Machine learning-based pathomics signature of histology slides as a novel prognostic indicator in primary central nervous system lymphoma.

PURPOSE: To develop and validate a pathomics signature for predicting the outcomes of Primary Central Nervous System Lymphoma (PCNSL). METHODS: In this study, 132 whole-slide images (WSIs) of 114 patients with PCNSL were enrolled. Quantitative features of hematoxylin and eosin (H&E) stained slides were extracted using CellProfiler. A pathomics signature was established and validated. Cox regression analysis, receiver operating characteristic (ROC) curves, Calibration, decision curve analysis (DCA), and net reclassification improvement (NRI) were performed to assess the significance and performance. RESULTS: In total, 802 features were extracted using a fully automated pipeline. Six machine-learning classifiers demonstrated high accuracy in distinguishing malignant neoplasms. The pathomics signature remained a significant factor of overall survival (OS) and progression-free survival (PFS) in the training cohort (OS: HR 7.423, p < 0.001; PFS: HR 2.143, p = 0.022) and independent validation cohort (OS: HR 4.204, p = 0.017; PFS: HR 3.243, p = 0.005). A significantly lower response rate to initial treatment was found in high Path-score group (19/35, 54.29%) as compared to patients in the low Path-score group (16/70, 22.86%; p < 0.001). The DCA and NRI analyses confirmed that the nomogram showed incremental performance compared with existing models. The ROC curve demonstrated a relatively sensitive and specific profile for the nomogram (1-, 2-, and 3-year AUC = 0.862, 0.932, and 0.927, respectively). CONCLUSION: As a novel, non-invasive, and convenient approach, the newly developed pathomics signature is a powerful predictor of OS and PFS in PCNSL and might be a potential predictive indicator for therapeutic response.

In Situ Polymerized Quasi-Solid Electrolytes Compounded with Ionic Liquid Empowering Long-Life Cycling of 4.45 V Lithium-Metal Battery.

High-voltage resistant quasi-solid-state polymer electrolytes (QSPEs) are promising for enhancing the energy density of lithium-metal batteries in practice. However, side reactions occurring at the interfaces between the anodes or cathodes and QSPEs considerably reduce the lifespan of high-voltage LMBs. In this study, a copolymer of vinyl ethylene carbonate (VEC) and poly(ethylene glycol) diacrylate (PEGDA) was used as the framework, with a cellulose membrane (CE) as the supporting layer. Based on density functional theory calculations, 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14TFSI), an ionic liquid, was screened because of its lowest unoccupied molecular orbital energy level as a modifying agent for the in situ P(VECx-EGy)/Pyrz/LiTFSI@CE QSPEs synthesis. Pyr14+, with a lithiophobic alkyl chain, forms a dense positive ion shielding layer on the protruding tips of deposited lithium, facilitating uniform and smooth lithium deposition. Pyr14TFSI assists in constructing a stable solid electrolyte interphase (SEI) layer on the Li surface enriched with LiF, Li3N, and RCOOLi. The modulation of lithium deposition behavior on the anode by Pyr14TFSI ensures stable Li plating/stripping for >1500 h. A Li-Cu cell exhibits stable cycling for >200 cycles at a current density of 0.05 mA cm-2, with an average Coulombic efficiency of 92.7%. In situ polymerization ensures that P(VECx-EGy)/Pyrz/LiTFSI@CE QSPEs exhibit excellent interface compatibility with the anode and the cathode. The CR2032 button cell Li|P(VEC1-EG0.06)/Pyr0.4/LiTFSI@CE|LiCoO2 demonstrates stable cycling with a negligible capacity decay of 0.083% per cycle for >390 cycles at 25 °C and 0.2 C when using a high-voltage LiCoO2 (4.45 V) cathode. Furthermore, a 7.1 mAh pouch cell achieves stable charge-discharge cycles, confirming the pronounced stability of the as-fabricated QSPE at the interfaces of the high-voltage LiCoO2 cathode and Li anode.

Intrinsic negative Poisson's ratio of the monolayer semiconductor ß-TeO2.

Monolayer semiconductors with unique mechanical responses are promising candidates for novel electromechanical applications. Here, through first-principles calculations, we discover that the monolayer ß-TeO2, a high-mobility p-type and environmentally stable 2D semiconductor, exhibits an unusual out-of-plane negative Poisson's ratio (NPR) when a uniaxial strain is applied along the zigzag direction. The NPR originates from the unique six-sublayer puckered structure and hinge-like Te-O bonds in the 2D ß-TeO2. We further propose that the sign of the Raman frequency change under uniaxial tensile strain could assist in determining the lattice orientation of monolayer ß-TeO2, which facilitates the experimental study of the NPR. Our results is expected to motivate further experimental and theoretical studies of the rich physical and mechanical properties of monolayer ß-TeO2.

