Glioma is difficult to treat due to the unique tumor microenvironment and blood-brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi-pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.

Objective To investigate the effect of esketamine combined with sufentanil for postoperative patient-controlled intravenous analgesia(PCIA)on rebound pain after single nerve block.Methods From January 2021 to December 2022,80 patients undergoing upper limb fracture surgery in Jinshan Hospital,Fudan University with single nerve block anesthesia were included and randomly divided into two groups:the Ket group(esketamine combined with sufentanil PCIA)and the Ctrl group(sufentanil PCIA),with 40 patients in each group.Several indicators were recorded,including pain scores at 8 h,12 h,24 h,and 48 h postoperatively,the time to first pain and its score,pain scores 30 min after pressing the PCIA pump self-control button,as well as opioid consumption at 24 h and 48 h postoperatively,and the number of PCIA button presses.Rebound pain was defined as a sudden transition from"no pain"to"severe pain"(NRS ≥ 7)requiring pressing the PCIA self-control button.Results Rebound pain occurred in 17(45.95％)patients in the Ctrl group and 12(36.36％)patients in the Ket group,with no statistically significant difference.The Ket group had significantly lower sufentanil consumption and fewer PCIA presses at 24 h postoperatively compared to the Ctrl group(P=0.007).At 48 h postoperatively,there was no significant difference in sufentanil consumption and PCIA presses among patients who experienced rebound pain in the two groups.At 30 min after pressing the PCIA button for breakthrough pain,12 patients(100.00％)in the Ket group had NRS＜4,compared to 3 patients(17.65％)in the Ctrl group,with a statistically significant difference(P=0.02).Conclusions Compared with using sufentanil alone for PCIA,the combination of esketamine and sufentanil does not reduce the incidence of rebound pain following single nerve block in upper limb fracture surgery.However,the combination of esketamine and sufentanil may provide a faster relief of rebound pain.

Objective To develop a highly sensitive and rapid nucleic acid detection method for the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). Methods We designed,developed,and manufactured an integrated disposable device for SARS-CoV-2 nucleic acid extraction and detection.The precision of the liquid transfer and temperature control was tested.A comparison between our device and a commercial kit for SARS-Cov-2 nucleic acid extraction was performed using real-time fluorescence reverse transcription polymerase chain reaction(RT-PCR).The entire process,from SARS-CoV-2 nucleic acid extraction to amplification,was evaluated. Results The precision of the syringe transfer volume was 19.2±1.9 μL(set value was 20),32.2±1.6(set value was 30),and 57.2±3.5(set value was 60).Temperature control in the amplification tube was measured at 60.0±0.0 ℃(set value was 60)and 95.1±0.2 ℃(set value was 95)respectively.SARS-Cov-2 nucleic acid extraction yield through the device was 7.10×106 copies/mL,while a commercial kit yielded 2.98×106 copies/mL.The mean time to complete the entire assay,from SARS-CoV-2 nucleic acid extraction to amplification detection,was 36 min and 45 s.The detection limit for SARS-CoV-2 nucleic acid was 250 copies/mL. Conclusion The integrated disposable devices may be used for SARS-CoV-2 Point-of-Care test(POCT).

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQ-containing regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients. Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM. Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups. Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Objective:This study aimed to develop a rapid and accurate integrated nucleic acid detection method tailored for the influenza virus.Methods:We designed primers and probes targeting the predominant influenza virus strains circulating in China in recent years. These were integrated with extraction and amplification reagents and a point of care testing (POCT) system to facilitate a seamless and expedited process involving nucleic acid extraction, reaction system preparation, amplification, and result interpretation for the influenza virus. The specificity of the POCT system was evaluated using cultured influenza viruses, while its cross-reactivity was assessed against common respiratory pathogens, including adenovirus and respiratory syncytial virus.Results:Our study successfully developed duplex amplification primers and probes for both influenza A and B viruses, achieving a detection threshold as low as 500 copies/ml. Specificity tests confirmed that the detection reagents did not show cross-reactivity with other respiratory pathogens such as adenovirus and respiratory syncytial virus. The POCT-based rapid nucleic acid detection method for influenza virus was established, it is capable of completing the entire process from nucleic acid extraction to amplification and result interpretation within 50 minutes, while enabling real-time data upload.Conclusions:The POCT-based rapid influenza virus detection kit developed in this study offers a " sample in, results out" convenience, making it suitable for rapid influenza virus detection in primary care settings. This innovation has significant potential for clinical application.

