PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

Spinal cord injury (SCI) is a devastating traumatic disease seriously impairing the quality of life in patients. Expectations to allow the hopeless central nervous system to repair itself after injury are unfeasible. Developing new approaches to regenerate the central nervous system is still the priority. Exosomes derived from mesenchymal stem cells (MSC-Exo) have been proven to robustly quench the inflammatory response or oxidative stress and curb neuronal apoptosis and autophagy following SCI, which are the key processes to rescue damaged spinal cord neurons and restore their functions. Nonetheless, MSC-Exo in SCI received scant attention. In this review, we reviewed our previous work and other studies to summarize the roles of MSC-Exo in SCI and its underlying mechanisms. Furthermore, we also focus on the application of exosomes as drug carrier in SCI. In particular, it combs the advantages of exosomes as a drug carrier for SCI, imaging advantages, drug types, loading methods, etc., which provides the latest progress for exosomes in the treatment of SCI, especially drug carrier.

Objective To observe the safety and effectiveness of single dose intravenous infusion of tranexamic acid(TX-A)in dual level posterior lumbar interbody fusion(PLIF),and to explore the changes and trends in perioperative white blood cell(WBC),erythrocyte sedimentation rate(ESR),and C-reactive protein(CRP).Methods Between October 2020 and September 2022,46 patients with lumbar degenerative disease were treated with dual level PLIF,including 18 males and 28 females,with an average age of(60.24±10.68)years old,from 34 to 80 years old.They were divided into observation group and control group according to different treatment methods.There were 28 patients in the observation group,including 12 males and 16 females,with an average age of(61.04±9.03)years old.There were 3 cases with lumbar disc herniation(LDH),lumbar spinal stenosis(LSS)18 cases,lumbar spondylolisthesis(LS)7 cases.TXA(1 g/100 ml)was administered intravenously 15 min before skin incision after general anesthesia.The control group consisted of 18 patients,including 6 males and 12 females,with an average age of(59.00±13.04)years old.There were 5 cases with LDH,LSS 9 cases,LS 4 cases,and TXA was not used.The operation time,intraoperative bleeding volume,postoperative drainage volume,postoperative deep vein thrombosis(DVT),postoperative hospital stay,postoperative activated partial thromboplastin time(APTT),prothrombin time(PT),thrombin time(TT),fibrinogen(FIB),platelet(PLT),red blood cell(RBC),hemoglobin(HB),hematocrit(HCT),the first day,the fourth day,the seventh day and the last tested after operation WBC,ESR and CRP were recorded.Results The postop-erative wounds of the patients healed well and there was no DVT.46 patients were followed up from 3 to 6 months.The intraop-erative blood loss was 400.0(300.0,500.0)ml and the postoperative drainage was 260.0(220.0,450.0)ml in the observation group,which were lower than the control group[600.0(400.0,1000.0)ml,395.0(300.0,450.0)ml],P＜0.05.There was no significant difference between the two groups in operation time,postoperative hospital stay,postoperative APTT,PT,TT,FIB,PLT,RBC,HB,HCT,and postoperative WBC,ESR and CRP at different times(P＞0.05).Conclusion Single dose intravenous infusion of TXA can reduce the blood loss of bi-segmental PLIF,and has no significant effect on WBC,ESR and CRP after op-eration.

Objective:To evaluate the application of digital visualization in preoperative planning for surgical clearance of vertebral infection lesions following percutaneous vertebroplasty (PVP).Methods:A retrospective study was conducted to analyze the 13 patients with infectious spondylitis following PVP who had undergone one-stage posterior debridement and interbody bone grafting combined with instrumentation at Department of Spinal Surgery, Zhengzhou Orthopaedics Hospital from January 2016 to December 2022. They were 4 males and 9 females with an age of (71.4±6.5) years. Before surgery, the CT raw data of the patients were imported into software Mimics to reconstruct a three-dimensional model of the spine. After the distribution of bone cement in the model and its relationships with the vertebral plate, pedicle, articular process, and spinal cord were observed, a safe area for spinal canal surgery was designed. Intraoperative operations were carried out according to the preoperative planning. Surgical time, intraoperative blood loss, improvements in American Spinal Injury Association (ASIA) grading, and postoperative complications were recorded. The therapeutic efficacy was evaluated by comparisons of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS), and Oswestry disability index (ODI) between preoperation, 2 weeks and 3 months postoperation, and the last follow-up.Results:Surgery went on successfully in all the 13 patients according to the preoperative planning. The surgical time was (275.9±28.3) min and the intraoperative blood loss (865.4±183.0) mL. All patients were followed up for (24.7±9.4) months. The levels of ESR, CRP, VAS, and ODI at 2 weeks, 3 months and the last follow-up were significantly lower than those before surgery ( P<0.05). At the last follow-up, X-ray and CT examinations showed good positions of internal fixation and sufficient bone graft fusion. The ASIA grading recovered from preoperative D to E in 5 patients. No incision infection, sinus formation, worsening of neurological symptoms, loosening or rupture of internal fixation, or worsening of neurological dysfunction were found. Conclusion:With the assistance of 3D visualization, the spinal cord, bone cement, and debridement area can be visualized directly to reduce nerve injury complications so that a safe and effective preoperative planning can be made for surgical clearance of vertebral infection lesions following PVP.

