the tumor is Siewert type Ⅰ and type Ⅱ adenocarcinoma of gastroesophageal junction,which infiltrates into above the dentate line,reverse puncture device method is recommended for reconstruction.

ObjectiveTo explore the mechanism of plumbagin as a novel ferroptosis inducer in bladder cancer inhibition. MethodBladder cancer T24 cells were used in this study. The effect of different concentrations of plumbagin （0.1， 1， 2， 3， 6， 12， 24， 48 μmol·L^-1） on the viability of T24 cells was detected by cell counting kit-8 （CCK-8）. The effect of different concentrations of plumbagin （1.5， 3， 6 μmol·L^-1） on the apoptosis of T24 cells was detected by annexin V-fluorescein isothiocyanate （Annexin V FITC）/PI apoptosis kit. Different inhibitors （ferroptosis inhibitor Fer-1， apoptosis inhibitor VAD， and necroptosis inhibitor Nec-1） were used in combination with plumbagin （6 μmol·L^-1）. Reactive oxygen species （ROS） fluorescent probe （DCFH-DA）， malonaldehyde （MDA）， and glutathione （GSH） kits were used to detect the effects of different concentrations of plumbagin （1.5， 3， 6 μmol·L^-1） on the level of ROS and the content of MDA and GSH in T24 cells， respectively. The effect of different concentrations of plumbagin （1.5， 3， 6 μmol·L^-1） on peroxide levels in T24 cells was detected by C11-BODIPY fluorescent probe. Western blot was used to detect the effect of different concentrations of plumbagin （1.5， 3， 6 μmol·L^-1） on the protein expression of solute carrier family 7 member 11 （SLC7A11）， glutathione peroxidase 4 （GPX4）， nuclear factor E₂-related factor-2 （Nrf-2）， and Kelch-like ECH-associated protein 1 （Keap1）. ResultCompared with the blank group， plumbagin could inhibit the activity of T24 cells （P<0.05） with IC₅₀ of 3.52 μmol·L^-1. At the concentrations of 1.5， 3， 6 μmol·L^-1， plumbagin significantly promoted the apoptosis of T24 cells （P<0.05） as compared with the blank group. Compared with the plumbagin group at 6 μmol·L^-1， the ferroptosis inhibitor and apoptosis inhibitor groups could reverse the inhibitory effect of 6 μmol·L^-1 plumbagin on the proliferation of T24 cells （P<0.05）. Compared with the blank group， the plumbagin groups at 1.5， 3， 6 μmol·L^-1 showed increased content of ROS， MDA， and lipid peroxides in T24 cells， decreased GSH level， and reduced SLC7A11， GPX4， and Nrf-2/Keap1 （P<0.05）. Conclusionplumbagin can induce ferroptosis， and its mechanism is related to the Nrf-2/Keap1 signaling pathway.

Objective:To uncover the effect of circ0025847 on the proliferation of colorectal cancer cells and its molecular mechanisms.Methods:qRT-PCR was utilized to analyze the expression of circ0025847 and QK1 in human colorectal cancer cells (HCT116, SW480) and normal mucosa cells (NCM460) .CCK-8 was used to analyze the effect of circ0025847 and QK1 on proliferation in colorectal cancer cells. Bioinformatics method was used to screen RBP which could bind to circ0025847. RNA pulldown and RIP was utilized to confirm whether QK1 binds to circ0025847.Effects of circ0025847 over-expression on QK1 expression was analyzed by Western blot.NC group, circ0025847 overexpression group and circ0025847 overexpression+ QK1 inhibitor group were established and the proliferation effect was determined by CCK8.Results:circ0025847 (the expression levels in NCM460, HCT116 and SW480 cells were 1.01±0.05, 0.49±0.08, 0.45±0.10) and QK1 (the expression levels in NCM460, HCT116 and SW480 cells were 0.98±0.07, 0.50±0.07, 0.47±0.09) expression was significantly downregulated in colorectal cancer cells. Overpression of circ0025847 and QK1 suppressed colorectal cancer cells growth.RNA pull-down and RIP clarified that circ0025847 bind to QK1 and circ0025847 positively regulate QK1 expression (7 199.20±12.44 VS 3 889.80±11.03) . circ0025847 inhibiting the proliferation of colorectal cancer cells by promoting the expression of QK1 was confirmed by rescue experiment.Conclusion:circ0025847 inhibits colorectal cancer cells proliferation via positively regulating QK1 expression, indicating that circ0025847 may be potential therapeutic target of colorectal cancer.

