Foxo1 is an iron-responsive transcriptional factor regulating systemic iron homeostasis.

The liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, that translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and BMP6 treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver non-heme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe-/- mice). In summary, our study identifies Foxo1 is a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.

The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture.

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.

sTREM2 in the prognostic evaluation of acute lung injury after cardiac surgery in infants.

BACKGROUND: Previous studies have shown that TREM2 plays a protective role in acute lung injury (ALI). This prospective study aimed to investigate the role of sTREM2 as a forecasting factor for ALI in infants after pediatric cardiac surgery undergoing cardiopulmonary bypass (CPB). METHODS: Seventy-five consecutive patients younger than 1 year who underwent cardiac surgery were enrolled in this study. Sixty-one fulfilled the inclusion criteria and had been divided into ALI and non-ALI groups. Children's demographic characteristics and clinical data were collected. Perioperative sTREM2 levels were analyzed at five timepoints. RESULTS: In this study, children in the ALI group were younger, lighter, with higher RACHS-1 scores and underwent significantly longer CPB time. Post-CPB ALI had an impact on clinical outcomes, which contributed to a longer duration of mechanical ventilation, ICU and hospital stay than non-ALI group. Significant differences were manifested off-CPB, 1 h/6 h after CPB, and day 1 after surgery between the two groups. Binary logistic models revealed that off-CPB sTREM2 was significantly associated with the incidence of post-CPB ALI after adjustment. ROC analysis showed that the AUC of off-CPB sTREM2 level was 0.791, and the optimal cutoff value was 788.6 pg/ml. CONCLUSIONS: The off-CPB sTREM2 level was an independent prognostic factor for post-CPB ALI in infants. IMPACT: Plasma sTREM2 works together with downstream TREM2 to regulate inflammation response by binding the receptor to other cells. Previous studies have shown that TREM2 plays a protective role in ischemia-reperfusion and has anti-inflammatory effects on acute lung injury (ALI). This study analyzed the risk factors of post-cardiopulmonary bypass (CPB) ALI. We found that weight and off-CPB sTREM2 level were independent prognostic factors for post-CPB ALI. Plasma sTREM2 may serve as an early biomarker in the prognostic evaluation of acute lung injury after cardiac surgery in infants.

Benefits of Chinese family caregivers of patients with urostomy: a qualitative study.

BACKGROUND: Family caregivers, also known as informal caregivers, are critical for the home care of patients with urostomy. The present study aimed to investigate the benefits of family caregivers in China while taking care of patients with urostomy from a positive perspective. METHODS: A qualitative research design was adopted, with a thematic analysis. The qualitative research software NVivo was used for data analysis. Twenty-two family caregivers of urostomy patients participated in an in-depth interview for 60-90 min. A qualitative analysis was performed using a thematic approach in accordance with the six-stage thematic analysis process reported by Braun and Clarke (2006). RESULTS: The following four benefits were identified: mastering knowledge and skills, promoting self-growth, establishing close family ties, and changing the way of life. Among these four themes, 11 sub-themes were constructed by coders. CONCLUSIONS: This study provides new insights into intervention measures for family caregivers of patients with urostomy, which could play an important role in developing the overall model of family-centered nursing.

Outcomes in pediatric extracorporeal cardiopulmonary resuscitation: A single-center retrospective study from 2007 to 2022 in China.

OBJECTIVE: We aimed to investigate the prognostic factors of pediatric extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: The retrospective study included a total of 77 pediatric cases (7 neonates and 70 children) who underwent ECPR after in-hospital and out-of-hospital cardiac arrest between July 2007 and December 2022. Primary endpoints were complications, while secondary endpoints included all-cause in-hospital mortality. RESULTS: Among the 45 cases experiencing complications, 4 neonates and 41 children had multiple simultaneous complications, primarily neurological issues in 25 cases. Additionally, organ failure occurred in 11 cases, and immunodeficiency was present in two cases. Furthermore, 9 cases experienced bleeding events, and 13 cases showed thrombosis. Patients with complications had lower weight, shorter ECMO durations, and longer CPR durations. Non-survivors had longer CPR durations and shorter durations of ECMO, ICU stay, and mechanical ventilation compared to survivors. Complications were more prevalent in non-survivors, particularly organ failure and bleeding events. CONCLUSION: Weight, CPR duration, and ECMO duration were associated with complications, suggesting areas for treatment optimization. The higher occurrence of complications in non-survivors underscores the importance of early detection and management to improve survival rates. Our findings suggest clinicians consider these factors in prognostic assessments to enhance the effectiveness of ECPR programs.