A protein network refinement method based on module discovery and biological information.

BACKGROUND: The identification of essential proteins can help in understanding the minimum requirements for cell survival and development to discover drug targets and prevent disease. Nowadays, node ranking methods are a common way to identify essential proteins, but the poor data quality of the underlying PIN has somewhat hindered the identification accuracy of essential proteins for these methods in the PIN. Therefore, researchers constructed refinement networks by considering certain biological properties of interacting protein pairs to improve the performance of node ranking methods in the PIN. Studies show that proteins in a complex are more likely to be essential than proteins not present in the complex. However, the modularity is usually ignored for the refinement methods of the PINs. METHODS: Based on this, we proposed a network refinement method based on module discovery and biological information. The idea is, first, to extract the maximal connected subgraph in the PIN, and to divide it into different modules by using Fast-unfolding algorithm; then, to detect critical modules according to the orthologous information, subcellular localization information and topology information within each module; finally, to construct a more refined network (CM-PIN) by using the identified critical modules. RESULTS: To evaluate the effectiveness of the proposed method, we used 12 typical node ranking methods (LAC, DC, DMNC, NC, TP, LID, CC, BC, PR, LR, PeC, WDC) to compare the overall performance of the CM-PIN with those on the S-PIN, D-PIN and RD-PIN. The experimental results showed that the CM-PIN was optimal in terms of the identification number of essential proteins, precision-recall curve, Jackknifing method and other criteria, and can help to identify essential proteins more accurately.

A Multifunctional Additive Based on the Cation-Anion Synergistic Effect for Highly Stable Zinc Metal Anodes.

The Zn dendrite and hydrogen evolution reaction have been a "stubborn illness" for the life span of zinc anodes, which significantly hinders the development of aqueous zinc batteries (AZBs). Herein, considering the ingenious molecular structure, a multifunctional additive based on the synergistic regulation of cations and anions at the interface is designed to promote a dendrite-free and stable Zn anode. Theoretical calculations and characterization results verified that the electrostatic shield effect of the cation, the solvation sheath structure, and the bilayer structural solid electrolyte film (SEI) jointly account for the uniform Zn deposition and side reaction suppression. Ultimately, a remarkably high average Coulombic efficiency (CE) of 99.4% is achieved in the Zn||Cu cell for 300 cycles, and a steady charge/discharge cycling over 3000 and 300 h at 1.0 mA cm-2/1.0 mAh cm-2 and 10 mA cm-2/10 mAh cm-2 is obtained in the Zn||Zn cell. Furthermore, the assembled full battery demonstrates a prolonged cycle life of 2000 cycles.

Fast Solution Blow Spinning of Lotus-Leaf-Inspired SiO2 Nanofiber Sponge for High Efficiency Purification.

Massive production of SiO2 nanofibers with both high durability and exceptional performance remains a significant challenge. Herein, a novel approach was introduced to achieve the massive production of SiO2 nanofibers with lotus-leaf-inspired surfaces by combining solution blowing spinning (SBS) and the polymer-derived ceramics method. Based on the SBS technique, three types of precursor nanofiber products were fast spined with methyl silsesquioxane polymer and polymethyl hydrogen siloxane employed as Si sources. The flow rate of the SBS spined Si-based ceramic nanofibers was enhanced to 20 mL·h-1. Furthermore, through the integration of hydrophobic-oleophilic SiO2 nanoparticles into the precursor solution, SiO2 nanofibers with lotus-leaf nanoprotrusion surfaces were fabricated. Nanoparticle-decorated SiO2 fibers demonstrated excellent hydrophobicity (138.3°), compression resilience (∼60%), proficiency in organic pollutant adsorption, high-temperature resistance (∼1100 °C), and outstanding thermal insulation properties (thermal conductivity of 0.0165 W·(m·K)-1).

Analysis of a Serious Adverse Reaction of Pulmonary Fibrosis Caused by Dronedarone.