Objective:To examine the short-term and long-term outcomes of tricuspid valve replacement (TVR) in patients with left ventricular dysfunction.Methods:The clinical data of 24 patients with left ventricular dysfunction who received TVR at Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University from November 1993 to August 2018 were consecutively enrolled. There were 14 males and 10 females, aged (41.9±13.2) years old (range: 19 to 66 years old). The preoperative ejection fraction was (42.9±6.4)% (range: 21% to 49%), while less than 35% in 3 patients. The scores of Charlson comorbidity index were as follows: 5 patients for 0, 6 patients for 1, 7 patients for 2, 1 patient for 3 and 5 patients for 4. The European system for cardiac operative risk evaluation (EuroSCORE) Ⅰ was 3.6±2.1 (range: 1 to 9). The EuroSCORE Ⅱ was (4.91±2.40)% (range: 1.58% to 11.60%). The model for end-staged liver disease score was 1.8±1.2 (range: 0.2 to 7.1). The simplified model for end-staged liver disease score was 5.6±2.5 (range: 1.5 to 13.4). Follow-up was conducted by clinic. The long-term survival rate was calculated by Kaplan-Meier method.Results:In-hospital mortality was 16.7% (4/24), including 1 patient for multiple organ failure and 3 patients for low cardiac output syndrome (LCOS). One patient needed continuous renal replacement therapy and 6 patients suffered from LCOS. The follow-up time was 1 to 19 years, with a median of 8 years. During the follow-up period, 4 patients died, including 2 deaths for cardiogenic cause, 1 death for anticoagulant complications, and 1 death for lung cancer. The 1, 5 and 10-year survival rates were 76.2%, 71.4% and 64.9%, respectively.Conclusion:The short-term and long-term clinical outcomes of TVR in patients with left ventricular dysfunction are acceptable, but the mortality and morbidity are still high.

Objective:To examine the short-term and long-term outcomes of tricuspid valve replacement (TVR) in patients with left ventricular dysfunction.Methods:The clinical data of 24 patients with left ventricular dysfunction who received TVR at Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University from November 1993 to August 2018 were consecutively enrolled. There were 14 males and 10 females, aged (41.9±13.2) years old (range: 19 to 66 years old). The preoperative ejection fraction was (42.9±6.4)% (range: 21% to 49%), while less than 35% in 3 patients. The scores of Charlson comorbidity index were as follows: 5 patients for 0, 6 patients for 1, 7 patients for 2, 1 patient for 3 and 5 patients for 4. The European system for cardiac operative risk evaluation (EuroSCORE) Ⅰ was 3.6±2.1 (range: 1 to 9). The EuroSCORE Ⅱ was (4.91±2.40)% (range: 1.58% to 11.60%). The model for end-staged liver disease score was 1.8±1.2 (range: 0.2 to 7.1). The simplified model for end-staged liver disease score was 5.6±2.5 (range: 1.5 to 13.4). Follow-up was conducted by clinic. The long-term survival rate was calculated by Kaplan-Meier method.Results:In-hospital mortality was 16.7% (4/24), including 1 patient for multiple organ failure and 3 patients for low cardiac output syndrome (LCOS). One patient needed continuous renal replacement therapy and 6 patients suffered from LCOS. The follow-up time was 1 to 19 years, with a median of 8 years. During the follow-up period, 4 patients died, including 2 deaths for cardiogenic cause, 1 death for anticoagulant complications, and 1 death for lung cancer. The 1, 5 and 10-year survival rates were 76.2%, 71.4% and 64.9%, respectively.Conclusion:The short-term and long-term clinical outcomes of TVR in patients with left ventricular dysfunction are acceptable, but the mortality and morbidity are still high.