Objective To investigate the value of dual-energy CT(DECT)quantitative parameters combined with clinical laboratory indicators in differentiation of portal vein tumor thrombus(PVTT)from thrombosis(PVT).Methods A case-control study was conducted on 65 patients diagnosed with portal vein thrombosis(n=39)or tumor embolus(n=26)who underwent abdominal dual-energy enhanced CT examination in our department from May 2022 to March 2024.Their clinical and imaging data were collected.Linear blending image(LB),non-linear blending image(NLB),40 keV and 100 keV virtual monoenergetic image(VMI),iodine image and electron density/effective atomic number image(Rho/Zeff)were reconstructed with the aid of post-processing workstation.The image characteristics of thrombus were evaluated in LB images,including whether the vessel wall at the thrombus was smooth,whether the vessel at the thrombus was widen,and whether the embolus was neovascularization.The quantitative parameters and clinical laboratory indicators of PVT and PVTT in DECT were compared.Laboratory indicators included apha-fetoprotein(AFP),carcinoembryonic antigen(CEA),alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Univariate and multivariate logistic regression analyses were employed to analyze DECT quantitative parameters,embolus image characteristics and clinical laboratory indicators.Then receiver operating characteristic(ROC)curve was plotted to evaluate the diagnostic efficiency of the quantitative parameters and combined model of DECT.Results Among the DECT parameters,except for Rho,the other parameters in PVTT were significantly higher than those in PVT(P＜0.05).Multivariate logistic regression analysis showed that there were obvious differences in LB,NLB,CEA and AST(P＜0.05),and NLB had better diagnostic efficacy(AUC:0.830,sensitivity:53.85％,specificity:100.00％,accuracy:81.54％).The combined model based on DECT quantitative parameters and clinical laboratory indicators(LB+NLB+CEA+AST)obtained the best diagnostic efficacy(AUC:0.983,sensitivity:96.15％,specificity:92.31％,accuracy:93.85％).Conclusion The combined imaging and clinical model based on DECT provides a reliable reference for the differential diagnosis of benign and malignant portal vein embolus,and it has potential application prospects.

Objective To analyze the anesthetic effect and hemodynamic impact of oxybutynin(OBI)combined with dexmedetomidine(DEX)on patients undergoing endoscopic dacryocystorhinostomy(En-DCR).Methods Patients who underwent En-DCR from February 2024 to May 2024 at Mianyang Wanjiang Eye Hospital were recruited.They were randomly divided into the DEX group(DEX administration only)and the combined group(DEX combined with OLI administration)according to the random number table method.The primary observational index in this study was the 24-h postoperative pain numerical rating scale(NRS)scores.The secondary observation indexes were heart rate(HR),mean arterial pressure(MAP),respiratory recovery time(SRT),extubation time(ET)and awakening time(AT),peak systolic value(PSV),end-diastolic blood flow velocity(EDV),resistance index(RI)and blood flow(BF).The occurrence of adverse events in patients during hospitalization was observed and recorded.Results A total of 80 patients were included in the study,with 40 in each of the DEX group and the combined group.In terms of analgesia,the NRS scores in the combined group were lower than those in the DEX group at T1(within 0.5 h after catheter removal),T2(4 h postoperatively),T3(8 h postoperatively),and T4(24 h postoperatively)(P＜0.05),and the remedial analgesia rate in the combined group was significantly lower than that in the DEX group(P＜0.05).Regarding anesthetic effects,HR and MAP at time points T6(during induction of anesthesia),T7(intraoperatively)and T8(during resuscitation)were lower in the combined group than in the DEX group(P＜0.05);and SRT,ET and AT were shorter in the combined group compared with the DEX group(P＜0.05).In terms of hemodynamics,at 24 h postoperatively,PSV,EDV and BF were significantly higher in both groups compared with those before anesthesia,whereas RI was significantly lower than before anesthesia(P＜0.05);PSV,EDV and BF were higher in the combined group than those in the DEX group,and RI was lower than that in the DEX group(P＜0.05).Regarding adverse reactions,the incidence of adverse reactions in the combined group was significantly lower than that in the DEX group(P＜0.05).Conclusion OLI combined with DEX prophylactic analgesia for patients with En-DCR is effective,not only to reduce postoperative pain,stabilize hemodynamics,shorten the time of extubation and awakening,and reduce the incidence of adverse reactions.

