Effects of personalized music listening on post-stroke cognitive impairment: A randomized controlled trial.

BACKGROUND AND PURPOSE: Previous studies have suggested that music listening has the potential to positively affect cognitive functions and mood in individuals with post-stroke cognitive impairment (PSCI), with a preference for self-selected music likely to yield better outcomes. However, there is insufficient clinical evidence to suggest the use of music listening in routine rehabilitation care to treat PSCI. This randomized control trial (RCT) aims to investigate the effects of personalized music listening on mood improvement, activities of daily living (ADLs), and cognitive functions in individuals with PSCI. MATERIALS AND METHODS: A total of 34 patients with PSCI were randomly assigned to either the music group or the control group. Patients in the music group underwent a three-month personalized music-listening intervention. The intervention involved listening to a personalized playlist tailored to each individual's cultural, ethnic, and social background, life experiences, and personal music preferences. In contrast, the control group patients listened to white noise as a placebo. Cognitive function, neurological function, mood, and ADLs were assessed. RESULTS: After three months of treatment, the music group showed significantly higher Montreal Cognitive Assessment (MoCA) scores compared to the control group (p=0.027), particularly in the domains of delayed recall (p=0.019) and orientation (p=0.023). Moreover, the music group demonstrated significantly better scores in National Institutes of Health Stroke Scale (NIHSS) (p=0.008), Barthel Index (BI) (p=0.019), and Zarit Caregiver Burden Interview (ZBI) (p=0.008) compared to the control group. No effects were found on mood as measured by the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD). CONCLUSION: Personalized music listening promotes the recovery of cognitive and neurological functions, improves ADLs, and reduces caregiver burden in patients with PSCI.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with rare KRAS mutations: a real-world retrospective study.

Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

Cyclic Ether-Based Electrolyte with a Weak Solvation Structure for Advanced Potassium Metal Batteries.

Potassium metal batteries (PMBs) are promising candidates for large-scale energy storage. Conventional carbonate electrolytes exhibit unsatisfactory thermodynamic stability against potassium (K) metal anode. Linear ether is widely adopted because of its compatibility with K metal, but the poor oxidation stability restricts the application with high-voltage cathodes. Herein, a weakly solvating cyclic ether is proposed as a solvent to stabilize the K-electrolyte interface and build a robust solid-electrolyte interphase (SEI). This weakly solvating electrolyte (WSE) possesses an anion-dominated solvation structure, which facilitates the anion decomposition for constructing an inorganic-rich SEI. The superior mechanical properties of the SEI, as examined by atomic force microscopy, prevent the SEI from fracture. Consequently, this WSE achieves highly reversible plating/stripping behavior of K metal for 1300 h with a high average Coulombic efficiency of 99.20%. Stable full cells are also demonstrated with a high-voltage cathode at harsh conditions. This work complements the design of WSEs for advanced PMBs by cyclic ether solvents.

Defect-rich W1-xMoxS2 solutions for efficient H2 evolution in acidic electrolytes.

An optimal W0.4Mo0.6S2 solid solution, equipped with rich intrinsic defects, exhibits excellent stability in both 0.5 M H2SO4 and 2.0 M NaCl, showing negligible activity degradation after continuous 50 hours of working, thereby showing outstanding practical prospects.

Hydrophilic materials based on hydrogel polymers for enrichment of glycopeptides from serum of colorectal cancer patients.

In this work, a composite hydrogel material consisting of chitosan-based composite hydrogel was prepared by a simple and rapid synthetic method and will be named three-dimensional (3D)-IL-COF-1@CS hydrogel. Possessing a stable 3D network structure and outstanding hydrophilicity, the novel hydrogel is capable of capturing glycopeptides. The 3D-IL-COF-1@CS hydrogel showed good sensitivity (0.1 fmol/µL) and selectivity (1:2000). In addition, 19 glycopeptides were captured in standard samples. In the analysis of human serum, 148 glycopeptides assigned to 72 glycoproteins were assayed in the serum of normal individuals, and 245 glycopeptides corresponding to 100 glycoproteins were found in the serum of colorectal cancer (CRC) patients. More importantly, several functional programs based on Gene Ontology analysis supported molecular biological processes that may be relevant to the pathogenesis of CRC, including aging, fibrinogen complex, and arylesterase activity. The low cost, simplicity, rapid synthesis, and good enrichment performance have a great future in glycoproteomics analysis and related diseases.

Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis.

Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.

Microencapsulated rice bran alleviates hyperlipidemia induced by high-fat diet via regulating lipid metabolism and gut microbiota.

Hyperlipidemia has been suggested to be associated with dysregulation of lipid metabolism and gut microbiota. The present study prepared microencapsulated rice bran (MRB) with high stability based on in situ rice bran oil embedding and investigated the effects of MRB on lipid metabolism and gut microbiota in hyperlipidemic mice induced by high-fat diet (HFD). Results showed that compared to HFD fed mice, lipid levels in serum and hepatic lipid accumulation were reduced in mice fed with MRB, which was potentially associated with the fact that MRB decreased the expression of genes related to lipogenesis (Srebp1c, Acc, Hmgcr, and Fas) and increased the expression of genes related to lipid catabolism (Hsl, Atgl) and oxidation (Acox, Cpt1, Ucp1) (p < 0.05). In gut, MRB supplementation significantly elevated the abundance of beneficial bacteria, such as Dubosiella and Faecalibaculum. In addition, significant increase in short-chain fatty acid was observed in mice from MRB groups when compared to HFD groups (p < 0.05). Overall, this study suggested that MRB could alleviate the hyperlipidemia induced by HFD, which was related to the alteration of lipid metabolism and gut microbiota.

Connectome-based Brain Marker Moderates the Relationship between Childhood Adversity and Transdiagnostic Psychopathology during Early Adolescence.

Importance: Identifying brain-based markers of resiliency that reliably predict who is and is not at elevated risk for developing psychopathology among children who experience adverse childhood experiences (ACEs) is important for improving our mechanistic understanding of these etiological links between child adversity and psychopathology and guiding precision medicine and prevention efforts for reducing psychiatric impact of ACEs. Objective: To examine associations between ACEs and transdiagnostic psychopathology during the transition from preadolescence to early adolescence and test whether these associations are moderated by a hypothesized resilience factor, a previously identified connectome variate (CV) that is associated with higher cognitive function and lower psychopathology. Design Setting and Participants: This study was conducted in a longitudinal design based on multicenter data from a community cohort of U.S. youth aged of 9-11 at baseline, who participated in the Adolescent Brain Cognitive Development (ABCD) study (N=7,382 at baseline and 6,813 at 2-year follow-up). Linear regression models and moderation analyses were used to characterize concurrent and prospective associations between lifetime ACEs and number of DSM-5 psychiatric disorders (indexing transdiagnostic psychopathology) and to determine if individual variations in these associations were moderated by the CV derived from resting-state fMRI at baseline. Main Outcomes and Measures: Cumulative number of current DSM-5 psychiatric disorders assessed using the computerized self-admin version Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) and lifetime ACEs assessed from child and parent reports at baseline (9-10 years) and 2-year-follow-up (11-12 years). Results: ACE total scores correlated positively with the cumulative number of current DSM-5 psychiatric disorders at both baseline (r =.258, p < .001) and 2-year follow-up (r =.257, p < .001). The baseline CV score moderated the ACE-disorder associations at baseline (B = -0.021, p < .001) and at 2-year follow-up (B = -0.018, p = .008), as well as the association between the changes in ACE and in the number of disorders from baseline to year 2 (B = -0.012, p = .045). Post-hoc analyses further showed that the moderation effect of CV on ACE-psychopathology associations was specific to the threat-related ACEs and to female youth. Conclusions and Relevance: These findings provide preliminary evidence for a connectome-based resiliency marker and suggest that functional connectivity strength in a broad system including frontal-parietal cortices and subcortical nuclei relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs--especially females and those experiencing threat-related ACEs--from developing transdiagnostic psychopathology.

Clinical characteristics and prognostic factors of non-malignant pleural effusions in hospitalised patients: a retrospective cohort study.

