Ether lipids influence cancer cell fate by modulating iron uptake.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome.

The epidermal growth factor receptor (EGFR) plays important roles in multiple cellular events, including growth, differentiation, and motility. A major mechanism of downregulating EGFR function involves its endocytic transport to the lysosome. Sorting of proteins into intracellular pathways involves cargo adaptors recognizing sorting signals on cargo proteins. A dileucine-based sorting signal has been identified previously for the sorting of endosomal EGFR to the lysosome, but a cargo adaptor that recognizes this signal remains unknown. Here, we find that phosphoglycerate kinase 1 (PGK1) is recruited to endosomal membrane upon its phosphorylation, where it binds to the dileucine sorting signal in EGFR to promote the lysosomal transport of this receptor. We also elucidate two mechanisms that act in concert to promote PGK1 recruitment to endosomal membrane, a lipid-based mechanism that involves phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and a protein-based mechanism that involves hepatocyte growth factor receptor substrate (Hrs). These findings reveal an unexpected function for a metabolic enzyme and advance the mechanistic understanding of how EGFR is transported to the lysosome.

Outcomes following surgical interventions for hypothalamic hamartomas: protocol for a systematic review and individual patient data meta-analysis.

INTRODUCTION: Hypothalamic hamartomas (HHs) are deep-seated congenital lesions that typically lead to pharmacoresistant epilepsy and a catastrophic encephalopathic syndrome characterised by severe neuropsychological impairment and decline in quality of life. A variety of surgical approaches and technologies are available for the treatment of HH-related pharmacoresistant epilepsy. There remains, however, a paucity of literature directly comparing their relative efficacy and safety. This protocol aims to facilitate a systematic review and meta-analysis that will characterise and compare the probability of seizure freedom and relevant postoperative complications across different surgical techniques performed for the treatment of HH-related pharmacoresistant epilepsy. METHODS AND ANALYSIS: This protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Participant Data guidelines. Three major databases, PubMed, Embase and Scopus, will be systematically searched from database inception and without language restrictions for relevant articles using our predefined search strategy. Title-abstract and full text screening using inclusion and exclusion criteria created a priori will be performed by two independent reviewers to identify eligible articles. Conflicts will be resolved via discussion with a third team member. Following data extraction of both study-level and individual patient data (IPD), a study-level and IPD meta-analysis will be performed. Study-level analysis will focus on assessing the degree of heterogeneity in the data and quantifying overall seizure outcomes for each surgical technique. The IPD analysis will use multivariable regression to determine perioperative predictors of seizure freedom and complications that can guide patient and technique selection. ETHICS AND DISSEMINATION: This work will not require ethics approval as it will be solely based on previously published and available data. The results of this review will be shared via conference presentation and submission to peer-reviewed neurosurgical journals. PROSPERO REGISTRATION: CRD42022378876.

Motion correction of 3D dynamic contrast-enhanced ultrasound imaging without anatomical B-Mode images: Pilot evaluation in eight patients.

