Impact of acute stress disorder on surfactant protein D levels in acute lung injury.

Many people sustain acute lung injuries in road traffic collisions, but few studies have dealt with such injuries in live models. This study aimed to explore the basic pathophysiological and inflammatory changes in adult rabbits following acute thoracic trauma. We randomly assigned 50 rabbits to control and injury groups. Rabbits in the injury group were subjected to right chest pressure (2600 g) using a Hopkinson bar. Measurements were taken in the control group and 0, 24, 48, and 72 h after injury in the injury group. Injury severity was evaluated in gross view; with haematoxylin and eosin (H&E) staining; and through the serum changes of tumor necrosis factor alpha (TNF-α), surfactant protein D (SP-D), and neutrophils. Secretion changes in SP-D in right lung injured tissues were estimated by western blotting and qPCR. Serum TNF-α levels increased rapidly immediately after injury, gradually recovering after 24, 48, and 72 h (p < 0.01). The percentage of neutrophils in the accompanying blood showed a consistent trend. Gross necropsy and H&E staining indicated different levels of bleeding, alveoli exudation, and inflammatory transformation after impact. ELISA depicted the same trend in circulation (F = 22.902, p < 0.01). Western blotting showed that SP-D protein levels in tissues decreased at 0 h and increased at 24, 48, and 72 h. We demonstrate the feasibility of a model of impact lung injury. Primary impact caused injury without external signs. Inflammation began immediately, and the lungs began recovering at 24, 48, and 72 h, as shown by increased SP-D levels in circulation and tissues.With complaints of ALI and inflammation, SP-D may be a potential biomarker after chest trauma.

The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis.

Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.

AGBL4 promotes malignant progression of glioblastoma via modulation of MMP-1 and inflammatory pathways.

Introduction: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, is notorious for its aggressive growth and dismal prognosis. This study aimed to elucidate the molecular underpinnings of GBM, particularly focusing on the role of AGBL4 and its connection to inflammatory pathways, to discover viable therapeutic targets. Methods: Single-cell sequencing was utilized to examine the expression levels of AGBL4 and functional assays were performed to assess the effects of AGBL4 modulation. Results: Our findings identified the significant upregulation of AGBL4 in GBM, which correlated with adverse clinical outcomes. Functional assays demonstrated that AGBL4 knockdown inhibited GBM cell proliferation, migration, and invasion and influenced inflammatory response pathways, while AGBL4 overexpression promoted these activities. Further investigation revealed that AGBL4 exerted its oncogenic effects through modulation of MMP-1, establishing a novel regulatory axis critical for GBM progression and inflammation. Discussion: Both AGBL4 and MMP-1 may be pivotal molecular targets, offering new avenues for targeted therapy in GBM management.

Quantitative analysis of paravertebral muscle asymmetry and its correlation with spinal deformity in patients with degenerative lumbar scoliosis: a retrospective case-control study.

Background: The degeneration and functional decline of paravertebral muscles (PVMs) are reported to be closely linked to the incidence of degenerative lumbar scoliosis (DLS), a spinal deformity of the mature skeleton. However, the functional role and degeneration of PVMs and their relationship to the development of spinal deformities remain controversial. Therefore, the present study analyzed the morphological changes in the PVMs of patients with DLS, and explored the relationship between PVM degeneration and spinal osseous parameters. Methods: In this retrospective case-control study, we evaluated the PVM parameters of patients with DLS (n=120) and compared them with patients free of DLS (control group, n=120). The cross-sectional area (CSA) and computed tomography (CT) values of the PVM at the lumbar vertebra 1-5 levels were measured. Further, the lumbar scoliosis Cobb, lumbar lordotic, and apical vertebral rotation angles were measured on CT and radiographs in the DLS group, and the relationship between PVM changes and these factors was analyzed. Results: In the control group, the PVM CSA and CT values differed insignificantly between the bilateral sides at all levels (P>0.05). In the DLS group, the CSAs of the multifidus (MF) and erector spinae (ES) were larger on the convex side than the concave side (P>0.05), whereas that of the psoas major (PM) was smaller on the convex side than the concave side (P<0.05). The CT value of the PVM was lower on the convex side at all levels (P<0.05). The CSA and CT values on both sides of the patients were lower in the DLS group than the control group at all levels (P<0.05). Further, the degree of PVM asymmetry at the apical vertebral level was positively correlated with the lumbar scoliosis (P<0.01) and apical vertebral rotation angles (P<0.05), but negatively correlated with the lumbar lordotic angle (P<0.05). Conclusions: Asymmetric degeneration of the PVM was observed bilaterally in DLS patients, and the degeneration was more pronounced on the concave side than the convex side. This asymmetrical degeneration was closely associated with the severity of lumbar scoliosis, vertebral rotation, and loss of lumbar lordosis, and a stronger correlation was observed with the MF and ES than with the PM.

