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Abstract Purpose Accurate detection and resection of the epileptogenic zone (EZ) in patients with long-term epilepsy-associated tumors (LEATs) are significantly correlated with favorable seizure prognosis. However, the relationship between tumors and the EZ remains unknown. This study aimed to evaluate the spatial relationship between LEATs and the EZ, as well as the electrophysiological features of LEATs. Methods We retrospectively studied five patients with LEATs who underwent deep electrode implantation and EZ resection in the hospital. The clinical characteristics, surgical outcomes, localizing features and intracranial SEEG results were reviewed. Results One female and four males (mean age: 25.2 years; median age: 24 years; range: 13–45 years) were included in the study. Five-to-eleven electrodes (mean: 8.4) were implanted per patient. The EZ was located in the tumor and nearby cortex in three cases and in the tumor and distant areas in two cases. Pathological examination revealed ganglioglioma in four cases, two of which were associated with hippocampal sclerosis, and the other case showed a multinodular and vacuolating neuronal tumor with gliosis. All patients were seizure-free for at least 24 months postoperatively. Conclusions SEEG provides valuable insights into the electrophysiological mechanisms of LEATs. The EZ often contains brain tissue around the tumor. However, only a few cases, particularly those with temporoparietal occipital (TPO) area involvement, a long history of epilepsy and other abnormalities on MRI, such as hippocampal sclerosis and focal cortical dysplasia, may include distant areas.

Abstract Multiple sclerosis (MS) is uncommon in China and the standard of care is underdeveloped, with limited utilization of disease-modifying treatment (DMT). An understanding of real-world disease burden (including direct medical, non-medical, and indirect costs, such as loss of productivity), is currently lacking in this population. To investigate the overall burden of managing patients with MS in China, a cross-sectional survey of physicians and their consulting patients with MS was conducted in 2021. Physicians provided information on healthcare resource utilization (HCRU; consultations, hospitalizations, tests, medication) and associated costs. Patients provided data on changes in their life, productivity, and impairment of daily activities due to MS. Results were stratified by disease severity using generalized linear models, with a p value

BackgroundThe Polymorphic Low-Grade Neuroepithelial Tumor of the Young (PLNTY) is a rare, epilepsy-associated brain tumor that has been increasingly recognized but is not well understood due to the scarcity of clinical reports. Our study reviews the clinical characteristics and treatment outcomes of 14 patients with PLNTY to enhance the understanding of this condition from an epilepsy surgery perspective.MethodsWe performed a retrospective analysis of 14 PLNTY cases at our hospital. A literature review on prior studies was also conducted.ResultsOur study included 8 males and 6 females, all presenting with epilepsy. Despite anti-seizure medication, 92.3% of patients continued to have seizures, with 58.3% diagnosed as having drug-resistant epilepsy. Neuroimaging revealed that 64.3% of the lesions were in the temporal lobe, with 75.0% showing calcification on CT, 71.4% exhibiting mixed signals on T2-weighted images, and 92.7% showing tumor enhancement. The transmantle sign was noted in 57.1% of T2 FLAIR sequences. EEGs indicated abnormal activity in 69.2% of patients, with 30.7% showing bilateral discharges. SEEG in two patients confirmed the tumor’s epileptogenicity. A 78.6% total resection rate was achieved, with a 90.0% postoperative seizure-free rate and an 85.7% excellent Engel grade 1 rate. No instances co-occurring with focal cortical dysplasia (FCD) were observed.ConclusionPLNTY is characterized by unique neuroimaging features and a strong association with epilepsy. SEEG is pivotal for cases with unclear lateralization, aiding in identifying the link between the tumor and seizures. Following established epilepsy surgery protocols for brain tumor management, early intervention and extended resection can improve the rate of postoperative seizure freedom.