Objective:To assess the deformation of the bladder-neck opening and the impact of the bladder-neck angle(BNA)on urination in male patients by fluid-structure interaction(FSI)analysis.Methods:We established geometric models of the blad-der,prostate and urethra were established,incorporating both normal and enlarged BNAs,and assessed the effects of BNA alteration on urinary flow by FSI simulation of the flow rate and pressure of the urine within the bladder,bladder neck and urethra,and that of pros-tate displacement as well.We retrospectively analyzed the clinical data on 145 male patients from the Second Hospital of Hebei Medical University between June 2020 and June 2023,39 with acute urine retention(the AUR group)and 106 without(the non-AUR group),and evaluate the impact of BNA on urination based on the urinary flow rate and prostate volume.Results:Comparative simulation a-nalysis showed significant differences in the total urethral pressure and flow rate between the normal and enlarged BNA models(P＜0.05).The maximum prostate displacement was found at the bladder neck,with moderate displacement and unchanged urethral diame-ter in the normal BNA model,but significant displacement and a reduced urethral opening diameter in the enlarged BNA model.FSI analysis confirmed an evident impact of enlarged BNA on urination,more significant in the AUR than in the non-AUR patients(P＜0.05).The BNAs in the patients with the maximum urinary flow rate(Qmax)of＜10,10-15 or＞15 ml/s were 83.7°±2.5°,67.5°±1.8° and 65.1°±4.8° respectively,with statistically significant difference between the former one and the latter two groups(P＜0.05).The BNAs in the patients with normal prostate volume or BPH of grade Ⅰ,Ⅱ,Ⅲ or Ⅳ were 65.0°±3.7°,67.2°±3.1°,71.5°±2.0°,82.8°±3.5° and 105.8°±6.0°,respectively(P＜0.05),with statistically significant difference between BPH grades Ⅲ and Ⅳ(P＜0.05)as well as between these two and the other three groups(P＜0.05),but not among the normal prostate volume,BPH grade Ⅰ and BPH grade Ⅱ groups(P＞0.05).Spearman correlation analysis indicated that BNA was strongly correlated with total prostate volume(TPV),transition zone volume(TZV),intravesical prostatic protrusion(IPP),prostatic urethral angle(PUA),IPSS,and Qmax(P＜0.05).Conclusion:Changes in BNA affect urination and are closely associated with the se-verity of prostate hyperplasia.The BNA may be an important anatomical factor for assessing the severity of lower urinary tract symptoms in BPH patients.

Objective:To explore the assessment value of liver enzyme changes before and after hepatectomy on the prognosis of patients with primary hepatocellular carcinoma(HCC). Methods:A retrospective analysis was conducted on the clinical data of 421 patients with primary HCC who received at the First and Second Affiliated Hospitals of Xi'an Jiaotong University from January 2016 to December 2020.The univariate and multivariate COX regression analyses were used to screen the risk factors affecting the prognosis of patients with primary HCC,and the optimal cut-off value was selected to group the most valuable indicators among them,further analyzing the different factors among subgroups.The Kaplan-Meier method was used to assess the prognosis of the subgroups,and the survival curves were plotted and statistically tested. Results:Multivariate COX regression analysis revealed that Barcelona Clinic Liver Cancer(BCLC)stage,tumor number,alpha-fetoprotein(AFP),the quantitative change of γ-glutamyl transpeptidase(GGT)and total bilirubin(TBIL)before and after surgery were independent risk factors affecting the prognosis of patients with primary HCC(P＜0.01),and there were differences in hepatitis B virus surface antigen(HBsAg),TNM stage,BCLC stage,tumor size,tumor number,tumor differentiation degree,AFP,surgery type,intraoperative bleeding volume,postoperative albumin-bilirubin(ALBI)and white blood cell count between the high and low GGT variation groups(P＜0.05).Kaplan-Meier survival analysis showed that the prognosis of patients with primary HCC between the high and low GGT variation groups was significantly different,with a hazard ratio of 2.603 for mortality and 1.449 for recurrence(both P＜0.01). Conclusion:The quantitative change of GGT before and after hepatectomy has an evaluation value for the prognosis of patients with primary HCC,and the quantitative change of GGT greater than 29.5 is an independent risk factor for the prognosis of patients with primary HCC.