Determination of vancomycin and meropenem in serum and synovial fluid of patients with prosthetic joint infections using UPLC-MS/MS.

Numerous studies have suggested that intra-articular administration of antibiotics following primary revision surgery may be one of the methods for treating prosthetic joint infection (PJI). Vancomycin and meropenem are the two most commonly used antibiotics for local application. Determining the concentrations of vancomycin and meropenem in the serum and synovial fluid of patients with PJI plays a significant role in further optimizing local medication schemes and effectively eradicating biofilm infections. This study aimed to establish a rapid, sensitive, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining the concentrations of vancomycin and meropenem in human serum and synovial fluid. Serum samples were processed using acetonitrile precipitation of proteins and dichloromethane extraction, while synovial fluid samples were diluted before analysis. Chromatographic separation was achieved in 6 min on a Waters Acquity UPLC BEH C18 column, with the mobile phase consisting of 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Quantification was carried out using a Waters XEVO TQD triple quadrupole mass spectrometer with an electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) mode was employed to detect the following quantifier ion transitions: 717.95-99.97 (norvancomycin), 725.90-100.04 (vancomycin), 384.16-67.99 (meropenem). The method validation conformed to the guidelines of the FDA and the Chinese Pharmacopoeia. The method demonstrated good linearity within the range of 0.5-50 µg/ml for serum and 0.5-100 µg/ml for synovial fluid. Selectivity, intra-day and inter-day precision and accuracy, extraction recovery, matrix effect, and stability validation results all met the required standards. This method has been successfully applied in the pharmacokinetic/pharmacodynamic (PK/PD) studies of patients with PJI.

LncRNA TUG1 mediates microglial inflammatory activation by regulating glucose metabolic reprogramming.

Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1ß (IL-1ß), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2.

Ventriculoperitoneal shunting obstruction: a multicentre clinical audit for cerebrospinal fluid parameters and its prediction role.

BACKGROUND: Shunt obstruction is a type of ventriculoperitoneal shunt (VPS) failure. Whether changes in cerebrospinal fluid (CSF) parameters can influence shunt outcomes or not is debatable. METHODS: In this study, we retrospectively included adult hydrocephalus patients who received VPS from 6 general hospitals in different provinces of China from November 2013 to September 2021. The inclusion criteria: Patients with hydrocephalus of all etiologies underwent shunt surgery from 6 general hospitals in different provinces of China were included in the study. The exclusion criteria: 1.Patients under the age of 18; 2.Patients who had previous shunt surgery; 3. Shunt failure from other factors; 4.Patients died from other causes; 5. Patients with incomplete data. The CSF of shunt patients had been analyzed at the time of shunt insertion. The CSF samples were collected and analyzed when the shunt was implanted. The relationship between CSF parameters and the incidence rate of shunt obstruction in one year was analyzed. RESULTS: A total of 717 eligible patients from 6 hospitals were included, of whom 59(8.23%) experienced obstruction. Multivariate logistic regression analysis identified that protein level(odds ratio [OR] 1.161, 95% CI 1.005 ~ 1.341, p = 0.043), decreased glucose level(< 2.5 mmol/L)(odds ratio 3.784, 95% confidence interval 1.872 ~ 7.652, p = 0.001) and protein level increase(> 0.45 g/L) (odds ratio 3.653, 95% confidence interval 1.931 ~ 6.910, p = 0.001)were independent risk factors of shunt obstruction. CONCLUSION: This study suggested that increased protein level (> 0.45 g/L) and decreased glucose level (< 2.5 mmol/L) in CSF indicated an increased risk of shunt obstruction in a patient with hydrocephalus. Thus, shunt surgery should be more carefully considered when the CSF glucose and protein were abnormal.

BAP31 Promotes Adhesion Between Endothelial Cells and Macrophages Through the NF-κB Signaling Pathway in Sepsis.

