Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin.

Angiogenin (ANG) is a secreted ribonuclease (RNase) with cell-type- and context-specific roles in growth, survival, and regeneration. Although these functions require receptor-mediated endocytosis and appropriate subcellular localization, the identity of the cell surface receptor remains undefined. Here, we show that plexin-B2 (PLXNB2) is the functional receptor for ANG in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells. Mechanistically, PLXNB2 mediates intracellular RNA processing that contribute to cell growth, survival, and regenerative capabilities of ANG. Antibodies generated against the ANG-binding site on PLXNB2 restricts ANG activity in vitro and in vivo, resulting in inhibition of established xenograft tumors, ANG-induced neurogenesis and neuroprotection, levels of pro-self-renewal transcripts in hematopoietic and patient-derived leukemic stem and progenitor cells, and reduced progression of leukemia in vivo. PLXNB2 is therefore required for the physiological and pathological functions of ANG and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases.

The Superaerophobic N-Doped Carbon Nanocage with Hydrogen Spillover Effort for Enhanced Hydrogen Evolution.

Under the high current density, the excessive strong adsorption of H* intermediates and H2 accumulation the catalysts are the major obstacle to the industrial application of hydrogen evolation reaction (HER) catalysts. Herein, through experimental exploration, it is found that the superaerophobic Nitrogen (N)-doped carbon material can promote the rapid release of H2 and provide H* desorption site for the hydrogen spillover process, which makes it have great potential as the catalysts support for hydrogen spillover. Based on this discovery, this work develops the hydrogen spillover catalyst with electron-rich Pt sites loaded on N-doped carbon nanocage (N-CNC) with adjustable work function. Through a series of comprehensive electrochemical tests, the existence of hydrogen spillover effort has been proved. Moreover, the in situ tests showed that pyrrolic-N can activate adjacent carbon sites as the desorption sites for hydrogen spillover. The Pt@N-1-CNC with the minimum work function difference (ΔΦ) between Pt NPs and support shows superior hydrogen evolution performance, only needs overpotential of 12.2 mV to reach current density of 10 mA cm-2 , outstanding turnover frequency (TOF) (44.7 s-1 @100 mV) and superior durability under the 360 h durability tests at current density of 50 mA cm-2 .

Dissociation between temporal attention and Consciousness: Unconscious temporal cue induces temporal expectation effect.

The debate over the independence of attention and consciousness is ongoing. Prior studies have established that invisible spatial cues can direct attention. However, our exploration extends beyond spatial dimensions to temporal information as a potent guide for attention. A intriguing question arises: Can unconscious temporal cues trigger attentional orienting? To investigate, we employed a modified reaction-time task in Experiments 1 and 2, using Gabor stimuli or human facial stimuli as temporal cues rendered invisible through continuous flash suppression. We aimed to uncover temporal expectation effects (TE effects) without conscious awareness. Moreover, Experiments 3 and 4 probed the boundaries of this unconscious processing, assessing whether conscious temporal cues could modulate TE effects. Our results confirm that invisible temporal cues can induce TE effects, and these effects can be overridden by conscious temporal cues. This dissociation between temporal attention and consciousness provide a new perspective on our understanding of their relationship.

Molecular analyses of exosome-derived miRNAs revealed reduced expression of miR-184-3p and decreased exosome concentration in patients with alveolar echinococcosis.

Both E. multilocularis and host-derived exosomes are involved in the pathogenic process of alveolar echinococcosis (AE). Exosomes secrete miRNAs that have regulatory roles in host-pathogen interactions in multiple ways. In the present study, we collected and purified supernatants of E. multilocularis cultures, as well as human plasma exosomes. High-throughput sequencing showed the identities of 45 exosomal miRNAs in E. multilocularis. The lengths of these miRNAs ranged from 19 to 25 nucleotides (nt), with the majority (n = 18) measuring 22 nt. Notably, emu-let-7-5p emerged as the most abundant among these miRNAs, with a detected count of 33,097 and also length of 22 nt. Nanoparticle tracking analysis (NTA) showed that the concentration of exosomes in the plasma of AE patients was lower compared to that in the healthy individuals. This result suggested that the concentration of plasma exosomes was able to distinguish AE patients from healthy individuals. Using qRT-PCR to assess the relative expression of 10 miRNAs of E. multilocularis, we showed that the expression of miR-184-3p was downregulated significantly in the exosomes of plasma from AE patients compared to that in the control group. In summary, this study indicates that AE induces a reduction in the concentration of human plasma exosomes, as well as downregulating miR-184-3p in infected individuals.

