Vasorin exocytosed from glioma cells facilitates angiogenesis via VEGFR2/AKT signaling pathway.

Glioma is a highly vascularized tumor of the central nervous system. Angiogenesis plays a predominant role in glioma progression and is considered an important therapeutic target. Our previous study showed that vasorin (VASN), a transmembrane protein, is overexpressed in glioma and promotes angiogenesis; however, the potential mechanism remains unclear. In this study, we found that human vascular endothelial cells (hECs) co-cultured with VASN-overexpressing glioma cells exhibited accelerated migration ability and increased expression of VASN originated from glioma cells. VASN was found in exosomes secreted by glioma cells and could be taken up by hECs. hECs showed more edge filopodia and significantly upregulated expression of endothelial tip cell marker gene and protein levels after co-culture with VASN-overexpressing glioma cells. In clinical glioma tissue and orthotopic transplantation glioma tissue, the vascular density and the number of vascular endothelial cells with a tip cell phenotype in VASN-overexpressed tissues were significantly higher than in tissues with low expression. At the molecular level, VASN interacted with VEGFR2 and caused internalization and autophosphorylation of VEGFR2 protein, and then activated the AKT signaling pathway. Our study collectively reveals the function and mechanism of VASN in facilitating angiogenesis in glioma, providing a new therapeutic target for glioma. Implications: These findings demonstrate that VASN exocytosed from glioma cells enhanced the migration of vascular endothelial cells by VEGFR2/AKT signaling pathway.

Effect of sludge humic acid-derived nano-biochars on anaerobic degradation of sulfamethoxazole by Shewanella oneidensis MR-1.

Some nano-biochars (nano-BCs) as electron mediators could enter into cells to directly promote intracellular electron transfer and cell activities. However, little information was available on the effect of nano-BCs on SMX degradation. In this study, nano-BCs were prepared using sludge-derived humic acid (SHA) and their effects on SMX degradation by Shewanella oneidensis MR-1 were investigated. Results showed that nano-BCs (Carbon dots, CDs, <10 nm) synthesized using SHA performed a better accelerating effect than that of the nano-BCs with a larger size (10-100 nm), which could be attributed to the better electron transfer abilities of CDs. The degradation rate of 10 mg/L SMX in the presence of 100 mg/L CDs was significantly increased by 84.6% compared to that without CDs. Further analysis showed that CDs could not only be combined with extracellular Fe(III) to accelerate its reduction, but also participate in the reduction of 4-aminobenzenesulphonic acid as an intermediate metabolite of SMX via coupling with extracellular Fe(III) reduction. Meanwhile, CDs could enter cells to directly participate in intracellular electron transfer, resulting in 32.2% and 25.2% increases of electron transfer system activity and ATP level, respectively. Moreover, the activities of SMX-degrading enzymes located in periplasm and cytoplasm were increased by around 2.2-fold in the presence of CDs. These results provide an insight into the accelerating effect of nano-BCs with the size of <10 nm on SMX degradation and an approach for SHA utilization.

3D printed high-precision porous scaffolds prepared by fused deposition modeling induce macrophage polarization to promote bone regeneration.

Macrophage-mediated bone immune responses significantly influence the repair of bone defects when utilizing tissue-engineered scaffolds. Notably, the scaffolds' physical structure critically impacts macrophage polarization. The optimal pore size for facilitating bone repair remains a topic of debate due to the imprecision of traditional methods in controlling scaffold pore dimensions and spatial architecture. In this investigation, we utilized fused deposition modeling (FDM) technology to fabricate high-precision porous polycaprolactone (PCL) scaffolds, aiming to elucidate the impact of pore size on macrophage polarization. We assessed the scaffolds' mechanical attributes and biocompatibility. Real-time quantitative reverse transcription polymerase chain reaction was used to detect the expression levels of macrophage-related genes, and enzyme linked immunosorbent assay for cytokine secretion levels.In vitroosteogenic capacity was determined through alkaline phosphatase and alizarin red staining. Our findings indicated that macroporous scaffolds enhanced macrophage adhesion and drove their differentiation towards the M2 phenotype. This led to the increased production of anti-inflammatory factors and a reduction in pro-inflammatory agents, highlighting the scaffolds' immunomodulatory capabilities. Moreover, conditioned media from macrophages cultured on these macroporous scaffolds bolstered the osteogenic differentiation of bone marrow mesenchymal stem cells, exhibiting superior osteogenic differentiation potential. Consequently, FDM-fabricated PCL scaffolds, with precision-controlled pore sizes, present promising prospects as superior materials for bone tissue engineering, leveraging the regulation of macrophage polarization.