BACKGROUND: Dynamic contrast-enhanced ultrasound (DCE-US) is highly susceptible to motion artifacts arising from patient movement, respiration, and operator handling and experience. Motion artifacts can be especially problematic in the context of perfusion quantification. In conventional 2D DCE-US, motion correction (MC) algorithms take advantage of accompanying side-by-side anatomical B-Mode images that contain time-stable features. However, current commercial models of 3D DCE-US do not provide side-by-side B-Mode images, which makes MC challenging. PURPOSE: This work introduces a novel MC algorithm for 3D DCE-US and assesses its efficacy when handling clinical data sets. METHODS: In brief, the algorithm uses a pyramidal approach whereby short temporal windows consisting of three consecutive frames are created to perform local registrations, which are then registered to a master reference derived from a weighted average of all frames. We applied the algorithm to imaging studies from eight patients with metastatic lesions in the liver and assessed improvements in original versus motion corrected 3D DCE-US cine using: (i) frame-to-frame volumetric overlap of segmented lesions, (ii) normalized correlation coefficient (NCC) between frames (similarity analysis), and (iii) sum of squared errors (SSE), root-mean-squared error (RMSE), and r-squared (R2 ) quality-of-fit from fitted time-intensity curves (TIC) extracted from a segmented lesion. RESULTS: We noted improvements in frame-to-frame lesion overlap across all patients, from 68% ± 13% without correction to 83% ± 3% with MC (p = 0.023). Frame-to-frame similarity as assessed by NCC also improved on two different sets of time points from 0.694 ± 0.057 (original cine) to 0.862 ± 0.049 (corresponding MC cine) and 0.723 ± 0.066 to 0.886 ± 0.036 (p ≤ 0.001 for both). TIC analysis displayed a significant decrease in RMSE (p = 0.018) and a significant increase in R2 goodness-of-fit (p = 0.029) for the patient cohort. CONCLUSIONS: Overall, results suggest decreases in 3D DCE-US motion after applying the proposed algorithm.

Lumbar Decompression with and without Fusion for Lumbar Stenosis with Spondylolisthesis: A Cost Utility Analysis.

STUDY DESIGN: Markov model. OBJECTIVE: To compare the cost-effectiveness of lumbar decompression alone (DA) with lumbar decompression with fusion (DF) for the management of adults undergoing surgery for lumbar stenosis with associated degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Rates of lumbar fusion have increased for all indications in the United States over the last 20 years. Recent randomized controlled trial data, however, have suggested comparable functional outcomes and lower reoperation rates for lumbar decompression and fusion as compared to lumbar decompression alone in the treatment of lumbar stenosis with degenerative spondylolisthesis. MATERIALS AND METHODS: A multi-state Markov model was constructed from the U.S. payer perspective of a hypothetical cohort of patients with LSS requiring surgery. Data regarding clinical improvement, costs, and reoperation were generated from contemporary randomized trial evidence, meta-analyses of recent prospective studies, and large retrospective cohorts. Base case, one-way sensitivity analysis, and probabilistic sensitivity analyses were conducted and results were compared to a willingness to pay threshold of $100,000 (in 2022 USD) over a 2-year time horizon. A discount rate of 3% was utilized. RESULTS: The incremental cost and utility of decompression with fusion relative to decompression alone were $12,778 and 0.00529 QALYs. The corresponding ICER of $2,416,281 far exceeded a willingness to pay threshold of $100,000. In sensitivity analysis, the results varied the most with respect to rate of improvement after lumbar decompression alone, rate of improvement after lumbar decompression and fusion, and odds ratio of reoperation between the two groups. 0% of one-way and probabilistic sensitivity analyses achieved cost-effectiveness at the willingness to pay threshold. CONCLUSIONS: Within the context of contemporary surgical data, DF is not cost effective compared with DA in the surgical management of LSS over a 2-year time horizon.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

miR-99b-3p/Mmp13 axis regulates NLRP3 inflammasome-dependent microglial pyroptosis and alleviates neuropathic pain via the promotion of autophagy.