UPLC-Q-Exactive-MS/MS and network pharmacology were employed to preliminarily study the active components and mechanism of Jinwugutong Capsules in the treatment of osteoporosis. Firstly, UPLC-Q-Exactive-MS/MS was employed to characterize the chemical components of Jinwugutong Capsules, and network pharmacology was employed to establish the "drug-component-target-pathway-disease" network. The key targets and main active components were thus obtained. Secondly, AutoDock was used for the molecular docking between the main active components and key targets. Finally, the animal model of osteoporosis was established, and the effect of Jinwugutong Capsules on the expression of key targets including RAC-alpha serine/threonine-protein kinase(AKT1), albumin(ALB), and tumor necrosis factor-alpha(TNF-α) was determined by enzyme-linked immunosorbent assay(ELISA). A total of 59 chemical components were identified from Jinwugutong Capsules, among which coryfolin, 8-prenylnaringenin, demethoxycurcumin, isobavachin, and genistein may be the main active components of Jinwugutong Capsules in treating osteoporosis. The topological analysis of the protein-protein interaction(PPI) network revealed 10 core targets such as AKT1, ALB, catenin beta 1(CTNNB1), TNF, and epidermal growth factor receptor(EGFR). The Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment showed that Jinwugutong Capsules mainly exerted the therapeutic effect by regulating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT) signaling pathway, neuroactive ligand-receptor interaction, mitogen-activated protein kinase(MAPK) signaling pathway, Rap1 signaling pathway and so on. Molecular docking showed that the main active components of Jinwugutong Capsules well bound to the key targets. ELISA results showed that Jinwugutong Capsules down-regulated the protein levels of AKT1 and TNF-α and up-regulated the protein level of ALB, which preliminarily verified the reliability of network pharmacology. This study indicates that Jinwugutong Capsules may play a role in the treatment of osteoporosis through multiple components, targets, and pathways, which can provide reference for the further research.
Animals ; Tumor Necrosis Factor-alpha/genetics* ; Network Pharmacology ; Capsules ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; Reproducibility of Results ; Tandem Mass Spectrometry

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Objective: To analyze the clinicopathological characteristics and prognosis of patients with small bowel tumors. Methods: This was a retrospective, observational study. We collected clinicopathological data of patients with primary jejunal or ileal tumors who had undergone small bowel resection in the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University between January 2012 and September 2017. The inclusion criteria included: (1) older than 18 years; (2) had undergone small bowel resection; (3) primary location at jejunum or ileum; (4) postoperative pathological examination confirmed malignancy or malignant potential; and (5) complete clinicopathological and follow-up data. Patients with a history of previous or other concomitant malignancies and those who had undergone exploratory laparotomy with biopsy but no resection were excluded. The clinicopathological characteristics and prognoses of included patients were analyzed. Results: The study cohort comprised 220 patients with small bowel tumors, 136 of which were classified as gastrointestinal stromal tumors (GISTs), 47 as adenocarcinomas, and 35 as lymphomas. The median follow-up for all patient was 81.0 months (75.9-86.1). GISTs frequently manifested as gastrointestinal bleeding (61.0%, 83/136) and abdominal pain (38.2%, 52/136). In the patients with GISTs, the rates of lymph node and distant metastasis were 0.7% (1/136) and 11.8% (16/136), respectively. The median follow-up time was 81.0 (75.9-86.1) months. The 3-year overall survival (OS) rate was 96.3%. Multivariate Cox regression-analysis results showed that distant metastasis was the only factor associated with OS of patients with GISTs (HR=23.639, 95% CI: 4.564-122.430, P<0.001). The main clinical manifestations of small bowel adenocarcinoma were abdominal pain (85.1%, 40/47), constipation/diarrhea (61.7%, 29/47), and weight loss (61.7%, 29/47). Rates of lymph node and distant metastasis in patients with small bowel adenocarcinoma were 53.2% (25/47) and 23.4% (11/47), respectively. The 3-year OS rate of patients with small bowel adenocarcinoma was 44.7%. Multivariate Cox regression-analysis results showed that distant metastasis (HR=4.018, 95%CI: 2.108-10.331, P<0.001) and adjuvant chemotherapy (HR=0.291, 95% CI: 0.140-0.609, P=0.001) were independently associated with OS of patients with small bowel adenocarcinoma. Small bowel lymphoma frequently manifested as abdominal pain (68.6%, 24/35) and constipation/diarrhea (31.4%, 11/35); 77.1% (27/35) of small bowel lymphomas were of B-cell origin. The 3-year OS rate of patients with small bowel lymphomas was 60.0%. T/NK cell lymphomas (HR= 6.598, 95% CI: 2.172-20.041, P<0.001) and adjuvant chemotherapy (HR=0.119, 95% CI: 0.015-0.925, P=0.042) were independently associated with OS of patients with small bowel lymphoma. Small bowel GISTs have a better prognosis than small intestinal adenocarcinomas (P<0.001) or lymphomas (P<0.001), and small bowel lymphomas have a better prognosis than small bowel adenocarcinomas (P=0.035). Conclusions: The clinical manifestations of small intestinal tumor are non-specific. Small bowel GISTs are relatively indolent and have a good prognosis, whereas adenocarcinomas and lymphomas (especially T/NK-cell lymphomas) are highly malignant and have a poor prognosis. Adjuvant chemotherapy would likely improve the prognosis of patients with small bowel adenocarcinomas or lymphomas.
Humans ; Prognosis ; Intestinal Neoplasms/diagnosis* ; Duodenal Neoplasms ; Gastrointestinal Stromal Tumors ; Lymphoma ; Adenocarcinoma/surgery* ; Constipation ; Abdominal Pain ; Retrospective Studies