[摘 要] 目的：评估放疗作为原位疫苗的联合治疗模式在晚期软组织肉瘤（STS）患者中的有效性和安全性。方法：回顾性分析2020年12月至2024年9月期间在南京大学医学院附属鼓楼医院肿瘤中心接受联合治疗模式的12例晚期STS患者的临床资料。12例患者均接受了联合治疗。放疗主要以大分割为主。靶向治疗：安罗替尼10例、阿帕替尼2例。免疫治疗以PD-1抗体为主。主要研究终点为疾病控制率（DCR），次要研究终点为客观有效率（ORR）及安全性。结果：接受联合治疗的12例STS患者中有0例CR，4例PR，7例SD，1例PD。ORR为33%，DCR为91.7%，其中靶病灶的DCR为100%。12例患者中，9例出现Ⅰ~Ⅱ级不良反应。最常发生的血液学不良反应是贫血（6例）、肝功能检查结果异常（3例）。最常发生的非血液学不良反应是尿蛋白（5例）、高血压（4例）、甲状腺功能异常（3例）、厌食（3例）、恶心呕吐（2例）；仅2例发生Ⅲ级血液毒性，有1例发生Ⅲ级气胸。结论：放疗作为原位疫苗的联合治疗模式在晚期STS患者中展现出较高的DCR，且未出现严重不良反应。该联合治疗模式具有良好的有效性与安全性。

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Shear thinning is an ideal feature of bioink because it can reduce the chance of blocking. For extrusion based biological printing, bioink will experience shear force when passing through the biological printer. The shear rate will increase with the increase of extrusion rate, and the apparent viscosity of shear-thinning bioink will decrease, which makes it easier to block, thus achieving the structural fidelity of 3D printing tissue. The manufacturing of complex functional structures in tissue trachea requires the precise placement and coagulation of bioink layer by layer, and the shear-thinning bioink may well meet this requirement. This review focuses on the importance of mechanical properties, classification and preparation methods of shear-thinning bioink, and lists its current application status in 3D printing tissue trachea to discuss the more possibilities and prospects of this biological material in tissue trachea.

Objective To evaluate the value of a machine learning-based biparametric magnetic resonance imaging(bpMRI)radiomics model in predicting clinically significant prostate cancer(csPCa)in the transitional zone.Methods A retrospective analysis was con-ducted on 507 cases in two medical centers.All patients underwent prostate MRI examinations before surgery,with complete patho-logical data.The case distribution was as follows:256 cases of csPCa,97 cases of clinically insignificant prostate cancer(ciPCa),and 154 cases of benign prostatic hyperplasia(BPH).Using the R language,the data from Center One was randomly divided into training and test groups at a ratio of 7∶3,and the data from Center Two as an independent external validation group.The image features from T2 WI and diffusion weighted imaging(DWI)were extracted,and the least absolute shrinkage and selection operator(LASSO)was used to reduce dimensionality and filter features.Two datasets were constructed based on T2 WI features alone and combined T2 WI and DWI features.Six prediction models were established using random forest(RF),logistic regression(LR),and support vector machine(SVM).The efficacy of six models of T2 WI features and combined T2 WI and DWI features in the diagnosis of prostate dis-eases through receiver operating characteristic(ROC)curve,area under the curve(AUC),and decision curve analysis(DCA)were compared and evaluated.Results In the training group,feature screening identified 7 and 8 features from the T2WI single sequence and the T2WI with DWI dual sequence for csPCa prediction in the transitional zone.The results showed that the T2WI with DWI dual sequence RF model had the highest AUC performance.The AUC of the training,test,and validation groups were 0.950,0.866,and 0.818,respectively.The test group accuracy was 0.805,sensitivity was 0.690,and specificity was 0.920;the validation group accu-racy was 0.726,sensitivity was 0.661,and specificity was 0.793.DCA showed that within a wide probability threshold range,the T2 WI with DWI dual sequence RF model had the greatest net benefit.Conclusion Based on the bpMRI radiomics model,non-invasive prediction of csPCa in the transitional zone can be achieved before surgery,which helps to make clinical diagnosis and treatment decisions.