BACKGROUND: Neuropathic pain significantly impairs quality of life, and effective interventions are limited. NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated microglial pyroptosis and the subsequent proinflammatory cytokine production are critical in exacerbating pain. Considering microglial pyroptosis as a potential target for developing specific analgesic interventions for neuropathic pain, our study investigated the pathogenesis and therapeutic targets in this condition. METHODS: In vitro experiments involved the co-culture of the immortalized BV-2 microglia cell line with lipopolysaccharide (LPS) to induce microglial pyroptosis. Differentially expressed microRNAs (miRNAs) were identified using high-throughput sequencing analysis. The downstream target genes of these miRNAs were determined through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, and the downstream target genes, combined with miRNAs, were predicted and verified through dual luciferase reporter gene assays. In vivo experiments were conducted to construct a chronic constriction injury (CCI) neuropathic pain model in rats and evaluate the analgesic effects of intrathecal injection of an adeno-associated virus vector (AAV) carrying miR-99b-3p. Gene expression was modulated through mimic or siRNA transfection. Western blot analysis assessed the expression of microglial pyroptosis and autophagy-related proteins, whereas RT-qPCR measured changes in proinflammatory cytokines expression. RESULTS: LPS-stimulated up-regulation of proinflammatory cytokines in microglia, accompanied by NLRP3-dependent pyroptosis, including increased NLRP3, GSDMD-N, Caspase1-p20, and mature-IL-1ß expression. High-throughput sequencing analysis revealed 16 upregulated and 10 downregulated miRNAs in LPS-stimulated microglia, with miR-99b-3p being the most downregulated. KEGG analysis revealed that the target genes of these miRNAs are primarily enriched in calcium, FoxO, and mitogen-activated protein kinase (MAPK) signal pathways. Furthermore, overexpression of miR-99b-3p through mimic transfection significantly inhibited the inflammatory response and NLRP3-mediated pyroptosis by promoting autophagy levels in activated microglia. In addition, we predicted that the 3' untranslated region (UTR) of matrix metalloproteinase-13 (Mmp13) could bind to miR-99b-3p, and knockdown of Mmp13 expression through siRNA transfection similarly ameliorated enhanced proinflammatory cytokines expression and microglial pyroptosis by enhancing autophagy. In vivo, Mmp13 was co-localized with spinal dorsal horn microglia and was suppressed by intrathecal injection of the AAV-miR-99b-3p vector. Moreover, overpressed miR-99b-3p alleviated CCI-induced mechanical allodynia and neuroinflammation while suppressing pyroptosis by enhancing autophagy in the spinal cord of CCI rats. CONCLUSION: miR-99b-3p exerts analgesic effects on neuropathic pain by targeting Mmp13. These antinociceptive effects are, at least in part, attributed to the promotion of autophagy, thereby inhibiting neuroinflammation and NLRP3-mediated pyroptosis in activated microglia.

Hemispheric epilepsy surgery for hemimegalencephaly: The UCLA experience.

OBJECTIVES: Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug-resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single-center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes. METHODS: This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less-than-hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes. RESULTS: Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non-operatively. At median last follow-up of 55 months (interquartile range [IQR] 20-92 months), 24 patients (49%) were seizure-free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non-verbal, and 15 of 38 (39%) were non-ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure-free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom. SIGNIFICANCE: This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.

OctoShaker: A versatile robotic biomechanical agitator for cellular and organoid research.

Mechanical forces have increasingly been recognized as a key regulator in the fate of cellular development and functionality. Different mechanical transduction methods, such as substrate stiffness and magnetic bead vibration, have been experimented with to understand the interaction between the biophysical cues and cellular outcome. In the exploration and utilization of the intrinsic cellular mechanism, bio-shakers, traditionally invented for stirring liquid, have garnered more interest as a tool to provide precise mechanical stimuli to aid in this study. Nonetheless, despite the usefulness of current bio-shaking technology, each type of shaker often offers a single mode of motion, insufficient for generating complex force dynamics needed to resemble the actual physical condition that occurs inside living organisms. In this study, we present OctoShaker, a robotic instrument capable of creating a multitude of motions that could be sequenced or programmed to mimic sophisticated hemodynamics in vivo. We demonstrated the programmed motion of circular convection and investigated its influence on micro-particle distribution in 96-well culture microplates. Biological samples, including HeLa cells and organoids, were tested, and unique resultant patterns were observed. We anticipate the open-source dissemination of OctoShaker in diverse biological applications, encompassing biomechanical studies for cellular and organoid research, as well as other disciplines that demand dynamic mechanical force generation.

A survey of potential acceptance of 9-valent HPV vaccine among Chinese male college students.

