WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis.

BACKGROUND: Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed. METHODS: The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot. RESULTS: In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects. CONCLUSION: In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.

Corrigendum: Machine learning prediction model for post- hepatectomy liver failure in hepatocellular carcinoma: a multicenter study.

[This corrects the article DOI: 10.3389/fonc.2022.986867.].

Efficient fabrication of single-wall carbon nanotube nanoreactors by defect-induced cutting.

Single-wall carbon nanotubes (SWCNTs) with ultra-thin channels are considered promising nanoreactors for confined catalysis, chemical reactions, and drug delivery. The fabrication of SWCNT nanoreactors by cutting usually suffers from low efficiency and poor controllability. Here we develop a defect-induced gas etching method to efficiently cut SWCNTs and to obtain nanoreactors with ultrasmall confined space. H2 plasma treatment was performed to generate defects in the walls of SWCNTs, then H2O vapor was used as a "knife" to cut SWCNTs at the defect sites, and short cut-SWCNTs with an average length of 175 nm were controllably obtained with a high yield of 75% under optimized conditions. WO3@SWCNT derivatives with different morphologies were synthesized using short cut-SWCNTs as nanoreactors. The radiation resistance of WO3@SWCNT hybrids improved obviously, thus providing a platform for the synthesis of novel SWCNT-based derivatives with fascinating properties.

The EEG Features of Four Cases of Subacute Sclerosing Panencephalitis in North China : SSPE EEG Features.

Objective. To analyze the EEG features of four subacute sclerosing panencephalitis cases in North China. Methods. We retrospectively analyzed the EEG features in four patients with subacute sclerosing panencephalitis and 12 patients in control group from North China. Results. The periodic long-interval diffuse discharges were found in all of the four cases with subacute sclerosing panencephalitis. The morphology and component of periodic complexes were varied in different patients and different wakefulness states. Some EEG parameter settings help to identify periodic long-interval diffuse discharges including the slowed sweep speed, decreased sensitivity and reduced number of montages. In each patient with subacute sclerosing panencephalitis, the periodic long-interval diffuse discharges associated with two types of brief episodes (1:1) during awake period were found and none of the patients in the control group had this EEG pattern. The score system based on the periodic discharges and brief episodes also shows that all the patients with SSPE reached score 5 while none of the patients in the control group has a score greater than 3, which suggests that this EEG pattern may have diagnostic value. Conclusions. In subacute sclerosing panencephalitis, the morphology and component of periodic long-interval diffuse discharges were varied in different patients and different wakefulness states. Specific EEG parameter settings help to identify periodic long-interval diffuse discharges. Periodic long-interval diffuse discharges associated with two types of brief episodes (1:1) during awake period may strongly suggest the diagnosis of subacute sclerosing panencephalitis.

Machine learning prediction model for post- hepatectomy liver failure in hepatocellular carcinoma: A multicenter study.

Introduction: Post-hepatectomy liver failure (PHLF) is one of the most serious complications and causes of death in patients with hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to develop a novel machine learning (ML) model based on the light gradient boosting machines (LightGBM) algorithm for predicting PHLF. Methods: A total of 875 patients with HCC who underwent hepatectomy were randomized into a training cohort (n=612), a validation cohort (n=88), and a testing cohort (n=175). Shapley additive explanation (SHAP) was performed to determine the importance of individual variables. By combining these independent risk factors, an ML model for predicting PHLF was established. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, and decision curve analyses (DCA) were used to evaluate the accuracy of the ML model and compare it to that of other noninvasive models. Results: The AUCs of the ML model for predicting PHLF in the training cohort, validation cohort, and testing cohort were 0.944, 0.870, and 0.822, respectively. The ML model had a higher AUC for predicting PHLF than did other non-invasive models. The ML model for predicting PHLF was found to be more valuable than other noninvasive models. Conclusion: A novel ML model for the prediction of PHLF using common clinical parameters was constructed and validated. The novel ML model performed better than did existing noninvasive models for the prediction of PHLF.

Noninvasively Assessed Portal Hypertension Grade Predicts Post-Hepatectomy Liver Failure in Patients With HepatocellCarcinoma: A Multicenter Study.