The intravascular large B cell lymphoma (IVLBCL) is a rare subtype of lymphoma. The IVBCL is usually found with systemic involvement, with a relative predilection for skin and the central nervous system (CNS), followed by a rapidly progressive course and poor prognosis with a high mortality rate. IVLBCL is difficult to diagnose based on conventional MRI alone. Herein, we presented a previously healthy 59-year-old woman who developed hemiparesis and altered mental status after her reinfection of SARS-CoV-2. The initial MRI revealed non-enhancing lesions in the splenium of the corpus callosum (CC), periventricular, and bilateral subcortical white matter with hyperintensity on diffusion weighted imaging (DWI). The patient was diagnosed with subacute infarction, and she was treated with antithrombotic therapy. Her neurological symptoms continued to deteriorate, and she developed unconsciousness. Her CSF test showed elevated white cell count and positive oligoclonal bands. The follow-up MRI was scanned 16 days later. Compared to the initial MRI, the periventricular and bilateral subcortical lesions enlarged on conventional MRI. The post-contrast 3D black blood Cube images demonstrated multiple parenchymal and diffuse meningeal enhancements and 3D arterial spin labeling showed increased perfusion in the CC splenium. These findings suggested the differential diagnosis of acute demyelinating encephalomyelitis (ADEM) after SARS-CoV-2 reinfection, versus intravascular lymphoma. After the treatment of intravenous immunoglobulin and methylprednisolone, her symptoms significantly improved. The second follow-up MRI two weeks later detected a new unenhanced lesion in the left temporal lobe. A brain biopsy was performed and IVLBCL was diagnosed. We reviewed the brain MRI findings of IVLBCL in the literature with the assistance of ChatGPT. Although less specific, the imaging features including “high signal lesions on DWI, meningeal thickening and enhancement, and masslike lesions” highly suggested the possibility of IVLBCL. The biopsy should be planned after imaging progression. The association between IVLBCL and SARS-CoV-2 reinfection is undefined.

Drought, a prevalent environmental stressor, has had significant consequences on soybean (Glycine max L.), notably impeding its growth and production. Therefore, it is crucial to gain insight into the regulatory responses of soybean plants exposed to drought stress during soybean flowering in the field. In this study, the cultivar ‘Liaodou 15’ was performed light drought (LD, 24.3% soil moisture content), moderate drought (MD, 20.6% soil moisture content) and severe drought (SD, 16.9% soil moisture content) treatments at flowering stages of soybean and then rehydrated (30% soil moisture content) until harvest. The yield-related indicators were measured and revealed that MD and SD treatments significantly reduced 6.3% and 10.8% of the 100-grain weight. Soybean plants subjected to three drought stresses showed that net photosynthetic rates were 20.8%, 51.5% and 71.8% lower in LD, MD and SD than that of CK. The WUE increased by 31.8%, 31.5% and 18.8% under three drought stress treatments compared to CK. In addition, proline content was 25.94%, 41.01% and 65.43% greater than that of CK under three drought stress treatments. The trend of the MDA content was consistent with that of the proline content. SOD activity was significantly increasing by 10.86%, 46.73% and 14.54% under three drought stress treatments. The activity of CAT in the SD treatment increased by 49.28%. All the indices recovered after rehydration. Furthermore, 54,78 and 51 different expressed metabolomics (DEMs) were identified in the LDCK/LD, MDCK/MD and SDCK/SD groups, respectively. There were 1,211, 1,265 and 1,288 different expressed genes (DEGs) were upregulated and 1,003, 1,819 and 1,747 DEGs were downregulated. Finally, combined transcriptomic and metabolomic analysis suggested that 437 DEGs and 24 DEMs of LDCK/LD group, 741 DEGs and 35 DEMs of MDCK/MD group, 633 DEGs and 23 DEMs of SDCK/SD group, were highly positively correlated in soybean plants under drought stress. Drought stress induced the expression of the PAO1, PAO4, PAO5 and P5CS genes to promote the accumulation of spermidine and proline. Our study elucidates the responses of drought-stressed soybean plants in the field and provides a genetic basis for the breeding of drought-tolerant soybean plants.

IntroductionThere is growing evidence indicating a complex interaction between blood metabolites and atopic dermatitis (AD). The objective of this study was to investigate and quantify the potential influence of plasma metabolites on AD through Mendelian randomization (MR) analysis.MethodsOur procedures followed these steps: instrument variable selection, primary analysis, replication analysis, Meta-analysis of results, reverse MR analysis, and multivariate MR (MVMR) analysis. In our study, the exposure factors were derived from the Canadian Longitudinal Study on Aging (CLSA), encompassing 8,299 individuals of European descent and identifying 1,091 plasma metabolites and 309 metabolite ratios. In primary analysis, AD data, was sourced from the GWAS catalog (Accession ID: GCST90244787), comprising 60,653 cases and 804,329 controls. For replication, AD data from the Finnish R10 database included 15,208 cases and 367,046 controls. We primarily utilized the inverse variance weighting method to assess the causal relationship between blood metabolites and AD.ResultsOur study identified significant causal relationships between nine genetically predicted blood metabolites and AD. Specifically, 1-palmitoyl-2-stearoyl-GPC (16:0/18:0) (OR = 0.92, 95% CI 0.89–0.94), 1-methylnicotinamide (OR = 0.93, 95% CI 0.89–0.98), linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1] (OR = 0.94, 95% CI 0.92–0.96), and 1-arachidonoyl-GPC (20:4n6) (OR = 0.94, 95% CI 0.92–0.96) were associated with a reduced risk of AD. Conversely, phosphate / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [2] (OR = 1.07, 95% CI 1.04–1.10), docosatrienoate (22:3n3) (OR = 1.07, 95% CI 1.04–1.10), retinol (Vitamin A) / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [2] (OR = 1.08, 95% CI 1.05–1.11), retinol (Vitamin A) / linoleoyl-arachidonoylglycerol (18:2/20:4) [1] (OR = 1.08, 95% CI 1.05–1.12), and phosphate / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1] (OR = 1.09, 95% CI 1.07–1.12 were associated with an increased risk of AD. No evidence of reverse causality was found in the previously significant results. MVMR analysis further confirmed that 1-palmitoyl-2-stearoyl-GPC (16:0/18:0) and 1-methylnicotinamide are independent and dominant contributors to the development of AD.ConclusionOur study revealed a causal relationship between genetically predicted blood metabolites and AD. This discovery offers specific targets for drug development in the treatment of AD patients and provides valuable insights for investigating the underlying mechanisms of AD in future research.