Human papillomavirus (HPV) has a great impact on world health. Vaccination is among the most important methods of preventing HPV infection. This study investigated Chinese male college students' knowledge of, attitude toward, and acceptance of the 9vHPV vaccine and the independent predictors. An online cross-sectional study was conducted among male college students at Chinese colleges and universities from March 12 to March 23, 2022. Based on a literature review of similar studies, a self-questionnaire was designed to investigate the students' knowledge of, attitude toward, and acceptance of the 9vHPV vaccine. Multivariate logistic regression analysis was performed to identify factors influencing their willingness to be vaccinated. In addition, the structural equation model was constructed. A total of 1,547 male college students completed the survey. Of all the students, 54.95% were unwilling to receive a 9vHPV vaccination, while only 45.05% expressed willingness. Multivariate logistic regression analysis revealed that the male college students willing to receive the vaccine included medical students, those in a romantic relationship, those whose relatives and friends had cervical cancer, those whose relatives and friends had received the 9vHPV vaccine, those supportive of promoting the vaccine for men, and those who would recommend the vaccine to their relatives and friends. Male college students exhibited high hesitancy toward the 9vHPV vaccine. Acceptance of the 9vHPV vaccine by male college students can be improved by deepening their accurate understanding of the vaccine and enhancing their positive attitude toward it.

In vivo evaluation of liver function by multimodal imaging in an alcohol-induced liver injury model.

Background: Visually evaluating liver function is a hot topic in hepatology research. There are few reliable and practical visualization methods for evaluating the liver function in vivo in experimental studies. In this study, we established a multimodal imaging approach for in vivo liver function evaluation and compared healthy mice with chronic alcoholic liver injury (cALI) model mice to explore its potential applicability in experimental research. Methods: In vivo fluorescence imaging (IVFI) technology was utilized to visually represent the clearance of indocyanine green from the liver of both healthy mice and mice with cALI. The reserve liver function was evaluated via IVFI using the Cy5.5-galactosylated polylysine probe, which targets the asialoglycoprotein receptor of hepatocytes. Hepatic microcirculation was assessed through laser speckle perfusion imaging of hepatic blood perfusion. The liver microstructure was then investigated by in vivo confocal laser endomicroscopy imaging. Finally, hepatic asialoglycoprotein receptor expression, histology, and the levels of serum alanine aminotransferase and aspartate aminotransferase were measured. Results: In vivo multimodal imaging results intuitively and dynamically showed that indocyanine green clearance [mean ± standard deviation (SD): 30.83±14.71, 95% confidence interval (CI): 20.3 to 41.35], the fluorescence signal intensity (mean ± SD: 1,217.92±117.63; 95% CI: 1,148.38 to 1,290.84) and fluorescence aggregation area (mean ± SD: 5,855.80±1,271.81; 95% CI: 5,051.57 to 6,653.88) of Cy5.5-galactosylated polylysine targeting the asialoglycoprotein receptor, and hepatic blood perfusion (mean ± SD: 1,494.86±299.33; 95% CI: 1,316.98 to 1,690.16) in model mice were significantly lower than those in healthy mice (all P<0.001). Compared to healthy mice, the model mice exhibited a significant decline in liver asialoglycoprotein receptor expression (mean ± SD: 219.03±16.34; 95% CI: 208.97 to 230.69; P<0.001), increased serum alanine aminotransferase (mean ± SD: 149.70±47.89 U/L; 95% CI: 81.75 to 128.89; P=0.01) and aspartate aminotransferase levels (mean ± SD: 106.30±36.13 U/L; 95% CI: 122.01 to 180.17; P=0.021), hepatocyte swelling and deformation, disappearance of the hepatic cord structure, partial necrosis, and disintegration of hepatocytes. The imaging features of fluorescence signals in liver regions, hepatic blood perfusion and microstructure were biologically related to hepatic asialoglycoprotein receptor expression, serum indices of liver function, and histopathology in model mice. Conclusions: Utilizing in vivo multimodal imaging technology to assess liver function is a viable approach for experimental research, providing dynamic and intuitive visual evaluations in a rapid manner.

