Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2.

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

Research progress on oncoprotein hepatitis B X­interacting protein (Review).

Hepatitis B X­interacting protein (HBXIP) is a membrane protein located on the lysosomal surface and encoded by the Lamtor gene. It is expressed by a wide range of tumor types, including breast cancer, esophageal squamous cell carcinoma and hepatocellular carcinoma, and its expression is associated with certain clinicopathological characteristics. In the past decade, research on the oncogenic mechanisms of HBXIP has increased and the function of HBXIP in normal cells has been gradually elucidated. In the present review, the following was discussed: The normal physiological role of the HBXIP carcinogenic mechanism; the clinical significance of high levels of HBXIP expression in different tumors; HBXIP regulation of transcription, post­transcription and post­translation processes in tumors; the role of HBXIP in improving the antioxidant capacity of tumor cells; the inhibition of ferroptosis of tumor cells and regulating the metabolic reprogramming of tumor cells; and the role of HBXIP in promoting the malignant progression of tumors. In conclusion, the present review summarized the existing knowledge of HBXIP, established its carcinogenic mechanism and discussed future related research on HBXIP.

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer.

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Subjective economic inequality evokes interpersonal objectification.

Interpersonal objectification, treating people as tools and neglecting their essential humanness, is a pervasive and enduring phenomenon. Across five studies (N = 1183), we examined whether subjective economic inequality increases objectification through a calculative mindset. Study 1 revealed that the perceptions of economic inequality at the national level and in daily life were positively associated with objectification. Studies 2 and 3 demonstrated a causal relationship between subjective economic inequality and objectification in a fictitious organization and society, respectively. Moreover, the effect was mediated by a calculative mindset (Studies 3-4). In addition, lowering a calculative mindset weakened the effect of subjective inequality on objectification (Study 4). Finally, increased objectification due to subjective inequality further decreased prosociality and enhanced exploitative intentions (Study 5). Taken together, our findings suggest that subjective economic inequality increases objectification, which further causes adverse interpersonal interactions.

Double-blinded, randomized clinical trial of Gegen Qinlian decoction pinpoints Faecalibacterium as key gut bacteria in alleviating hyperglycemia.

Background: Accumulating evidence suggests that metabolic disorders, including type 2 diabetes mellitus (T2DM), can be treated with traditional Chinese medicine formulas, such as the Gegen Qinlian decoction (GQD). This study elucidates the mechanisms by which gut microbes mediate the anti-diabetic effects of GQD. Methods: We conducted a double-blind randomized clinical trial involving 120 untreated participants with T2DM. During the 12-week intervention, anthropometric measurements and diabetic traits were recorded every 4 weeks. Fecal microbiota and serum metabolites were measured before and after the intervention using 16S rDNA sequencing, liquid chromatography-mass spectrometry, and Bio-Plex panels. Results: Anti-diabetic effects were observed in the GQD group in the human trial. Specifically, glycated hemoglobin, fasting plasma glucose, and two-hour postprandial blood glucose levels were significantly lower in the GQD group than in the placebo group. Additionally, Faecalibacterium was significantly enriched in the GQD group, and the short-chain fatty acid levels were higher and the serum inflammation-associated marker levels were lower in the GQD group compared to the placebo group. Moreover, Faecalibacterium abundance negatively correlated with the levels of serum hemoglobin, fasting plasma glucose, and pro-inflammatory cytokines. Finally, the diabetes-alleviating effect of Faecalibacterium was confirmed by oral administration of Faecalibacterium prausnitzii (DSMZ 17677) in T2DM mouse model. Conclusions: GQD improved type 2 diabetes primarily by modulating the abundance of Faecalibacterium in the gut microbiota, alleviating metabolic disorders and the inflammatory state. Trial registration: Registry No. ChiCTR-IOR-15006626.

Genetic mutation profiling reveals biomarkers for targeted therapy efficacy and prognosis in non-small cell lung cancer.