Prognostic significance and survival benefits of postoperative adjuvant chemotherapy in patients with stage IA lung adenocarcinoma with non-predominant micropapillary components.

BACKGROUND: The prognostic significance of adjuvant chemotherapy (ACT) for patients with stage IA micropapillary non-predominant (MPNP) lung adenocarcinoma (LUAD) remains unknown. This study aimed to investigate the effects of postoperative ACT in patients with stage IA MPNP-LUAD. METHODS: A total of 149 patients with pathological stage IA MPNP-LUAD who underwent surgery at our center were retrospectively analyzed. Propensity score matching (PSM) analysis was conducted to reduce potential selection bias. Kaplan-Meier analyses were used to assess the impact of ACT on recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS). Subgroup analyses were performed for the survival outcomes based on the percentage of micropapillary components. Cox proportional hazards regression analyses were applied to identify risk factors associated with survival. RESULTS: The receipt or non-receipt of postoperative ACT had no significant effect on RFS, OS, and DSS among all enrolled patients with stage IA MPNP-LUAD (P > 0.05). For patients with a micropapillary component > 5%, the 5-year rates of RFS, OS, and DSS were significantly higher in the ACT group compared to the observation group, both before and after PSM (P < 0.05). However, the differences between the two groups were not significant for patients with a micropapillary component ≤ 5% (P > 0.05). The resection range (HR = 0.071; 95% CI: 0.020-0.251; P < 0.001), tumor size (HR = 2.929; 95% CI: 1.171-7.330; P = 0.022), and ACT (HR = 0.122; 95% CI: 0.037-0.403; P = 0.001) were identified as independent prognostic factors for RFS through Cox regression analysis. CONCLUSION: Patients with stage IA MPNP-LUAD who have a micropapillary component greater than 5% might benefit from postoperative ACT, while those with a micropapillary component ≤ 5% did not appear to derive the same benefit from postoperative ACT.

Enhanced metal-free photocatalyst performance by synergistic Coupling of internal magnetic field and piezoelectric field.

Graphitic carbon nitride (g-C3N4) is a promising metal-free photocatalyst; however, its high carrier recombination rate and insufficient redox capacity limit its degradation effect on antibiotics. In order to overcome these shortcomings, the photocatalytic activity is improved by regulating the spin polarization state, constructing the internal electric field, and applying the external piezoelectric field. In this paper, the chlorine-doped and nitrogen-deficient porous carbon nitride composite carbon quantum dots (Nv-Cl/UPCN@CQD) has been synthesized successfully. The doping position of chlorine and spin polarization properties are verified by DFT calculation. The key intermediates *O2- and *OOH for the synthesis of reactive oxygen species were detected by in-situ infrared testing, which promotes the production of •O2- and H2O2. The degradation rate constant of Nv-Cl/UPCN@CQD for removal of tetracycline is 8.45 times higher than that of g-C3N4. The active oxygen production and degradation efficiency of piezoelectric photocatalysis under the synergistic effect of intense stirring and vis-light irradiation are much higher than those of photocatalysis and piezoelectric catalysis, and the conversion of H2O2 to •OH is promoted by piezoelectric field. This paper provides a reliable way to improve the performance of piezoelectric photocatalysts by adjusting their energy band, electronic structure and piezoelectric force.

Activation of RIG-I/MDA5 Signaling and Inhibition of CD47-SIRPα Checkpoint with a Dual siRNA-Assembled Nanoadjuvant for Robust Cancer Immunotherapy.