microRNA-146a modulates behavioural activity, neuroinflammation, and oxidative stress in adult mice.

Small non-coding miRNA act as key regulators of several physiological processes due to their ability to interact with numerous target mRNA within a network. Whilst several miRNA can act in concert to regulate target mRNA expression, miR-146a has emerged as a critical modulator of inflammation by targeting key upstream signalling proteins of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and reductions in this miRNA have been observed in several neurological and neurodegenerative disorders. However, a targeted assessment of behaviour and neural tissues following the loss of miR-146a has not been documented. In this study, we examined the behavioural and neuroinflammatory phenotype of mice lacking miR-146a to determine the role of this miRNA in neurological function. Adult miR-146a-/- mice displayed no overt developmental phenotype with the exception of enlarged spleens. Behavioural testing revealed a mild but significant reduction in exploratory locomotor activity and increase in anxiety-like behaviour, with no changes in short-term spatial memory, fear conditioning, or sensorimotor gating. In the brain, the lack of miR-146a resulted in a significant compensatory miR-155 expression with no significant changes in expression of the target Interleukin 1 Receptor Associated Kinase (Irak) gene family. Despite these effects on upstream NF-κB mediators, downstream expression of cytokine and chemokine messengers was significantly elevated in miR-146a-/- mice compared to wild-type controls. Moreover, this increase in inflammatory cytokines was observed alongside an induction of oxidative stress, driven in part by nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, and included reduced thiol antioxidant concentrations and increased oxidised protein carbonyl concentrations. In female miR-146a mice, this increase in oxidative stress resulted in an increased expression of superoxide dismutase 1 (SOD1). Together, this suggests miR-146a plays a key role in regulating inflammation even in the absence of inflammatory stimuli and reduced levels of this miRNA have the capacity to induce limited behavioural effects whilst exacerbating both inflammation and oxidative stress in the brain.

Investigating causal relationships between the gut microbiota and inflammatory skin diseases: A Mendelian randomization study.

BACKGROUND: Numerous inflammatory skin diseases are associated with the gut microbiota. Studies of the association between gut microbiota and inflammatory skin diseases have yielded conflicting results owing to confounding factors, and the causal relationship between them remains undetermined. METHODS: Two-sample Mendelian randomization (MR) was used to examine the association between gut microbiota and four common inflammatory skin diseases: acne, psoriasis, urticaria and atopic dermatitis. The summary statistics of the gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium along with the summary statistics of the four diseases were obtained from the FinnGen consortium. Causal relationships were assessed using the inverse variance weighted (IVW), weighted median, MR-Egger and maximum likelihood methods, and several sensitivity analyses were performed to ensure the accuracy of the results. Finally, reverse and multivariable MR analyses were performed to verify the robustness of the results. RESULTS: We found causal associations of Bacteroidaceae [odds ratio (OR), 2.25; 95% confidence interval (CI), 1.48-3.42; pivw = 0.0001], Allisonella (OR, 1.42; 95% CI, 1.18-1.70; pivw = 0.0002) and Bacteroides (OR, 2.25; 95% CI, 1.48-3.42; pivw = 0.0001) with acne, the Eubacterium fissicatena group with psoriasis (OR, 1.22; 95% CI, 1.10-1.35; pivw = 0.0002) and Intestinibacter with urticaria (OR, 1.28; 95% CI, 1.13-1.45; pivw = 0.0001). These results were corrected for a false discovery rate. Sensitivity analyses were performed to validate the robustness of the associations and reverse MR confirmed that the results were not influenced by the reverse effect. CONCLUSION: Our study revealed that some gut microbiota are risk factors for inflammatory skin diseases, providing new information on potential therapeutic targets. Additionally, a possible association with the gut-skin axis was confirmed. Further research is required to elucidate the mechanisms underlying these relationships.