Abstract Objective Stroke is a rare but fatal complication of advanced cancer with Trousseau syndrome, especially as initial symptoms. Here, we report the clinical characteristics, treatment, and prognosis of patients with non-small cell lung cancer (NSCLC) who initially presenting with acute multiple cerebral infarction. Methods The clinical characteristics, imaging, treatment, and oncological outcomes of 10 patients diagnosed with Trousseau syndrome and NSCLC between 2015 and 2021 at Guangdong Sanjiu Brain Hospital were retrospectively collected and analyzed. The clinical course of two typical cases were presented. Results All 10 patients with pathologically confirmed lung adenocarcinoma initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%). The median age was 63.5 years. Eight and two cases were stage III and IV, respectively, at the initial diagnosis. Five patients underwent driver gene testing, revealing three patients with EGFR-sensitive mutations, one patient with ALK fusion, and one patient with wild-type EGFR. All 10 patients received antiplatelet therapy, and six patients subsequently received anti-cancer treatment. The median overall survival of the patients was 8.5 months (95% confidence interval) and 1-year survival rate was 57.1%. Patients who received antitumor treatment, especially those harboring driver gene mutations and received tyrosine kinase inhibitors, had better neurological symptom recovery and superior oncological prognosis (median overall survival, not reached versus 7.4 months, p = 0.038). Conclusion Trousseau syndrome, presenting as multiple cerebral infarctions, is a rare complication of lung adenocarcinoma. Both antiplatelet and antitumor treatment are recommended to achieve better neurological recovery and oncological prognosis in these patients.

Abstract Infant‐type hemispheric glioma, a new subtype of pediatric high‐grade glioma, arises in the cerebral hemispheres. Despite better survival outcomes, the treatment of infant‐type hemispheric glioma is still facing challenges. Here, we reported a case of QKI‐ALK fusion, infant‐type hemispheric glioma with lung metastasis who achieved a complete clinical response after lorlatinib treatment. This typical case demonstrated the importance of appropriate molecularly targeted treatments in ALK‐fused tumors, and lorlatinib may serve as an effective complement to conventional chemotherapy and radiotherapy in primary glioma harboring ALK fusions and its metastasis.

Endothelial cell (EC) permeability is essential to vascular homeostasis in diabetes. MicroRNAs are critical gene regulators whose roles in the EC permeability have yet to be characterized. This study aims to examine the change in cell permeability induced by miR-200 and miR-466 in ECs. Human aortic ECs and dermal microvascular ECs from healthy subjects and type 2 diabetic patients were used. Our in vitro experiments unveiled higher expressions of miR-200 family members and miR-466 in diabetic ECs and in healthy ECs when exposed to high glucose. Overexpression of both miR-200 and miR-466 significantly increased EC permeability through transcriptional suppression of Claudin-5, the cell tight junction protein, by directly binding to its 3′ untranslated region. In a mouse model of chronic hyperglycemia mimicking type 2 diabetes in humans (db/db mice), the delayed closure rate of a full-thickness excisional wound was partly rescued by topical application of the miR-200 inhibitor. The topical application of both miR-200 and miR-466 inhibitors exhibited improved efficacy in accelerating wound closure compared with the topical application of miR-200 inhibitor alone. Our study demonstrated the potentially effective approach of miR-200/miR-466 cocktail inhibition to restore vascular integrity and tissue repair in hyperglycemia.