Introduction: The genetic heterogeneity of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations may affect clinical responses and outcomes to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aims to investigate the genomic factors that influence the efficacy and clinical outcomes of first-line, second-line and third-line treatments in NSCLC and explore the heterogeneity of resistance mechanisms. Materials and methods: This real-world study comprised 65 patients with EGFR mutant NSCLC. Molecular alterations were detected using a customized DNA panel before and after administering targeted therapy. The efficacy and prognosis of each treatment line were evaluated. Results: In first-generation EGFR-TKIs treatment, gefitinib showed favorable efficacy compared to icotinib and erlotinib, particularly in patients with EGFR L858R mutations. The resistance mechanisms to first-generation EGFR-TKIs varied among different EGFR mutation cohorts and different first-generation EGFR-TKIs. In second-line EGFR-TKIs treatment, EPH receptor A3 (EPHA3), IKAROS family zinc finger 1 (IKZF1), p21 (RAC1) activated kinase 5 (PAK5), DNA polymerase epsilon, catalytic subunit (POLE), RAD21 cohesin complex component (RAD21) and RNA binding motif protein 10 (RBM10) mutations were markedly associated with poorer progression-free survival (PFS). Notably, EPHA3, IKZF1 and RBM10 were identified as independent predictors of PFS. The mechanisms of osimertinib resistance exhibited heterogeneity, with a higher proportion of non-EGFR-dependent resistant mutations. In third-line treatments, the combination of osimertinib and anlotinib demonstrated superior efficacy compared to other regimens. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) mutation was an independent risk indicator of shorter OS following third-line treatments. Conclusions: Comprehending the tumor evolution in NSCLC is advantageous for assessing the efficacy and prognosis at each stage of treatment, providing valuable insights to guide personalized treatment decisions for patients.

Probiotics supplementation during pregnancy or infancy on multiple food allergies and gut microbiota: a systematic review and meta-analysis.

CONTEXT: Probiotics show promise in preventing and managing food allergies, but the impact of supplementation during pregnancy or infancy on children's allergies and gut microbiota remains unclear. OBJECTIVE: This study aimed to assess the effects of maternal or infant probiotic supplementation on food allergy risk and explore the role of gut microbiota. DATA SOURCES: A systematic search of databases (PubMed, Cochrane Library, Embase, and Medline) identified 37 relevant studies until May 20, 2023. DATA EXTRACTION: Two independent reviewers extracted data, including probiotics intervention details, gut microbiota analysis, and food allergy information. DATA ANALYSIS: Probiotics supplementation during pregnancy and infancy reduced the risk of total food allergy (relative risk [RR], 0.79; 95% CI, 0.63-0.99), cow-milk allergy (RR, 0.51; 95% CI, 0.29-0.88), and egg allergy (RR, 0.57; 95% CI, 0.39-0.84). Infancy-only supplementation lowered cow-milk allergy risk (RR, 0.69; 95% CI, 0.49-0.96), while pregnancy-only had no discernible effect. Benefits were observed with over 2 probiotic species, and a daily increase of 1.8 × 109 colony-forming units during pregnancy and infancy correlated with a 4% reduction in food allergy risk. Children with food allergies had distinct gut microbiota profiles, evolving with age. CONCLUSIONS: Probiotics supplementation during pregnancy and infancy reduces food allergy risk and correlates with age-related changes in gut microbial composition in children. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023425988.

Oleispirillum naphthae gen. nov., sp. nov., a bacterium isolated from oil sludge, and proposal of Oleispirillaceae fam. nov.