The Genetic Association of MMP-2 Gene Polymorphisms with the Susceptibility to Alzheimer's Disease.

BACKGROUND: A hospital-based case-control study was carried out to elucidate the association of Matrix metalloproteinase-2 (MMP-2) gene candidate polymorphisms with the susceptibility to Alzheimer's disease (AD) in the Chinese Han population. METHODS: A total of 200 AD cases and an equal number of healthy controls were recruited to undergo genotyping of specific loci within the MMP-2 gene loci (rs243866, rs2285053, rs243865). Logistic regression analysis was applied to examine the association of the genotypes and alleles of MMP-2 gene polymorphisms with AD after adjusting clinical confounding factors. RESULTS: Within AD group, a high proportion of rs243866 genotype carriers were found, and the difference remained significant despite adjusting for other clinical indicators. Among individuals with the rs243866 AA genotype and rs243865 TT genotype, the onset age of AD occurred at a younger age. Early-onset AD risk in rs243866 AA genotype carriers was 6.528 times higher than those in GG genotype carriers, and individuals with rs243865 TT genotype faced a 4.048-fold increased risk compared to those with CC genotype. CONCLUSIONS: MMP-2 gene rs243866 and rs243865 polymorphisms were closely associated with the onset age of AD. The presence of rs243866 AA genotype emerged as a crucial predictor of AD risk.

Association between plant-based dietary pattern and biological aging trajectory in a large prospective cohort.

BACKGROUND: Aging is a dynamic and heterogeneous process that may better be captured by trajectories of aging biomarkers. Biological age has been advocated as a better biomarker of aging than chronological age, and plant-based dietary patterns have been found to be linked to aging. However, the associations of biological age trajectories with mortality and plant-based dietary patterns remained unclear. METHODS: Using group-based trajectory modeling approach, we identified distinctive aging trajectory groups among 12,784 participants based on a recently developed biological aging measure acquired at four-time points within an 8-year period. We then examined associations between aging trajectories and quintiles of plant-based dietary patterns assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) among 10,191 participants who had complete data on dietary intake, using multivariable multinomial logistics regression adjusting for sociodemographic and lifestyles factors. Cox proportional hazards regression models were applied to investigate the association between aging trajectories and all-cause mortality. RESULTS: We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (OR = 0.75, 95% CI: 0.65, 0.86 for PDI; OR = 0.73, 95% CI: 0.62, 0.85 for hPDI) or high-degree (OR = 0.63, 95% CI: 0.46, 0.86 for PDI; OR = 0.62, 95% CI: 0.44, 0.88 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (OR = 1.72, 95% CI: 1.48, 1.99) or high-degree (OR = 1.70, 95% CI: 1.21, 2.38) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (HR = 1.56, 95% CI: 1.29, 1.89) or high-degree (HR = 3.72, 95% CI: 2.73, 5.08) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. CONCLUSIONS: We identified three distinctive aging trajectories in a large Asian cohort and found that adopting a plant-based dietary pattern, especially when rich in healthful plant foods, was associated with substantially lowered pace of aging.

Testing of two SNP array-based genealogy algorithms using extended Han Chinese pedigrees and recommendations for improved performances in forensic practice.