Animal models of metabolic disorders are essential to studying pathogenic mechanisms and developing therapies for diabetes, but the induction protocols vary, and sexual dimorphism often exists. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, blood glucose and lipid profiles were measured. The high-fat (HF) diet damaged insulin sensitivity and increased triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and liver lipid deposition. STZ increased blood glucose and liver fibrosis with less effects on blood lipids or liver lipid deposition. The combination of DIO and STZ treatments led to significant liver lipid deposition and fibrosis. Female mice showed delayed body weight gain on HF diet and resisted STZ-induced hyperglycemia. However, once they developed DIO, which occurs around 26 weeks of HF diet, the female mice were prone to STZ-induced hyperglycemia. In hindlimb ischemia, male mice in the DIO-STZ group showed significantly worse neovascularization compared with DIO or STZ groups. The DIO-STZ females showed significantly worse recovery than the DIO-STZ males. Our observations suggest that DIO-STZ is a plausible model for studying metabolic and cardiovascular disorders in obesity and diabetes. Moreover, the findings in female animals stress the need to assess sexual dimorphism and investigate the underlying mechanisms that contribute to the worse vasculopathy manifestations in females in metabolic models.

Drought is the most common environmental stress and has had dramatic impacts on soybean (Glycine max L.) growth and yield worldwide. Therefore, to investigate the response mechanism underlying soybean resistance to drought stress, the drought-sensitive cultivar “Liaodou 15” was exposed to 7 (mild drought stress, LD), 17 (moderate drought stress, MD) and 27 (severe drought stress, SD) days of drought stress at the flowering stage followed by rehydration until harvest. A total of 2214, 3684 and 2985 differentially expressed genes (DEGs) in LD/CK1, MD/CK2, and SD/CK3, respectively, were identified by RNA-seq. Weighted gene co-expression network analysis (WGCNA) revealed the drought-response TFs such as WRKY (Glyma.15G021900, Glyma.15G006800), MYB (Glyma.15G190100, Glyma.15G237900), and bZIP (Glyma.15G114800), which may be regulated soybean drought resistance. Second, Glyma.08G176300 (NCED1), Glyma.03G222600 (SDR), Glyma.02G048400 (F3H), Glyma.14G221200 (CAD), Glyma.14G205200 (C4H), Glyma.19G105100 (CHS), Glyma.07G266200 (VTC) and Glyma.15G251500 (GST), which are involved in ABA and flavonoid biosynthesis and ascorbic acid and glutathione metabolism, were identified, suggesting that these metabolic pathways play key roles in the soybean response to drought. Finally, the soybean yield after rehydration was reduced by 50% under severe drought stress. Collectively, our study deepens the understanding of soybean drought resistance mechanisms and provides a theoretical basis for the soybean drought resistance molecular breeding and effectively adjusts water-saving irrigation for soybean under field production.

Background: Gastric cancer (GC) is a digestive system tumor with high morbidity and mortality. It is urgently required to identify genes to elucidate the underlying molecular mechanisms. The aim of this study is to identify the key genes which may affect the prognosis of GC patients and be a therapeutic strategy for GC patients by bioinformatic analysis.Methods: The significant prognostic differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. The protein–protein interaction (PPI) network was established by STRING and screening key genes by MCODE and CytoNCA plug-ins in Cytoscape. Functional enrichment analysis, construction of a prognostic risk model, and nomograms verify key genes as potential therapeutic targets.Results: In total, 997 genes and 805 genes were related to the prognosis of GC in the GSE84437 and TCGA datasets, respectively. We define the 128 genes shared by the two datasets as prognostic DEGs (P-DEGs). Then, the first four genes (MYLK, MYL9, LUM, and CAV1) with great node importance in the PPI network of P-DEGs were identified as key genes. Independent prognostic risk analysis found that patients with high key gene expression had a poor prognosis, excluding their age, gender, and TNM stage. GO and KEGG enrichment analyses showed that key genes may exert influence through the PI3K-Akt pathway, in which extracellular matrix organization and focal adhesion may play important roles in key genes influencing the prognosis of GC patients.Conclusion: We found that MYLK, MYL9, LUM, and CAV1 are potential and reliable prognostic key genes that affect the invasion and migration of gastric cancer.

Background: Glioblastoma (GBM) is the most common and malignant type of brain tumor. A large number of studies have shown that the immunotherapy of tumors is effective, but the immunotherapy effect of GBM is not poor. Thus, further research on the immune-related hub genes of GBM is extremely important.Methods: The GBM highly correlated gene clusters were screened out by differential expression, mutation analysis, and weighted gene co-expression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) and proportional hazards model (COX) regressions were implemented to construct prognostic risk models. Survival, receiver operating characteristic (ROC) curve, and compound difference analyses of tumor mutation burden were used to further verify the prognostic risk model. Then, we predicted GBM patient responses to immunotherapy using the ESTIMATE algorithm, GSEA, and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm.Results: A total of 834 immune-related differentially expressed genes (DEGs) were identified. The five hub genes (STAT3, SEMA4F, GREM2, MDK, and SREBF1) were identified as the prognostic risk model (PRM) screened out by WGCNA and LASSO analysis of DEGs. In addition, the PRM has a significant positive correlation with immune cell infiltration of the tumor microenvironment (TME) and expression of critical immune checkpoints, indicating that the poor prognosis of patients is due to TIDE.Conclusion: We constructed the PRM composed of five hub genes, which provided a new strategy for developing tumor immunotherapy.

