The molecular signature and prognosis of glioma with preoperative intratumoral hemorrhage: a retrospective cohort analysis.

BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.

Bifunctional porphyrin-based metal-organic polymers for electrochemical water splitting.

Electrochemical water splitting offers the potential for environmentally friendly hydrogen and oxygen gas generation. Here, we present the synthesis, characterization, and electrochemical analyses of four organic polymers where metalloporphyrins are the active center nodes. These materials were obtained from the polymerization reaction of poly(p-phenylene terephtalamide) (PPTA) with the respective amino-functionalized metalloporphyrins, where M = Fe, 1; Co, 2; Ni, 3; Cu, 4. Scanning and transmission electron microscopy images (SEM and TEM) show that these polymers exhibit a layer-type morphology, which is attributed to hydrogen bonding and π-π stacking between the metalloporphyrin nodes. The synthesized materials were characterized by X-ray photoelectron spectroscopy (XPS), X-ray powder diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), UV-Vis spectroscopy, and Fourier-transform infrared spectroscopy (FT-IR). Among the materials studied, the cobalt-based polymer, 2, demonstrates a bifunctional electrocatalytic activity for oxygen (OER) and hydrogen (HER) evolution reactions with overpotentials (η10) of 337 mV and 435 mV, respectively. The Fe, 1, and Ni, 2, polymers are less active for HER with maximum current densities (jmax) of 12.6 and 19.1 mA cm-2 and η10 678 mV, 644 mV. Polymer 2 achieves a jmax of 37.7 mA cm-2 for HER and 133 mA cm-2 for OER. The copper-based material, 4, on the other hand, shows selectivity towards HER with an overpotential (η) of 436 mV and a maximum current density (j) of 45.5 mA cm-2. The bifunctional electrocatalytic performance was tested in the overall water-splitting setup, where polymer 2 requires a cell voltage of 1.64 V at 10 mA cm-2. This work presents a novel approach to heterogenized molecular systems, providing materials with exceptional structural characteristics and enhanced electrocatalytic capabilities.

The Crosstalk between the EGFR and IFN-γ Pathways and Synergistic Roles in Survival Prediction and Immune Escape in Gliomas.

Glioma is the most common primary malignant brain tumor. The poor prognosis of gliomas, especially glioblastoma (GBM), is associated with their unique molecular landscape and tumor microenvironment (TME) features. The epidermal growth factor receptor (EGFR) gene is one of the frequently altered loci in gliomas, leading to the activation of the EGFR signaling pathway and thus, promoting the genesis of gliomas. Whether there exist factors within the TME that can lead to EGFR activation in the context of gliomas is currently unexplored. In total, 702 samples from The Cancer Genome Atlas (TCGA) and 325 samples from The Chinese Glioma Genome Atlas (CGGA) were enrolled in this study. Gene signatures related to EGFR signaling and interferon-γ (IFN-γ) response were established via the LASSO-COX algorithm. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) analysis were applied for function exploration. Kaplan-Meier (KM) curves and single sample GSEA (ssGSEA) of immune cell subpopulations were performed to analyze the prognosis and TME characteristics of different subgroups. Moreover, Western blotting (WB) and flow cytometry (FCM) demonstrated the correlation between IFN-γ and EGFR signaling activation and the subsequent induction of programmed death ligand 1 (PD-L1) expression. An EGFR signaling-related risk score was established, and a higher score was correlated with poorer prognosis and a more malignant phenotype in gliomas. Biological function analysis revealed that a higher EGFR-related score was significantly associated with various cytokine response pathways, especially IFN-γ. Long-term (7 days) exposure to IFN-γ (400 ng/mL) induced the activation of EGFR signaling in the u87 cell line. Next, an IFN-γ response-related risk score was established; the combination of these two scores could be used to further reclassify gliomas into subtypes with different clinical features and TME features. Double high-risk samples tended to have a poorer prognosis and more immunosuppressive TME. Additionally, FCM discovered that the activation of EGFR signaling via EGF (100 ng/mL) could trigger PD-L1 protein expression. This research indicates that IFN-γ, an inflammatory cytokine, can activate the EGFR pathway. The combination of EGFR signaling and IFN-γ response pathway can establish a more precise classification of gliomas.

Free-base porphyrin polymer for bifunctional electrochemical water splitting.

Water splitting is considered a promising approach for renewable and sustainable energy conversion. The development of water splitting electrocatalysts that have low-cost, long-lifetime, and high-performance is an important area of research for the sustainable generation of hydrogen and oxygen gas. Here, we report a metal-free porphyrin-based two-dimensional crystalline covalent organic polymer obtained from the condensation of terephthaloyl chloride and 5,10,15,20-tetrakis(4-aminophenyl) porphyrin which is stabilized by an extensive hydrogen bonding network. This material exhibits bifunctional electrocatalytic performance towards water splitting with onset overpotentials, η, of 36 mV and 110 mV for HER (in 0.5 M H2SO4) and OER (in 1.0 M KOH), respectively. The as-synthesized material is also able to perform water splitting in neutral phosphate buffer saline solution, with 294 mV for HER and 520 mV for OER, respectively. Characterized by electrochemical impedance spectroscopy (EIS) and chronoamperometry, the as-synthesized material also shows enhanced conductivity and stability compared to its molecular counterpart. Inserting a non-redox active zinc metal center in the porphyrin unit leads to a decrease in electrochemical activity towards both HER and OER, suggesting the four-nitrogen porphyrin core is the active site. The high performance of this metal-free material towards water splitting provides a sustainable alternative to the use of scarce and expensive metal electrocatalysts in energy conversion for industrial applications.

Lewis Acid Site Assisted Bifunctional Activity of Tin Doped Gallium Oxide and Its Application in Rechargeable Zn-Air Batteries.

The enhanced safety, superior energy, and power density of rechargeable metal-air batteries make them ideal energy storage systems for application in energy grids and electric vehicles. However, the absence of a cost-effective and stable bifunctional catalyst that can replace expensive platinum (Pt)-based catalyst to promote oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) at the air cathode hinders their broader adaptation. Here, it is demonstrated that Tin (Sn) doped ß-gallium oxide (ß-Ga2 O3 ) in the bulk form can efficiently catalyze ORR and OER and, hence, be applied as the cathode in Zn-air batteries. The Sn-doped ß-Ga2 O3 sample with 15% Sn (Snx =0.15 -Ga2 O3 ) displayed exceptional catalytic activity for a bulk, non-noble metal-based catalyst. When used as a cathode, the excellent electrocatalytic bifunctional activity of Snx =0.15 -Ga2 O3 leads to a prototype Zn-air battery with a high-power density of 138 mW cm-2 and improved cycling stability compared to devices with benchmark Pt-based cathode. The combined experimental and theoretical exploration revealed that the Lewis acid sites in ß-Ga2 O3 aid in regulating the electron density distribution on the Sn-doped sites, optimize the adsorption energies of reaction intermediates, and facilitate the formation of critical reaction intermediate (O*), leading to enhanced electrocatalytic activity.