OBJECTIVE: Non-malignant pleural effusions (NMPE) are common in hospitalised patients. Data on NMPE inpatients are scarce and the factors influencing the prognosis are unknown. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: We conducted a retrospective cohort of inpatients (n=86 645) admitted to the Chinese PLA General Hospital from 2018 to 2021, based on electronic medical records. The observations of 4934 subjects with effusions confirmed by chest radiological tests (CT or X-ray) without a diagnosis of malignancy were followed during admission. Logistic regression was used to analyse organ damage and other factors associated with in-hospital death. Patients were clustered according to their laboratory indicators, and the association between the clustering results and outcomes was studied. OUTCOME: The outcome of this study was in-hospital mortality. RESULTS: Among 4934 patients, heart failure + pneumonia + renal dysfunction was the most common (15.12%) among 100 different diagnostic groups. 318 (6.4%) patients died during hospitalisation. Lung (OR 3.70, 95% CI 2.42 to 5.89), kidney (OR 2.88, 95% CI 2.14 to 3.90) and heart (1.80, 95% CI 1.29 to 2.55) damage were associated with in-hospital mortality. Hierarchical clustering of laboratory indicators (estimated glomerular filtration rate, white blood cell count, platelet count, haemoglobin, N-terminal pro-B-type natriuretic peptide, serum albumin) demonstrated the ability to discriminate patients at high risk of in-hospital death. CONCLUSION: Comorbidities and multiorgan failure are the prominent characteristics of NMPE patients, which increase the risk of in-hospital mortality, and comprehensive intervention for specific comorbidity patterns is suggested.

Mechanisms of traditional Chinese medicine overcoming of radiotherapy resistance in breast cancer.

Breast cancer stands as the most prevalent malignancy among women, with radiotherapy serving as a primary treatment modality. Despite radiotherapy, a subset of breast cancer patients experiences local recurrence, attributed to the intrinsic resistance of tumors to radiation. Therefore, there is a compelling need to explore novel approaches that can enhance cytotoxic effects through alternative mechanisms. Traditional Chinese Medicine (TCM) and its active constituents exhibit diverse pharmacological actions, including anti-tumor effects, offering extensive possibilities to identify effective components capable of overcoming radiotherapy resistance. This review delineates the mechanisms underlying radiotherapy resistance in breast cancer, along with potential candidate Chinese herbal medicines that may sensitize breast cancer cells to radiotherapy. The exploration of such herbal interventions holds promise for improving therapeutic outcomes in the context of breast cancer radiotherapy resistance.

Metabolic health and genetic predisposition in inflammatory bowel disease: Insights from a prospective cohort study.

BACKGROUND: Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD: This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS: During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION: Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

Mineralization and microbial utilization of poly(lactic acid) microplastic in soil.

The current carbon dioxide (CO2) evolution-based standard method for determining biodegradable microplastics (MPs) degradation neglects its priming effect on soil organic matter decomposition, which misestimates their biodegradability. Here, a 13C natural abundance method was used to estimate the mineralization of poly(lactic acid) (PLA) MP in various agricultural soils, and to trace its utilization in different microbial groups. In alkaline soils, the PLA-derived CO2 emissions increased with increasing soil carbon/nitrogen (C/N) ratios, and the mineralization of PLA MP concentrations ranged from 3-33 %, whereas the CO2 evolution method probably over- or under-estimated the mineralization of PLA in alkaline soils with different soil C/N ratios. Low PLA mineralization (1-5 %) were found in the acidic soil, and the standard method largely overestimated the mineralization of PLA MP by 1.3- to 3.3-fold. Moreover, the hydrolysate of PLA MP was preferentially assimilated by Gram-negative bacteria, but Gram-positive bacterial decomposition mainly contributed to the release of PLA-derived CO2 at low MP concentrations (≤ 1 %). Overall, the 13C natural abundance method appears to be suitable for tracking the mineralization and microbial utilization of biodegradable PLA in soils, and the PLA-derived C is mainly assimilated and decomposed by bacterial groups.

Exploitation of porphyrin-based titanium-rich porous organic polymers for targeted phosphopeptide enrichment from the serum of colorectal cancer individuals.