Distant genetic relatives can be linked to a crime scene sample by computing identity-by-state (IBS) and identity-by-descent (IBD) shared by individuals. To test the methods of genetic genealogy estimation and optimal the parameters for forensic investigation, a family-based genetic genealogy analysis was performed using a dataset of 262 Han Chinese individuals from 11 families. The dataset covered relative pairs from 1st- to 14th degrees. But the 7th-degree relative is the most distant kinship to be fully investigated, and each individual has ∼200 relatives within the 7th degree. The KING algorithm by calculating IBS and IBD statistics can correctly discriminate the first-degree relationships of monozygotic twin, parent-offspring and full sibling. The inferred relationship was reliable within the fifth-degree, false positive rate <1.8%. The IBD segment algorithm, GERMLINE + ERSA, could provide reliable inference result prolonged to eighth degree. Analysis of IBD segments produced obviously false negative estimations (<27.4%) rather than false positives (0%) within the eighth-degree inferences. We studied different minimum IBD segment threshold settings (changed from >0 to 6 cM); the inferred results did not make much difference. In distant relative analysis, genetically undetectable relationships begin to occur from the sixth degree (second cousin once removed), which means the offspring after seven meiotic divisions may share no ancestor IBD segment at all. Application of KING and GERMLINE + ERSA worked complementarily to ensure accurate inference from first degree to eighth degree. Using simulated low call rate data, the KING algorithm shows better tolerance to marker decrease compared with the GERMLINE + ERSA segment algorithm.

Analysis of multidrug-resistant determinants of clinically isolated Acinetobacter baumannii CYZ via whole genome sequencing.

Acinetobacter baumannii is a multidrug-resistant coccobacillus responsible for severe nosocomial infectious diseases. This study mainly focuses on investigating the antimicrobial resistance features of a clinically isolated strain (A. baumannii CYZ) using the PacBio Sequel II sequencing platform. The chromosomal size of A. baumannii CYZ is 3,960,760 bp, which contains a total of 3803 genes with a G + C content of 39.06%. Functional analysis performed using the Clusters of Orthologous Groups of Proteins (COGs), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, as well as the Comprehensive Antibiotic Resistance Database (CARD) revealed a complicated set of antimicrobial resistance determinants in the genome of A. baumannii CYZ, which were mainly classified into multidrug efflux pumps and transport systems, ß-lactamase relative and penicillin-binding proteins, aminoglycoside modification enzymes, alternation of antibiotic target sites, lipopolysaccharide relative, and other mechanisms. A total of 35 antibiotics were tested for the antimicrobial susceptibility of A. baumannii CYZ, and the organism exhibited a stronger antimicrobial resistance ability. The phylogenetic relationship indicated that A. baumannii CYZ has high homology with A. baumannii ATCC 17978; however, the former also exhibited its specific genome characteristics. Our research results give insight into the genetic antimicrobial-resistant features of A. baumannii CYZ as well as provide a genetic basis for the further study of the phenotype.

Efficient HCl leaching of platinum group metals from waste three-way catalysts: A study on kinetics and mechanisms.

Waste three-way catalysts (TWCs) have attracted much attention due to the presence of platinum group metals (PGMs) and hazardous substances such as heavy metals and organic matter. The extraction of PGMs from waste TWCs using hydrochloric acid (HCl) has been extensively researched. However, the addition of oxidizing agents like H2O2 and aqua regia is necessary to facilitate PGMs dissolution, which poses significant environmental and operational hazards. Hence, developing a green PGMs recovery process without oxidants is imperative. Previously, we investigated the process of Li2CO3 calcination pretreatment to enhance the leaching of PGMs from waste TWCs by HCl, focusing on the process and mechanism of Li2CO3 calcination pretreatment. In this study, we focused on the leaching process of HCl after pretreatment. Our investigation includes a detailed examination of leaching kinetics and mechanisms. The optimal leaching conditions were: leaching temperature of 150 °C, leaching time of 2 h, HCl concentration of 12 M, and liquid-solid ratio of 10 mL/g. The experiments resulted in maximum leaching rates of about 96%, 97%, and 97% for Pt, Pd, and Rh, respectively. However, given the presence of heavy metals, attention needs to be paid to the harmless treatment of waste acids and leaching residues. The Pt and Pd leaching process is controlled by a mixture of interfacial chemical reactions and internal diffusion, and dominated by internal diffusion, while the leaching process of Rh is controlled by interfacial chemical reactions. Li+ in Li2PtO3, Li2PdO2, and Li2RhO3 preferentially leached and underwent ion-exchange reactions with H+, promoting the dissolution of Pt, Pd, and Rh in HCl.