Purpose: To investigate the role of B cell receptor associated protein 31 (BAP31) in the pathogenesis of sepsis. Methods: Cecal ligation and puncture (CLP)-induced C57BL/6J mice, and LPS-challenged endothelial cells (HUVECs) were established to mimic a sepsis animal model and a sepsis cell model, respectively. Cre/LoxP and shRNA methods were used for BAP31 knockdown in vivo and in vitro respectively. Neutrophils/macrophages-endothelial cocultures were used to evaluate neutrophils or macrophages infiltration and adhesion to endothelial cells. Cox proportional hazards model was used to evaluate the survival time of mice. Western blotting (WB) and Quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect toll-like receptor (TLR) signaling pathway, transforming growth factor ß activated kinase 1 (TAK1) signaling pathway and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathway. Results: Deletion of BAP31 reduced CLP-induced mortality of mice, histological damage with less interstitial edema, and neutrophils and macrophages infiltration. IHC and IF showed that BAP31 knockdown significantly decreases the expressions of ICAM1 and VCAM1 both in vivo and in vitro. Coculture showed that LPS-induced neutrophils or macrophages adhesion to endothelial cells was significantly weakened in BAP31 knockdown cells. In addition, BAP31 knockdown of endothelial cells decreased the expression of CD80 and CD86 on the surface of macrophages as well as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) during sepsis. Mechanistically, LPS-induced the activation of TLR4, MyD88 and TRAF6, and the phosphorylation of TAK1, PI3K, AKT, IκBα and IKKα/ß, resulting in activation of nuclear factor kappa B (NF-κB) p65 in endothelial cells. However, BAP31 knockdown significantly reversed the expressions of associated proteins. Conclusion: BAP31 up-regulated the expressions of ICAM1 and VCAM1 in endothelial cells leading to sepsis-associated organ injury. This may be involved in activation of TLR signaling pathway, TAK1 pathway, and PI3K-AKT signaling pathway.

Diabetic conditions promote drug coating degradation but prevent endothelial coverage after stenting.

The endothelialization of drug-eluting stents is delayed after implantation in patients with diabetes. Although numerous factors were implicated in hyperglycemia-induced endothelial dysfunction, the effects of stent drug coating degradation on endothelial dysfunction remains unclear. We hypothesized that diabetic conditions promote drugcoating degradation and enhance antiproliferative agent release, but that the rapid release of these antiproliferative agents inhibits endothelial cell proliferation leading to poor reendothelialization post-stenting. To verify this hypothesis, a dynamic hyperglycemic circulation system was introduced to measure the profile of drugcoating degradation in vitro. Flow cytometry and RNA sequencing were performed to evaluate endothelial cell proliferation. Moreover, a Type 1 diabetic rabbit model was generated and a rescue experiment conducted to evaluate the effects of rapid drugcoating elution on endothelial coverage in vivo. The main findings were as follows: 1) diabetic conditions promoted drugcoating degradation and increased antiproliferative agent release; 2) this increase in antiproliferative agent release inhibited endothelial cell proliferation and delayed endothelial coverage; and 3) strict glycemic control attenuated drugcoating degradation and promoted endothelial coverage post-stenting. This is the first study to illustrate rapid drugcoating degradation and its potential effects on endothelial recovery under diabetic conditions, highlighting the importance of strict glycemic management in patients with diabetes after drug-eluting stent implantation. STATEMENT OF SIGNIFICANCE: Diabetic conditions promote drug coating degradation and increase the release of antiproliferative agents. Rapid drug coating degradation under diabetic conditions inhibits endothelial cell proliferation and delays endothelialization. Strict glycemic control attenuates drug coating degradation and promotes endothelialization.

Acute toxicology on Danio rerio embryo and adult from Chinese traditional medicine preparation Danggui Shaoyao san.

