Segmentation of the left atrial appendage based on fusion attention.

In clinical practice, the morphology of the left atrial appendage (LAA) plays an important role in the selection of LAA closure devices for LAA closure procedures. The morphology determination is influenced by the segmentation results. The LAA occupies only a small part of the entire 3D medical image, and the segmentation results are more likely to be biased towards the background region, making the segmentation of the LAA challenging. In this paper, we propose a lightweight attention mechanism called fusion attention, which imitates human visual behavior. We process the 3D image of the LAA using a method that involves overview observation followed by detailed observation. In the overview observation stage, the image features are pooled along the three dimensions of length, width, and height. The obtained features from the three dimensions are then separately input into the spatial attention and channel attention modules to learn the regions of interest. In the detailed observation stage, the attention results from the previous stage are fused using element-wise multiplication and combined with the original feature map to enhance feature learning. The fusion attention mechanism was evaluated on a left atrial appendage dataset provided by Liaoning Provincial People's Hospital, resulting in an average Dice coefficient of 0.8855. The results indicate that the fusion attention mechanism achieves better segmentation results on 3D images compared to existing lightweight attention mechanisms.

Clinical roles of EGFR amplification in diffuse gliomas: a real-world study using the 2021 WHO classification of CNS tumors.

Background: The 2021 World Health Organization Classification of Central Nervous System Tumors updates glioma subtyping and grading system, and incorporates EGFR amplification (Amp) as one of diagnostic markers for glioblastoma (GBM). Purpose: This study aimed to describe the frequency, clinical value and molecular correlation of EGFR Amp in diffuse gliomas based on the latest classification. Methods: We reviewed glioma patients between 2011 and 2022 at our hospital, and included 187 adult glioma patients with available tumor tissue for detection of EGFR Amp and other 59 molecular markers of interest. Clinical, radiological and pathological data was analyzed based on the status of EGFR Amp in different glioma subtypes. Results: 163 gliomas were classified as adult-type diffuse gliomas, and the number of astrocytoma, oligodendroglioma and GBM was 41, 46, and 76. EGFR Amp was more common in IDH-wildtype diffuse gliomas (66.0%) and GBM (85.5%) than IDH-mutant diffuse gliomas (32.2%) and its subtypes (astrocytoma, 29.3%; oligodendroglioma, 34.8%). EGFR Amp did not stratify overall survival (OS) in IDH-mutant diffuse gliomas and astrocytoma, while was significantly associated with poorer OS in IDH-wildtype diffuse gliomas, histologic grade 2 and 3 IDH-wildtype diffuse astrocytic gliomas and GBM. Conclusion: Our study validated EGFR Amp as a diagnostic marker for GBM and still a useful predictor for shortened OS in this group.

Glioma hexokinase 3 positively correlates with malignancy and macrophage infiltration.

BACKGROUND: Glioma is the main subtype of primary central nervous system (CNS) tumor with high malignancy and poor prognosis under current therapeutic approaches. Glycolysis and suppressive tumor microenvironment (TME) are key markers of glioma with great importance for aggressive features of glioma and inferior clinical outcomes. Hexokinase 3 (HK3) is an important rate-limiting enzyme in glycolysis, but its function in glioma remains unknown. METHODS: This study comprehensively assessed the expression distribution and immunological effect of HK3 via pan-cancer analysis based on datasets from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA). Furthermore, it explored the malignant phenotype and genomic landscape between low-HK3 and high-HK3 expression groups in gliomas from Chinese Glioma Genome Atlas (CGGA) and TCGA. Moreover, data from the TIMER website predicted the relationship between macrophage infiltration and HK3 expression. Also, single-cell sequencing data were used to validate the relationship. RESULTS: For pan-cancer patients, HK3 was expressed in various cancers. The results showed that HK3 was highly expressed in gliomas and positively correlated with tumor-infiltrating immune cells (TIICs), immune checkpoints, immunomodulators, and chemokines. Meanwhile, HK3 expression was highest in normal immune cells and tissues. In gliomas, the expression of HK3 was found to be closely correlated with the malignant clinical characteristics and the infiltration of macrophages. Also, HK3 was proven to be positively associated with macrophage through single-cell sequencing data and immunohistochemistry techniques. Finally, it is predicted that samples with high HK3 expression are often malignant entities and also significant genomic aberrations of driver oncogenes. CONCLUSIONS: This is the first comprehensive research to figure out the relationship between HK3 and TME characteristics in gliomas. HK3 is positively associated with macrophage infiltration and can induce the immunosuppressive TME and malignant phenotype of gliomas.