Antigen-presenting cells (APCs) play a crucial role in the anti-tumor immunity as they are responsible for capturing, processing, and presenting tumor antigens to T cells. However, their activation is often limited by the absence of adjuvants and the suppressive effects of immune checkpoints, such as CD47-SIRPα. Herein, we present a nanoadjuvant that is self-assembled from long RNA building blocks generated through rolling circle transcription (RCT) reaction and further modified with cationic liposomes. Owing to the high load of densely packed RNA, this nanoadjuvant could robustly activate RIG-I/MDA5 signaling in APCs, leading to the maturation of dendritic cells (DCs) and the polarization of tumor-associated macrophages (TAMs) toward an anti-tumor M1-like phenotype. In addition, with a well-designed template, the generated long RNA from RCT reaction includes two kinds of siRNA targeting both CD47 in tumor cells and SIRPα in APCs. This dual gene silencing results in efficient inhibition of the CD47-SIRPα checkpoint. Collectively, the robust activation of RIG-I/MDA5 signaling and efficient inhibition of CD47-SIRPα checkpoint enhance the phagocytic activity of APCs, which in turn promotes the cross-priming of effector T cells and the activation of anti-tumor immune responses. This study therefore provides a simple and robust RNA nanoadjuvant for cancer immunotherapy.

Patient-derived Immunocompetent Tumor Organoids: A Platform for Chemotherapy Evaluation in the Context of T-cell Recognition.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of PtIV compounds exhibited potent tumor-killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

Chemoenzymatic Measurement of LacNAc in Single-Cell Multiomics Reveals It as a Cell-Surface Indicator of Glycolytic Activity of CD8+ T Cells.

Despite the rich information about the physiological state of a cell encoded in the dynamic changes of cell-surface glycans, chemical methods to capture specific glycan epitopes at the single-cell level are quite limited. Here, we report a chemoenzymatic method for the single-cell detection of N-acetyllactosamine (LacNAc) by labeling LacNAc with a specific DNA barcode. The chemoenzymatic labeling does not alter the transcriptional status of immune cells and is compatible with multiple scRNA-seq platforms. Integrated analysis of LacNAc and the transcriptome of T cells at the single-cell level reveals that the amount of cell-surface LacNAc is significantly upregulated in activated CD8+ T cells but maintained at basal levels in resting CD8+ T cells (i.e., naive and central memory T cells). Further analysis confirms that LacNAc levels are positively correlated with the glycolytic activity of CD8+ T cells during differentiation. Taken together, our study demonstrates the feasibility of the chemoenzymatic detection of cell-surface glycan in single-cell RNA sequencing-based multiomics with TCR sequence and cell-surface epitope information (i.e., scTCR and CITE-seq), and provides a new way to characterize the biological role of glycan in diverse physiological states.

Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis.

BACKGROUND: Lymphocyte-activation gene 3 (LAG3) is a recently discovered immune checkpoint molecule that has been linked to immunosuppression and the advancement of cancer in different types of solid tumors. This study aimed to evaluate the prognostic importance of LAG3 and its role in the immune system within solid tumors. METHODS: Extensive literature searches were conducted using the Pubmed, EMBASE, and Cochrane Library databases to identify relevant studies exploring the effect of LAG3 on survival outcomes. Pooled hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to evaluate the prognostic values of LAG3. Afterwards, subgroup analysis and sensitivity analysis were conducted. Pan-cancer analysis investigated the possible relationships between LAG3 expression and genetic alterations, RNA methylation modification-related genes, genomic instability, immune checkpoint genes, and infiltration of immune cells. RESULTS: A total of 43 studies with 7,118 patients were included in this analysis. Higher expression of LAG3 was associated with worse overall survival (HR = 1.10, 95% CI 1.01-1.19, P = 0.023), but not disease-free survival (HR = 1.41, 95% CI 0.96-2.07, P = 0.078), progression-free survival (HR = 1.12, 95% CI 0.90-1.39, P = 0.317) or recurrence-free survival (HR = 0.98, 95% CI 0.81-1.19, P = 0.871). Subgroup analysis showed that LAG3 might play different prognostic roles in different solid tumors. LAG3 expression was positively associated with immune cell infiltration and immune checkpoint genes in all of the cancers included. LAG3 expression was also found to be associated with microsatellite instability (MSI), copy number variation (CNV), simple nucleoside variation (SNV), tumor mutation burden (TMB), and neoantigen in various types of cancers. CONCLUSIONS: Elevated expression of LAG3 is linked to poorer prognosis among patients diagnosed with solid cancers. LAG3 might play varying prognostic roles in different types of solid tumors. Given its substantial involvement in cancer immunity and tumorigenesis, LAG3 has garnered attention as a promising prognostic biomarker and a potential target for immunotherapy.