Two-dimensional molecular condensation in cell signaling and mechanosensing.

Membraneless organelles (MLO) regulate diverse biological processes in a spatiotemporally controlled manner spanning from inside to outside of the cells. The plasma membrane (PM) at the cell surface serves as a central platform for forming multi-component signaling hubs that sense mechanical and chemical cues during physiological and pathological conditions. During signal transduction, the assembly and formation of membrane-bound MLO are dynamically tunable depending on the physicochemical properties of the surrounding environment and partitioning biomolecules. Biomechanical properties of MLO-associated membrane structures can control the microenvironment for biomolecular interactions and assembly. Lipid-protein complex interactions determine the catalytic region's assembly pattern and assembly rate and, thereby, the amplitude of activities. In this review, we will focus on how cell surface microenvironments, including membrane curvature, surface topology and tension, lipid-phase separation, and adhesion force, guide the assembly of PM-associated MLO for cell signal transductions.

Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.

Bedside nurses' antimicrobial stewardship practice scope and competencies in acute hospital settings: A scoping review.

AIM: To identify and map bedside nurses' practice scope and competencies regarding antimicrobial stewardship in acute hospital settings, and develop a competency framework for them. BACKGROUND: Antimicrobial stewardship requires multidisciplinary engagement including nursing. However, bedside nurses' antimicrobial stewardship practice scope and competencies in acute hospital settings remain unclear. DESIGN: Scoping review. METHODS: Using a five-stage framework proposed by Arksey and O'Malley and following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. RESULTS: A total of 1422 records were retrieved, and 41 studies were included. In addition to the six practices recommended, this review summarized bedside nurses' contributions to five additional fields as well. Correspondingly, the competencies required by bedside nurses were summarized into eight domains: specialized knowledge, safety medication administration, leadership, education, diagnostic stewardship, infection prevention and control, professional development and professional quality. CONCLUSION: Nurses' practice scope overlaps greatly with routine nursing practice in antimicrobial stewardship, confirming the evidence that nurses are ideal partners in antimicrobial stewardship. This review developed a competency framework at both basic and advanced levels. Among them, professional knowledge is the foundation, while professional quality motivates nurses to participate. In addition to competency assessment, it can also be used for training and human resource deployment based on seniority or professional level. This could bridge the knowledge gap and improve the engagement of nurses in heavy workload situations. RELEVANCE TO CLINICAL PRACTICE: This practice scope will provide opportunities for nurses to engage in antimicrobial stewardship. Moreover, nursing competencies identified in this field could facilitate the development of competency-based education interventions, talent assessments, training and recruitment programs. DATA RESOURCES: PubMed, EMBASE, Web of Science, CINHAL, PsycINFO, Cochrane Library, ProQuest and Scopus were searched from inception to November 2022, with an updated search in March 2023. IMPACT: This scoping review provides evidence for best nursing practice scope and competency in antimicrobial stewardship in hospitals. However, it is also in line with the commitment of all nurses in the global community to combat antimicrobial resistance, which has become a global threat. An antimicrobial stewardship competency framework for bedside nurses was developed at both the basic and advanced levels. It would facilitate talent assessment, training, recruitment and human resource management by guiding the development of competency-based education interventions. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Patterning of Oncogenic Ras Clustering in Live Cells Using Vertically Aligned Nanostructure Arrays.

As a dominant oncogenic protein, Ras is well-known to segregate into clusters on the plasma membrane for activating downstream signaling. However, current technologies for direct measurements of Ras clustering are limited to sophisticated high-resolution techniques like electron microscopy and fluorescence lifetime imaging. To further promote fundamental investigations and the related drug development, we hereby introduce a nanobar-based platform which effectively guides Ras clusters into quantifiable patterns in live cells that is resolvable under conventional microscopy. Major Ras isoforms, K-Ras, H-Ras, and N-Ras, were differentiated, as well as their highly prevalent oncogenic mutants G12V and G13D. Moreover, the isoform specificity and the sensitivity of a Ras inhibitor were successfully characterized on nanobars. We envision that this nanobar-based platform will serve as an effective tool to read Ras clustering on the plasma membrane, enabling a novel avenue both to decipher Ras regulations and to facilitate anti-Ras drug development.