A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-containing therapy.

Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2-13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4-13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223-0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268-0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506-0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184-0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566-0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516-0.816), 0.654 (95% CI: 0.470-0.823), and 0.675 (95% CI: 0.491-0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.

Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification.

Cognitive impairment is a common feature among patients with diffuse glioma. The objective of the study is to investigate the relationship between preoperative cognitive function and clinical as well as molecular factors, firstly based on the new 2021 World Health Organization's updated classification of central nervous system tumors. A total of 110 diffuse glioma patients enrolled underwent preoperative cognitive assessments using the Mini-Mental State Examination and Montreal Cognitive Assessment. Clinical information was collected from medical records, and gene sequencing was performed to analyze the 18 most influenced genes. The differences in cognitive function between patients with and without glioblastoma were compared under both the 2016 and 2021 WHO classification of tumors of the central nervous system to assess their effect of differentiation on cognition. The study found that age, tumor location, and glioblastoma had significant differences in cognitive function. Several genetic alterations were significantly correlated with cognition. Especially, IDH, CIC, and ATRX are positively correlated with several cognitive domains, while most other genes are negatively correlated. For most focused genes, patients with a low number of genetic alterations tended to have better cognitive function. Our study suggested that, in addition to clinical characteristics such as age, histological type, and tumor location, molecular characteristics play a crucial role in cognitive function. Further research into the mechanisms by which tumors affect brain function is expected to enhance the quality of life for glioma patients. This study highlights the importance of considering both clinical and molecular factors in the management of glioma patients to improve cognitive outcomes.

MOTC: Abdominal Multi-objective Segmentation Model with Parallel Fusion of Global and Local Information.

Convolutional Neural Networks have been widely applied in medical image segmentation. However, the existence of local inductive bias in convolutional operations restricts the modeling of long-term dependencies. The introduction of Transformer enables the modeling of long-term dependencies and partially eliminates the local inductive bias in convolutional operations, thereby improving the accuracy of tasks such as segmentation and classification. Researchers have proposed various hybrid structures combining Transformer and Convolutional Neural Networks. One strategy is to stack Transformer blocks and convolutional blocks to concentrate on eliminating the accumulated local bias of convolutional operations. Another strategy is to nest convolutional blocks and Transformer blocks to eliminate bias within each nested block. However, due to the granularity of bias elimination operations, these two strategies cannot fully exploit the potential of Transformer. In this paper, a parallel hybrid model is proposed for segmentation, which includes a Transformer branch and a Convolutional Neural Network branch in encoder. After parallel feature extraction, inter-layer information fusion and exchange of complementary information are performed between the two branches, simultaneously extracting local and global features while eliminating the local bias generated by convolutional operations within the current layer. A pure convolutional operation is used in decoder to obtain final segmentation results. To validate the impact of the granularity of bias elimination operations on the effectiveness of local bias elimination, the experiments in this paper were conducted on Flare21 dataset and Amos22 dataset. The average Dice coefficient reached 92.65% on Flare21 dataset, and 91.61% on Amos22 dataset, surpassing comparative methods. The experimental results demonstrate that smaller granularity of bias elimination operations leads to better performance.

Clinical characteristics and prognostic analysis of patients with HIV and glioma: A case series and literature review.

