Therapeutic impacts of GNE­477­loaded H2O2 stimulus­responsive dodecanoic acid­phenylborate ester­dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer­associated death in young people. GNE­477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus­responsive dodecanoic acid (DA)­phenylborate ester­dextran (DA­B­DEX) polymeric micelle delivery system for GNE­477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE­477 loaded DA­B­DEX (GNE­477@DBD) tumor­targeting drug delivery system was established and the release of GNE­477 was measured. The cellular uptake of GNE­477@DBD by three OS cell lines (MG­63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA­B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA­B­DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE­477@DBD by cells with sustained release of GNE­477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT­qPCR, demonstrated that GNE­477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE­477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2­responsive DA­B­DEX presents a promising delivery system for hydrophobic anti­tumor drugs for OS therapy.

Preparation of HA-MAO coatings on ß-type alloys and its corrosion resistance in high glucose environments.

Aim to provide practical clinical guidance for the treatment of implants in diabetic patients, this study investigated the corrosion mechanism of bionic coatings containing different Ca/P ratios in diabetic environments. The bionic coatings were prepared in ß-titanium alloys using micro-arc oxidation (MAO) technology and evaluated for corrosion mechanism, biocompatibility, and safety by cytotoxicity, electrochemical corrosion, and coating bonding force experiments. Ca and P from the electrolyte were integrated into the coating during MAO discharge process to form hydroxyapatite. The coating Ca/P ratio initially increased and then decreased with the electrolyte Ca/P ratio. In vitro cellular experiments demonstrated that increasing the porosity of HA-containing coatings would be beneficial to the growth of cells adhering to their surfaces. Corrosion tests revealed that the corrosion tendency of the coating at higher sugar content was more severe, and a proper elevation of the Ca/P ratio was better for the corrosion resistance of the coating. The bonding analysis of the coatings before and after corrosion showed that an increase in the Ca/P ratio would improve the bonding of the MAO coatings in higher glucose content environments, thus improving the safety of the implants in diabetic patients.

[Progress of intraosseous basivertebral nerve ablation for symptomatic Modic alterations].

Chronic lumbar and back pain caused by degenerative vertebral endplates presents a challenging issue for patients and clinicians. As a new minimally invasive spinal treatment method, radiofrequency ablation of vertebral basal nerve in bone can denature the corresponding vertebral basal nerve through radiofrequency ablation of degenerative vertebral endplate. It blocks the nociceptive signal transmission of the vertebral base nerve, thereby alleviating the symptoms of low back pain caused by the degenerative vertebral endplate. At present, many foreign articles have reported the operation principle, operation method, clinical efficacy and related complications of radiofrequency ablation of the vertebral basal nerve. The main purpose of this paper is to conduct a comprehensive analysis of the current relevant research, and provide a reference for the follow-up clinical research.

Exenatide for obesity in children and adolescents: Systematic review and meta-analysis.

Objectives: There is no curative treatment for childhood obesity. We aim to synthesize published Randomized Controlled Trials (RCTs) evidence on the efficacy of exenatide in obese children and adolescents. Methods: We conducted a comprehensive search and analysis of relevant studies in popular databases such as PubMed, Web of Science, Embase, and Cochrane Library. Our focus was on RCTs that examined the effectiveness of exenatide for treating obesity in children. We primarily assessed changes in body weight, body mass index (BMI), fasting plasma glucose (FPG), or HbA1c levels. Additionally, we considered any adverse events reported during the treatment period, with particular attention to hypoglycemia. To evaluate the quality of RCTs included in our study, we employed the Cochrane bias assessment tool. Results: Five studies met the inclusion criteria. A group of 100 children were assigned to receive treatment with exenatide. Compared with controls, exenatide therapy reduced body weight and BMI by -0.6% (95% CI -0.93, -0.27), -1.11% (95% CI -1.91, -0.31), respectively. Undesirable consequences encompass gastrointestinal symptoms, with the majority of instances being characterized by mild severity. Conclusion: Exenatide demonstrates efficacy in the treatment of pediatric and adolescent obesity. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=413706.

Efficacy and safety of adalimumab in pediatric patients with Crohn's disease: A systematic review and meta-analysis.