Salt-Supported Nickel Oxides for Boosted Hydrogen Production: The Critical Role of Halogen.

Hydrogen production from organic waste by gasification and reforming technologies offers major benefits to both the environment and climate. The long-term stability and regeneration of the reforming catalyst are still the biggest challenges because of carbon deposition. Here we report a recyclable salt-supported nickel oxide NiO/NaX (X: F, Cl, Br) catalyst for effective autothermal reforming of the oxygenated volatile organic compound (OVOC) ethyl acetate to hydrogen. The optimal hydrogen selectivity achieved 82.0% at 650 °C and the durability reached 43 h. Interestingly, with the decreasing of halogen electronegativity (F > Cl > Br) in NaX, the corresponding hydrogen selectivity of the catalysts decreased. Although NiO/NaX catalysts possess a very small specific surface area and a dense microstructure, their catalytic performance is better than that of normal Ni-based catalysts loaded on high-specific-surface-area supports. Detailed investigations revealed the critical roles played by halogen during the reforming reaction. First, the strong electronegative halogen in NaX induced the formation of hydrogen bonds with the reactants and reaction intermediates, which may prolong the surface residence time of such species, thus ensuring efficient hydrogen production over small-specific-surface-area catalysts under high-temperature conditions. Second, the halogen of the support NaX weakening the Ni-O bonds of the exposed Ni atoms in NiO/NaX made it easier for NiO to be reduced to Ni0, thus reducing the reaction activation energy and prompting the rapid catalytic reaction. The strength of such metal-support interaction can be easily modulated by varying the halogen electronegativity. This study provides a new prospect for the design of innovative recyclable heterogeneous catalysts with low specific surface area but high activity.

Automatic segmentation of hepatocellular carcinoma on dynamic contrast-enhanced MRI based on deep learning.

Objective. Precise hepatocellular carcinoma (HCC) detection is crucial for clinical management. While studies focus on computed tomography-based automatic algorithms, there is a rareness of research on automatic detection based on dynamic contrast enhanced (DCE) magnetic resonance imaging. This study is to develop an automatic detection and segmentation deep learning model for HCC using DCE.Approach: DCE images acquired from 2016 to 2021 were retrospectively collected. Then, 382 patients (301 male; 81 female) with 466 lesions pathologically confirmed were included and divided into an 80% training-validation set and a 20% independent test set. For external validation, 51 patients (42 male; 9 female) in another hospital from 2018 to 2021 were included. The U-net architecture was modified to accommodate multi-phasic DCE input. The model was trained with the training-validation set using five-fold cross-validation, and furtherly evaluated with the independent test set using comprehensive metrics for segmentation and detection performance. The proposed automatic segmentation model consisted of five main steps: phase registration, automatic liver region extraction using a pre-trained model, automatic HCC lesion segmentation using the multi-phasic deep learning model, ensemble of five-fold predictions, and post-processing using connected component analysis to enhance the performance to refine predictions and eliminate false positives.Main results. The proposed model achieved a mean dice similarity coefficient (DSC) of 0.81 ± 0.11, a sensitivity of 94.41 ± 15.50%, a precision of 94.19 ± 17.32%, and 0.14 ± 0.48 false positive lesions per patient in the independent test set. The model detected 88% (80/91) HCC lesions in the condition of DSC > 0.5, and the DSC per tumor was 0.80 ± 0.13. In the external set, the model detected 92% (58/62) lesions with 0.12 ± 0.33 false positives per patient, and the DSC per tumor was 0.75 ± 0.10.Significance.This study developed an automatic detection and segmentation deep learning model for HCC using DCE, which yielded promising post-processed results in accurately identifying and delineating HCC lesions.