Cerebral glial tumors have become increasingly common in human immunodeficiency virus (HIV)-positive patients. The present study aimed to report a series of such cases, explore their clinical and pathological characteristics and subject all the reported cases to a survival analysis. The characteristics, management and prognosis of 10 HIV-positive patients with brain gliomas enrolled in a single hospital were investigated in detail. Immunohistochemical assessment of CD31, CD68 and CD163 was performed in the 10 HIV-positive patients with glioma and 18 HIV-negative patients with glioma. The relevant literature was also reviewed using relevant search terms. The potential predictive factors were screened by univariate and multivariate logistic regression analyses, and a nomogram was established based on the potential predictive factors. A total of 50 patients, including the 10 primary cases, were included in the survival analysis. The median survival time was 9 months. The gliomas of HIV-negative patients had a lower cell count of CD163+ cells than those of HIV-positive patients. High CD4+ T-cell count and the use of highly active antiretroviral therapy (HAART) tended to increase the median survival duration, although not significantly according to the log-rank analysis. In the univariate analysis, only surgery, radiotherapy (RT) and World Health Organization (WHO) tumor grade had significant associations with overall survival. In the multivariate analysis, only RT and WHO grade were independent predictors. In conclusion, gliomas may occur more frequently in HIV-positive populations than is currently recognized. The survival duration of most HIV-positive patients with glioma is determined by the tumor rather than HIV status. Adjuvant radiotherapy and the WHO grade of the glioma are predicted to be independent prognostic factors. Surgical resection followed by RT plus regular HAART is recommended for patients with glioma who are HIV-positive.

Gut microbiota disorders aggravate terbuthylazine-induced mitochondrial quality control disturbance and PANoptosis in chicken hepatocyte through gut-liver axis.

Terbuthylazine (TBA) is a widely prevalent pesticide pollutant, which is a global concern due to its environmental residual. However, the toxic mechanism of TBA have not been fully solved. Here, we explored that TBA exposure disrupts the intestinal flora and aggravated disturbance of mitochondrial quality control and PANapoptosis in hepatocytes via gut-liver axis. Our findings demonstrated that TBA exposure induced significant damage to the jejunum barrier, evidenced by a marked decrease in the expression of Occludin and ZO-1. Moreover. TBA led to intestinal microflora disorder, manifested as the decreased abundance of Firmicutes, and increased abundance of the Nitrospirota, Chloroflexi, Desulfobacterota, Crenarchaeota, Myxococcota, and Planctomycetota. Meanwhile, intestinal microflora disorder affected the biological processes of lipid metabolism and cell growth and death of hepatocytes by RNA-Seq analysis. Furthermore, TBA could induced mitochondrial quality control imbalance, including mitochondrial redox disorders, lower activity of mitochondrial fusion and biogenesis decrease, and increasing level of mitophagy. Subsequently, TBA significantly increased expression levels of pyroptosis, apoptosis and necroptosis-related proteins. In general, these results demonstrated the underlying mechanisms of TBA-induced hepatotoxicity induced via the gut-liver axis, which provides a theoretical basis for further research of ecotoxicology of TBA.

A nonsense mutation in VHL causing Von Hippel-Lindau syndrome in a large Chinese family-a genetic study of familial neoplastic disease.

Von Hippel-Lindau (VHL) syndrome is a multi-organ neoplastic disease characterized by highly vascular and cystic tumors in the central nervous system (CNS), retina, and visceral lesions, which are mainly caused by germline mutations in VHL. We aimed to detect novel mutations in VHL gene in families with VHL. Here, a large consanguineous four-generation family with variant phenotypes of VHL syndrome was recruited, and its molecular genetics were tested via Sanger sequencing. And various tools and databases were used to predict the variant pathogenicity, frequency, and protein function. Genetic investigation detected a c.351G > A nonsense mutation in VHL that altered the downstream reading frame and created a premature TGA stop signal, resulting in severely truncated pVHL (p.Trp117Ter). This mutation is absent from most public databases, and functional prediction bioinformatic tools demonstrated that this residue is conserved and that this variant is highly likely to be deleterious. The c.315G > A nonsense mutation in VHL is the causal mutation of this kindred that may lead to clear familial aggregation of VHL syndrome because of the dysfunction of the truncated pVHL.

IFN-γ Triggered IFITM2 Expression to Induce Malignant Phenotype in Elderly GBM.