PURPOSE: There is currently no curative treatment for childhood Crohn's disease (CD). This meta-analysis aimed to validate the efficacy and safety of adalimumab (ADA) in pediatric patients with CD. MATERIALS AND METHODS: We searched all relevant studies in the PubMed, Web of Science, Embase, and Cochrane Library databases. The primary outcomes were induction (≤ 12 weeks) and maintenance (up to 48 weeks) of remission and response. Secondary outcomes were severe adverse events and opportunistic infections to ADA. The Cochrane bias assessment tool was used to assess the risk of bias in randomized controlled trials. The methodological quality of the single-arm studies was assessed using the methodological index for non-randomized studies tool. RESULTS: Ten clinical trials involving a total of 885 patients were included. Results indicated that 59% (95% confidence interval [CI] 39-80%) of the subjects treated with ADA achieved induction of remission, and 60% (95% CI 35-86%) of the subjects treated with ADA achieved induction of response, 57% (95% CI 44-70%) achieved maintenance of remission, and 63% (95% CI 26-69%) achieved maintenance of response. CONCLUSION: Current evidence indicates that ADA is effective in children and adolescents with CD and that adverse events vary but are usually not severe. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/ , identifier CRD42023402199.

Clinical utilization of methylprednisolone in conjunction with tranexamic acid for accelerated rehabilitation in total hip arthroplasty.

PURPOSE: This study aimed to evaluate the efficacy and safety of combined methylprednisolone (MP) and tranexamic acid (TXA) in promoting accelerated rehabilitation following total hip arthroplasty (THA). We further investigated effective strategies for rapid rehabilitation post-THA. METHODS: Conducted as a randomized controlled trial involving 80 patients, the study allocated subjects into two groups. The control group received saline and TXA, whereas the experimental group was administered with an additional dose of MP. Several clinical parameters, including markers of inflammation, pain, nausea, and coagulation factors, were meticulously assessed in both groups. RESULTS: It was observed that the group receiving the MP + TXA treatment showcased significant reductions in postoperative levels of CRP and IL-6, as well as an alleviation in pain scores. Furthermore, this group demonstrated lower incidences of postoperative nausea and fatigue, facilitating enhanced hip joint mobility. Interestingly, this group did exhibit blood glucose fluctuations within the first 24 h postoperatively. However, there was no notable difference between the groups concerning transfusion rate, postoperative hospital stay duration, and coagulation profile, and no severe complications were reported. CONCLUSION: The findings suggest that the combined administration of MP and TXA can appreciably enhance postoperative recovery, by reducing inflammatory markers, alleviating pain, reducing nausea and fatigue, and improving hip mobility, without leading to an increased risk of severe perioperative complications. This highlights the potential role of this combined therapy in facilitating improved postoperative patient experiences.

A network meta-analysis of multiple modalities for the treatment of complex proximal humeral fractures in older adults.

OBJECTIVE: Four principal treatment modalities are applied to treat complex proximal humeral fractures in older adults: conservative treatment, open reduction internal fixation, hemiarthroplasty, and reverse shoulder arthroplasty. However, among these, the optimal treatment modality has yet to be determined. Therefore, a network meta-analysis was carried out to compare treatment modalities and assess their effectiveness. METHODS: The databases PUBMED, EM-BASE, the Cochrane Central Register of Controlled Trials, Web of Science, and CNKI were searched for randomised controlled trials on complex proximal humeral fractures in older people, ranging from inception of each database to May 2023. RESULTS: This meta-analysis included 14 randomised controlled trials, containing 791 patients aged over 60 years who were treated for complex proximal humeral fractures. Reverse shoulder arthroplasty and hemiarthroplasty yielded the highest Constant shoulder scores, whilst conservative treatment performed poorly. Hemiarthroplasty and open reduction internal fixation yielded the best performances on the visual analogue pain scale, whilst conservative treatment performed poorly. Reverse shoulder arthroplasty and open reduction internal fixation allowed for maximum forward flexion and outreach of range of motion, whilst hemiarthroplasty allowed for the least. Open reduction internal fixation and reverse shoulder arthroplasty allowed for maximum internal rotation of the range of motion, whilst conservative treatment allowed for the least. Hemiarthroplasty and conservative treatment allowed for maximum external rotation of the range of motion, whilst open reduction internal fixation allowed for the least. CONCLUSION: Compared with open reduction internal fixation, reverse shoulder arthroplasty yields better Constant shoulder scores and allows for greater forward flexion and outreach of range of motion of the shoulder joint in complex proximal humerus fractures in older patients. Meanwhile, hemiarthroplasty yields the best visual analogue scale scores and allows for maximum external rotation of the range of motion. However, open reduction with internal fixation remains the preferred clinical treatment for complex proximal humeral fractures in older patients.

Predictive value of neutrophil gelatinase-associated lipocalin in children with acute kidney injury: A systematic review and meta-analysis.