A microaerophilic, Gram-negative, motile, and spiral-shaped bacterium, designated Y-M2T, was isolated from oil sludge of Shengli oil field. The optimal growth condition of strain Y-M2T was at 25 °C, pH 7.0, and in the absence of NaCl. The major polar lipid was phosphatidylethanolamine. The main cellular fatty acid was iso-C17  :  0 3-OH. It contained Q-9 and Q-10 as the predominant quinones. The DNA G+C content was 68.1 mol%. Strain Y-M2T showed the highest 16S rRNA gene sequence similarity to Telmatospirillum siberiense 26-4bT (91.1 %). Phylogenetic analyses based on 16S rRNA gene and genomes showed that strain Y-M2T formed a distinct cluster in the order Rhodospirillales. Genomic analysis showed that Y-M2T possesses a complete nitrogen-fixation cluster which is phylogenetically close to that of methanogene. The nif cluster, encompassing the nitrogenase genes, was found in every N2-fixing strain within the order Rhodospirillales. Phylogeny, phenotype, chemotaxonomy, and genomic results demonstrated that strain Y-M2T represents a novel species of a novel genus in a novel family Oleispirillaceae fam. nov. in the order Rhodospirillales, for which the name Oleispirillum naphthae gen. nov., sp. nov. was proposed. The type strain is Y-M2T (=CCAM 827T=JCM 34765T).

Global gene expression profiling of perirenal brown adipose tissue whitening in goat kids reveals novel genes linked to adipose remodeling.

BACKGROUND: Brown adipose tissue (BAT) is known to be capable of non-shivering thermogenesis under cold stimulation, which is related to the mortality of animals. In the previous study, we observed that goat BAT is mainly located around the kidney at birth, and changes to white adipose tissue (WAT) in the perirenal adipose tissue of goats within one month after birth. However, the regulatory factors underlying this change is remain unclear. In this study, we systematically studied the perirenal adipose tissue of goat kids in histological, cytological, and accompanying molecular level changes from 0 to 28 d after birth. RESULTS: Our study found a higher mortality rate in winter-born goat kids, with goat birthing data statistics. Then we used thermal imaging revealing high temperature in goat hips at postnatal 0 d and gradually decrease during 28 d. This is consistent with the region of perirenal BAT deposition and highlights its critical role in energy expenditure and body temperature regulation in goat kids. Additionally, we found a series of changes of BAT during the first 28 d after birth, such as whitening, larger lipid droplets, decreased mitochondrial numbers, and down-regulation of key thermogenesis-related genes (UCP1, DIO2, UCP2, CIDEA, PPARGC1a, C/EBPb, and C/EBPa). Then, we used RNA-seq found specific marker genes for goat adipose tissue and identified 12 new marker genes for BAT and 10 new marker genes for WAT of goats. Furthermore, 12 candidate genes were found to potentially regulate goat BAT thermogenesis. The mechanism of the change of this biological phenomenon does not involve a large-scale death of brown adipocytes and subsequent proliferation of white adipocytes. While apoptosis may play a limited role, it is largely not critical in this transition process. CONCLUSIONS: We concluded that perirenal BAT plays a crucial role in thermoregulation in newborn goat kids, with notable species differences in the expression of adipose tissue marker genes, and we highlighted some potential marker genes for goat BAT and WAT. Additionally, the change from BAT to WAT does not involve a large-scale death of brown adipocytes and subsequent proliferation of white adipocytes.

Intermediate soil acidification induces highest nitrous oxide emissions.

Global potent greenhouse gas nitrous oxide (N2O) emissions from soil are accelerating, with increases in the proportion of reactive nitrogen emitted as N2O, i.e., N2O emission factor (EF). Yet, the primary controls and underlying mechanisms of EFs remain unresolved. Based on two independent but complementary global syntheses, and three field studies determining effects of acidity on N2O EFs and soil denitrifying microorganisms, we show that soil pH predominantly controls N2O EFs and emissions by affecting the denitrifier community composition. Analysis of 5438 paired data points of N2O emission fluxes revealed a hump-shaped relationship between soil pH and EFs, with the highest EFs occurring in moderately acidic soils that favored N2O-producing over N2O-consuming microorganisms, and induced high N2O emissions. Our results illustrate that soil pH has a unimodal relationship with soil denitrifiers and EFs, and the net N2O emission depends on both the N2O/(N2O + N2) ratio and overall denitrification rate. These findings can inform strategies to predict and mitigate soil N2O emissions under future nitrogen input scenarios.

Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Increased Nasal Blimp1 + Treg Cells After Sublingual Immunotherapy Reflect the Efficacy of Treatment in Allergic Rhinitis.

INTRODUCTION: Allergen-specific immunotherapy (AIT) plays a pivotal role in altering the immune status and tissue responses in allergic rhinitis (AR). This study focuses on the impact of sublingual immunotherapy (SLIT) involving dust mite drops, exploring the modulation of regulatory T cells (Treg) and their specific marker, BLIMP1, in the nasal mucosa. METHODS: Immune cells were isolated from nasal lavage fluid of patients with AR undergoing SLIT (n = 94). Treg cells were analyzed for BLIMP1 expression, and chemokine levels associated with Treg recruitment were assessed using Luminex assay. Patients were categorized on the basis of SLIT efficacy and followed for changes after discontinuation. RESULTS: SLIT induced a significant increase in nasal Treg cells (7.09 ± 2.59% vs. 0.75 ± 0.27%, P < 0.0001). BLIMP1 expression in Treg cells notably increased after SLIT (0.36 ± 0.22% to 16.86 ± 5.74%, P < 0.0001). Ineffective SLIT cases exhibited lower levels of nasal Treg and Blimp1 + Treg cells (both P < 0.0001). Receiver operating characteristic (ROC) analysis confirmed their potential as efficacy predictors (AUC = 0.908 and 0.968, respectively). SLIT discontinuation led to a significant reduction in Treg and Blimp1 + Treg cells (P < 0.001), emphasizing their maintenance during treatment. Pro-inflammatory cytokines decreased (P < 0.001), while CCL2 associated with Treg recruitment increased (P = 0.0015). CONCLUSION: Elevated nasal Blimp1 + Treg cells serve as a predictive biomarker for SLIT responsiveness in pediatric AR. Their influence on immunotherapy effectiveness contributes to a nuanced understanding of SLIT mechanisms, allowing for disease stratification and personalized treatment plans. This study offers scientific support for predicting SLIT efficacy, enhancing the prospects of improved treatment outcomes in AR.

Effects of crystalline lens rise and anterior chamber parameters on vault after implantable collamer lens placement.

BACKGROUND: To analyze vault effects of crystalline lens rise (CLR) and anterior chamber parameters (recorded by Pentacam) in highly myopic patients receiving implantable collamer lenses (ICLs), which may avoid subsequent complications such as glaucoma and cataract caused by the abnormal vault. METHODS: We collected clinical data of 137 patients with highly myopic vision, who were all subsequent recipients of V4c ICLs between June 2020 and January 2021. Horizontal ciliary sulcus-to-sulcus diameter (hSTS) and CLR were measured by ultrasonic biomicroscopy (UBM), and a Pentacam anterior segment analyzer was used to measure horizontal white-to-white diameter (hWTW), anterior chamber depth (ACD), anterior chamber angle (ACA), anterior chamber volume (ACV), CLR, and postoperative vault (Year 1 and Month 1). The lens thickness (LT) was determined by optical biometry (IOL Master instrument). The predictive model was generated through multiple linear regression analyses of influential factors, such as hSTS, CLR, hWTW, ACD, ACA, ACV, ICL size, and LT. The predictive performance of the multivariate model on vault after ICL was assessed using the receiver operating characteristic (ROC) curve with area under the curve (AUC) as well as the point of tangency. RESULTS: Average CLR assessed by UBM was lower than the average value obtained by Pentacam (0.561 vs. 0.683). Bland-Altman analysis showed a good consistency in the two measurement methods and substantial correlation (r = 0.316; P = 0.000). The ROC curve of Model 1 (postoperative Year 1) displayed an AUC of 0.847 (95% confidence interval [CI]: 74.19-95.27), with optimal threshold of 0.581 (sensitivity, 0.857; specificity, 0.724). In addition, respective values for Model 2 (postoperative Month 1) were 0.783 (95% CI: 64.94-91.64) and 0.522 (sensitivity, 0.917; specificity, 0.605). CONCLUSION: CLR and anterior chamber parameters are important determinants of postoperative vault after ICL placement. The multivariate regression model we constructed may serve in large part as a predictive gauge, effectively avoid postoperative complication.