Advanced age is an important risk factor for the worse clinical presentation of gliomas, especially glioblastoma (GBM). The tumor microenvironment (TME) in elderly GBM (eGBM) patients is considerably different from that in young ones, which causes the inferior clinical outcome. Based on the data from the Chinese Glioma Genome Atlas RNA sequence (CGGA RNA-seq), the Cancer Genome Atlas RNA array (TCGA RNA-array), and gene set enrichment (GSE) 16011 array sets, the differential genes and function between eGBM (≥ 60 years old) and young GBM (yGBM, 20-60 years old) groups were explored. Immunohistochemistry (IHC) was utilized to depict the abundance of CD8+ cells (the main resource of IFN-γ) and IFITM2 protein expression in GBM samples. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting (WB) were performed to verify the link between IFN-γ and IFITM2. Moreover, the small-interfering RNA (siRNA) of IFITM2 was used to explore the function of IFITM2 in GBM. Characterized by inflammatory TME and higher IFITM2 expression, eGBM harbored a shorter survival time. Chemotaxis and inflammatory cytokine-related genes were enriched in the eGBM group, with more infiltrative CD8+ T cells. The IHC of CD8 and IFITM2-staining could demonstrate these results. In addition, the IFN-γ response pathway was activated in eGBM and resulted in a dismal outcome. Next, it was found that IFITM2 triggered by IFN-γ played a key role in IFN-γ-induced malignant phenotype in eGBM.

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

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

Insight into the Progress in CAR-T Cell Therapy and Combination with Other Therapies for Glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain cancer in adults. It is always resistant to existing treatments, including surgical resection, postoperative radiotherapy, and chemotherapy, which leads to a dismal prognosis and a high relapse rate. Therefore, novel curative therapies are urgently needed for GBM. Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved life expectancy for hematological malignancies patients, and thus it increases the interest in applying CAR-T cell therapy for solid tumors. In the recently published research, it is indicated that there are numerous obstacles to achieve clinical benefits for solid tumors, especially for GBM, because of GBM anatomical characteristics (the blood-brain barrier and suppressive tumor microenvironment) and the tumor heterogeneity. CAR-T cells are difficult to penetrate blood-brain barrier, and immunosuppressive tumor microenvironment (TME), which induces CAR-T cell exhaustion, impairs CAR-T cell therapy response. Moreover, under the pressure of CAR-T cell therapy, the tumor heterogeneity and tumor plasticity drive tumor evolution and therapy resistance, such as antigen escape. Nonetheless, scientists strive for strategies to overcome these hurdles, including novel CAR-T cell designs and regional delivery. For instance, the structure of multi-antigen-targeted CAR-T cells can enrich CAR-T accumulation in tumor TME and eliminate abundant tumor cells to avoid tumor antigen heterogeneity. Additionally, paired with an immune modifier and one or more stimulating domains, different generation of innovations in the structure and manufacturing of CAR-T cells have improved efficacy and persistence. While single CAR-T cell therapy receives limited clinical survival benefit. Compared with single CAR-T cell therapy, the combination therapies have supplemented the treatment paradigm. Combinatorial treatment methods consolidate the CAR-T cells efficacy by regulating the tumor microenvironment, optimizing the CAR structure, targeting the CAR-T cells to the tumor cells, reversing the tumor-immune escape mechanisms, and represent a promising avenue against GBM, based on multiple impressive research. Moreover, exciting results are also reported to be realized through combining effective therapies with CAR-T cells in preclinical and clinical trials samples, have aroused inspiration to explore the antitumor function of combination therapies. In summary, this study aims to summarize the limitation of CAR-T cell therapies and introduces novel strategies to enhance CAR-T cell function as well as prospect the potential of the therapeutic combination.

Novel insight into histological and molecular astrocytoma, IDH-mutant, Grade 4 by the updated WHO classification of central nervous system tumors.