Purpose: Neutrophil gelatin lipase carrier protein (NGAL) has been used as an early biomarker to predict acute kidney injury (AKI). However, the predictive value of NGAL in urine and blood in children with acute kidney injury in different backgrounds remains unclear. Therefore, we conducted this systematic review and meta-analysis to explore the clinical value of NGAL in predicting AKI in children. Methods: Computerized databases were searched for relevant the studies published through August 4th, 2022, which included PUBMED, EMBASE, COCHRANE and Web of science. The risk of bias of the original included studies was assessed by using the Quality Assessment of Studies for Diagnostic Accuracy (QUADA-2). At the same time, subgroup analysis of these data was carried out. Results: Fifty-three studies were included in this meta-analysis, involving 5,049 patients, 1,861 of whom were AKI patients. The sensitivity and specificity of blood NGAL for predicting AKI were 0.79 (95% CI: 0.69-0.86) and 0.85 (95% CI: 0.75-0.91), respectively, and SROC was 0.89 (95% CI: 0.86-0.91). The sensitivity and specificity of urine NGAL for predicting AKI were 0.83 (95% CI: 0.78-0.87) and 0.81 (95% CI: 0.77-0.85), respectively, and SROC was 0.89 (95% CI: 0.86-0.91). Meanwhile, the sensitivity and specificity of overall NGAL (urine and blood NGAL) for predicting AKI in children were 0.82 (95% CI: 0.77-0.86) and 0.82 (95% CI: 0.78-0.86), respectively, and SROC was 0.89 (95% CI: 0.86-0.91). Conclusion: NGAL is a valuable predictor for AKI in children under different backgrounds. There is no significant difference in the prediction accuracy between urine NGAL and blood NGAL, and there is also no significant difference in different measurement methods of NGAL. Hence, NGAL is a non-invasive option in clinical practice. Based on the current evidence, the accuracy of NGAL measurement is the best at 2 h after cardiopulmonary bypass (CPB) and 24 h after birth in asphyxiated newborns. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022360157.

The Role of Vti1a in Biological Functions and Its Possible Role in Nervous System Disorders.

Vesicle transport through interaction with t-SNAREs 1A (Vti1a), a member of the N-ethylmaleimide-sensitive factor attachment protein receptor protein family, is involved in cell signaling as a vesicular protein and mediates vesicle trafficking. Vti1a appears to have specific roles in neurons, primarily by regulating upstream neurosecretory events that mediate exocytotic proteins and the availability of secretory organelles, as well as regulating spontaneous synaptic transmission and postsynaptic efficacy to control neurosecretion. Vti1a also has essential roles in neural development, autophagy, and unconventional extracellular transport of neurons. Studies have shown that Vti1a dysfunction plays critical roles in pathological mechanisms of Hepatic encephalopathy by influencing spontaneous neurotransmission. It also may have an unknown role in amyotrophic lateral sclerosis. A VTI1A variant is associated with the risk of glioma, and the fusion product of the VTI1A gene and the adjacent TCF7L2 gene is involved in glioma development. This review summarizes Vti1a functions in neurons and highlights the role of Vti1a in the several nervous system disorders.

Efficacy and safety of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukemia: A systematic review and meta-analysis.

Objectives: Several clinical trials have been conducted to evaluate the effects of blinatumomab in childhood B cell acute lymphoblastic leukemia (B-ALL). We conducted this meta-analysis to validate the efficacy and safety of blinatumomab in pediatric patients with relapsed/refractory B-ALL (R/R B-ALL). Methods: We searched and investigated all relevant studies in the PubMed, Web of Science, Embase, and Cochrane Library databases. The primary outcomes were complete response (CR), overall survival (OS), event free survival (EFS), minimal residual disease (MRD) response, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and were calculated separately for randomized controlled trials (RCTs) and single-arm studies. The secondary end points were adverse effects (AEs) and the relapse rate. The Cochrane, bias assessment tool, was used to assess the risk of bias in RCTs. The methodological quality of single-arm studies was assessed using the methodological index for non-randomized studies (MINORS) tool. Results: The meta-analysis included two RCTs and 10 single-arm studies, including 652 patients in total. Our study showed that in the single-arm studies, the combined CR rate was 0.56 (95% confidence interval (CI): 0.45 -0.68), the odds ratios (ORs) of OS was 0.43 (95% CI 0.32 -0.54), the EFS rate was 0.30 (95% CI: 0.20 -0.40), the MRD response was 0.51 (95% CI: 0.34 -0.68), allo-HSCT rate was 0.62 (95% CI: 0.50 -.74), the AE rate was 0.65 (95% CI: 0.54 -0.76) and the relapse rate was 0.32 (95% CI: 0.27 -0.38). In the RCTs, the blinatumomab-treated group compared with the chemotherapy group had a combined OS rate of 0.12 (95% CI: 0.05 -0.19) and an EFS rate of 2.16 (95% CI: 1.54 -3.03). The pooled MRD response rate was 4.71 (95% CI:2.84 -7.81), allo-HSCT was 3.24 (95% CI: 1.96 -5.35), the AE rate was 0.31 (95% CI: 0.16 -0.60), and the relapse rate was 0 .69 (95% CI: 0.43 -1.09). Conclusion: According to this meta-analysis, blinatumomab shows potent therapeutic efficacy and limited AEs in children with R/R B- ALL. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022361914.