ETHNOPHARMACOLOGICAL RELEVANCE: Although the Traditional Chinese Medicine (TCM) prescription of Danggui Shaoyao San (DSS) presents substantial clinical efficacy and promising clinical prospects, the safety of DSS and its extracts have been inadequately investigated. The larva-adult duality of the zebrafish model offers a more efficient approach for evaluating the safety of herbal preparations in the fields of toxicology and pharmacology. AIM OF THE STUDY: To investigate the acute toxicity of the extract derived from Danggui Shaoyao San, a traditional Chinese medicine preparation, on both Danio rerio embryos and adult organisms. MATERIALS AND METHODS: The components of DSS were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The hatching rate of Danio rerio juveniles with different concentrations of DSS was calculated and the morphological changes of juveniles after administration were observed through a microscope. The behavioral trajectory of the adult fish was recorded by the observation tower of the automated Danio rerio analysis system, and DSS's effects on the behavior was analyzed. The pathological changes of Danio rerio gills, livers, kidneys, intestines and spermaries were examined using HE staining. RESULTS: Compared with the control group, 25, 50 and 100 mg/L of DSS did not elicit any significant impacts on the hatching rate and morphology. Both 200 mg/L and the propylene glycol 2% reduced the hatching rate and caused the morphological teratogenic changes of the juvenile fish. The dosage of DSS below 100 mg/L had no discernible effect on the behavior of the adult fish, whereas the application of propylene glycol 2% was found to stimulate the adult fish, resulting in a notable increase in high-speed movement distance. 100 mg/L DSS group was not observed to cause any noticeable damage to the gills, livers, intestines and spermaries of Danio rerio, only mild nephrotoxicity was detected. The propylene glycol 2% group was found to result in pathological changes such as hyperplasia of epithelial cells on secondary lamellae, liver cell outline loss or atypia, tubal disorganization, goblet cell hypertrophy and irregularly arranged spermatozoa. CONCLUSION: A viable approach for conducting toxicological studies on TCM preparations was developed and tested in this research. The findings showed that Danggui Shaoyao San has minimal acute toxicity to embryos and adult organisms at concentrations up to 100 mg/L. These results indicate that Danggui Shaoyao San is a safe TCM preparation.

[Research progress on Rhododendron molle in treatment of rheumatoid arthritis].

Rheumatoid arthritis(RA), as a chronic autoimmune disease, has a high incidence and disability rate, causing significant suffering to patients. Due to its complex pathogenesis, it has not been fully elucidated to date, and its treatment remains a challenging problem in the medical field. Although western medicine treatment options have certain efficacy, they require prolonged use and are expensive. Additionally, they carry risks of multiple infections and adverse reactions like malignancies. The Chinese herbal medicine Rhododendron molle is commonly used in folk medicine for its properties of dispelling wind, removing dampness, calming nerves, and alleviating pain in the treatment of diseases like rheumatic bone diseases. In recent years, modern clinical and pharmacological studies have shown that the diterpenoids in R. molle are effective components, exhibiting immune-regulatory, anti-inflammatory, and analgesic effects. This makes it a promising candidate for treating RA with a broad range of potential applications. However, R. molle has certain toxic properties that hinder its clinical application and lead to the wastage of its resources. This study reviewed recent research progress on the mechanism of R. molle in preventing and treating RA, focusing on its chemical components, anti-inflammatory and analgesic properties and summarized the adverse reactions associated with R. molle, aiming to offer new ideas for finding natural remedies for RA and methods to reduce toxicity while enhancing the effectiveness of R. molle. The study seeks to clarify the safety and efficacy of R. molle and its extracts, providing a theoretical basis for its application prospects and further promoting the development and utilization of R. molle resources.

Associations between vertebral bone marrow fat and sagittal spine alignment as assessed by chemical shift-encoding-based water-fat MRI.

BACKGROUND: The relationship between sagittal spine alignment and vertebral bone marrow fat is unknown. We aimed to assess the relationship between vertebral bone marrow fat and sagittal spine alignment using chemical shift-encoding-based water-fat magnetic resonance imaging (MRI). METHODS: A total of 181 asymptomatic volunteers were recruited for whole spine X-ray and lumbar MRI. Spine typing was performed according to the Roussouly classification and measurement of vertebral fat fraction based on the chemical shift-encoding-based water-fat MRI. One-way analysis of variance (ANOVA) was used to analyze the differences in vertebral fat fraction between spine types. The post hoc least significant difference (LSD) test was utilized for subgroup comparison after ANOVA. RESULTS: Overall, the vertebral fat fraction increased from L1 to L5 and was the same for each spine type. The vertebral fat fraction was the highest in type 1 and lowest in type 4 at all levels. ANOVA revealed statistically significant differences in fat fraction among different spine types at L4 and L5 (P < .05). The post hoc LSD test showed that the fat fraction of L4 was significantly different (P < .05) between type 1 and type 4 as well as between type 2 and type 4. The fat fraction of L5 was significantly different between type 1 and type 3, between type 1 and type 4, and between type 2 and type 4 (P < .05). CONCLUSION: Our study found that vertebral bone marrow fat is associated with sagittal spine alignment, which may serve as a new additional explanation for the association of sagittal alignment with spinal degeneration.

Budesonide-liposomes inclusion complex in thermosensitive gel alleviates DSS-induced ulcerative colitis in mice.