Objective: This study aims to analyze a severe adverse reaction of pulmonary fibrosis induced by dronedarone hydrochloride tablets, and to provide a reference for clinical rational medication through drug precautions. Methods: A case of pulmonary fibrosis induced by dronedarone hydrochloride tablets, along with related literature was retrospectively analyzed. Results: Patients over 65 years old with a history of exposure to amiodarone may increase the incidence of pulmonary toxicity induced by dronedarone, and dronedarone should not be selected as a substitute treatment drug for patients with amiodarone-induced pulmonary toxicity. Conclusions: It is recommended that clinicians monitor the diffusion capacity of carbon monoxide and lung ventilation function of patients before and after using dronedarone for treatment. For patients with a history of amiodarone exposure, intermittent monitoring of chest X-rays and lung function is necessary. If lung function decreases, dronedarone should be immediately discontinued.

Integrated multiomic analysis reveals disulfidptosis subtypes in glioblastoma: implications for immunotherapy, targeted therapy, and chemotherapy.

Introduction: Glioblastoma (GBM) presents significant challenges due to its malignancy and limited treatment options. Precision treatment requires subtyping patients based on prognosis. Disulfidptosis, a novel cell death mechanism, is linked to aberrant glucose metabolism and disulfide stress, particularly in tumors expressing high levels of SLC7A11. The exploration of disulfidptosis may provide a new perspective for precise diagnosis and treatment of glioblastoma. Methods: Transcriptome sequencing was conducted on samples from GBM patients treated at Tiantan Hospital (January 2022 - December 2023). Data from CGGA and TCGA databases were collected. Consensus clustering based on disulfidptosis features categorized GBM patients into two subtypes (DRGclusters). Tumor immune microenvironment, response to immunotherapy, and drug sensitivity were analyzed. An 8-gene disulfidptosis-based subtype predictor was developed using LASSO machine learning algorithm and validated on CGGA dataset. Results: Patients in DRGcluster A exhibited improved overall survival (OS) compared to DRGcluster B. DRGcluster subtypes showed differences in tumor immune microenvironment and response to immunotherapy. The predictor effectively stratified patients into high and low-risk groups. Significant differences in IC50 values for chemotherapy and targeted therapy were observed between risk groups. Discussion: Disulfidptosis-based classification offers promise as a prognostic predictor for GBM. It provides insights into tumor immune microenvironment and response to therapy. The predictor aids in patient stratification and personalized treatment selection, potentially improving outcomes for GBM patients.

OH2 oncolytic virus: A novel approach to glioblastoma intervention through direct targeting of tumor cells and augmentation of anti-tumor immune responses.

Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.

Attention-based investigation and solution to the trade-off issue of adversarial training.

Adversarial training has become the mainstream method to boost adversarial robustness of deep models. However, it often suffers from the trade-off dilemma, where the use of adversarial examples hurts the standard generalization of models on natural data. To study this phenomenon, we investigate it from the perspective of spatial attention. In brief, standard training typically encourages a model to conduct a comprehensive check to input space. But adversarial training often causes a model to overly concentrate on sparse spatial regions. This reduced tendency is beneficial to avoid adversarial accumulation but easily makes the model ignore abundant discriminative information, thereby resulting in weak generalization. To address this issue, this paper introduces an Attention-Enhanced Learning Framework (AELF) for robustness training. The main idea is to enable the model to inherit the attention pattern of standard pre-trained model through an embedding-level regularization. To be specific, given a teacher model built on natural examples, the embedding distribution of teacher model is used as a static constraint to regulate the embedding outputs of the objective model. This design is mainly supported with that the embedding feature of standard model is usually recognized as a rich semantic integration of input. For implementation, we present a simplified AELFs that can achieve the regularization with single cross entropy loss via the parameter initialization and parameter update strategy. This avoids the extra consistency comparison operation between embedding vectors. Experimental observations verify the rationality of our argument, and experimental results demonstrate that it can achieve remarkable improvements in generalization under the high-level robustness.

Corrigendum: ATP6V0C is associated with febrile seizures and epilepsy with febrile seizures plus.

[This corrects the article DOI: 10.3389/fnmol.2022.889534.].

Medium-intensity statin with ezetimibe versus high-intensity statin in acute ischemic cerebrovascular disease (MESIA): A randomized clinical trial.