Theobromine mitigates IL-1ß-induced oxidative stress, inflammatory response, and degradation of type II collagen in human chondrocytes.

Osteoarthritis is one of the major causes of disability in elderly adults. Chondrocytes are responsible for the formation and remodeling of articular cartilage in joint tissue. The dysfunction of chondrocytes is a significant factor in the development of osteoarthritis. In the current study, we found that theobromine, a constituent of the cacao plant, possesses a preventive effect against interleukin (IL)-1ß-induced chondrocyte dysfunction. Theobromine ameliorates IL-1ß-induced production of cellular reactive oxygen species (ROS) and inflammatory mediators including cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). The presence of theobromine suppresses IL-1ß-induced inducible nitro oxide synthase (iNOS) expression and cellular nitro oxide (NO) production. Theobromine also suppresses IL-1ß-induced production of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), as well as matrix metalloproteinases (MMP)-3 and MMP-13. Additionally, theobromine mitigates IL-1ß-induced type II collagen degradation. Mechanistically, we show that theobromine inhibits IL-1ß-induced IκBα activation, nuclear factor-κB (NF-κB) protein p65 accumulation, and transfected NF-κB promoter activity, indicating that theobromine suppresses the NF-κB pathway in chondrocytes. Collectively, our study demonstrates that the natural molecule theobromine has a protective effect to counter cytokine-induced chondrocyte dysfunction, implying its beneficial effect in the prevention of osteoarthritis.

Synthesis and evaluation of hydroxychalcones as multifunctional non-purine xanthine oxidase inhibitors for the treatment of hyperuricemia.

A series of hydroxychalcone derivatives have been designed, synthesized and evaluated for human xanthine oxidase (XO) inhibitory activity. Most of the tested compounds acted moderate XO inhibition with IC50 values in the micromolar rang. Molecular docking and kinetic studies have been performed to explain the binding modes of XO with the selected compounds. In addition, in vitro antioxidant screening results indicated that some of the hydroxychalcones possessed good anti-free radical activities. Furthermore, the preferred compounds 16 and 18 were able to significantly inhibit hepatic xanthine oxidase activity and reduced serum uric acid level of hyperuricemic mice in vivo. In summary, compounds 16 and 18 with balanced activities of antioxidant, XO inhibition and serum uric acid reduction, which are promising candidates for the treatment of hyperuricemia and gout.

[Role of transient receptor potential melastatin 8 channels in migraine mechanism in rats].

OBJECTIVE: To investigate the role of transient receptor potential melastatin 8 (TRPM8) channels in migraine mechanism in rats by measuring the changes in expression of TRPM8 in the trigeminal nerve of rats with migraine. METHODS: Twenty male Sprague-Dawley rats were randomly and equally divided into a blank control group and a model group. Nitroglycerin (10 mg/kg) was injected subcutaneously in the back of the neck once a week for 5 weeks, to prepared a rat model of migraine without aura. Normal saline was injected subcutaneously instead of nitroglycerin in the control group. At 4 hours after the final injection, behavior scoring of all rats was performed, and then the trigeminal nerve ganglions of rats in both groups were collected for measurement of expression of N-methyl-D-aspartate receptor (NMDAR), protein kinase A (PKA), and TRPM8 using immunohistochemical staining, immunofluorescence, and Western blot, respectively. RESULTS: The behavior score in each week during the rat model preparing was significantly higher in the model group than in the control group (P<0.05). The expression of NMDAR, PKA, and TRPM8 in the model group was significantly higher than in the control group (P<0.01). Both the behavior score and the expression of NMDAR were positively correlated with the expression of TRPM8 (r=0.822 and 0.794 respectively; P<0.01). CONCLUSIONS: TRPM8 may be involved in migraine mechanism probably by activation of the NMDAR pathway.