Focal cortical dysplasia (FCD) type IIIa is an easily ignored cause of intractable temporal lobe epilepsy. This study aimed to analyze the clinical, electrophysiological, and imaging characteristics in FCD type IIIa and to search for predictors associated with postoperative outcome in order to identify potential candidates for epilepsy surgery. We performed a retrospective review including sixty-six patients with FCD type IIIa who underwent resection for drug-resistant epilepsy. We evaluated the clinical, electrophysiological, and neuroimaging features for potential association with seizure outcome. Univariate and multivariate analyses were conducted to explore their predictive role on the seizure outcome. We demonstrated that thirty-nine (59.1%) patients had seizure freedom outcomes (Engel class Ia) with a median postsurgical follow-up lasting 29.5 months. By univariate analysis, duration of epilepsy (less than 12 years) (p = 0.044), absence of contralateral insular lobe hypometabolism on PET/MRI (pLog-rank = 0.025), and complete resection of epileptogenic area (pLog-rank = 0.004) were associated with seizure outcome. The incomplete resection of the epileptogenic area (hazard ratio = 2.977, 95% CI 1.218–7.277, p = 0.017) was the only independent predictor for seizure recurrence after surgery by multivariate analysis. The results of past history, semiology, electrophysiological, and MRI were not associated with seizure outcomes. Carefully included patients with FCD type IIIa through a comprehensive evaluation of their clinical, electrophysiological, and neuroimaging characteristics can be good candidates for resection. Several preoperative factors appear to be predictive of the postoperative outcome and may help in optimizing the selection of ideal candidates to benefit from epilepsy surgery.

Since autophagy and the immune microenvironment are deeply involved in the tumor development and progression of Lower-grade gliomas (LGG), our study aimed to construct an autophagy-related risk model for prognosis prediction and investigate the relationship between the immune microenvironment and risk signature in LGG. Therefore, we identified six autophagy-related genes (BAG1, PTK6, EEF2, PEA15, ITGA6, and MAP1LC3C) to build in the training cohort (n = 305 patients) and verify the prognostic model in the validation cohort (n = 128) and the whole cohort (n = 433), based on the data from The Cancer Genome Atlas (TCGA). The six-gene risk signature could divide LGG patients into high- and low-risk groups with distinct overall survival in multiple cohorts (all p < 0.001). The prognostic effect was assessed by area under the time-dependent ROC (t-ROC) analysis in the training, validation, and whole cohorts, in which the AUC value at the survival time of 5 years was 0.837, 0.755, and 0.803, respectively. Cox regression analysis demonstrated that the risk model was an independent risk predictor of OS (HR > 1, p < 0.05). A nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its robust predictive capacity. KM analysis revealed a significant difference in the subgroup analyses’ survival. Functional enrichment analysis revealed that these autophagy-related signatures were mainly involved in the phagosome and immune-related pathways. Besides, we also found significant differences in immune cell infiltration and immunotherapy targets between risk groups. In conclusion, we built a powerful predictive signature and explored immune components (including immune cells and emerging immunotherapy targets) in LGG.

It is well-known that genomic mutational analysis plays a significant role in patients with NSCLC for personalized treatment. Given the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS. Patients with BM and treated by SRS were eligible in this study. The primary endpoint was overall survival (OS). Cox regression models were used to identify independent prognostic factors. A survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. From January 2016 to December 2019, a total of 356 BM patients were eligible. The median OS was 17.7 months [95% confidence interval (CI) 15.5–19.9] and the actual OS at 1- and 2-years measured 63.2 and 37.6%, respectively. A nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, gene mutation status, and serum lactate dehydrogenase. The nomogram was validated in a separate cohort and demonstrated good calibration and good discriminative ability (C-index = 0.780, AUC = 0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced when compared with classical prognostic indices, including the Graded Prognostic Assessment (0.708), recursive partitioning analysis (0.587), and the SRS (0.536). Kaplan–Meier curves showed significant differences in OS among the stratified low-, median- and high-risk groups (P < 0.001). In conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry, and molecular biological surrogates. Although this nomogram should be validated by independent external study, it has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.