A porphyrin-based titanium-rich porous organic polymer (Th-PPOPs@Ti4+) was designed based on immobilized metal ion affinity chromatography technique and successfully applied to phosphopeptide enrichment with 5,10,15,20-tetrakis(4-carboxyphenyl) porphine tetramethyl ester (TCPTE), 2,3-dihydroxyterephthalaldehyde (DHTA), and 2,3,4-trihydroxybenzaldehyde (THBA) as raw materials. Th-PPOPs@Ti4+ exhibited remarkable sensitivity (0.5 fmol), high selectivity (ß-casein: BSA = 1:2000, molar ratio), outstanding recovery (95.0 ± 1.9%), reusability (10 times), and superior loading capacity (143 mg·g-1). In addition, Th-PPOPs@Ti4+ exhibited excellent ability to specifically capture phosphopeptides from the serum of colorectal cancer (CRC) individuals and normal subjects. Sixty phosphopeptides assigned to 35 phosphoproteins were obtained from the serum of CRC individuals, and 43 phosphopeptides allocated to 28 phosphoproteins were extracted in the serum of healthy individuals via nano-LC-MS/MS. Gene ontology assays revealed that the detected phosphoproteins may be inextricably tied to CRC-associated events, including response to estrogen, inflammatory response, and heparin binding, suggesting that it is possible that these correlative pathways may be implicated in the pathogenesis of CRC.

Clinical evaluation of temporal bone anatomical abnormalities and surgical method selection in patients with congenital aural atresia.

OBJECTIVES: To analyze anatomic variations of the temporal bone in congenital aural atresia (CAA) and their correlation with the Jahrsdoerfer score, in order to guide clinical selection of surgical treatment methods. MATERIAL AND METHODS: We retrospectively studied 53 patients (72 ears) with unilateral or bilateral CAA, including 34 ears with normal hearing as controls. Audiological and imaging data were collected and analyzed. We evaluated the Jahrsdoerfer score and anatomical variations, including tegmen mastoideum position, anterior sigmoid sinus displacement, and elevated jugular bulb. RESULTS: The average air conduction hearing threshold (PTA4) ranged from 0.5 to 4 kHz was 65.48 ± 8.19 dBHL, with an average Jahrsdoerfer score of 4.93 ± 2.78. In CAA group, there was a higher prevalence and severity of anterior sigmoid sinus and low position of the tegmen mastoideum (P < 0.01). However, there was no significant difference in incidence rates among groups with high jugular bulb (P > 0.05). Anterior sigmoid sinus and high jugular bulb showed no correlation with the Jahrsdoerfer score, while the low position of the tegmen mastoideum had a weak correlation. The Jahrsdoerfer score did not adequately predict temporal bone anatomical abnormalities in CAA patients. CONCLUSION: CAA exhibit a higher incidence and greater severity of temporal bone anatomical abnormalities compared to the control group, and the Jahrsdoerfer score inadequately assesses these abnormalities. Anomalies like low position of the tegmen mastoideum, anterior sigmoid sinus, and high jugular bulb should also be considered as independent factors influencing surgical decisions for atresiaplasty.

Dietary L-arabinose-induced gut dysbiosis exacerbates Salmonella infection outcome.

The gut microbiota is essential for providing colonization resistance against pathogens. Dietary sugars markedly shift the composition of the intestinal microbiota and alter host susceptibility to enteric infections. Here, we demonstrate the effect of L-arabinose on bacterial infection by using a mouse infection model with Salmonella enterica serovar Typhimurium (S. Tm). In the presence of microbiota, L-arabinose induces a dramatic expansion of Enterobacteriaceae, thereby decreasing the microbiota diversity and causing more severe systemic infection. However, L-arabinose supplementation does not alter the disease progression of Salmonella infection in a microbiota-depleted mouse model. More importantly, short-term supplementation of L-arabinose fails to exert anti-diabetic effects in Salmonella-infected hyperglycemia mice and still promotes infection. Overall, our work reveals that a high intake of dietary L-arabinose supports a bloom of Enterobacteriaceae in Salmonella-infected gut, further accelerating the process of systemic infection.IMPORTANCEL-arabinose is a promising natural sweetener and food additive for the regulation of hyperglycemia. Since diabetic subjects are more susceptible to infections, the safety of dietary L-arabinose in diabetic patients experiencing infection remains a concern. Our findings reveal that L-arabinose exacerbates Salmonella infection outcome by inducing gut microbiota dysbiosis in mice. High dietary intake of L-arabinose may be deleterious for diabetic individuals undergoing infection.

Ti4+ functionalized zirconium metal-organic frameworks with polymer brushes for specific identification of phosphopeptides in human serum and skimmed milk.