Purpose: To determine the predictive value of portal hypertension (PH) for the development of post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). Patients and methods: This study enrolled a total of 659 patients with HCC that received hepatectomy as a first-line therapy. PH was classified as grade 0, 1, and 2 according to whether the indirect criteria for PH were met: 1) patients had obvious varicose veins and 2) splenomegaly was present and platelet count < 100 × 109/L. The effects of each variable on the occurrence of PHLF were assessed using univariate and multivariate analyses. Results: PH grade 2 (odds ratio [OR] = 2.222, p = 0.011), higher age (OR = 1.031, p = 0.003), hepatitis C infection (OR = 3.711, p = 0.012), open surgery (OR = 2.336, p < 0.001), portal flow blockage (OR = 1.626, p = 0.023), major hepatectomy (OR = 2.919, p = 0.001), hyperbilirubinemia (≥ 17.2 µmol/L, OR = 2.113, p = 0.002), and high levels of alpha-fetoprotein (> 400n g/ml, OR = 1.799, p = 0.008) were significantly associated with PHLF occurrence. We performed a subgroup analysis of liver resection and found that the extent of liver resection and PH grade were good at distinguishing patients at high risk for PHLF, and we developed an easy-to-view roadmap. Conclusion: PH is significantly related to the occurrence of PHLF in patients who underwent hepatectomy. Noninvasively assessing PH grade can predict PHLF risk.

Prediction of high infiltration levels in pituitary adenoma using MRI-based radiomics and machine learning.

BACKGROUND: Infiltration is important for the surgical planning and prognosis of pituitary adenomas. Differences in preoperative diagnosis have been noted. The aim of this article is to assess the accuracy of machine learning analysis of texture-derived parameters of pituitary adenoma obtained from preoperative MRI for the prediction of high infiltration. METHODS: A total of 196 pituitary adenoma patients (training set: n = 176; validation set: n = 20) were enrolled in this retrospective study. In total, 4120 quantitative imaging features were extracted from CE-T1 MR images. To select the most informative features, the least absolute shrinkage and selection operator (LASSO) and variance threshold method were performed. The linear support vector machine (SVM) was used to fit the predictive model based on infiltration features. Furthermore, the receiver operating characteristic curve (ROC) was generated, and the diagnostic performance of the model was evaluated by calculating the area under the curve (AUC), accuracy, precision, recall, and F1 value. RESULTS: A variance threshold of 0.85 was used to exclude 16 features with small differences using the LASSO algorithm, and 19 optimal features were finally selected. The SVM models for predicting high infiltration yielded an AUC of 0.86 (sensitivity: 0.81, specificity 0.79) in the training set and 0.73 (sensitivity: 0.87, specificity: 0.80) in the validation set. The four evaluation indicators of the predictive model achieved good diagnostic capabilities in the training set (accuracy: 0.80, precision: 0.82, recall: 0.81, F1 score: 0.81) and independent verification set (accuracy: 0.85, precision: 0.93, recall: 0.87, F1 score: 0.90). CONCLUSIONS: The radiomics model developed in this study demonstrates efficacy for the prediction of pituitary adenoma infiltration. This model could potentially aid neurosurgeons in the preoperative prediction of infiltration in PAs and contribute to the selection of ideal surgical strategies.

Identification and Validation of a Seizure-Free-Related Gene Signature for Predicting Poor Prognosis in Lower-Grade Gliomas.

BACKGROUND: Lower-grade gliomas (LGGs) patients presented seizure-free have a worse survival than those presented with seizures. However, the current knowledge on its potential value in LGGs remains scarce. PURPOSE: This study aimed to identify a novel gene signature associated with seizures-free for predicting poor prognosis for LGGs patients. MATERIALS AND METHODS: The RNA expression and clinical information of LGGs patients were downloaded from the Cancer Genome Atlas database. Differentially expressed genes (DEGs) were screened out between LGGs patients presented seizures-free and seizures. The novel gene signature was constructed by Lasso and multivariate regression analyses for predicting prognosis in LGGs. Its prognostic value was assessed and validated by Kaplan-Meier analyses and receiver operating characteristic (ROC) curves. Multivariate regression analysis was applied to identify the independent prognostic value of the gene signature. Furthermore, bioinformatics analysis was performed to elucidate the molecular mechanisms. RESULTS: A total of 253 DEGs were screened out between LGG patients presented with seizures and free of seizures. A 5-gene signature (HIST1H4F, HORMAD2, LILRA3, PRSS33, and TBX20 genes) was constructed from these 253 DEGs. Kaplan-Meier analyses and ROC curves assessed and validated the good performance of the 5-gene signature in differentiating and predicting prognosis of high- and low-risk patients. Multivariate regression analysis determined the independent prognostic value of the 5-gene signature. According to bioinformatics analysis, DEGs were mainly enriched in biological processes related to positive regulation of transcription from RNA polymerase II promoter, G-protein coupled receptor signaling pathway, and pathways of cytokine-cytokine receptor interaction, chemokine signaling pathway. CONCLUSION: Our findings suggested that the 5-gene signature might serve as a potential prognostic biomarker and provide guidance for the personalized LGGs management.