How does the correction in lumbar lordosis affect the spinopelvic realignments in degenerative lumbar scoliosis underwent scoliosis surgery?

BACKGROUND: To evaluate the effects of correction in lumbar lordosis (LL) that have on full-body realignments in patients with degenerative lumbar scoliosis (DLS) who had undergone long sacroiliac fusion surgery. METHODS: A multi-center retrospective study including 88 DLS patients underwent the surgical procedure of long sacroiliac fusion with instrumentations was performed. Comparisons of radiographic and quality-of-life (QoL) data among that at the pre-operation, the 3rd month and the final follow-up were performed. The correlations between the LL correction and the changes in other spinopelvic parameters were explored using Pearson-correlation linear analysis and linear regression analysis. The correlation coefficient (r) and the adjusted r2 were calculated subsequently. RESULTS: All radiographic and QoL data improved significantly (P < 0.001) after the surgical treatments. The LL correction correlated (P < 0.001) with the changes in the sacral slope (SS, r = 0.698), pelvic tilt (PT, r = -0.635), sagittal vertical axis (SVA, r = -0.591), T1 pelvic angle (TPA, r = -0.782), and the mismatch of pelvic incidence minus lumbar lordosis (PI-LL, r = -0.936), respectively. Moreover, LL increased by 1° for each of the following spinopelvic parameter changes (P < 0.001): 2.62° for SS (r2 = 0.488), -4.01° for PT (r2 = 0.404), -4.86° for TPA (r2 = 0.612), -2.08° for the PI-LL (r2 = 0.876) and -15.74 mm for SVA (r2 = 0.349). Changes in the thoracic kyphosis (r = 0.259) and pelvic femur angle (r = 0.12) were independent of the LL correction, respectively. CONCLUSIONS: LL correction correlated significantly to the changes in spinopelvic parameters; however, those independent variables including the thoracic spine and hip variables probably be remodeled themselves to maintain the full-body balance in DLS patients underwent the correction surgery.

Effects of maize straw and its biochar application on soil organic carbon chemical composition and carbon degradation genes in a Moso bamboo forest.

We investigated the effects of maize straw and its biochar application on soil organic carbon chemical composition, the abundance of carbon degradation genes (cbhI) and the composition of cbhI gene community in a Moso bamboo forest, to provide the theoretical and scientific basis for enhancing carbon sequestration. We conducted a one-year field experiment in a subtropical Moso bamboo forest with three treatments: control (0 t C·hm-2), maize straw (5 t C·hm-2), and maize straw biochar (5 t C·hm-2). Soil samples were collected at the 3rd and 12th months after the treatment. Soil organic carbon chemical composition, the abundance and community composition of cbhI gene were determined by solid-state 13C NMR, real-time fluorescence quantitative PCR, and high-throughput sequencing, respectively. The results showed that compared with the control, maize straw treatment significantly increased the content of O-alkyl C and decreased aromatic C content, while maize straw biochar treatment showed an opposite effect. Maize straw treatment significantly increased the abundance of cbhI gene and the relative abundance of Penicillium, Gaeumannomyces and Marasmius. However, maize straw biochar treatment reduced the abundance of this gene. The relative abundance of dominant cbhI in soils was positively correlated with the content of O-alkyl C and negatively correlated with the content of aromatic C. Results of redundancy analysis showed that maize straw treatment had a significant effect on the microbial community composition of cbhI gene by changing soil O-alkyl C content, while maize straw biochar affected the microbial community composition of cbhI gene by changing soil pH, organic carbon, and aromatic C content. Maize straw biochar treatment was more effective in increasing soil organic carbon stability and reducing microbial activity associated with carbon degradation in the subtropical Moso bamboo forest ecosystem compared with maize straw treatment. Therefore, the application of biochar has positive significance for maintaining soil carbon storage in subtropical forest ecosystems.