A Comparison Between Two Different Definitions of Contrast-Associated Acute Kidney Injury for Long-Term Mortality in Patients with Chronic Kidney Disease Undergoing Coronary Angiography.

Background: Contrast-associated acute kidney injury (CA-AKI) is a prevalent complication following coronary angiography (CAG). However, there is ongoing controversy surrounding its precise definition. Although previous studies have demonstrated the successful application of appropriate definitions in managing high-risk CA-AKI patients, there remains limited research on the association between different definitions and prognosis specifically in patients with chronic kidney disease (CKD). Methods: A total of 4197 CKD patients undergoing coronary angiography (CAG) were included in this study. Two definitions of contrast-associated acute kidney injury (CA-AKI) were used: CA-AKIA, which was defined as an increase of ≥0.5 mg/dL or >25% in serum creatinine (SCr) from baseline within 72 hours after CAG, and CA-AKIB, which was defined as an increase of ≥0.3 mg/dL or >50% in SCr from baseline within 48 hours after CAG. Cox regression analysis was employed to assess the association between these two definitions and long-term mortality. Additionally, population attributable risks (PARs) were calculated to evaluate the impact of CA-AKI definitions on long-term prognosis. Results: During the median follow-up period of 4.70 (2.50-7.78) years, the overall long-term mortality was 23.6%, and the long-term mortality in patients with CA-AKI according to both CA-AKIA and CA-AKIB criteria were 33.5% and 33.8%, respectively. We found that CA-AKIA (HR: 1.45, 95% CI: 1.23-1.70, p<0.001) and CA-AKIB (HR: 1.44, 95% CI: 1.23-1.69, p<0.001) were associated with long-term mortality. The PARs were the highest for CA-AKIA (5.87%), followed by CA-AKIB (5.70%). Conclusion: Contrast-associated acute kidney injury (CA-AKI) is a frequently observed complication in CKD patients undergoing coronary angiography (CAG), and both definitions of CA-AKI are significantly correlated with a poor long-term prognosis. Consequently, in the clinical management of CKD patients, it is crucial to prioritize CA-AKI, irrespective of the specific CA-AKI definition used.

FAK-p38 signaling serves as a potential target for reverting matrix stiffness-modulated liver sinusoidal endothelial cell defenestration.

Liver sinusoidal endothelial cells (LSECs) are highly specific endothelial cells which play an essential role in the maintenance of liver homeostasis. During the progression of liver fibrosis, matrix stiffening promotes LSEC defenestration, however, the underlying mechanotransduction mechanism remains poorly understood. Here, we applied stiffness-tunable hydrogels to assess the matrix stiffening-induced phenotypic changes in primary mouse LSECs. Results indicated that increased stiffness promoted LSEC defenestration through cytoskeletal reorganization. LSECs sensed the increased matrix stiffness via focal adhesion kinase (FAK), leading to the activation of p38-mitogen activated protein kinase activated protein kinase 2 (MK2) pathway, thereby inducing actin remodeling via LIM Kinase 1 (LIMK1) and Cofilin. Interestingly, inhibition of FAK or p38-MK2 pathway was able to effectively restore the fenestrae to a certain degree in LSECs isolated from early to late stages of liver fibrosis mice. Thus, this study highlights the impact of mechanotransduction in LSEC defenestration, and provides novel insights for potential therapeutic interventions for liver fibrosis.

Insights into the Acceleration Mechanism of Intracellular N and Fe Co-doped Carbon Dots on Anaerobic Denitrification Using Proteomics and Metabolomics Techniques.

Bulk carbon-based materials can enhance anaerobic biodenitrification when they are present in extracellular matrices. However, little information is available on the effect of nitrogen and iron co-doped carbon dots (N, Fe-CDs) with sizes below 10 nm on this process. This work demonstrated that Fe-NX formed in N, Fe-CDs and their low surface potentials facilitated electron transfer. N, Fe-CDs exhibited good biocompatibility and were effectively absorbed by Pseudomonas stutzeri ATCC 17588. Intracellular N, Fe-CDs played a dominant role in enhancing anaerobic denitrification. During this process, the nitrate removal rate was significantly increased by 40.60% at 11 h with little nitrite and N2O accumulation, which was attributed to the enhanced activities of the electron transport system and various denitrifying reductases. Based on proteomics and metabolomic analysis, N, Fe-CDs effectively regulated carbon/nitrogen/sulfur metabolism to induce more electron generation, less nitrite/N2O accumulation, and higher levels of nitrogen removal. This work reveals the mechanism by which N, Fe-CDs enhance anaerobic denitrification and broaden their potential application in nitrogen removal.