Modeling three-dimensional underwater acoustic propagation over multi-layered fluid seabeds using the equivalent source method.

This paper develops an efficient three-dimensional (3D) underwater acoustic propagation model with multi-layered fluid seabeds based on the equivalent source method (ESM). It solves the Helmholtz equation exactly by a superposition of fields generated by equivalent sources. A linear system coupling ESM equations is derived by imposing boundary conditions and solved iteratively using the generalized minimum residual method. Unlike a direct ESM solver, matrix-vector products in each iteration are evaluated by a pre-corrected fast Fourier transformation (PFFT), significantly reducing the numerical cost and enabling efficient solution of 3D large-scale propagation. Moreover, sound speed profiles can be taken into account by dividing the water column into sub-layers, each of which requires an individual PFFT procedure using an FFT subgrid scheme. Simulations of propagation over a Gaussian canyon validate the PFFT-accelerated ESM (PFFT-ESM). The capability of the PFFT-ESM for 3D scattering problems is demonstrated by further presenting the Gaussian canyon simulations with corrugated surface waves.

The dependence of Cu2O morphology on different surfactants and its application for non-enzymatic glucose detection.

Herein, the Cu2O yolk-shell nanospheres, nanocubes and microcubes were successfully prepared by a simple seed-medium process. The formation of the Cu2O yolk-shell nanospheres can be attributed to the self-assembly process caused by the introduction of the seed medium. The formation mechanism of our obtained Cu2O yolk-shell nanospheres and the dependence of Cu2O morphology on different surfactants have been studied. The obtained samples were applied in the field of non-enzymatic glucose detection. The electrochemical response characteristics of the modified electrodes toward glucose were investigated by cyclic voltammetry (CV) and chronoamperometry (CA). The electrode modified with C-Cu2O (obtained by using CTAB as surfactant) shared the highest sensitivity of 3123 µAmM-1 cm-2, whereas, the electrode modified with S-Cu2O (obtained by using SDBS as surfactant) exhibited the lowest LOD of 0.87 µM and the widest linear range of 0.05-10.65 mM. All obtained sensors showed fast response to the addition of glucose. The obtained electrodes showed better responses to glucose than other coexisting interferences, indicating that the obtained electrodes had the acceptable selectivity to glucose. In addition, the stability for 5 consecutive weeks had also been studied and exhibited satisfactory results. The obtained electrode was also used to detect the glucose content in real serum. The acceptable selectivity, stability together with the excellent sensing ability in real serum make the obtained electrodes a potential for practical applications.

Atomic-resolution study on the interface structure and strain state reversion of the Bi2Sr2CuO6+δ/MgO heterostructure.

Due to the crucial influence of interface structure and strain on the performance of heterojunctions, they have received extensive attention in recent years. In this article, the interface structure and strain of the Bi2Sr2CuO6+δd(Bi-2201)/MgO superconducting heterojunction prepared by molecular beam epitaxy were investigated by aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), energy-dispersive X-ray spectroscopy (EDX), and geometric phase analysis (GPA). The interfacial atomic sequence is determined as MgO-(CuO-CuO-Cu/BiO)-(Bi-2201)n, where a 0.53 nm thick CuO interlayer accompanied by Bi/Cu atomic co-occupation is observed between the Bi-2201 film and the MgO substrate. In addition, there is a typical coherent lattice-matching epitaxial interface between CuO/MgO with no defects and a semi-coherent domain-matching epitaxial interface between Bi-2201/CuO accompanied by an ideal misfit dislocation network. Because misfit dislocations almost compensate for the strain caused by lattice mismatch, the final Bi-2201 film undergoes in-plane compressive strain (εxx ~ -0.573%) rather than expected tensile strain relative to bulk Bi-2201, which is attributed to the thermal expansion mismatch. The compressive strain gradually releases as the distance from the heterointerface increases.

Phase Transformation of a K2GeF6 Polymorph for Phosphors Driven by a Simple Precipitation-Dissolution Equilibrium and Ion Exchange.

Tuning crystal phase transformations is very important for obtaining polymorphs for phosphors with the ideal optical properties and stability. Mn4+-doped K2GeF6 (KGF) is a typical polymorphic phosphor, but the thermodynamic and kinetic mechanism of its phase transformation is still unclear. Herein, the phase transformation of polymorphs varying from P63mc KGF and trigonal KGF to P63mc Si4+-doped KGF is realized by introducing the synergistic action of an HF solution and Si4+ ions. The full structural refinements of KGF polymorphs at room temperature and the electronic band structure calculations were performed. The results show that the Si4+-doped hexagonal KGF polymorph with good photoluminescence properties is the most stable phase according to the calculated total energy landscape and relative formation energy. The morphologic changes were monitored in situ to clearly understand the rapid phase transformation mechanism, which proves that the phase transformation is driven by a simple precipitation-dissolution equilibrium and ionic exchange.