Objective:To evaluate the effect of stroke volume variation(SVV) goal-directed fluid therapy on postoperative pulmonary complications(PPCs) after pediatric living donor liver transplantation.Methods:One hundred and twenty pediatric patients undergoing pediatric living-donor liver transplantation(all diagnosed with congenital biliary atresia) were divided into 2 groups( n=60 each) using the random number table method: control group and SVV group. Intraoperative fluid management was guided by central venous pressure and mean arterial pressure in control group, while by SVV combined with cardiac output in SVV group. Intraoperative circulation, fluid intake and usage of vasoactive drug were recorded. Central venous blood samples were collected to determine the concentrations of serum Clara cell 16 kDa protein, interleukin-6, and tumor necrosis factor-alpha before anesthesia(T 0), at the end of anhepatic phase(T 1), at 3 h of neohepatic phase(T 2), at the end of surgery(T 3) and at 24 h after operation(T 4). Pulmonary ultrasonography was performed before surgery, at the end of surgery and at 1, 3 and 7 days after surgery. The pediatric patients were followed up for 1 week after surgery to record the PPCs, including acute lung injury, pulmonary infection, pulmonary atelectasis, pleural effusion and acute respiratory distress syndrome. Results:Compared with control group, the incidence of PPCs, acute lung injury and pulmonary infection was significantly decreased, the pulmonary ultrasound score was decreased at the end of surgery and at 1, 3 and 7 days after surgery, the usage of intraoperative dobutamine was increased, the duration of postreperfusion syndrome was shortened, the fluid intake and epinephrine usage were reduced, and the serum Clara cell 16 kDa protein, tumor necrosis factor-alpha and interleukin-6 concentrations were decreased at T 1-T 4 in SVV group( P<0.05). Conclusions:SVV goal-directed fluid management can reduce the development of PPCs in pediatric living donor liver transplantation.

Objective:To evaluate the value of preoperative serum miRNA-146a-5p expression in predicting postoperative delirium (POD) in the pediatric patients undergoing living donor liver transplantation.Methods:Eighty pediatric patients with congenital biliary atresia, aged 5-12 months, with body mass index of 4-10 kg, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, undergoing elective living donor liver transplantation in our hospital, were selected. Venous blood samples were collected at 1 day before surgery, and serum miRNA-146a-5p expression was detected by quantitative real-time polymerase chain reaction. The children′s cognitive function was evaluated using the Mini-Mental State Examination and the Modified Montreal Cognitive Assessment at 1 day before operation and at 1, 3 and 7 days after operation. The pediatric patients were divided into POD group and non-POD group according to whether POD occurred within 7 days after surgery. Multiple logistic regression analysis was used to evaluate the relationship between serum miRNA-146a-5p expression and POD, Pearson′s correlation analysis was used to analyze the correlation between miRNA-146a-5p and POD, and the receiver operating characteristic curves were used to evaluate the accuracy of serum miRNA-146a-5p concentrations in predicting the occurrence of POD.Results:There were 30 cases in POD group and 50 cases in non-POD group, and the incidence of POD was 38%. The results of multiple logistic regression analysis showed that down-regulated serum miR-146a-5p expression was an independent risk factor for POD in pediatric patients undergoing living donor liver transplantation ( P<0.05). The incidence of POD was negatively correlated with serum miRNA-146a-5p expression ( r=-0.658, P<0.001). The area under the receiver operating characteristic curve of serum miRNA-146a-5p expression in predicting POD was 0.870 in pediatric patients undergoing living donor liver transplantation, with a sensitivity of 0.825 and a specificity of 0.875. Conclusions:Preoperative serum miRNA-146a-5p expression has a certain predictive value for POD in the pediatric patients undergoing living donor liver transplantation.

Objective:To evaluate the relationship between serum exosomes and microglial pyroptosis during brain injury in a young rat model of hepatic ischemia-reperfusion (I/R).Methods:Forty-six clean-grade healthy male Sprague-Dawley rats, aged 2-3 weeks, weighing 40-60 g, were allocated into 4 groups using a random number table method: sham operation group (group S, n=10), hepatic I/R group (group I/R, n=13), treatment with serum exosome in sham-operated young rat group (group S-Exosome, n=10), and treatment with serum exosomes in young rats with I/R group (group I/R-Exosome, n=13). The common trunk of the portal vein, left hepatic artery and bile duct was clamped for 60 min resulting in ischemia of 70% of the liver in anesthetized animals.After 6 h of reperfusion, the serum was collected to extract exosomes in S group and I/R group, and the serum exosome suspension 100 μl of S group and I/R group was injected through the tail vein in S-Exosome group and I/R-Exosome group, respectively.The expression of serum exosome marker proteins CD9 and CD81 was determined by Western blot in S group and I/R group.Serum and hippocampi were obtained from each group at 6 h after the corresponding treatment.The expression of NOD-like receptor protein 3 (NLRP3), gasdermin D (GSDMD), pro-caspase-1, cleaved-caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC) in the hippocampus was detected using Western blot, and the expression of GSDMD in hippocampal tissues was determined by immunohistochemistry.The levels of interleukin-1beta (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) in serum and hippocampal tissues and S100β and NSE in serum were determined by enzyme-linked immunosorbent assay.In group I/R-Exosome, 3 rats were selected, and their serum exosomes were extracted, labeled with PKH26 red fluorescence and then injected via the tail vein, and the co-localization between exosomes and microglia was identified by immunofluorescence technique. Results:Compared with group S, the expression of serum CD9 and CD81 was significantly up-regulated in group I/R, the expression of NLRP3, GSDMD, cleaved-caspase-1 and ASC in hippocampal tissues was significantly up-regulated, the levels of IL-18, IL-1β and TNF-α in serum and hippocampal tissues and S100β and NSE in serum were increased in I/R and I/R-Exosome groups ( P<0.05), and no significant change was found in the parameters mentioned above in group S-Exosome ( P>0.05). The positive expression of GSDMD was significantly increased in I/R and I/R-Exosome groups ( P<0.05), no positive expression of GSDMD was found in S and S-Exosome groups ( P>0.05), and the results of immunofluorescence showed the co-localization between exosomes and microglia. Conclusions:The mechanism by which hepatic I/R induces brain injury may be related to serum exosomes-mediated microglial pyroptosis in young rats.