BACKGROUND: High-risk stroke patients are recommended to receive high-intensity statin therapy to reduce the risk of stroke recurrence. However, doubling the dosage of statin drugs did not increase the achievement rate of LDL-C target or provide additional clinical benefits, but significantly increased the risk of adverse reactions. Statins and ezetimibe work through different mechanisms and the combined use of statins and ezetimibe significantly improves outcomes with comparable safety profiles. We tested the hypothesis that moderate-intensity statin with ezetimibe may offer advantages over the conventional high-intensity statin regimen in terms of efficacy and safety. METHODS: We conducted a randomized controlled trial. Eligible participants were aged 18 years or older with acute ischemic cerebrovascular disease. We randomly assigned (1:1) participants within the acute phase of ischemic stroke, i.e., within 1 week after the onset of mild ischemic stroke (NIHSS score ≤ 5), within 1 month for severe cases (NIHSS score ≥ 16), and within 2 weeks for the rest, as well as patients with TIA within 1 week of symptom onset, to receive either moderate-intensity statin with ezetimibe (either 10-20 mg atorvastatin calcium tablets plus a 10 mg ezetimibe tablet, or 5-10 mg rosuvastatin calcium tablets once per day plus a 10 mg ezetimibe tablet once per day) or high-intensity statin (40 mg atorvastatin calcium tablets or 20 mg rosuvastatin calcium tablets once per day) for 3 months. Randomization was performed using a random number table method. The primary efficacy outcome was the level and achievement rate of LDL-C after 3 months of treatment, specifically LDL-C ≤ 1.8 mmol/L or a reduction in LDL-C ≥ 50 %. The secondary outcome was the incidence of new stroke or transient ischemic attack (TIA) within 3 months. The safety outcome was liver and renal function tests, and the occurrence of statin-related muscle events within 3 months. FINDINGS: This trial took place between March 15, 2022, and March 7, 2023. Among 382 patients screened, 150 patients were randomly assigned to receive either medium-intensity statins with ezetimibe (n = 75) or high-intensity statins (n = 75). Median age was 60.0 years (IQR 52.75-70.25); 49 (36.6 %) were women and 85 (63.4 %) were men. The target achievement of LDL-C at 3 months occurred in 62 (89.86 %) of 69 patients in the medium-intensity statin with ezetimibe group and 46 (70.77 %) of 65 patients in the high-intensity statin group (P=0.005, OR=0.273, 95 % CI: 0.106, 0.705). The reduction magnitude of LDL-C in moderate-intensity statin with ezetimibe group was significantly higher (-56.540 % vs -47.995 %, P=0.001). Moderate-intensity statin with ezetimibe group showing a trend of a greater reduction in LDL-C absolute value than high-intensity statin group but without statistical significance (-1.77±0.90 vs -1.50±0.89, P=0.077). New AIS or TIA within 3 months, liver and renal function tests, and the occurrence of statin-related muscle events within 3 months were also statistically insignificant. Multivariate logistic regression analysis showed that both gender and lipid-lowering regimen as independent risk factors influencing the rate of LDL-C achievement in individuals diagnosed with acute ischemic cerebrovascular disease, but only lipid-lowering regimen had predictive value. INTERPRETATION: Compared to guideline-recommended high-intensity statin therapy, moderate-intensity statin with ezetimibe further improved the achievement rate of LDL-C in patients with acute ischemic cerebrovascular disease, with a higher reduction magnitude in LDL-C. In terms of safety, there was no significant difference between the two regimens, suggesting that moderate-intensity statin with ezetimibe can also be considered as an initial treatment option for patients with acute ischemic cerebrovascular disease.

NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation.

NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14R290C/+ knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE.

Overexpression of cry1c* Enhances Resistance against to Soybean Pod Borer (Leguminivora glycinivorella) in Soybean.

Soybean [Glycine max (L.) Merr.], an essential staple food and oil crop worldwide, boasts abundant vegetable proteins and fats beneficial for both human and animal consumption. However, the soybean pod borer (Leguminivora glycinivorella) (SPB) stands as the most destructive soybean insect pest in northeast China and other northeastern Asian regions, leading to significant annual losses in soybean yield and economic burden. Therefore, this study aims to investigate the introduction of a previously tested codon-optimized cry1c gene, cry1c*, into the soybean genome and assess its effect on the SPB infestation by generating and characterizing stable transgenic soybeans overexpressing cry1c*. The transgenic soybean lines that constitutively overexpressed cry1c* exhibited a significant reduction in the percentage of damaged seeds, reaching as low as 5% in plants under field conditions. Additionally, feeding transgenic leaves to the larvae of S. exigua, S. litura, and M. separta resulted in inhibited larval growth, decreased larval body weight, and lower survival rates compared to larvae fed on wild-type leaves. These findings showed that the transgenic lines maintained their resistance to SPB and other lepidopteran pests, especially the transgenic line KC1. Southern blotting and genome-wide resequencing analysis revealed that T-DNA integration occurred as a single copy between loci 50,868,122 and 50,868,123 of chromosome 10 in the transgenic line KC1. Therefore, the transgenic line KC1, overexpressing high levels of cry1c* in leaves and seeds, holds strong potential for commercial use in the integrated management of SPB and other lepidopteran pests.