Optimized In Situ Doping Strategy Stabling Single-Crystal Ultrahigh-Nickel Layered Cathode Materials.

Single-crystal Ni-rich cathodes offer promising prospects in mitigating intergranular microcracks and side reaction issues commonly encountered in conventional polycrystalline cathodes. However, the utilization of micrometer-sized single-crystal particles has raised concerns about sluggish Li+ diffusion kinetics and unfavorable structural degradation, particularly in high Ni content cathodes. Herein, we present an innovative in situ doping strategy to regulate the dominant growth of characteristic planes in the single-crystal precursor, leading to enhanced mechanical properties and effectively tackling the challenges posed by ultrahigh-nickel layered cathodes. Compared with the traditional dry-doping method, our in situ doping approach possesses a more homogeneous and consistent modifying effect from the inside out, ensuring the uniform distribution of doping ions with large radius (Nb, Zr, W, etc). This mitigates the generally unsatisfactory substitution effect, thereby minimizing undesirable coating layers induced by different solubilities during the calcination process. Additionally, the uniformly dispersed ions from this in situ doping are beneficial for alleviating the two-phase coexistence of H2/H3 and optimizing the Li+ concentration gradient during cycling, thus inhibiting the formation of intragranular cracks and interfacial deterioration. Consequently, the in situ doped cathodes demonstrate exceptional cycle retention and rate performance under various harsh testing conditions. Our optimized in situ doping strategy not only expands the application prospects of elemental doping but also offers a promising research direction for developing high-energy-density single-crystal cathodes with extended lifetime.

Expert consensus on difficulty assessment of endodontic therapy.

Endodontic diseases are a kind of chronic infectious oral disease. Common endodontic treatment concepts are based on the removal of inflamed or necrotic pulp tissue and the replacement by gutta-percha. However, it is very essential for endodontic treatment to debride the root canal system and prevent the root canal system from bacterial reinfection after root canal therapy (RCT). Recent research, encompassing bacterial etiology and advanced imaging techniques, contributes to our understanding of the root canal system's anatomy intricacies and the technique sensitivity of RCT. Success in RCT hinges on factors like patients, infection severity, root canal anatomy, and treatment techniques. Therefore, improving disease management is a key issue to combat endodontic diseases and cure periapical lesions. The clinical difficulty assessment system of RCT is established based on patient conditions, tooth conditions, root canal configuration, and root canal needing retreatment, and emphasizes pre-treatment risk assessment for optimal outcomes. The findings suggest that the presence of risk factors may correlate with the challenge of achieving the high standard required for RCT. These insights contribute not only to improve education but also aid practitioners in treatment planning and referral decision-making within the field of endodontics.

Exploring hydrological controls on dissolved organic carbon export dynamics in a typical flash flood catchment using a process-based model.