Neonatal electroencephalography recordings.

The growth processes involved early in gestation and further into the intricate signaling networks in the brain form the basis for rapid cortical electrical bursting patterns. This leads to the quantification of cortical activity from the electroencephalogram (EEG) in full-term hypoxic infants and preterm infants. The associated neurological sequelae in both populations are foregrounded by a summary into current epidemiology and common clinical practices. The present review article highlights recent advances in physics and neuroscience, which will help in development of reliable predictors of outcome for full-term and preterm neonates after birth.

Amyloidogenesis induced by diet cholesterol and copper in a model mouse for Alzheimer's disease and protection effects of zinc and fluvastatin.

Alzheimer's disease (AD) is one of the severe chronic diseases characterized with amyloid beta (Aß) aggregation and formation of senile-plaque (SP) like structures. Numerous risk factors including trace metals and cholesterol in diet have been identified as potential players for the onset of Aß aggregation. To further illustrate the effects of copper and cholesterol in AD pathology, we employed an AD model mouse strain (Tg2567) and examined the histological and biochemical changes in the mouse brains and blood. When supplied with 0.1 mg/L copper in drinking water and 2% cholesterol in the food, the mice showed significant deposit of amyloid beta (Aß) and SP plaque formation in hippocampus and temporal cortex regions in their brains. These mice also showed elevated superoxide dismutase (SOD) activity and increased ceruloplasmin (CP) concentration, and reduced glutathione peroxidase (Gpx) activity in the blood. The physiological function tests indicated these mice were significantly impeded on learning and memory. We further examined the counteracting effects of 0.1 mg/L zinc and 1.0 mg/L fluvastatin (Cholesterol-lowering drug). The combination of zinc and fluvastatin effectively reversed the copper/cholesterol caused memory loss, anatomic amyloid deposits and the biochemical changes in the blood. This work provides more evidence of high-level cholesterol and copper as risk factors to trigger amyloid aggregation and mental dementia; zinc and reduction of food cholesterol levels can protect the animals from amyloid accumulation and learning impairment. The beneficial outcomes of zinc and fluvastatin could hint some potential usages in preventive measures for high-risk AD individuals, but further rigorous test are needed.

Beta-secretase/BACE1 promotes APP endocytosis and processing in the endosomes and on cell membrane.

Amyloid-ß proteins deposition and aggregation occur in extracellular space and form neuritic plaques in Alzheimer's disease (AD) brain. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)/ ß-secretase and γ-secretase Presenilin 1 (PSEN1) conduct sequential cleavage of amyloid- ß precursor protein (APP) and yield amyloid- ß proteins. However the details of the interactions of APP with the enzymes and transportation of catalytic products are unclear. Here we reveal distinctive targeting patterns of the proteins in subcellular organelles in N2A cells. We find all three proteins co-localize in endosomes with APP and PSEN1 co-localize and associate on cell membrane and nucleus. By selectively knocking down BACE1 or PSEN 1 with siRNA, we discover that BACE1 functions as the enzyme initiating the first cleavage step and serves a scaffold for APP and PSEN1 endocytosis. PSEN1 knocking-down only leads to the reduction of BACE1 in cell membrane and nucleus. We conclude that BACE1 facilitates the transportation of APP and formation of the complex with γ-secretase, resulting in the stepwise cleavages of APP. After BACE1 cleavage APP binds to PSEN1 and transfers to cell membrane or nucleus for final processing and amyloid genesis.

Two nonsense somatic mutations in MEN1 identified in sporadic insulinomas.

Insulinomas are functional pancreatic neuroendocrine tumors that cause hypoglycemia and severe morbidity. The aim of our study was to identify gene mutations responsible for tumorigenesis of sporadic insulinoma. Whole exome sequencing analysis was performed on tumors and paired peripheral blood from three patients with insulinomas. After initial analysis, somatic mutations were obtained and a deleterious protein product was further predicted by various bioinformatic programs. Whole exome sequencing identified 55 rare somatic mutations among three insulinoma patients, including MEN1 gene nonsense mutations (c. 681C>G; p.Tyr227* in exon 4 of MEN1 and c. 346G>T; p.Glu116* in exon 2 of MEN1) in two different tumor samples. The mutations resulted in a significant truncation of the protein and a non-functional gene product, which was involved in defective binding of menin to proteins implicated in genetic and epigenetic mechanisms. Our results extend the growing list of pathogenic MEN1 mutations in sporadic cases of insulinoma.