BACKGROUND: The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021 defined astrocytoma, IDH-mutant, Grade 4. However, the understanding of this subtype is still limited. We conducted this study to describe the features of astrocytoma, IDH-mutant, Grade 4 and explored the similarities and differences between histological and molecular subtypes. METHODS: Patients who underwent surgery from January 2011 to January 2022, classified as astrocytoma, IDH-mutant, Grade 4 were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis. RESULTS: Altogether 33 patients with astrocytoma, IDH-mutant, Grade 4 were selected, including 20 with histological and 13 with molecular WHO Grade 4 astrocytoma. Tumor enhancement, intratumoral-necrosis like presentation, larger peritumoral edema, and more explicit tumor margins were frequently observed in histological WHO Grade 4 astrocytoma. Additionally, molecular WHO Grade 4 astrocytoma showed a tendency for relatively longer overall survival, while a statistical significance was not reached (47 vs. 25 months, p = 0.22). TP53, CDK6, and PIK3CA alteration was commonly observed, while PIK3R1 (p = 0.033), Notch1 (p = 0.027), and Mycn (p = 0.027) alterations may affect the overall survival of molecular WHO Grade 4 astrocytomas. CONCLUSIONS: Our study scrutinized IDH-mutant, Grade 4 astrocytoma. Therefore, further classification should be considered as the prognosis varied between histological and molecular WHO Grade 4 astrocytomas. Notably, therapies aiming at PIK3R1, Notch 1, and Mycn may be beneficial.

Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors.

Introduction: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors. This study aimed to characterize the clinical, radiological, molecular, and survival features of GBM under the current classification scheme and explore survival determinants. Methods: We re-examined the genetic alterations of IDH-wildtype diffuse gliomas at our institute from 2011 to 2022, and enrolled GBMs for analysis after re-classification. Univariable and multivariable analyses were used to identify survival determinants. Results: Among 209 IDH-wildtype gliomas, 191 were GBMs, including 146 hist-GBMs (76%) and 45 mol-GBMs (24%). Patients with mol-GBMs were younger, less likely to develop preoperative motor dysfunction, and more likely to develop epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences of contrast enhancement and intratumoral necrosis. Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN, with distinct patterns observed between the two subtypes. The median overall survival (mOS) of GMB was 12.6 months. Mol-GBMs had a higher mOS than hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement of deep brain structure or functional area, and genetic alterations in CDK4, CDK6, CIC, FGFR3, KMT5B, and MYB were predictors for a worse prognosis, while MGMT promoter methylation, maximal tumor resection, and treatment based on the Stupp protocol were predictive for better survival. Conclusion: The definition of GBM and its clinical, radiological, molecular, and prognostic characteristics have been altered under the current classification.

Nervonic acid improves liver inflammation in a mouse model of Parkinson's disease by inhibiting proinflammatory signaling pathways and regulating metabolic pathways.

BACKGROUND: Nervonic acid (NA) - a type of bioactive fatty acid that is found in natural sources - can inhibit inflammatory reactions and regulate immune system balance. Therefore, the use of NA for the treatment of neurodegenerative diseases has received considerable attention. Our previous study found that NA inhibited inflammatory responses in the brain of Parkinson's disease (PD) mouse models. In addition to the brain, PD is also associated with visceral organ dysfunction, especially impaired liver function. Thus, studying the role of NA in PD-mediated inflammation of the liver is particularly important. METHODS: A combined transcriptome and metabolomic approach was utilized to investigate the anti-inflammatory effects of NA on the liver of PD mice. Inflammatory signaling molecules and metabolic pathway-related genes were examined in the liver using real-time PCR and western blotting. RESULTS: Liver transcriptome analysis revealed that NA exerted anti-inflammatory effects by controlling several pro-inflammatory signaling pathways, such as the down-regulation of the tumor necrosis factor and nuclear factor kappa B signaling pathways, both of which were essential in the development of inflammatory disease. In addition, liver metabolomic results revealed that metabolites related to steroid hormone biosynthesis, arachidonic acid metabolism, and linoleic acid metabolism were up-regulated and those related to valine, leucine, and isoleucine degradation pathways were down-regulated in NA treatment groups compared with the PD model. The integration of metabolomic and transcriptomic results showed NA significantly exerted its anti-inflammatory function by regulating the transcription and metabolic pathways of multiple genes. Particularly, linoleic acid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis were the crucial pathways of the anti-inflammatory action of NA. Key genes in these metabolic pathways and key molecules in inflammatory signaling pathways were also verified, which were consistent with transcriptomic results. CONCLUSION: These findings provide novel insights into the liver protective effects of NA against PD mice. This study also showed that NA could be a useful dietary element for improving and treating PD-induced liver inflammation.