The dynamics of dissolved organic carbon (DOC) export from headwater catchments are of critical importance for the global carbon balance and are driven by complex runoff processes. Most previous studies have used statistical relationships between runoff and DOC concentration to estimate DOC export dynamics. Thus, the coupling mechanisms between runoff generation and DOC export dynamics at the process level were obscured in the fitting parameters and have rarely been addressed. In this study, high-frequency (hourly) discharge and DOC export from a typical flash flood experimental headwater catchment with an area of 1.8 km2 were simulated using a process-based model (INCA-C). The results showed that the INCA-C model successfully captured the hourly dynamics of both discharge and DOC concentrations with a Nash-Sutcliffe efficiency (NSE) of 0.47-0.81 and 0.28-0.70 among moderate events and 0.81-0.85 and 0.19-0.90 among extreme events, respectively. The DOC was exported with distinct concentration dynamics, fluxes, and contributions from the four flow pathways under different storm intensities. At higher intensities, the DOC fluxes were exported by subsurface flows, particularly from shallow organic soil, with greater peaks and shorter time-to-peaks. Exported DOC is primarily sourced from subsurface runoff from the mineral layer (73 %-77 %) during moderate events, whereas it is primarily sourced from subsurface runoff from the organic layer (61 %-79 %) during extreme events. The two contrasting contributions suggest that hydrological pathway controls and DOC dynamic patterns can shift owing to runoff generation influenced by storm intensity. The distinct and variable controls of different flow pathways on DOC export highlight the need to explain the role of hydrology in regulating DOC storm exports through process-based modelling.

Chinese Providers' Perspectives on Early Integration of Palliative Care in Pediatric Oncology: A Mixed-Methods Study.

BACKGROUND: Internationally, early integration of palliative care in pediatric oncology has been widely recognized. However, little is known about the perspective of Chinese providers in this regard. OBJECTIVE: The aim of this study was to explore the perspective of Chinese providers on the early integration of palliative care in pediatric oncology. METHODS: This was a convergent mixed-methods study with a survey among 141 Chinese providers (101 nurses, 38 oncologists, and 2 social workers) and 12 individual interviews (5 oncologists, 5 nurses, and 2 social workers). RESULTS: Three categories existed by comparison and merging of quantitative and qualitative findings: (1) attitudes toward early integration of pediatric palliative care: 75% of the participants endorsed early integration because it would bring benefits to patients and their families-participants had concerns about misunderstandings of palliative care among other stakeholders; (2) patient-provider interactions relating to early integration: participants held contradictory views toward the impact on and influencers of early integration regarding patient-provider interactions; and (3) participants suggested a system to support early integration by addressing parents' misconceptions and providers' training, and institutional facilitation. CONCLUSIONS: Chinese pediatric oncology providers generally exhibit a reserved willingness toward the early integration of palliative care. They agree that palliative care would be beneficial but have concerns about providing structural support and addressing cultural influencers. IMPLICATIONS FOR PRACTICE: Findings of this study emphasize the significance of convening stakeholders and establishing a pediatric palliative care-friendly system in a developing country, particularly by addressing structural support, resource allocation, clarified responsibilities, and capacity building.

Extracellular vesicle-encapsulated miR-25-3p promotes epithelial-mesenchymal transition and migration of endometrial epithelial cells by inducing macrophage polarization.

The pathogenesis of adenomyosis is closely related to the epithelial-mesenchymal transition and macrophages. MicroRNAs have been extensively investigated in relation to the epithelial-mesenchymal transition in a range of malignancies. However, there is a paucity of research on extracellular vesicles derived from the eutopic endometrium of adenomyosis and their encapsulated microRNAs. In this study, we investigated the role of microRNA-25-3p derived from extracellular vesicles in inducing macrophage polarization and promoting the epithelial-mesenchymal transition in endometrial epithelial cells of patients with adenomyosis and controls. We obtained eutopic endometrial samples and isolated extracellular vesicles from the culture supernatant of primary endometrial cells. Real-time quantitative PCR analysis demonstrated that microRNA-25-3p was highly expressed in extracellular vesicles, as well as in macrophages stimulated by extracellular vesicles from eutopic endometrium of adenomyosis; and macrophages transfected with microRNA-25-3p exhibited elevated levels of M2 markers, while displaying reduced levels of M1 markers. After co-culture with the above polarized macrophages, endometrial epithelial cells expressed higher levels of N-cadherin and Vimentin, and lower protein levels of E-cadherin and Cytokeratin 7. It was revealed that microRNA-25-3p encapsulated in extracellular vesicles from eutopic endometrial cells could induce macrophage polarization toward M2, and the polarized macrophages promote epithelial-mesenchymal transition in epithelial cells. However, in vitro experiments revealed no significant disparity in the migratory capacity of endometrial epithelial cells between the adenomyosis group and the control group. Furthermore, it was observed that microRNA-25-3p-stimulated polarized macrophages also facilitated the epithelial-mesenchymal transition and migration of endometrial epithelial cells within the control group. Thus, the significance of microRNA-25-3p-induced polarized macrophages in promoting the development of adenomyosis is unclear, and macrophage infiltration alone may be adequate for this process. We emphasize the specificity of the local eutopic endometrial microenvironment and postulate its potential significance in the pathogenesis of adenomyosis.