Evaluation of the safety and efficacy of perform enterectomy in colorectal cancer patients aged 80 or older. A meta-analysis and a systematic review.

BACKGROUND: Colorectal cancer (CRC) is one of the four most common cancers in the world. At present, human beings have stepped into an aging society, and the number of over eighties colorectal cancer patients has increased year by year. However, few high-quality studies focused on the post-operation complications and long-term outcomes of octogenarian patients with colorectal cancer. This meta-analysis, based on published studies, aims to assess the safety of treating octogenarian CRC patients with surgery. METHODS: Databases, including PubMed, Embase, and Cochrane Library were searched until July 2022. The incidence of preoperative comorbidities, postoperative complications, and mortality was assessed using odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Furthermore, the hazard ratios (HRs) with 95% CIs were applied for survival outcomes. RESULTS: A total of 13,790 patients with CRC in 21 studies were included. Our results demonstrated that octogenarian patients were associated with a higher burden of comorbidities (OR = 3.03; 95% CI: 2.03, 4.53; P = .000), high incidences of overall postoperative complications (OR = 1.63; 95% CI: 1.29, 2.06; P = .000), high internal medicine postoperative complications (OR = 2.38; 95% CI: 1.76, 3.21; P = .000), high in-hospital mortality (OR = 4.01; 95% CI: 3.06, 5.27; P = .000) and poor overall survival (OR = 2.13; 95% CI: 1.78, 2.55; P = .000). But there is no statistical difference in surgery-related postoperative complications(OR = 1.16; 95% CI: 0.94, 1.43; P = .16) and DFS (OR = 1.03; 95% CI: 0.83, 1.29; P = .775). CONCLUSIONS: Extremely elderly patients with colorectal cancer have the high burden of comorbidities, high postoperative complications and mortality. However, survival outcomes (DFS) in patients 80 years and older are similar to younger patients. Clinicians should administer individualized treatment for such patients. Physiologic age rather than chronological age should determine cancer management for each individual.

Predicting survival and prognosis in early-onset locally advanced colon cancer: a retrospective observational study.

OBJECTIVE: To predict cancer-specific survival, a refined nomogram model and brand-new risk-stratifying system were established to classify the risk levels of patients with early-onset locally advanced colon cancer (LACC). METHODS: The clinical factors and survival outcomes of LACC cases from the SEER database from 2010 to 2019 were retrieved retrospectively. Early-onset and late-onset colon cancer were grouped according to the age (50 years old) at diagnosis. Differences between groups were compared to identify mutual significant variables. A multivariate Cox regression analysis was further performed and then constructed a nomogram. We compared it with the AJCC-TNM system. The external validation was performed for evaluation. Finally, a risk-stratifying system of patients with early-onset LACC was established. RESULTS: A total of 32,855 LACC patients were enrolled in, 4548 (13.84%) patients were included in the early-onset LACC group, and 28,307 (86.16%) patients were included in the late-onset LACC group. The external validation set included 228 early-onset LACC patients. Early-onset colon cancers had poorer prognosis (T4, N2, TNM stage III, CEA, tumor deposit, and nerve invasion), and a higher proportion received radiotherapy and systemic therapy (P<0.001). In the survival analysis, cancer-specific survival (CSS) was better in patients with early-onset LACC than in those with late-onset LACC (P <0.001). This nomogram constructed based on the results of COX analysis showed better accuracy in CSS prediction of early-onset LACC patients than AJCC-TNM system in the training set and external validation set (0.783 vs 0.728; 0.852 vs 0.773). CONCLUSION: We developed a novel nomogram model to predict CSS in patients with early-onset LACC it provided a reference in prognosis prediction and selection of individualized treatment, helping clinicians in decision-making.

Risk patterns associated with transient hearing impairment and permanent hearing loss in infants born very preterm: A retrospective study.