BackgroundMolecular characteristics are essential for the classification and grading of gliomas. However, diagnostic classification of midline glioma is still debatable and substantial molecular and clinical heterogeneity within each subgroup suggested that they should be further stratified. Here, we studied the mutation landscape of Chinese midline glioma patients in hope to provide new insights for glioma prognosis and treatment.MethodsTissue samples from 112 midline glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their somatic interactions and prognostic effect using overall survival data. Pathway-based survival analysis was performed for ten canonical oncogenic pathways.ResultsWe identified several currently established diagnostic and prognostic biomarkers of glioma, including TP53 (33%), EGFR (26%), TERT (24%), PTEN (21%), PIK3CA (14%), ATRX (14%), BRAF (13%), and IDH1/2 (6%). Among all genetic aberrations with more than 5% occurrence rate, six mutations and three copy number gains were greatly associated with poor overall survival (univariate, P < 0.1). Of these, TERT mutations (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.37–6.61; P = 0.01) and PIK3CA mutations (HR, 2.04; 95% CI, 1.08–3.84; P = 0.02) remained significant in multivariate analyses. Additionally, we have also identified a novel MCL1 amplification (found in 31% patients) as a potential independent biomarker for glioma (multivariate HR, 2.78; 95% CI, 1.53–5.08; P < 0.001), which was seldom reported in public databases. Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12–2.95; P = 0.01) and cell cycle pathways (HR, 1.97; 95% CI, 1.15–3.37; P = 0.01), both of which stayed meaningful after multivariate adjustment.ConclusionsIn this study, we discovered shorter survival in midline glioma patients with PIK3CA and TERT mutations and with abnormal PI3K and cell cycle pathways. We also revealed a novel prognostic marker, MCL1 amplification that collectively provided new insights and opportunities in understanding and treating midline gliomas.

Background: Gliomas are the malignance of a poor prognosis. The current WHO classification remains unable to predict survival outcomes accurately. Novel surrogates are highly required for improved stratification of patients and hence, allowing to delivery of the most appropriate treatment. Methods: Transcriptional profiles of 301 glioma cases on the platform of Chinese Glioma Genome Atlas (CGGA) were retrospectively studied. Results: Extracellular matrix (ECM) scores were established by integrating a panel of most featured gene-signatures, correlating well with pathological tumor stages. Linear regression analysis revealed that the ECM score corroborated with the infiltration status of monocytes, M0 and M1 macrophages. Furthermore, the WHO stage II-IV dependent abundance of those 3 immune cells was determined. Univariate and multivariate analysis of clinicopathological characteristics in the GBM cohort identified M1 enrichment score as an independent risk factor. A high abundance of M1 macrophages was associated with poor survival outcomes and radiotherapy response in IDH-wildtype GBM. Conclusions: Our study demonstrated that M1 macrophages correlated with WHO grades and predicted robustly for the survival performance for GBM patients. Increased infiltration of M1 macrophages was associated with a poor radiation response for IDH-wildtype GBM. Together, it will facilitate more precise stratifications of glioma patients based on molecular and immunological surrogates.

Background: Doxorubicin (DOX) has antitumor effects mediated by cell viability inhibition and by inducing cellular apoptosis. However, it has limited use in clinical applications due to various factors such as hydrophobicity, dose-dependent toxicity effects on normal tissues, short cycle retention time, and low targeting ability. This study aims at enhancing hydrophilicity of DOX to restrict its toxic effects to within or around the tumor sites and also to improve its targeting ability to enhance antitumor efficiency. Methods: Micelles composed of biodegradable poly (ethylene glycol)-poly (lactic acid) copolymers (PEG-PLA) were employed to deliver DOX via a self-assembly method and were coupled to VEGF antibodies. The morphology, size, and physical stability of PEG-PLA-DOX targeting VEGF micelles (VEGF-PEG-PLA-DOX micelles) were assessed. Then, the release ability of DOX from these micelles was monitored, and their drug loading capacity was calculated. MTT assay revealed the in vitro antitumor effect of VEGF-PEG-PLA-DOX micelles. Moreover, ROS release was measured to evaluate apoptotic effects of these nanoparticle micelles. In vivo therapeutic efficiencies of VEGF-PEG-PLA-DOX micelles on a lung cancer nude mouse model was evaluated. Results: DOX-loaded micelles were obtained with a drug loading capacity of 12.2% and were monodisperse with 220 nm average diameter and a controlled in vitro DOX release for extended periods. In addition, VEGF-PEG-PLA-DOX micelles displayed a larger cell viability inhibitory effect as measured via MTT assays and greater cell apoptosis induction through in vitro ROS levels compared with PEG-PLA-DOX micelles or free DOX. Furthermore, VEGF-PEG-PLA-DOX micelles could improve in vivo antitumor effects of DOX by reducing tumor volume and weight. Conclusions: VEGF-PEG-PLA-DOX micelles displayed a larger anti-tumor effect both in in vitro A549 cells and in an in vivo lung cancer nude mouse model compared with PEG-PLA-DOX micelles or free DOX, and hence they have potential clinical applications in human lung cancer therapy.