An online survival predictor in glioma patients using machine learning based on WHO CNS5 data.

Background: The World Health Organization (WHO) CNS5 classification system highlights the significance of molecular biomarkers in providing meaningful prognostic and therapeutic information for gliomas. However, predicting individual patient survival remains challenging due to the lack of integrated quantitative assessment tools. In this study, we aimed to design a WHO CNS5-related risk signature to predict the overall survival (OS) rate of glioma patients using machine learning algorithms. Methods: We extracted data from patients who underwent an operation for histopathologically confirmed glioma from our hospital database (2011-2022) and split them into a training and hold-out test set in a 7/3 ratio. We used biological markers related to WHO CNS5, clinical data (age, sex, and WHO grade), and prognosis follow-up information to identify prognostic factors and construct a predictive dynamic nomograph to predict the survival rate of glioma patients using 4 kinds machine learning algorithms (RF, SVM, XGB, and GLM). Results: A total of 198 patients with complete WHO5 molecular data and follow-up information were included in the study. The median OS time of all patients was 29.77 [95% confidence interval (CI): 21.19-38.34] months. Age, FGFR2, IDH1, CDK4, CDK6, KIT, and CDKN2A were considered vital indicators related to the prognosis and OS time of glioma. To better predict the prognosis of glioma patients, we constructed a WHO5-related risk signature and nomogram. The AUC values of the ROC curves of the nomogram for predicting the 1, 3, and 5-year OS were 0.849, 0.835, and 0.821 in training set, and, 0.844, 0.943, and 0.959 in validation set. The calibration plot confirmed the reliability of the nomogram, and the c-index was 0.742 in training set and 0.775 in validation set. Additionally, our nomogram showed a superior net benefit across a broader scale of threshold probabilities in decision curve analysis. Therefore, we selected it as the backend for the online survival prediction tool (Glioma Survival Calculator, https://who5pumch.shinyapps.io/DynNomapp/), which can calculate the survival probability for a specific time of the patients. Conclusion: An online prognosis predictor based on WHO5-related biomarkers was constructed. This therapeutically promising tool may increase the precision of forecast therapy outcomes and assess prognosis.

[Clinical features and genetic analysis of a patient with type 2 neurofibromatosis manifested as oculomotor nerve palsy].

OBJECTIVE: To report on a rare case of Neurofibromatosis type 2 (NF2) manifesting as oculomotor nerve palsy and explore its genetic basis. METHODS: A patient with NF2 who had presented at Beijing Ditan Hospital Affiliated to Capital Medical University on July 10, 2021 was selected as the study subject. Cranial and spinal cord magnetic resonance imaging (MRI) was carried out on the patient and his parents. Peripheral blood samples were collected and subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: MRI revealed bilateral vestibular Schwannomas, bilateral cavernous sinus meningiomas, popliteal neurogenic tumors, and multiple subcutaneous nodules in the patient. DNA sequencing revealed that he has harbored a de novo nonsense variant of the NF2 gene, namely c.757A>T, which has replaced a codon (AAG) encoding lysine (K) at position 253 with a stop codon (TAG). This has resulted in removal of the Merlin protein encoded by the NF2 gene from position 253 onwards. The variant was not found in public databases. Bioinformatic analysis suggested that the corresponding amino acid is highly conserved. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting+PP3+PP4). CONCLUSION: The heterozygous nonsense variant c.757A>T (p.K253*) of the NF2 gene probably underlay the disease in this patient with an early onset, atypical but severe phenotype.

Constituents, Antibacterial Effect, and Cytotoxicity of Essential Oil from Aerial Parts of Notopterygium incisum.