Unraveling submicron-scale mechanical heterogeneity by three-dimensional X-ray microdiffraction.

Shear banding is a ubiquitous phenomenon of severe plastic deformation, and damage accumulation in shear bands often results in the catastrophic failure of a material. Despite extensive studies, the microscopic mechanisms of strain localization and deformation damage in shear bands remain elusive due to their spatial-temporal complexities embedded in bulk materials. Here we conducted synchrotron-based X-ray microdiffraction (µXRD) experiments to map out the 3D lattice strain field with a submicron resolution around fatigue shear bands in a stainless steel. Both in situ and postmortem µXRD results revealed large lattice strain gradients at intersections of the primary and secondary shear bands. Such strain gradients resulted in severe mechanical heterogeneities across the fatigue shear bands, leading to reduced fatigue limits in the high-cycle regime. The ability to spatially quantify the localized strain gradients with submicron resolution through µXRD opens opportunities for understanding the microscopic mechanisms of damage and failure in bulk materials.

Changes in transcranial electrical motor-evoked potentials during the early and reversible stage of permanent spinal cord ischemia predict spinal cord injury in a rabbit animal model.

The present study examined changes in the transcranial electrical motor-evoked potentials (TceMEP) waveform to predict neurological deficits and histopathological changes during the early and reversible stage of different levels of permanent spinal cord ischemic injury in a rabbit animal model. A total of 24 New Zealand rabbits were randomly divided into four groups of 6 rabbits each. Group 1 underwent a ligation of the lumbar artery at three levels (L1-L3), group 2 underwent a ligation of the lumbar artery at four levels (L1-L4) and group 3 underwent a ligation of the lumbar artery at five levels (L1-L5). The sham group contained 6 rabbits and did not receive ligation. TceMEP was recorded within 5 min of ligation and, 2 days later, motor function was assessed and the spinal cords were removed for histological examination. Following spinal cord injury, the relationship between variations in the TceMEP waveform and motor function and pathological damage was analyzed. It was observed that the amplitude of TceMEP began to decrease within 1 min of lumbar artery ligation and that the amplitude stabilized within 5 min. These amplitude changes that occurred within 5 min of different levels of permanent spinal cord ischemic injury were positively related to changes in motor function following recovery from anesthesia and 2 days after ligation. The Pearson correlation coefficient was 0.980 and 0.923 for these two time points, respectively (P<0.001). In addition, the amplitude changes were positively related to pathological damage, with a Pearson correlation coefficient of 0.945 (P<0.001). The results of the present study suggested that amplitude changes in TceMEP are particularly sensitive to ischemia. Ischemia may be detected within 1 min and the amplitude changes begin to stabilize within 5 min following ligation of the lumbar artery. The use of intraoperative monitoring of TceMEP allows for the detection of spinal cord ischemic injury with no time delay, which may allow for protective measures to be taken to prevent the occurrence of irreversible spinal cord injury.

CISD2 promotes the proliferation of glioma cells via suppressing beclin­1­mediated autophagy and is targeted by microRNA­449a.

CDGSH iron sulfur domain 2 (CISD2) has been found to be important in carcinogenesis. However, the role of CISD2 in glioma remains to be elucidated. The present study aimed to investigate the role of CISD2 in glioma using the reverse transcription­quantitative polymerase chain reaction, western blotting, co­immunoprecipitation assay, immunofluorescence staining and other methods. The results demonstrated that the mRNA and protein levels of CISD2 were found to be upregulated in glioma tissues, compared with the levels in matched normal tissues. Clinical data analysis showed that the level of CISD2 was negatively correlated with the survival rates of patients with glioma. In addition, high levels of CISD2 were associated with advanced clinical stage, relapse, vascular invasion and increased tumor size. The inhibition of CISD2 suppressed the proliferation and survival of glioma cells in vitro and in vivo. Mechanistically, it was found that small interfering RNA­induced knock down of CISD2 inhibited the proliferation of glioma cells through activating beclin­1­mediated autophagy. The results also revealed that CISD2 was a target of microRNA (miR)­449a. Together, the results of the present study demonstrated that CISD2 was increased in glioma samples and was associated with poor prognosis and aggressive tumor behavior. The miR­449a/CISD2/beclin­1­mediated autophagy regulatory network contributed to the proliferation of glioma cells. Targeting this pathway may be a promising strategy for glioma therapy.