PURPOSE: A novel formulation for Ulcerative Colitis (UC) treatment by rectal administration with budesonide liposomes (Bud Lip) and thermosensitive gel (Gel) was developed for future clinical use. To evaluate the anti-inflammatory activity and colon mucosal protection of this novel formulation compared with the other three in mice. METHODS: Bud Lip was prepared by reverse evaporation method and then dispersed in solutions with PL407 and PL188 by a cold method. Male mice were induced to UC by dextran sulfate sodium (DSS) and were treated for 14 days by rectal administration, as follows: Bud enema (a conventional suspension formulation); Bud Lip; Bud Gel; Bud Lip-Gel; saline. And a negative control without colitis was also used. Disease activity index (DAI), and macroscopic and microscopic damage scores in colon tissues were used to evaluate the effect of therapy. The levels of IL-6 and IL-10 in serum and the concentrations of TNF-α and IL-10 and myeloperoxidase (MPO) activity in colon tissue were also introduced. RESULTS: In UC mice model, Bud Lip-Gel showed inflammation was alleviated significantly, and the treatment was highly associated with lower DAI, less macroscopic and microscopic colonic damage and downregulation of pro-inflammatory cytokines TNF-α, IL-6 and MPO. Bud Lip-Gel had advantages over Bud, Bud Lip, Bud Gel in the treatment of active UC. CONCLUSION: Novel Bud liposomes complex in thermosensitive Gel effectively mitigated symptoms, alleviated macroscopic and microscopic colon damage, and reduced inflammatory reaction in UC mice, which might be a potential strategy for UC treatment.

The diagnostic efficacy of ultrasonographically-based measurements of minimum and maximum fascia-tumor distance in differentiating superficial from deep lobe benign parotid tumors.

OBJECTIVES: The objective was to calculate the efficacy of ultrasonographically-based measurements of minimum and maximum fascia-tumor distance (MiFTD and MaFTD) of benign salivary gland tumors to identify tumor location in the superficial or deep lobe of the parotid gland. STUDY DESIGN: MiFTDs and MaFTDs were measured on pre-operative ultrasonographic images of 102 tumors. Tumor location was classified at surgery as superficial or deep based on relation to the facial nerve, with 74 tumors in the superficial lobe and 28 in the deep lobe. The diagnostic efficacy of differences in MiFTD and MaFTD between locations was calculated with the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Statistical significance was established at P < .05. RESULTS: Mean MiFTD and MaFTD values were significantly smaller in the superficial lobe tumors than in the deep lobe lesions (P < .001). Tumors with cutoff values of MiFTD >2.7 mm or MaFTD >21.1 mm were considered deep lobe lesions. When using the cutoff values for both MiFTD and MaFTD, the AUC was 0.893, whereas sensitivity and specificity were .821 and .919, respectively. CONCLUSIONS: Ultrasonography can help in the preoperative localization of tumors in the superficial and deep lobes of the parotid gland. This can facilitate proper surgical treatment selection and minimize the risk of adverse consequences of facial nerve damage while improving cosmetic outcomes.

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK1/2 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic apoptosis and pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

Focus on Radiation Protection Improves Both Correct Behavior and Procedural Performance During Simulation-Based Training - A Randomized Comparison.

BACKGROUND: To explore whether simulation-based endovascular training with focus on radiation safety could improve correct behavior without jeopardizing the learning of procedural skills. METHODS: Twenty-four residents without previous endovascular experience completed 10 clinical scenarios on a virtual-reality endovascular simulator with software for peripheral endovascular interventions. Participants were randomized to receive feedback (n = 12) or not (n = 12) on radiation protection (RP) performance after each case. Expert assessments were done at the first, second, fourth, seventh, and 10th case on RP and endovascular skills (ES). Automatic simulator metrics on procedure time, contrast dose, handling errors, and estimated radiation exposure to patient and operator were registered. Outcome metrics were analyzed by two-way mixed analysis of variance pairwise comparisons with independent t-tests. Correlations were explored using Pearson's r for internal consistency reliability. RESULTS: The RP performance was similar in both groups at their first attempt (P = 0.61), but the feedback group significantly outperformed the control group over time (P < 0.001 for all comparisons). The feedback group was however slower to learn the ES at start (P = 0.047 at second performance), but after 7 attempts no difference was shown (P = 0.59). The feedback group used more time (19.5 vs. 15.3 min; P = 0.007) but less contrast (60 vs. 100 mL; P < 0.001). The number of errors was the same in both groups, but all metrics regarding radiation exposure favored the feedback group (P-values from 0.001 to 0.008). CONCLUSIONS: Simulation-based training (SBT) is effective to acquire basic endovascular intervention skills and concurrently learn RP behavior when feedback on radiation culture is provided.