Notopterygium incisum Ting ex H. T. Chang (N. incisum) is a precious Chinese traditional medicine distributed in high-altitude regions of southwest China. The aim of this study was to investigate the composition, antibacterial activity, and cytotoxicity of essential oil from aerial parts of N. incisum. N. incisum essential oil (NI-EO) was extracted by hydro-distillation, and gas chromatography/mass spectrometry (GC-MS) analysis showed that the major components of NI-EO were D-limonene (18.42%) and γ-terpinene (15.03%). The antibacterial activity and mechanism study showed that the diameters of inhibition zone (DIZs) of NI-EO against E. coli and S. aureus were 14.63 and 11.25 mm and the minimum inhibitory concentrations were 3.75 and 7.5 µL/mL, respectively. NI-EO not only caused intracellular biomacromolecule leakage and cell deformation by destroying bacterial cell wall integrity and cell membrane permeability, but also degraded the mature biofilm. The low toxicity of NI-EO was demonstrated in an assay on bovine mammary epithelial cells. These results implied that NI-EO was mainly composed of monoterpenes and sesquiterpenes and had excellent antibacterial activity and showed low levels of cytotoxicity. It is expected to be applied as a natural antibacterial agent in the future.

Characteristic analysis and identification of novel molecular biomarkers in elderly glioblastoma patients using the 2021 WHO Classification of Central Nervous System Tumors.

Introduction: Elderly glioblastoma (GBM) patients is characterized by high incidence and poor prognosis. Currently, however, there is still a lack of adequate molecular characterization of elderly GBM patients. The fifth edition of the WHO Classification of Central Nervous System Tumors (WHO5) gives a new classification approach for GBM, and the molecular characteristics of elderly GBM patients need to be investigated under this new framework. Methods: The clinical and radiological features of patients with different classifications and different ages were compared. Potential prognostic molecular markers in elderly GBM patients under the WHO5 classification were found using Univariate Cox regression and Kaplan-Meier survival analysis. Results: A total of 226 patients were included in the study. The prognostic differences between younger and elderly GBM patients were more pronounced under the WHO5 classification. Neurological impairment was more common in elderly patients (p = 0.001), while intracranial hypertension (p = 0.034) and epilepsy (p = 0.038) were more common in younger patients. Elderly patients were more likely to have higher Ki-67(p = 0.013), and in elderly WHO5 GBM patients, KMT5B (p = 0.082), KRAS (p = 0.1) and PPM1D (p = 0.055) were each associated with overall survival (OS). Among them, KRAS and PPM1D were found to be prognostic features unique to WHO5 elderly GBM patients. Conclusion: Our study demonstrates that WHO5 classification can better distinguish the prognosis of elderly and younger GBM. Furthermore, KRAS and PPM1D may be potential prognostic predictors in WHO5 elderly GBM patients. The specific mechanism of these two genes in elderly GBM remains to be further studied.

Ethane Ammoxidation over Sn/H-Zeolite Catalysts: Toward the Factors Contributing to the Yield of Acetonitrile.

Different Sn/H-zeolite (ß, MOR, SSZ-13, FER, and Y zeolite) catalysts are prepared with the improved impregnation method. The effects of reaction temperature and the composition of the reaction gas (ammonia, oxygen, and ethane) on the catalytic reaction are investigated. Adjusting the fraction of ammonia and/or ethane in the reaction gas can effectively strengthen the ethane dehydrogenation (ED) route and ethylamine dehydrogenation (EA) route and inhibit the ethylene peroxidation (EO) route, whereas the adjustment of oxygen cannot effectively promote acetonitrile formation because it cannot avoid enhancing the EO route. By comparing the acetonitrile yields on different Sn/H-zeolite catalysts at 600 °C, it is revealed that the ammonia pool effect, the residual Brönsted acid in the zeolite, and the Sn-Lewis acid synergistically catalyze ethane ammoxidation. Moreover, a higher L/B ratio of the Sn/H zeolite is beneficial to the improvement of acetonitrile yield. With a certain application potential, the Sn/H-FER-zeolite catalyst shows an ethane conversion of 35.2% and an acetonitrile yield of 22.9% at 600 °C; although a similar catalytic performance was observed on the best Co-zeolite catalyst in literature, the Sn/H-FER-zeolite catalyst is more selective to ethene and CO than the Co catalyst. In addition, the selectivity to CO2 is less than 2% of that on the Sn-zeolite catalyst. This may be attributed to the special 2D topology and pore/channel system of the FER zeolite, which guarantee an ideal synergistic effect of the ammonia pool, the residual Brönsted acid in the zeolite, and the Sn-Lewis acid for the Sn/H-FER-catalyzed ethane ammoxidation reaction.