Walking Dead Macrophage-Based Positive Enhancement MRI for Ultrahighly Efficient Diagnosis of Nephritis.

Nephritis is an inflammatory condition of the glomerulus, and the clinical gold standard for its diagnosis is a kidney biopsy. However, obtaining biopsy results can take several days, which does not meet the requirement of rapid diagnosis, especially for rapidly progressive types. To achieve an effective and noninvasive diagnosis, we propose a nephritis-specific, positive magnetic resonance imaging (MRI) contrast agent based on Gd3+ anchored walking dead macrophage Gd-RAW. Gd-RAW exhibits high selectivity for inflammatory renal parenchyma and provides comparable results to histopathology methods. The Gd-RAW-based MRI contrast agent reduces the diagnostic time of nephritis from 14 days of biopsy to 1 h. Furthermore, in a unilateral nephritis model constructed by increasing the glycerol concentration, the T1WI of renal parenchyma exhibits an increased signal-to-noise ratio, which is crucial for evaluating nephritic severity. This work promotes rapid diagnosis of nephritis and potentially provides sufficient evidence for clinicians to offer timely treatment to patients. The methodology of paramagnetic ion-anchored macrophage corpse also opens up new prospects for designing more specific and biosafe MRI contrast agents.

Exploring the mediating role of PsyCap in the relationship between orientation training and work engagement: the perspective of COR and SRT theories.

In the domain of organizational socialization, a new research paradigm and trend concerns work engagement path way to studying newcomer assimilation through the lens of socialization resource theory (SRT). Drawing on theories of SRT and COR (conservation of resources), the present study develops and validates an integrative model, in which the effect of orientation training on work engagement involves the mediator of PsyCap and moderators of leader-member exchange (LMX) and education. SmartPLS 3.0 was used to analyze the data with 567 respondents with 5,000 bootstraps from 3- to 5-star hotels in Mainland China. The empirical results indicate that newcomers' PsyCap fully mediates the relationship between orientation training and work engagement. They also suggest that education and LMX, respectively, moderate the effects of orientation training on PsyCap and work engagement. Theoretical and practical implications of these findings are drawn in the context of organizational socialization and human resources development.

Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer's Disease.

Oxidative stress due to Cu2+-triggered aggregation of ß-amyloid protein (Aß) and reactive oxygen species (ROS) overexpression in the brain is an important hallmark of early stages of Alzheimer's disease (AD) pathogenesis. The ideal modulator for improving the oxidative stress microenvironment in AD brains should take both Cu2+ and ROS into consideration, which has been rarely reported. Here, a combined therapeutic strategy was achieved by co-encapsulating superoxide dismutase (SOD) and catalase (CAT) in imine-linked covalent organic frameworks (COFs), which were modified with peptide KLVFF (T5). The nanocomposite SC@COF-T5 exhibited an oxidative stress eradicating ability through ROS elimination and Cu2+ chelation, combined with the inhibition of Aß42 monomer aggregation and disaggregation of Aß42 fibrils. In vivo experiments indicated that SC@COF-T5 with a high blood-brain barrier (BBB) penetration efficiency was effective to reduce Aß deposition, expression of pro-inflammatory cytokines, ROS levels, and neurologic damage in AD model mice, consequently rescuing memory deficits of AD mice. This work not only confirms the feasibility and merits of the therapeutic strategy regarding multiple targets for treatment of early AD pathogenesis but also opens up a novel direction for imine-linked COFs in biomedical applications.

Lighting a Fire: Gasdermin-Mediated Pyroptosis Remodels the Glioma Microenvironment and Promotes Immune Checkpoint Blockade Response.

Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and "pRRophetic" package in R were used to estimate temozolomide (TMZ) sensitivity. The "Submap" package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.

A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma.

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.

Expression profiles and prognostic significance of WNT family members in glioma via bioinformatic analysis.

AIMS: The dysregulation and essential role of WNTs in glioma have been widely implicated. However, there is a paucity of literature on the expression status of all the 19 WNTs in glioma. Our study was aimed to evaluate the expression and prognostic values of the 19 WNTs in glioma. METHODS: mRNA expression and clinical data were retrieved from the Cancer Genome Atlas (TCGA) database, Chinese Glioma Genome Atlas (CGGA), GTEx and ONCOMINE databases. The 50 frequent neighbor genes of WNT5A and WNT10B were shown with PPI network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. RESULTS: We found that the mRNA expression of WNT5A was significantly higher in glioma; however, the WNT10B expression was significantly lower in glioma. Furthermore, the expression of WNT5A and WNT10B was associated with the clinicopathology of glioma. The survival analysis revealed that the higher expressions of WNT5A and WNT16 were associated poor overall survival (OS) in patients with glioma. Conversely, overexpression of WNT3, WNT5B, and WNT10B was associated with better OS. Finally, Go and KEGG analysis revealed WNT5A was associated with multiple signal translations, and crucial oncogenes (EGFR and MDM2) and 2 important tumor suppressors (PTEN and IKN4a/ARF) were found closely correlated with WNT5A in glioma. CONCLUSION: Among 19WNTs, WNT5A can serve as a candidate to diagnose and therapy glioma, while WNT10B might be valuable for anti-glioma research. The presumed direction was provided to explore the relation of WNTs signal and multiple pathways in glioma.

Connective tissue growth factor as an unfavorable prognostic marker promotes the proliferation, migration, and invasion of gliomas.

BACKGROUND: In consideration of the difficulty in diagnosing high heterogeneous glioma, valuable prognostic markers are urgent to be investigated. This study aimed to verify that connective tissue growth factor (CTGF) is associated with the clinical prognosis of glioma, also to analyze the effect of CTGF on the biological function. METHODS: In this study, glioma and non-tumor tissue samples were obtained in 2012 to 2014 from the Department of Neurosurgery of Nanfang Hospital of Southern Medical University, Guangzhou, China. Based on messenger RNA (mRNA) data from the Cancer Genome Atlas (TCGA) and CCGA dataset, combined with related clinical information, we detected the expression of CTGF mRNA in glioma and assessed its effect on the prognosis of glioma patients. High expression of CTGF mRNA and protein in glioma were verified by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. The role of CTGF in the proliferation, migration, and invasion of gliomas were respectively identified by methylthiazoletetrazolium assay, Transwell and Boyden assay in vitro. The effect on glioma cell circle was assessed by flow cytometry. For higher expression of CTGF in glioblastoma (GBM), the biological function of CTGF in GBM was investigated by gene ontology (GO) analysis. RESULTS: In depth analysis of TCGA data revealed that CTGF mRNA was highly expressed in glioma (GBM, n = 163; lowly proliferative glioma [LGG], n = 518; non-tumor brain tissue, n = 207; LGG, t = 2.410, GBM, t = 2.364, P < 0.05). CTGF mRNA and protein expression in glioma (86%) was significantly higher than that in non-tumor tissues (18%) verified by collected samples. Glioma patients with higher expression of CTGF showed an obviously poorer overall survival (35.4 and 27.0 months compared to 63.3 and 55.1 months in TCGA and Chinese Glioma Genome Atlas (CGGA) databases separately, CGGA: χ = 7.596, P = 0.0059; TCGA: χ = 10.46, P = 0.0012). Inhibiting CTGF expression could significantly suppress the proliferation, migration, and invasion of gliomas. CTGF higher expression had been observed in GBM, and GO analysis demonstrated that the function of CTGF in GBM was mainly associated with metabolism and energy pathways (P < 0.001). CONCLUSIONS: CTGF is highly expressed in glioma, especially GBM, as an unfavorable and independent prognostic marker for glioma patients and facilitates the progress of glioma.