In the present study, click chemistry and Schiff base reactions were simultaneously applied to prepare polymer brush (PEG)-functionalized MOF materials (UiO-66-NH2) and immobilized with Ti4+ (MOF-Brush-THBA-Ti4+) for phosphopeptide analysis. The material has a detection limit of 0.5 fmol, a selectivity of 2000:1, and a loading capacity of 133 mg/g for phosphopeptides. It also demonstrated great repeatability (10 cycles) and recovery rate (96.7 ± 1.4%). During the analysis of bio-samples, 4 specific phosphopeptides were identified in endogenous breast cancer serum, while 11 phosphopeptides were identified in skimmed milk. Moreover, 47 phosphopeptides correlated with 29 phosphorylated proteins were selectively identified from normal control serum, and 66 phosphopeptides correlated with 26 phosphorylated proteins were identified from breast cancer serum. Further analysis of gene ontology (GO) revealed that the detected phosphorylated proteins associated with breast cancer included positive regulation of receptor-mediated endocytosis, proteolysis, extracellular exosome, heparin binding, and chaperone binding. These findings suggest that these associated pathways might contribute to the etiology of breast cancer. Overall, this application exhibits enormous potential in the identification of phosphorylated peptides within bio-samples.

Urinary Equol and Equol-Predicting Microbial Species Are Favorably Associated With Cardiometabolic Risk Markers in Chinese Adults.

BACKGROUND: The association between soy isoflavones intake and cardiometabolic health remains inconclusive. We investigated the associations of urinary biomarkers of isoflavones including daidzein, glycitein, genistein, equol (a gut microbial metabolite of daidzein), and equol-predicting microbial species with cardiometabolic risk markers. METHODS AND RESULTS: In a 1-year study of 305 Chinese community-dwelling adults aged ≥18 years, urinary isoflavones, fecal microbiota, blood pressure, blood glucose and lipids, and anthropometric data were measured twice, 1 year apart. Brachial-ankle pulse wave velocity was also measured after 1 year. A linear mixed-effects model was used to analyze repeated measurements. Logistic regression was used to calculate the adjusted odds ratio (aOR) and 95% CI for the associations for arterial stiffness. Each 1 µg/g creatinine increase in urinary equol concentrations was associated with 1.47%, 0.96%, and 3.32% decrease in triglycerides, plasma atherogenic index, and metabolic syndrome score, respectively (all P<0.05), and 0.61% increase in high-density lipoprotein cholesterol (P=0.025). Urinary equol was also associated with lower risk of arterial stiffness (aOR, 0.28 [95% CI, 0.09-0.90]; Ptrend=0.036). We identified 21 bacterial genera whose relative abundance was positively associated with urinary equol (false discovery rate-corrected P<0.05) and constructed a microbial species score to reflect the overall equol-predicting capacity. This score (per 1-point increase) was inversely associated with triglycerides (percentage difference=-1.48%), plasma atherogenic index (percentage difference=-0.85%), and the risk of arterial stiffness (aOR, 0.27 [95% CI, 0.08-0.88]; all P<0.05). CONCLUSIONS: Our findings suggest that urinary equol and equol-predicting microbial species may improve cardiometabolic risk parameters in Chinese adults.

Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma.

BACKGROUND: Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear. METHODS: We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target. RESULTS: We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo. CONCLUSIONS: Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

Effect of proactive personality on career adaptability of higher vocational college students: the mediating role of college experience.

For higher vocational students, the college stage is an important period in their career development, and the college experience plays an important role in the relationship between their proactive personality and career adaptability, which in turn has a significant impact on their future career development. From the perspective of social cognitive career theory and taking 476 vocational students as samples, this paper explores the mediating role of college experience between proactive personality and career adaptability of vocational college students. The college experience scale is revised for higher vocational students, and it is verified to have good reliability and validity. SPSS and Amos were used to conduct correlation analysis，and the PROCESS macro was used for mediating effect analysis. The results show that the college experience of vocational students plays a partial mediating role in the effect of proactive personality on career adaptability. This work innovatively uses social cognitive career theory to explore the role of college experience in the relationship between proactive personality and career adaptability among vocational students. The theoretical models are established and empirical verification is conducted, confirming that higher vocational students' college experience can affect their career adaptability. These results provide empirical evidence for vocational colleges to improve the career guidance of college students, and intervention measures are proposed to enhance students' career adaptability during school years, thus promoting their sustainable development.

Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia.

Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.