Preparation methods and research progress of super-hydrophobic anti-icing surface.

The problem of surface icing poses a serious threat to people's economy and safety, especially in the fields of aerospace, wind power generation and circuit transmission. Super-hydrophobic has excellent anti-icing performance, so it has been widely studied. As the most promising anti-icing technology, superhydrophobic anti-icing surface should not only be simple to prepare, but also have excellent comprehensive performance, which can meet the anti-icing task under harsh working conditions and long-term durability. This paper summarizes the basic performance requirements of superhydrophobic surface for anti-icing operation, and then summarizes the preparation methods and existing problems of superhydrophobic surface in recent years. Finally, the future development trend of superhydrophobic anti-icing surface is prospected and discussed, hoping to provide certain technical guidance for the subsequent research of high-performance superhydrophobic anti-icing surface.

Circulating organochlorine pesticide levels, genetic predisposition and the risk of incident type 2 diabetes.

Persistent organochlorine pesticide (OCP) has been associated with type 2 diabetes (T2D), and genetic polymorphism might modify such an association. However, prospective evidence remains scarce. We conducted a nested case-control study comprising 1006 incident diabetic cases and 1006 matched non-diabetic controls [sex and age (±5 years)] from 2008 to 2013 (mean follow-up period: ∼4.6 years) based on the Dongfeng-Tongji cohort in Shiyan City of China, determined baseline levels of nineteen OCPs, and examined the associations of circulating OCPs, both individually and collectively, with incident T2D risk. We also constructed overall genetic risk score (GRS) based on 161 T2D-associated variants and five pathway-specific cluster GRSs based on established variants derived from the Asian population. Compared with the first quartile of serum ß-BHC levels, the multivariable-adjusted ORs (95% CIs) of incident T2D risk in the second, third, and fourth quartiles were 0.98 (0.70-1.39), 1.43 (0.99-2.07), and 1.75 (1.14-2.68), respectively (FDR-adjusted Ptrend = 0.03). A positive association was observed between serum OCP mixture and incident T2D risk and can be largely attributed to ß-BHC. Furthermore, serum ß-BHC and p,p'-DDE showed significant interactions with the GRS for lipodystrophy, a T2D-related pathway representing fat redistribution to viscera, on T2D risk (Pinteraction < 0.05). In conclusion, higher circulating OCP levels were independently associated with an increased risk of T2D, with ß-BHC possibly being the major contributor. Genetic predisposition to T2D-related morbidity, such as visceral adiposity, should be considered when assessing the risk of T2D conferred by OCPs.

Association of serum phthalates exposure with incident type 2 diabetes risk in Chinese population: A nested case-control study.

Prospective epidemiological evidence was lacking on the association of phthalates (PAEs) exposure with incident type 2 diabetes mellitus (T2DM) risk. In present nested case-control study, we identified 1006 T2DM cases and matched 1006 controls based on Dongfeng-Tongji cohort study, and 6 PAEs were detected in baseline serum. The conditional logistic regression model, Bayesian kernel machine regression (BKMR) model and Quantile-based g-computation were applied to evaluate the associations of determined PAEs, either as individuals or as a mixture, with incident T2DM risk. Subgroup analysis was conducted to identify the potential sensitive population of PAEs effects on T2DM. After multiple adjustment, no statistically significant association was observed between single or mixture of PAEs and incident T2DM risk in the whole population. However, serum levels of Di-n-butyl phthalate (DnBP) [OR= 2.06; 95% CI: (1.11-3.96)], Σdibutyl phthalate (ΣDBP) [OR= 1.96; 95% CI: (1.06-3.76)], and Σlow-molecular- weight phthalate (ΣLMW) [OR= 2.27; 95% CI: (1.17-4.57)] were significantly associated with T2DM in current drinker group. Moreover, significant potential interactions were observed among Di-iso-butyl phthalate (DiBP), DnBP, Butyl-benzyl phthalate (BBP), ΣDBP, and ΣLMW with drinking status on T2DM risk (P for interaction = 0.036, 0.005, 0.049. 0.010, and 0.005). We did not find significant associations between serum PAEs levels and T2DM in the whole population. However, current alcohol drinkers expose to higher levels of DnBP, ΣDBP, and ΣLMW had higher risk of T2DM.