Guiding Irregular Nuclear Morphology on Nanopillar Arrays for Malignancy Differentiation in Tumor Cells.

For more than a century, abnormal nuclei in tumor cells, presenting subnuclear invaginations and folds on the nuclear envelope, have been known to be associated with high malignancy and poor prognosis. However, current nuclear morphology analysis focuses on the features of the entire nucleus, overlooking the malignancy-related subnuclear features in nanometer scale. The main technical challenge is to probe such tiny and randomly distributed features inside cells. We here employ nanopillar arrays to guide subnuclear features into ordered patterns, enabling their quantification as a strong indicator of cell malignancy. Both breast and liver cancer cells were validated as well as the quantification of nuclear abnormality heterogeneity. The alterations of subnuclear patterns were also explored as effective readouts for drug treatment. We envision that this nanopillar-enabled quantification of subnuclear abnormal features in tumor cells opens a new angle in characterizing malignant cells and studying the unique nuclear biology in cancer.

The comparison between experimental nursing and routine nursing interventions on the quality of life of stoma patients: A systematic review and meta-analysis.

The advance in nursing care for stoma patients is a challenging issue, which will influence the life quality. The quality of life is a major issue in the recovery of stoma patients. The evidence of experimental nursing has not been explored enough. A systematic search and a meta-analysis were performed for the studies of experimental nursing interventions versus routine warming interventions on patients with a stoma. The comparisons between nursing interventions were performed to find which kind of intervention will be superior in improving life quality. After a restricted selection, 10 studies, 460 subjects with experimental nursing intervention, and 478 controls with the routine nursing intervention were enrolled in a variety of causes of the stoma. The focused outcome was the quality of life. The meta-analysis was performed by Review Manager 5.4. Among the stoma patients, the meta-analysis favours the experimental nursing intervention group with higher scores of life quality when compared to the routine nursing intervention group. The meta-analysis results were with positive mean differences, significant tests for overall effect, and significant heterogeneities in the random-effects model. The experimental nursing intervention showed higher positive effects on the quality of life when compared to routine nursing intervention for stoma patients. Experimental nursing intervention might be an option for stoma nursing practitioners to improve stoma care.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Matr3 reshapes m6A modification complex to alleviate macrophage inflammation during atherosclerosis.

Atherosclerosis, characterized as the chronic inflammation of the arterial wall, is one of the leading causes of coronary artery disease (CAD), and macrophages are found to play essential roles in the initiation and progression of inflammation in atherosclerosis. N6-methyladenosine (m6A) modification, as the most abundant epi-transcriptomic modification in mRNA, is found to mediate the atherogenic inflammatory cascades in vascular endothelium. The detailed molecular mechanism of m6A methylation regulating inflammatory response during atherosclerosis is still not fully known. In this study, we find oxidized low-density lipoprotein (oxLDL) stimulation increases methyltransferases Mettl3 and Mettl14 expressions in macrophages, whereas the total m6A modification level in macrophages decreases under oxLDL stimulation. Matrin-3 (Matr3), an RNA binding protein, is identified to play a suppressive role on oxLDL-mediated macrophage inflammatory responses through inhibiting activation of pro-inflammatory signaling, mitogen-activated protein kinase (Mapk) by m6A-mediated mRNA decay via regulating the formation of Mettl3-Mettl14 complex. Moreover, we find that Matr3 expression decreases in the oxLDL-stimulated macrophages, and the peripheral blood-derived monocytes from patients with CAD, and overexpression of Matr3 significantly alleviates atherosclerosis development in vivo. Our study for the first time clarifies the role of Matr3 on macrophage inflammatory responses during atherosclerotic development, and supplies deep understanding on the relationship of m6A modification and inflammatory responses in atherosclerosis.