AIM: To determine the risk patterns associated with transient hearing impairment (THI) and permanent hearing loss (PHL) of infants born very preterm who failed hearing screenings. METHOD: We enrolled 646 infants (347 males, 299 females) born at no more than 30 weeks' gestation between 2006 and 2020 who received auditory brainstem response screening at term-equivalent age. Audiological examinations of infants who failed the screening revealed THI, when hearing normalized, or PHL, defined as a persistent unilateral or bilateral hearing threshold above 20 dB. Principal component analysis (PCA) was used to characterize risk patterns. RESULTS: Among the 646 infants, 584 (90.4%) had normal hearing, 42 (6.5%) had THI, and 20 (3.1%) had PHL. Compared with the group with normal hearing, the THI and PHL groups had significantly higher rates of neurodevelopmental impairment at 24 months corrected age. PCA of risk patterns showed the THI group and especially the PHL group had more severe haemodynamic and respiratory instability. Moreover, severe intraventricular haemorrhage (IVH) was also a risk for PHL. Propensity score matching revealed an association of haemodynamic and respiratory instability with PHL. INTERPRETATION: In infants born preterm, the severity and duration of haemodynamic and respiratory instability are risk patterns for both THI and PHL; severe IVH is an additional risk for PHL. WHAT THIS PAPER ADDS: Neurodevelopmental delay was more common in infants born preterm who failed hearing screening. Principal component analysis revealed the risk patterns associated with hearing impairment. Haemodynamic-respiratory instability was associated with transient and permanent hearing impairment outcomes. Severe haemodynamic-respiratory instability and intraventricular haemorrhage was associated with permanent hearing loss.

Air pollution exposure and ovarian reserve impairment in Shandong province, China: The effects of particulate matter size and exposure window.

BACKGROUND: Lack of evidence exists on whether air pollution exposure may affect ovarian reserve, especially for Chinese women. OBJECTIVES: To explore the association between exposure to various air pollutants and anti-Müllerian hormone (AMH), a predictor of ovarian reserve, over different exposure windows in Shandong Province, China. METHODS: We enrolled 18,878 women who had AMH measurements in the Center for Reproductive Medicine, Shandong University during 2010-2019. Daily average concentrations of ambient particulate matter with diameters ≤1 µm/2.5 µm/10 µm (PM1, PM2.5, and PM10), nitrogen dioxide (NO2) and ozone (O3) were developed at a spatial resolution of 0.01° × 0.01°, and assigned to the residential addresses. Three exposure windows were considered, i.e., the process from primary to small antral follicle stage (W1), from primary to secondary follicle stage (W2), and from secondary to small antral follicle stage (W3). The air pollution-AMH association was fitted using the multivariable linear mixed effect model with adjustment for potential confounders. Stratified analyses were performed by age group, overweight status, residential region, and educational level. RESULTS: The level of AMH changed by -8.8% (95% confidence interval (CI): -12.1%, -5.3%), -2.1% (95% CI: -3.5%, -0.6%), -1.9% (95% CI: -3.3%, -0.5%), and -4.5% (95% CI: -7.1%, -1.9%) per 10 µg/m3 increase in PM1, PM2.5, PM10, and NO2, respectively, during W1. The effect estimates were significant during W2 for PM1, PM2.5 and NO2 while minimal association was observed in W3. Greater vulnerability for certain air pollutants were observed for women who lived in inland areas and were less educated. CONCLUSIONS: We found that ovarian reserve was negatively associated with air pollution exposure for women, particularly from the primary to secondary follicle stage. The effect estimate increased by the reduction in the diameter of PMs, which also varied across population sub-groups.

A nomogram for predicting the recurrence of small bowel obstruction after gastrectomy in patients with gastric cancer.

BACKGROUND: This study aimed to create a nomogram for predicting the recurrence of small bowel obstruction (SBO) after gastrectomy in patients with gastric cancer (GC) in order to provide better guidance for its diagnosis and treatment. METHODS: A total of 173 patients undergone gastrectomy and developed SBO from January 2015 to October 2022 were admitted into this case-control study. The risk factors of postoperative recurrent SBO were analyzed by univariate and multivariate regression, and a nomogram for predicting the recurrent SBO after gastrectomy was developed using R Studio. RESULTS: Thirty-nine cases of postoperative recurrent SBO occurred among the 173 GC patients who underwent radical gastrectomy, and the percentage of recurrent SBO was 22.54% (39/173). Age [odds ratio (OR) = 0.938, p = 0.026], WBC count (OR = 1.547, p < 0.001), tumor size (OR = 1.383, p = 0.024), postoperative metastasis (OR = 11.792, p = 0.030), and the interval from gastrectomy to first SBO (OR = 1.057, p < 0.001) were all identified as independent risk factors for postoperative recurrent SBO by logistic regression analysis. The receiver operating characteristic curve, the calibration curve, the model consistency index, and the decision curve analysis showed that the nomogram had good predictive performance. CONCLUSION: Based on these factors, we created a nomogram to predict the occurrence of postoperative recurrent SBO. This novel nomogram could serve as a crucial early warning indicator that would guide doctors to make informed decisions while managing patients with gastric cancer.