Taking precautions in advance: a lower level of activities of daily living may be associated with a higher likelihood of memory-related diseases.

Introduction: Memory-related diseases (MDs) pose a significant healthcare challenge globally, and early detection is essential for effective intervention. This study investigates the potential of Activities of Daily Living (ADL) as a clinical diagnostic indicator for MDs. Utilizing data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS), encompassing 10,062 Chinese individuals aged 45 or older, we assessed ADL using the Barthel Index (BI) and correlated it with the presence of MDs. Statistical analysis, supplemented by machine learning algorithms (Support Vector Machine, Decision Tree, and Logistic Regression), was employed to elucidate the relationship between ADL and MDs. Background: MDs represent a significant public health concern, necessitating early detection and intervention to mitigate their impact on individuals and society. Identifying reliable clinical diagnostic signs for MDs is imperative. ADL have garnered attention as a potential marker. This study aims to rigorously analyze clinical data and validate machine learning algorithms to ascertain if ADL can serve as an indicator of MDs. Methods: Data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS) were employed, encompassing responses from 10,062 Chinese individuals aged 45 or older. ADL was assessed using the BI, while the presence of MDs was determined through health report questions. Statistical analysis was executed using SPSS 25.0, and machine learning algorithms, including Support Vector Machine (SVM), Decision Tree Learning (DT), and Logistic Regression (LR), were implemented using Python 3.10.2. Results: Population characteristics analysis revealed that the average BI score for individuals with MDs was 70.88, significantly lower than the average score of 87.77 in the control group. Pearson's correlation analysis demonstrated a robust negative association (r = -0.188, p < 0.001) between ADL and MDs. After adjusting for covariates such as gender, age, smoking status, drinking status, hypertension, diabetes, and dyslipidemia, the negative relationship between ADL and MDs remained statistically significant (B = -0.002, ß = -0.142, t = -14.393, 95% CI = -0.002, -0.001, p = 0.000). The application of machine learning models further confirmed the predictive accuracy of ADL for MDs, with area under the curve (AUC) values as follows: SVM-AUC = 0.69, DT-AUC = 0.715, LR-AUC = 0.7. Comparative analysis of machine learning outcomes with and without the BI underscored the BI's role in enhancing predictive abilities, with the DT model demonstrating superior performance. Conclusion: This study establishes a robust negative correlation between ADL and MDs through comprehensive statistical analysis and machine learning algorithms. The results validate ADL as a promising diagnostic indicator for MDs, with enhanced predictive accuracy when coupled with the Barthel Index. Lower levels of ADL are associated with an increased likelihood of developing memory-related diseases, underscoring the clinical relevance of ADL assessment in early disease detection.

The Burden of Proof studies: assessing the evidence of risk.

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses-termed the Burden of Proof studies-designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk-outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk-outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk-outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

Health effects associated with vegetable consumption: a Burden of Proof study.

Previous research suggests a protective effect of vegetable consumption against chronic disease, but the quality of evidence underlying those findings remains uncertain. We applied a Bayesian meta-regression tool to estimate the mean risk function and quantify the quality of evidence for associations between vegetable consumption and ischemic heart disease (IHD), ischemic stroke, hemorrhagic stroke, type 2 diabetes and esophageal cancer. Increasing from no vegetable consumption to the theoretical minimum risk exposure level (306-372 g daily) was associated with a 23.2% decline (95% uncertainty interval, including between-study heterogeneity: 16.4-29.4) in ischemic stroke risk; a 22.9% (13.6-31.3) decline in IHD risk; a 15.9% (1.7-28.1) decline in hemorrhagic stroke risk; a 28.5% (-0.02-51.4) decline in esophageal cancer risk; and a 26.1% (-3.6-48.3) decline in type 2 diabetes risk. We found statistically significant protective effects of vegetable consumption for ischemic stroke (three stars), IHD (two stars), hemorrhagic stroke (two stars) and esophageal cancer (two stars). Including between-study heterogeneity, we did not detect a significant association with type 2 diabetes, corresponding to a one-star rating. Although current evidence supports increased efforts and policies to promote vegetable consumption, remaining uncertainties suggest the need for continued research.

Health effects associated with consumption of unprocessed red meat: a Burden of Proof study.

Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression-relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity-to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0-200 g d-1. While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.