The workability and mechanical performance of coral sand-cement mortar (coral mortar, for short) and the modification effects of mineral admixtures on the coral mortar were studied in this paper. The results showed that the strength of coral mortar was lower than that of standard mortar, but the strength of coral mortar was improved by compositing with the mineral admixture, which can be attributed to the improvement of the microstructure and interface transition area. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to explore the microscopic mechanism involved in the mechanical properties, volume stability, and hydration of mortar. The analyses revealed that the internal curing effect of coral sand improved the mechanical properties of mortar and its ability to resist shrinkage. The uneven surface of coral sand formed a meshing state of close combination with the hardened cement mortar, which helped to improve the volume stability of mortar. The Ca2+ and Mg2+ ions from coral sand participated in the hydration reaction of cement, which contributed to generating more hydration products. Moreover, the microaggregate filling and pozzolanic effects of fly ash and slag improved the mechanical properties of coral mortar and resistance to chloride ion diffusion.

The effects of nano-TiO2 (NT) on microstructures and mechanical properties of cement mortars were studied by scanning electron microscopy (SEM), X-ray diffraction (XRD), and mercury intrusion porosimetry (MIP). Results show that 3% NT can remarkably increase the tensile/flexural strengths (i.e., the toughness is improved) and promote the precipitation of AFt crystal. The flexural and tensile strengths have significant positive correlation to the formation amount of AFt. The pores of mortars can be significantly refined and shift to harmless pores by controlling the growth of CH crystal and increasing the hydration reaction rate. The durability of cement-based materials is discussed by testing their water absorption and water-vapour permeability. Results show that the addition of 3% NT can decrease the water absorption ratio by 40–65%, water absorption coefficients by more than 40%, and water-vapour permeability coefficients by 43.9%, indicating that 3% NT can effectively improve the compactness and durability of cement-based materials.

Abstract Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator that plays critical roles in tumours. However, the DNA methylation alteration patterns driven by UHRF1 and the related differentially expressed tumour-related genes remain unclear. In this study, a UHRF1-shRNA MCF-7 cell line was constructed, and whole-genome bisulfite sequencing and RNA sequencing were performed. The DNA methylation alteration landscape was elucidated, and DNA methylation-altered regions (DMRs) were found to be distributed in both gene bodies and adjacent regions. The DMRs were annotated and categorized into 488 hypermethylated/1696 hypomethylated promoters and 1149 hypermethylated/5501 hypomethylated gene bodies. Through an integrated analysis with the RNA sequencing data, 217 methylation-regulated upregulated genes and 288 downregulated genes were identified, and these genes were primarily enriched in nervous system development and cancer signalling pathways. Further analysis revealed 21 downregulated oncogenes and 15 upregulated TSGs. We also showed that UHRF1 silencing inhibited cell proliferation and migration and suppressed tumour growth in vivo. Our study suggested that UHRF1 and the oncogenes or TSGs it regulates might serve as biomarkers and targets for breast cancer treatment.

To address the problems of poor speed performance and the large influence of the distributed capacitance of traditional pilot differential protection, a pilot protection scheme based on the characteristics of the transient voltage waveform is proposed. First, the expression of the relationship between the fault voltage of the current-limiting reactor and the measuring point is derived. From the theoretical derivation, it can be inferred that for internal faults, the voltage ratio of the current-limiting reactor to the measuring point on both sides of the HVDC line is constant over a short period. For external faults, the voltage ratio of the current-limiting reactor to the measuring point varies exponentially on the fault side, while on the other side, it remains constant. Based on the above characteristics, the waveform characteristics of the voltage ratio of the current-limiting reactor to the measuring point are used to establish a protection criterion. A pilot protection scheme based on the standard deviation coefficient is proposed. The simulation results show that this method can reliably identify internal and external faults and has high sensitivity and selectivity. Moreover, this method is reliable for different types of faults and fault resistances. In addition, the proposed protection scheme can identify the type of fault in a short time window, requires a low sampling frequency, and does not require data synchronization.