The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy.

Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile-α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up-regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non-competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 µM BBE against ACR-induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR-intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR-poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1-dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1-dependent axonal destruction pathway.

Virus-Like Particle-Induced cGAS-STING Activation and AIM2 Inflammasome-Mediated Pyroptosis for Robust Cancer Immunotherapy.

cGAS-STING-mediated DNA sensing is demonstrated to be critical for launching antitumor immunity. However, DNA-based cGAS-STING agonists are rarely reported owing to low cell permeability, poor biostability and, especially, limited length of exogenous DNA. Here, we present a virus-like particle which is self-assembled from long DNA building blocks generated through rolling-circle amplification (RCA) and covered with cationic liposomes. Based on long and densely packed DNA structure, it could efficiently induce liquid phase condensation of cGAS and activate STING signaling to produce inflammatory cytokines. Moreover, this virus-like particle could also trigger the formation of AIM2 inflammasome to induce gasdermin D-mediated pyroptosis, boosting antitumor immunity. Thus, this study provides a simple and robust strategy for cancer immunotherapy for clinical application. This is the first study to report the intrinsic immunogenicity of RCA products, thus facilitating their biomedical applications.

Angiogenin and plexin-B2 axis promotes glioblastoma progression by enhancing invasion, vascular association, proliferation and survival.

BACKGROUND: Angiogenin is a multifunctional secreted ribonuclease that is upregulated in human cancers and downregulated or mutationally inactivated in neurodegenerative diseases. A role for angiogenin in glioblastoma was inferred from the inverse correlation of angiogenin expression with patient survival but had not been experimentally investigated. METHODS: Angiogenin knockout mice were generated and the effect of angiogenin deficiency on glioblastoma progression was examined. Angiogenin and plexin-B2 genes were knocked down in glioblastoma cells and the changes in cell proliferation, invasion and vascular association were examined. Monoclonal antibodies of angiogenin and small molecules were used to assess the therapeutic activity of the angiogenin-plexin-B2 pathway in both genetic and xenograft animal models. RESULTS: Deletion of Ang1 gene prolonged survival of PDGF-induced glioblastoma in mice in the Ink4a/Arf-/-:Pten-/- background, accompanied by decreased invasion, vascular association and proliferation. Angiogenin upregulated MMP9 and CD24 leading to enhanced invasion and vascular association. Inhibition of angiogenin or plexin-B2, either by shRNA, monoclonal antibody or small molecule inhibitor, decreases sphere formation of patient-derived glioma stem cells, reduces glioblastoma proliferation and invasion and inhibits glioblastoma growth in both genetic and xenograft animal models. CONCLUSIONS: Angiogenin and its receptor, plexin-B2, are a pair of novel regulators that mediate invasion, vascular association and proliferation of glioblastoma cells. Inhibitors of the angiogenin-plexin-B2 axis have therapeutic potential against glioblastoma.

Risk factors and natural history of parastomal hernia after radical cystectomy and ileal conduit.

OBJECTIVE: To investigate the incidence, risk factors and natural history of parastomal hernia (PSH). MATERIALS AND METHODS: We reviewed the records of patients who underwent radical cystectomy (RC) and ileal conduit (IC) procedure between 2007 and 2020. Patients who had available follow-up computed tomography (CT) imaging were included in this study. All CT scans were re-reviewed for detection of PSH according to Moreno-Matias classification. Patients who developed hernia were followed up and classified into stable or progressive (defined as radiological upgrading and/or need for surgical intervention) groups. Multivariable Cox regression was performed to identify independent predictors of hernia development and progression. RESULTS: A total of 361 patients were included in this study. The incidence of radiological PSH was 30%, graded as I (56.5%), II (12%) and III (31.5%). The median (interquartile range [IQR]) time to radiological hernia was 8 (5-15) months. During the median (IQR) follow-up of 27 (13-47) months in 108 patients with a hernia, 26% patients progressed. The median (IQR) time to progression was 12 (6-21) months. On multivariable analysis, female gender (hazard ratio [HR] 1.86), diabetes (HR 1.81), chronic obstructive pulmonary disease (COPD; HR 1.78) and higher body mass index (BMI; HR 1.07 for each unit) were independent predictors for radiological PSH development. No significant factor was found to be associated with hernia progression. CONCLUSION: Radiological PSH after RC and IC occurred in 30% of patients, a quarter of whom progressed in a median time of 12 months. Female gender, diabetes, COPD and high BMI were independent predictors for radiological hernia development.