Background::The pharmacokinetic and clinical behaviors of many proton pump inhibitors (PPIs) in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms. This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole. We also explored the influence of Helicobacter pylori ( H. pylori) infection status and CYP2C19 polymorphism on anaprazole. Methods::In this multicenter, randomized, double-blind, double-dummy, positive-drug parallel-controlled, phase III study, Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg + anaprazole placebo or rabeprazole placebo + anaprazole 20 mg once daily for 4 weeks. The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review. Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks. Furthermore, exploratory subgroup analysis of the primary endpoint by H. pylori status and CYP2C19 polymorphism was conducted. Adverse events were monitored for safety. Non-inferiority analysis was conducted for the primary endpoint. Results::The study enrolled 448 patients (anaprazole, n = 225; rabeprazole, n = 223). The 4-week healing rates were 90.9% and 93.7% for anaprazole and rabeprazole, respectively (difference, -2.8% [95% confidence interval, -7.7%, 2.2%]), demonstrating non-inferiority of anaprazole to rabeprazole. Overall duodenal ulcer symptoms improved in 90.9% and 92.5% of patients, respectively. Improvement rates of individual symptoms were similar between the groups. Healing rates did not significantly differ by H. pylori status or CYP2C19 genotype for either treatment group. The incidence of treatment-emergent adverse events was similar for anaprazole (72/220, 32.7%) and rabeprazole (84/219, 38.4%). Conclusions::The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration::ClinicalTrials.gov, NCT04215653.

Objective:To evaluate the effect of hepatic ischemia-reperfusion (I/R) rats-derived exosomes on microglial pyroptosis.Methods:Twenty clean-grade healthy male Sprague-Dawley rats, aged 2-3 weeks, weighing 20-50 g, were divided into 2 groups ( n=10 each) using a random number table method: sham operation group (group S) and hepatic I/R group (group I/R). The serum of rats in S group and I/R group was collected, and exosomes were isolated from the sera using differential centrifugations.Microglial cells were co-cultured with PKH26-labeled exosomes for 6 h. The intake of exosomes in microglial cells was determined using immunofluorescence staining.Primary microglial cells were seeded onto 6-well culture plates at a density of 5×10 5 cells/ml and were divided into 4 groups ( n=6 each) using a random number table method: control group (group C), 10 7 cells/ml I/R-exosomes treated group (group 10 7), 10 8 cells/ml I/R-exosomes treated group (group 10 8), and 10 9 cells/ml I/R-exosomes treated group (group 10 9). Microglia in each group were co-cultured with the corresponding concentration of I/R-exosomes for 6 h. The expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cleaved-caspase-1 and gasdermin-D (GSDMD) was detected using Western blot.Primary microglial cells were divided into 3 groups ( n=24 each) by a random number table method: control group (group C), sham operation-exosomes treated group (group S-exosome) and I/R-exosomes treated group (group I/R-exosome). In S-exosome group and I/R-exosome group, exosomes 10 8 cells/ml in S group and I/R group were given, respectively, to incubate cells for 6 h. The expression of NLRP3, ASC and GSDMD mRNA was determined by real-time polymerase chain reaction, and the levels of interleukin-18 (IL-18), IL-1β and tumor necrosis factor-alpha (TNF-α) in the cell culture supernatant were measured by enzyme-linked immunosorbent assay. Results:The results from immunofluorescence staining showed that I/R-exosomes colocalized with microglia.The 10 8 cells/ml I/R-exosomes and 10 9 cells/ml I/R-exosomes up-regulated the expression of NLRP3, ASC, GSDMD and cleaved-caspase-1 in microglial cells ( P<0.01). Compared with group C and group S-exosome, the expression of NLRP3, ASC and GSDMD mRNA in microglial cells was up-regulated, and the levels of IL-18, IL-1β and TNF-α in the supernatant were elevated in group I/R-exosome ( P<0.01). Conclusions:Hepatic I/R rats-derived exosomes can promote microglial pyroptosis.