Background The incidence and mortality of cervical cancer remain high in female malignant tumors worldwide. There is still a lack of diagnostic and prognostic markers for cervical carcinoma. This study aimed to screen differentially expressed genes (DEGs) between normal and cervical cancer tissues to identify candidate genes for further research. Methods Uterine cervical specimens were resected from our clinical patients after radical hysterectomy. Three patients’ transcriptomic datasets were built by the next generation sequencing (NGS) results. DEGs were selected through the edgeR and DESeq2 packages in the R environment. Functional enrichment analysis, including GO/DisGeNET/KEGG/Reactome enrichment analysis, was performed. Normal and cervical cancer tissue data from the public databases TCGA and GTEx were collected to compare the expression levels of 10 selected DEGs in tumor and normal tissues. ROC curve and survival analysis were performed to compare the diagnostic and prognostic values of each gene. The expression levels of candidate genes were verified in 15 paired clinical specimens via quantitative real-time polymerase chain reaction. Results There were 875 up-regulated and 1,482 down-regulated genes in cervical cancer samples compared with the paired adjacent normal cervical tissues according to the NGS analysis. The top 10 DEGs included APOD, MASP1, ACKR1, C1QTNF7, SFRP4, HSPB6, GSTM5, IGFBP6, F10 and DCN. GO, DisGeNET and Reactome analyses revealed that the DEGs were related to extracellular matrix and angiogenesis which might influence tumorigenesis. KEGG enrichment showed that PI3K-Akt signaling pathway might be involved in cervical cancer tumorigenesis and progression. The expression levels of selected genes were decreased in tumors in both the public database and our experimental clinical specimens. All the candidate genes showed excellent diagnostic value, and the AUC values exceeded 0.90. Additionally, APOD, ACKR1 and SFRP4 expression levels could help predict the prognosis of patients with cervical cancer. Conclusions In this study, we selected the top 10 DEGs which were down-regulated in cervical cancer tissues. All of them had dramatically diagnostic value. APOD, ACKR1 and SFRP4 were associated with the survivals of cervical cancer. C1QTNF7, HSPB6, GSTM5, IGFBP6 and F10 were first reported to be candidate genes of cervical carcinoma.

Abstract Background DNA methylation is an essential epigenetic modification. However, its contribution to trait changes and diversity in the domestication of perennial fruit trees remains unknown. Results Here, we investigate the variation in DNA methylation during pear domestication and improvement using whole-genome bisulfite sequencing in 41 pear accessions. Contrary to the significant decrease during rice domestication, we detect a global increase in DNA methylation during pear domestication and improvement. We find this specific increase in pear is significantly correlated with the downregulation of Demeter-like1 (DML1, encoding DNA demethylase) due to human selection. We identify a total of 5591 differentially methylated regions (DMRs). Methylation in the CG and CHG contexts undergoes co-evolution during pear domestication and improvement. DMRs have higher genetic diversity than selection sweep regions, especially in the introns. Approximately 97% of DMRs are not associated with any SNPs, and these DMRs are associated with starch and sucrose metabolism and phenylpropanoid biosynthesis. We also perform correlation analysis between DNA methylation and gene expression. We find genes close to the hypermethylated DMRs that are significantly associated with fruit ripening. We further verify the function of a hyper-DMR-associated gene, CAMTA2, and demonstrate that overexpression of CAMTA2 in tomato and pear callus inhibits fruit ripening. Conclusions Our study describes a specific pattern of DNA methylation in the domestication and improvement of a perennial pear tree and suggests that increased DNA methylation plays an essential role in the early ripening of pear fruits.

The firmness of table grape berries is a crucial quality parameter. Despite extensive research on postharvest fruit softening, its precise molecular mechanisms remain elusive. To enhance our comprehension of the underlying molecular factors, we initially identified differentially expressed genes (DEGs) by comparing the transcriptomes of folic acid (FA)-treated and water-treated (CK) berries at different time points. We then analyzed the sequences to detect alternatively spliced (AS) genes associated with postharvest softening. A total of 2,559 DEGs were identified and categorized into four subclusters based on their expression patterns, with subcluster-4 genes exhibiting higher expression in the CK group compared with the FA treatment group. There were 1,045 AS-associated genes specific to FA-treated berries and 1,042 in the CK-treated berries, respectively. Gene Ontology (GO) annotation indicated that the AS-associated genes in CK-treated berries were predominantly enriched in cell wall metabolic processes, particularly cell wall degradation processes. Through a comparison between treatment-associated AS genes and subcluster-4 DEGs, we identified eight genes, including Pectinesterase 2 (VvPE2, Vitvi15g00704), which encodes a cell wall-degrading enzyme and was predicted to undergo an A3SS event. The reverse transcription polymerase chain reaction further confirmed the presence of a truncated transcript variant of VvPE2 in the FA-treated berries. Our study provides a comprehensive analysis of AS events in postharvest grape berries using transcriptome sequencing and underscores the pivotal role of VvPE2 during the postharvest storage of grape berries.

Impaired endothelial cell (EC)-mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein-coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39KO) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39WT) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress. [ABSTRACT FROM AUTHOR]