The efficacy of pre-operative conization in patients undergoing surgical treatment for early-stage cervical cancer: A meta-analysis.

BACKGROUND: Minimal invasive surgery (MIS) has been reported to increase the risk of cancer relapse and death compared with traditional open surgery in patients with early-stage cervical cancer (CC). Pre-operative conization is a protective procedure that as developed to reduce the risk caused by MIS. METHODS: Relevant publications were identified by searching medical databases prior to the December 31, 2022. The primary aim of this meta-analysis was to evaluate the efficacy of pre-operative conization on disease-free survival (DFS) in early-stage CC. The secondary objective was to assess the efficacy of pre-operative conization on overall survival (OS) in early-stage CC. RESULTS: Twelve studies were eligible for analysis. The pooled result of pre-operative conization showed a significantly improved DFS when compared with non-conization patients (HR, 0.28; 95% CI, 0.19-0.41), furthermore, pre-operative conization improved DFS by 75% (HR, 0.25; 95% CI, 0.13-0.46) in stage IB1 patients. In patients who underwent MIS, pre-operative conization also led to a significant improvement in DFS when compared with non-conization patients (HR, 0.21; 95% CI, 0.09-0.54). However, in patients who underwent pre-operative conization, MIS increased the risk of recurrence by 34% when compared with open abdominal radical hysterectomy (HR, 1.34; 95% CI, 0.41-4.38), although this difference was not statistically significant. Finally, the OS of early-stage CC was not significantly affected by surgical approach or conization. CONCLUSION: Pre-operation conization represents a protective effect and can improve DFS when compared with non-conization in early-stage CC, especially in stage IB CC. There was no statistical evidence to indicate that pre-operation conization could improve OS. High-quality randomized controlled trials are required to verify these results.

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein.

Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).

A Bio-Inspired Spiking Attentional Neural Network for Attentional Selection in the Listening Brain.

Humans show a remarkable ability in solving the cocktail party problem. Decoding auditory attention from the brain signals is a major step toward the development of bionic ears emulating human capabilities. Electroencephalography (EEG)-based auditory attention detection (AAD) has attracted considerable interest recently. Despite much progress, the performance of traditional AAD decoders remains to be improved, especially in low-latency settings. State-of-the-art AAD decoders based on deep neural networks generally lack the intrinsic temporal coding ability in biological networks. In this study, we first propose a bio-inspired spiking attentional neural network, denoted as BSAnet, for decoding auditory attention. BSAnet is capable of exploiting the temporal dynamics of EEG signals using biologically plausible neurons and an attentional mechanism. Experiments on two publicly available datasets confirm the superior performance of BSAnet over other state-of-the-art systems across various evaluation conditions. Moreover, BSAnet imitates realistic brain-like information processing, through which we show the advantage of brain-inspired computational models.

Determination of exciton binding energy using photocurrent spectroscopy of Ge quantum-dot single-hole transistors under CW pumping.

We reported exciton binding-energy determination using tunneling-current spectroscopy of Germanium (Ge) quantum dot (QD) single-hole transistors (SHTs) operating in the few-hole regime, under 405-1550 nm wavelength (λ) illumination. When the photon energy is smaller than the bandgap energy (1.46 eV) of a 20 nm Ge QD (for instance, λ = 1310 nm and 1550 nm illuminations), there is no change in the peak voltages of tunneling current spectroscopy even when the irradiation power density reaches as high as 10 µW/µm2. In contrast, a considerable shift in the first hole-tunneling current peak towards positive VG is induced (ΔVG ≈ 0.08 V at 0.33 nW/µm2 and 0.15 V at 1.4 nW/µm2) and even additional photocurrent peaks are created at higher positive VG values (ΔVG ≈ 0.2 V at 10 nW/µm2 irradiation) by illumination at λ = 850 nm (where the photon energy matches the bandgap energy of the 20 nm Ge QD). These experimental observations were further strengthened when Ge-QD SHTs were illuminated by λ = 405 nm lasers at much lower optical-power conditions. The newly-photogenerated current peaks are attributed to the contribution of exciton, biexciton, and positive trion complexes. Furthermore, the exciton binding energy can be determined by analyzing the tunneling current spectra.