Clinical characteristics and risk factors of non-mild outcomes in patients with Omicron variant COVID-19 in Shanghai, China.

INTRODUCTION: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant rapidly appeared in Shanghai, China in early March 2022. Although a few studies have analyzed the risk factors of the severe type, identifying risk factors for non-mild COVID-19 outcomes (general/severe/critical type) which occur with radiographic evidence of pneumonia is lacking. METHODOLOGY: The COVID-19 patients admitted to a district-level designated hospital from April 26 to May 21 were enrolled in this retrospective study. The clinical manifestations and laboratory examinations were analyzed. Logistic regression was employed to evaluate risk factors for non-mild outcomes. RESULTS: Of the 311 patients, 196 (63.0%) were mild and 115 (37.0%) were non-mild. Among them, 215 cases (69.1%) were unvaccinated. Male, ≥ 60 years age, and chronic kidney disease were risk factors of progressing to non-mild. Patients with more than two comorbidities were more likely to become non-mild, whereas two/booster doses vaccinated patients had a lower risk of developing to non-mild. The median negative conversion days (NCDs) were 12 days. Non-mild, > 2 comorbidities, delayed admission (> 3 days), and Paxlovid (Pfizer, Freiburg, Germany) treatment significantly lengthened the NCDs. CONCLUSIONS: Our results call for special concern for full and booster vaccination of the elderly, which will effectively protect from progression of COVID-19 to non-mild state. In the meantime, symptomatic COVID-19 patients should be treated as soon as possible.

Machine learning decision support model for discharge planning in stroke patients.

BACKGROUND/AIM: Efficient discharge for stroke patients is crucial but challenging. The study aimed to develop early predictive models to explore which patient characteristics and variables significantly influence the discharge planning of patients, based on the data available within 24 h of admission. DESIGN: Prospective observational study. METHODS: A prospective cohort was conducted at a university hospital with 523 patients hospitalised for stroke. We built and trained six different machine learning (ML) models, followed by testing and tuning those models to find the best-suited predictor for discharge disposition, dichotomized into home and non-home. To evaluate the accuracy, reliability and interpretability of the best-performing models, we identified and analysed the features that had the greatest impact on the predictions. RESULTS: In total, 523 patients met the inclusion criteria, with a mean age of 61 years. Of the patients with stroke, 30.01% had non-home discharge. Our model predicting non-home discharge achieved an area under the receiver operating characteristic curve of 0.95 and a precision of 0.776. After threshold was moved, the model had a recall of 0.809. Top 10 variables by importance were National Institutes of Health Stroke Scale (NIHSS) score, family income, Barthel index (BI) score, FRAIL score, fall risk, pressure injury risk, feeding method, depression, age and dysphagia. CONCLUSION: The ML model identified higher NIHSS, BI, and FRAIL, family income, higher fall risk, pressure injury risk, older age, tube feeding, depression and dysphagia as the top 10 strongest risk predictors in identifying patients who required non-home discharge to higher levels of care. Modern ML techniques can support timely and appropriate clinical decision-making. RELEVANCE TO CLINICAL PRACTICE: This study illustrates the characteristics and risk factors of non-home discharge in patients with stroke, potentially contributing to the improvement of the discharge process. REPORTING METHOD: STROBE guidelines.