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression.

Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well-known arginine methyltransferase, was identified as a SMYD4-binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E-cadherin, RBL2, and miR-29b-1-5p. Moreover, miR-29b-1-5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4-PRMT5 axis as a potential therapeutic target for the treatment of HCC.

Acute combined effects of concurrent physical activities on autonomic nervous activation during cognitive tasks.

Backgrounds: The validity of heart rate variability (HRV) has been substantiated in mental workload assessments. However, cognitive tasks often coincide with physical exertion in practical mental work, but their synergic effects on HRV remains insufficiently established. The study aims were to investigate the combined effects of cognitive and physical load on autonomic nerve functions. Methods: Thirty-five healthy male subjects (aged 23.5 ± 3.3 years) were eligible and enrolled in the study. The subjects engaged in n-back cognitive tasks (1-back, 2-back, and 3-back) under three distinct physical conditions, involving isotonic contraction of the left upper limb with loads of 0 kg, 3 kg, and 5 kg. Electrocardiogram signals and cognitive task performance were recorded throughout the tasks, and post-task assessment of subjective experiences were conducted using the NASA-TLX scale. Results: The execution of n-back tasks resulted in enhanced perceptions of task-load feelings and increased reaction times among subjects, accompanied by a decline in the accuracy rate (p < 0.05). These effects were synchronously intensified by the imposition of physical load. Comparative analysis with a no-physical-load scenario revealed significant alterations in the HRV of the subjects during the cognitive task under moderate and high physical conditions. The main features were a decreased power of the high frequency component (p < 0.05) and an increased low frequency component (p < 0.05), signifying an elevation in sympathetic activity. This physiological response manifested similarly at both moderate and high physical levels. In addition, a discernible linear correlation was observed between HRV and task-load feelings, as well as task performance under the influence of physical load (p < 0.05). Conclusion: HRV can serve as a viable indicator for assessing mental workload in the context of physical activities, making it suitable for real-world mental work scenarios.

Effect of High Altitude Environment on Pharmacokinetic and Pharmacodynamic of Warfarin in Rats.

BACKGROUND: High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anticoagulant of the coumarin class commonly used in clinical practice, but it has a narrow therapeutic window and wide individual variation. However, the effect of high altitude environment on PK and pharmacodynamic (PD) of warfarin is unclear. OBJECTIVE: The objective of this study is to investigate the effect of a high altitude environment on PK and PD of warfarin in rats. METHOD: Rats were randomly divided into plain group and high altitude group and blood samples were collected through the orbital venous plexus after administration of 2 mg/kg warfarin. Warfarin concentrations in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and PK parameters were calculated by the non-compartment model using WinNonlin 8.1 software. Meanwhile, the expression of PXR, P-gp and CYP2C9 in liver tissues was also determined by western blotting. The effect of high altitude environment on PD of warfarin was explored by measuring activated partial thromboplastin time (APTT) and prothrombin time (PT) values and then calculated international normalized ratio (INR) values based on PT. RESULTS: Significant changes in PK behaviors and PD of warfarin in high altitude-rats were observed. Compared with the plain-rats, the peak concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increased significantly by 50.9% and 107.46%, respectively. At the same time, high altitude environment significantly inhibited the expression of PXR, P-gp and CYP2C9 in liver tissues. The results of the PD study showed that high altitude environments significantly prolonged PT, APTT and INR values. CONCLUSION: High altitude environment inhibited the metabolism and increased the absorption of warfarin in rats and increased the effect of anticoagulant effect, suggesting that the optimal dose of warfarin for patients at high altitude should be reassessed.

Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

Prognostic factors analysis of diffuse midline glioma.

PURPOSE: This study retrospectively analyzes cases of diffuse midline glioma treated with radiotherapy, with the aim of investigating the prognosis of the tumor and its influencing factors. METHODS: From January 2018 to November 2022, we treated 64 patients who were pathologically diagnosed with diffuse midline glioma. Among them, 41 underwent surgical resection, and 23 underwent biopsy procedures. All patients received postoperative radiotherapy. We followed up with the patients to determine the overall survival rate and conducted univariate and multivariate analyses on relevant indicators. RESULTS: The median survival time for the entire patient group was 33.3 months, with overall survival rates of 92.9%, 75.4%, and 45.0% at 1 year, 2 years, and 3 years, respectively. Univariate and multivariate analyses indicated that older patients had a better prognosis. CONCLUSION: Patient age is an independent prognostic factor for patients with diffuse midline glioma undergoing radiation therapy.