Objective:To explore the clinical efficacy of apatinib combined with tirelizumab in the treatment of advanced gastric cancer patients who failed first-line chemotherapy, as well as its impact on peripheral blood tumor angiogenesis regulatory factor levels and long-term survival.Methods:A prospective study was conducted on 144 advanced gastric cancer patients who failed first-line chemotherapy and were admitted to the Handan Central Hospital from January 2020 to December 2021. They were divided into two groups using a random number table method, with 72 patients in each group. The control group was treated with tirezizumab alone, while the observation group was treated with apatinib combined with tirezizumab. After four consecutive courses of treatment, the short-term efficacy of both groups was observed. We compared the levels of serum tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen (CA)199, CA724, CA125], tumor angiogenesis regulatory factors [vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1 α), insulin-like growth factor-1 (IGF-1), matrix metalloproteinase-9 (MMP-9)], and quality of life scores between two groups before and after treatment. Long term follow-up was conducted on all patients, and the long-term survival status of two groups was statistically analyzed. Two groups of adverse reactions were compared.Results:The objective remission rate and disease control rate (51.39%, 80.56%) of the observation group were significantly higher than those of the control group (31.94%, 61.11%, all P<0.05). After treatment, the serum levels of CEA, CA199, CA724, CA125, VEGF, SDF-1α, IGF-1, and MMP-9 in both groups were significantly reduced compared with those before treatment (all P<0.05), and the observed group showed a more significant decrease in the above indicators (all P<0.05). After treatment, the scores of physical function, emotional function, social function, role function, and overall health status in the European Organization for Research and Treatment of Cancer Core Scale C30 were significantly higher than before treatment (all P<0.05), and the increase was more significant in the observation group (all P<0.05). The median progression free survival and median overall survival in the observation group were 5.9 months and 13.1 months, respectively, significantly longer than those in the control group (4.5 months and 9.6 months) (all P<0.05). During the treatment period, both groups experienced varying degrees of adverse reactions such as hypertension, leukopenia, thrombocytopenia, and liver and kidney damage, but both were mainly grade Ⅰ-Ⅱ. The overall adverse reactions were clinically controllable and tolerable by patients. The incidence of hypertension, thrombocytopenia, hand foot syndrome, and oral ulcers in the observation group was significantly higher than that in the control group (all P<0.05). Conclusions:The combination of apatinib and tirezizumab can effectively regulate the levels of peripheral blood tumor markers and angiogenic regulatory factors in advanced gastric cancer patients who have failed first-line chemotherapy, improve short-term anti-tumor efficacy, and bring more survival benefits to patients.

Short-chain fatty acids are metabolites of the intestinal flora and serve as the main energy source for intestinal epithelial cells. At the same time, as important signaling molecules, it regulate a variety of cellular inflammatory responses and homeostatic proliferation through receptor-dependent and independent pathways. Short-chain fatty acids regulate the gut-liver axis and thereby directly act on the liver, participating in the pathogenesis and transformation of various liver diseases, including alcoholic liver disease, metabolic dysfunction-related liver disease, autoimmune liver disease, liver fibrosis, and hepatocellular carcinoma. In addition, short-chain fatty acids can inhibit HBV DNA replication. This article reviews the research progress on the role of short-chain fatty acids in aspects of the pathogenesis and transformation of chronic liver diseases.

Objective:To investigate effect of trimetazidine(TMZ)on immune function of Streptococcus pneumoniae(SP)pneumonia rats through cyclic guanylate adenylate synthase(cGAS)-stimulator of interferon gene(STING)pathway.Methods:Rats were randomly separated into model group,TMZ group and DMXAA group(cGAS-STING signaling pathway activator).SP pneumonia rat model was replicated by intranasal instillation of SP,while rats in control group were infused with an equal amount of physiological saline.ELISA was applied to detect IL-1β and IL-10 levels.Flow cytometry was applied to detect CD4+T and CD8+T levels.Spleen and thymus indexes of rats in each group were compared.Transmission turbidity method was applied to detect IgG and IgA levels.HE staining was applied to observe pathological changes in lung tissue.Western blot was applied to detect cGAS-STING pathway proteins expressions.Results:Compared with control group,rats in model group showed an increase in alveolar wall and lung interstitium,accompanied by edema,bleeding and inflammatory cell infiltration,IL-1β,CD8+T cells levels,lung tissue pathological injury score,cGAS,STING expressions were increased,IL-10,CD4+T cells levels,CD4+T/CD8+T,spleen and thymus indexes,IgG,IgA levels were decreased(P<0.05).Compared with model group,rats in TMZ group showed reduced thickening of alveolar walls,great improve-ment in alveolar structure,and less infiltration of inflammatory cells,IL-1β,CD8+T cells levels,lung tissue pathological injury score,cGAS,STING expressions were decreased,IL-10,CD4+T cells levels,CD4+T/CD8+T,spleen and thymus indexes,IgG,IgA levels were increased(P<0.05).Compared with TMZ group,IL-1β,CD8+T levels,pathological injury score of lung tissue,cGAS and STING expressions in DMXAA group were increased,while IL-10,CD4+T cells levels,CD4+T/CD8+T,spleen and thymus index,IgG and IgA levels were decreased(P<0.05).Conclusion:TMZ may inhibit inflammation by inhibiting cGAS-STING signaling pathway,and enhance immune function of rats with SP pneumonia.