Early-life respiratory trajectories and neurodevelopmental outcomes in infants born very and extremely preterm: A retrospective study.

AIM: To determine whether early-life respiratory trajectories are associated with neurodevelopmental impairment (NDI) in infants born very and extremely preterm. METHOD: The daily type of respiratory supports in the first 8 weeks after birth were analysed in 546 infants (285 males, 261 females; median gestational age = 28.0 weeks, interquartile range = 3 weeks), comprising 301 infants born very preterm (gestation = 28-30 weeks) and 245 infants born extremely preterm (gestation <28 weeks), who survived to discharge from 2004 to 2018 and received follow-up assessment by Bayley Scales of Infant and Toddler Development at a corrected age of 24 months. NDI included cognition or motor impairment, moderate and severe cerebral palsy, or visual and hearing impairment. RESULTS: Clustering analysis identified three respiratory patterns with increasing severity: improving; slowly improving; and delayed improvement. These were significantly associated with increasing rates of NDI in infants born very and extremely preterm and smaller head circumference in infants born extremely preterm (both p < 0.001). By day 28, the proportion of infants who were under different categories of ventilation support significantly differed according to the three trajectory groups in infants born very and extremely preterm (both p < 0.05). Models that included adverse respiratory trajectories demonstrated more negative impacts on neurodevelopment than those without. INTERPRETATION: An adverse early-life respiratory trajectory was associated with NDI at follow-up, especially in infants born extremely preterm, suggesting a lung-brain axis of preterm birth. WHAT THIS PAPER ADDS: Clustering analysis identified three respiratory trajectories with increasing severity in infants born preterm. Increasing severity of respiratory trajectories was associated with increasing rates of neurodevelopmental impairment. Adverse respiratory trajectories had a significantly negative impact on neurodevelopmental outcomes.

OBJETIVO: Determinar se as trajetórias respiratórias no início da vida estão associadas ao comprometimento do neurodesenvolvimento (CND) em bebês nascidos muito e extremamente prematuros. MÉTODOS: O tipo diário de suporte respiratório nas primeiras 8 semanas após o nascimento foi analisado em 546 bebês (285 meninos, 261 meninas; idade gestacional mediana = 28,0 semanas, intervalo interquartil = 3 semanas), compreendendo 301 bebês nascidos muito prematuros (gestação = 28-30 semanas) e 245 bebês nascidos extremamente prematuros (gestação < 28 semanas), que sobreviveram à alta entre 2004 e 2018 e receberam avaliação de seguimento por meio da Bayley Scales of Infant and Toddler Development na idade corrigida de 24 meses. O CND incluiu deficiência cognitiva ou motora, paralisia cerebral moderada e grave ou deficiência visual e auditiva. RESULTADOS: A análise de agrupamento identificou três padrões respiratórios com gravidade crescente: melhorando; melhorando lentamente; e melhora tardia. Estes foram significativamente associados com taxas crescentes de CND em bebês nascidos muito e extremamente prematuros e menor perímetro cefálico em bebês nascidos extremamente prematuros (ambos p < 0,001). No dia 28, a proporção de bebês que estavam sob diferentes categorias de suporte ventilatório diferiu significativamente de acordo com os três grupos de trajetória em bebês nascidos muito prematuros e extremamente prematuros (ambos p < 0,05). Os modelos que incluíram trajetórias respiratórias adversas demonstraram mais impactos negativos no neurodesenvolvimento do que aqueles sem. INTERPRETAÇÃO: Uma trajetória respiratória adversa no início da vida foi associada ao CND no seguimento, especialmente em bebês nascidos extremamente prematuros, sugerindo um eixo pulmão-cérebro de nascimento prematuro.