A cuproptosis-related lncRNA signature for predicting prognosis and immune response in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) has a high incidence and poor prognosis. Cuproptosis is a novel type of cell death, which differs from previously reported types of cell death such as apoptosis, autophagy, proptosis, ferroptosis, necroptosis, etc. Long non-coding RNAs (lncRNAs) play multiple roles in HCC. Methods: We downloaded information from The Cancer Genome Atlas (TCGA) database, and obtained cuproptosis-related genes from published studies. The cuproptosis-related lncRNAs were obtained by correlation analysis, and subsequently used to construct a prognostic cuproptosis-related lncRNA signature. Analyses of overall survival (OS), progression-free survival (PFS), receiver operating characteristic (ROC) curve with the area under the curve (AUC) values and the index of concordance (c-index) curve were used to evaluate the signature. The tumor microenvironment (TME) was analyzed by ESTIMATE algorithm. The immune cell data was downloaded from the Tumor Immune Estimation Resource (TIMER) 2.0 database. Immune-related pathways were analyzed by single-sample gene set enrichment analysis (ssGSEA) algorithm. Immunophenoscore (IPS) scores from The Cancer Immunome (TCIA) database were used to evaluate immunotherapy response. The "pRRophetic" was employed to screen drugs for high-risk patients. The candidate lncRNA expression levels were detected by Real Time Quantitative PCR. Results: We constructed a cuproptosis-related lncRNA signature containing seven lncRNAs: AC125437.1, PCED1B-AS1, PICSAR, AP001372.2, AC027097.1, LINC00479, and SLC6A1-AS1. This signature had excellent accuracy, and was independent of the stratification of clinicopathological features. Further study showed that high-risk tumors under this signature had higher TMB, fewer TME components and higher tumor purity. The tumors with high risk were not enriched in immune cell infiltration or immune process pathways, and high-risk patients had a poor response to immunotherapy. Moreover, 29 drugs such as sorafenib, dasatinib and paclitaxel were screened for high-risk HCC patients to improve their prognosis. The expression levels of the candidate lncRNAs in HCC tissue were significantly increased (except PCED1B-AS1). Conclusions: Our prognostic cuproptosis-related lncRNA signature was accurate and effective for predicting the prognosis of HCC. The immunotherapy was unsuitable for high-risk HCC patients with this signature.

MNK, mTOR or eIF4E-selecting the best anti-tumor target for blocking translation initiation.

Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.

Influence of resilience on depression among nurses in clean operating departments: The mediating effect of life satisfaction.

BACKGROUND: A clean operating room is an important part of surgical and critical treatment in hospitals. The workload is substantial, the pace is rapid, and the working environment is intense; therefore, nurses who work in clean operating rooms are constantly challenged, which can lead to anxiety, depression, and other mental health issues. Life satisfaction and resilience are important factors that ensure mental health. Therefore, exploring the mediating role of life satisfaction in the influence of resilience on depression among nurses in clean operating rooms can help improve nursing services and teamwork. AIM: To explore the mediating effect of satisfaction on the influence of resilience on depression among nurses in a clean operating department. METHODS: From April to November 2022, 196 nurses from the Department of Clean Operating at Harbin Medical University Cancer Hospital participated in this study. Participants were selected using convenience sampling. Participants' gender, age, marital status, position, length of service, personal monthly income, daily working hours, employment status, and professional title were collected, and the Connor-Davidson resilience scale, satisfaction with life scale, and self-rating depression scale were used to evaluate resilience, life satisfaction, and depression. The researchers conducted professional training in advance, introduced the research methods to the participants before the investigation, and explained the study's significance and purpose. Surveys were distributed and collected on-site. Each questionnaire took 30 min to complete. RESULTS: The average scores for life satisfaction, resilience, and depression were 3.13 (± 0.28), 4.09 (± 0.78), and 56.21 (± 8.70), respectively. The correlation between resilience and depression was negative (r = -0.829, P < 0.01). Life satisfaction was positively related to resilience (r = 0.855, P < 0.01) and negatively related to depression (r = -0.778, P < 0.01). The relationship between resilience and depression was partially mediated by life satisfaction. The value of the mediating effect was -6.853 (26.68% of the total effect). CONCLUSION: Life satisfaction partially mediates the link between resilience and depression among nurses in clean operating departments.

Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.

Fangchinoline derivatives inhibits PI3K signaling in vitro and in vivo in non-small cell lung cancer.

Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC50 value of 0.26 µM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC50 value of 27.05 µM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC.

The antihyperuricemia activity of Astragali Radix through regulating the expression of uric acid transporters via PI3K/Akt signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR) is the dry root of the leguminous plants Astragalus membranaceus (Fisch) Beg. var. mongholicus (Beg) Hsiao, and Astragalus membranaceus (Fisch) Bge., being used as a medicinal and edible resource. AR is used in traditional Chinese medicine prescriptions to treat hyperuricemia, but this particular effect is rarely reported, and the associated mechanism of action is still need to be elucidated. AIM OF THE STUDY: To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models. MATERIALS AND METHODS: In our study, the chemical profile of AR was analysed by UHPLC-QE-MS, as well as the mechanism of action of AR and the representative compounds on hyperuricemia was studied through the constructed hyperuricemia mouse and cellular models. RESULTS: The main compounds in AR were terpenoids, flavonoids and alkaloids. Mice group treated with the highest AR dosage showed significantly lower (p < 0.0001) serum uric acid (208 ± 9 µmol/L) than the control group (317 ± 11 µmol/L). Furthermore, UA increased in a dose-dependence manner in urine and faeces. Serum creatinine and blood urea nitrogen standards, as well as xanthine oxidase in mice liver, decreased (p < 0.05) in all cases, indicating that AR could relieve acute hyperuricemia. UA reabsorption protein (URAT1 and GLUT9) was down-regulated in AR administration groups, while the secretory protein (ABCG2) was up-regulated, indicating that AR could promote the excretion of UA by regulating UA transporters via PI3K/Akt signalling pathway. CONCLUSION: This study validated the activity, and revealed the mechanism of AR in reducing UA, which provided experimental and clinical basis for the treatment of hyperuricemia with it.

Prognostic value of temporal muscle thickness, a novel radiographic marker of sarcopenia, in patients with brain tumor: A systematic review and meta-analysis.

Sarcopenia has been identified as a prognostic factor among certain types of cancer. However, it is unclear whether there is prognostic value of temporalis muscle thickness (TMT), a potential surrogate for sarcopenia, in adults patients with brain tumors. Therefore, we searched the Medline, Embase, and PubMed to systematically review and meta-analyze the relationship between TMT and overall survival, progression-free survival, and complications in patients with brain tumors and the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) were evaluated. The quality in prognostic studies (QUIPS) instrument was employed to evaluate study quality. Nineteen studies involving 4570 patients with brain tumors were included for qualitative and quantitative analysis. Meta-analysis revealed thinner TMT was associated with poor overall survival (HR, 1.72; 95% CI, 1.45-2.04; P < 0.01) in patients with brain tumors. Sub-analyses showed that the association existed for both primary brain tumors (HR, 2.02; 95% CI, 1.55-2.63) and brain metastases (HR, 1.39; 95% CI, 1.30-1.49). Moreover, thinner TMT also was the independent predictor of progression-free survival in patients with primary brain tumors (HR, 2.88; 95% CI, 1.85-4.46; P < 0.01). Therefore, to improve clinical decision making it is important to integrate TMT assessment into routine clinical settings in patients with brain tumors.