Corrigendum: Acute osimertinib exposure induces electrocardiac changes by synchronously inhibiting the currents of cardiac ion channels.

[This corrects the article DOI: 10.3389/fphar.2023.1177003.].

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design.

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.

Acute osimertinib exposure induces electrocardiac changes by synchronously inhibiting the currents of cardiac ion channels.

Introduction: As the third generation of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib has demonstrated more significant cardiotoxicity than previous generations of EGFR-TKIs. Investigating the mechanism of osimertinib cardiotoxicity can provide a reference for a comprehensive understanding of osimertinib-induced cardiotoxicity and the safety of the usage of this drug in clinical practice. Methods: Multichannel electrical mapping with synchronous ECG recording was used to investigate the effects of varying osimertinib concentrations on electrophysiological indicators in isolated Langendorff-perfused hearts of guinea pigs. Additionally, a whole-cell patch clamp was used to detect the impact of osimertinib on the currents of hERG channels transfected into HEK293 cells and the Nav1.5 channel transfected into Chinese hamster ovary cells and acute isolated ventricular myocytes from SD rats. Results: Acute exposure to varying osimertinib concentrations produced prolongation in the PR interval, QT interval, and QRS complex in isolated hearts of guinea pigs. Meanwhile, this exposure could concentration-dependently increase the conduction time in the left atrium, left ventricle, and atrioventricular without affecting the left ventricle conduction velocity. Osimertinib inhibited the hERG channel in a concentration-dependent manner, with an IC50 of 2.21 ± 1.29 µM. Osimertinib also inhibited the Nav1.5 channel in a concentration-dependent manner, with IC50 values in the absence of inactivation, 20% inactivation, and 50% inactivation of 15.58 ± 0.83 µM, 3.24 ± 0.09 µM, and 2.03 ± 0.57 µM, respectively. Osimertinib slightly inhibited the currents of L-type Ca2+ channels in a concentration-dependent manner in acutely isolated rat ventricular myocytes. Discussion: Osimertinib could prolong the QT interval; PR interval; QRS complex; left atrium, left ventricle, and atrioventricular conduction time in isolated guinea pig hearts. Furthermore, osimertinib could block the hERG, Nav1.5, and L-type Ca2+ channels in concentration-dependent manners. Therefore, these findings might be the leading cause of the cardiotoxicity effects, such as QT prolongation and decreased left ventricular ejection fraction.

Activated KRAS reprograms neural progenitor cells to glioma stem cell­like phenotype.

Glioma is the most common primary brain tumor. Glioma stem cells (GSCs) are the origin of gliomagenesis and may develop from normal neural progenitor cells (NPCs). However, how neoplastic transformation occurs in normal NPCs and the role of the Ras/Raf/MAPK pathway in NPC transformation is unclear. The present study generated NPCs from human embryonic stem cells (ESCs) carrying gene alterations in the Ras/Raf/MAPK pathway. The CCK­8 proliferation, single­cell clonal expansion, cell migration, RT­qPCR, immunofluorescence staining, western blotting, transcriptome and Seahorse analyses, and intracranial implantation assay were performed to identify the characterization of transformed NPCs in vitro and in vivo. Brain organoids were used to verify the phenotypes transforming in NPCs. KRAS­activated NPCs exhibited increased proliferation and migration in vitro. KRAS­activated NPCs showed atypical morphology and formed aggressive tumors in immunodeficient mice. At the molecular level, KRAS­activated NPCs displayed neoplasm­associated metabolic and gene expression profiles. Moreover, activation of KRAS led to substantial cell proliferation and abnormal structure in ESC­derived brain organoids. The present study showed that activated KRAS transformed normal NPCs to GSC­like cells and established a simple cellular model to investigate gliomagenesis.