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There are various issues for CO2 flooding and storage in Shengli Oilfield, which are characterized by low light hydrocarbon content of oil and high miscible pressure, strong reservoir heterogeneity and low sweep efficiency, gas channeling and difficult whole-process control. Through laboratory experiments, technical research and field practice, the theory and technology of CO2 high pressure miscible flooding and storage are established. By increasing the formation pressure to 1.2 times the minimum miscible pressure, the miscibility of the medium-heavy components can be improved, the production percentage of oil in small pores can be increased, the displacing front developed evenly, and the swept volume expanded. Rapid high-pressure miscibility is realized through advanced pressure flooding and energy replenishment, and technologies of cascade water-alternating-gas (WAG), injection and production coupling and multistage chemical plugging are used for dynamic control of flow resistance, so as to obtain the optimum of oil recovery and CO2 storage factor. The research results have been applied to the Gao89-Fan142 in carbon capture, utilization and storage (CCUS) demonstration site, where the daily oil production of the block has increased from 254.6 t to 358.2 t, and the recovery degree is expected to increase by 11.6 percentage points in 15 years, providing theoretical and technical support for the large-scale development of CCUS.

Abstract Background Pituitary adenomas (PAs) are the second most common intracranial tumor. While current diagnostic practices rely primarily on histological testing, they often fail to capture the molecular complexities of pituitary adenomas, underscoring the need for a molecular-based classification to refine therapeutic strategies and prognostic assessments. This study aims to provide a molecularly unbiased classification of pituitary adenomas and explore their unique gene expression patterns and clinical features. Methods We performed unsupervised hierarchical clustering of the gene expression profiles of 117 PA samples to identify three distinct molecular subtypes. Subsequently, we analyzed the compiled transcriptomic profiles of each individual subtype for pathway enrichment. We also validated the new classification with a validation set containing 158 PAs and 24 pituitary adenoma stem cells (PASCs). Results Consensus clustering of transcriptomic data from 117 pituitary adenoma (PA) samples identified three distinct molecular subtypes, each showing unique gene expression patterns and associated biological processes: Group I is enriched in signaling pathways, such as the cAMP signaling pathway and the calcium signaling pathway. Group II is primarily related to metabolic processes, including nitrogen metabolism and arginine biosynthesis in cancer. Group III predominantly shows enrichment in immune responses and potential malignant transformation of the disease, especially through cancer-related pathways such as the JAK–STAT signaling pathway and the PI3K–Akt signaling pathway. The immune profiling revealed distinct patterns for each subtype: Group I had higher dendritic cells and fewer CD8+ T cells, Group II had more monocytes and macrophages, and Group III had elevated levels of T cells. Additionally, there were differences in clinical characteristics and prognosis among the subtypes, with Group III having a worse prognosis, despite the smaller tumor size compared to other groups. Notably, differences in PASCs correlated with the molecular subtypes, with Group III stem cells being enriched in tumorigenesis pathways, PI3K–Akt signaling pathway and Ras signaling pathway. Conclusion Our study introduces a novel molecular classification for pituitary adenomas, independent of traditional histological methods. Each subtype features distinct genetic, molecular, and immunological profiles. We have isolated pituitary adenoma stem-like cells (PASCs), pairing them with tumor tissues for detailed transcriptomic analysis. These PASCs exhibit diverse molecular traits consistent with the new classification.

Objectives: We aimed to evaluate the analytical performance of second-trimester maternal serum screening in China, and to compare if there are differences in sigma levels across different methods and months. Methods: A retrospective study was conducted to assess the analytical quality levels of laboratories by calculating the Sigma metrics with prenatal screening biomarkers: AFP, Total β-hCG, free β-hCG, uE3. Data from 591 laboratories were selected. Sigma metrics were computed using the formula: Sigma metrics(σ) = (%TEa - |%Bias|)/%CV. The Friedman test and Mann-Whitney test were used to compare differences across various methods and different months. The Hodges–Lehmann was used for determining 95 % confidence intervals of pseudo-medians. Results: Only uE3 showed significant monthly variations in sigma calculations. However, around 8 % of laboratories across all four analytes demonstrated sigma levels both above 6 and below 3 in different months. Laboratories utilizing time-resolved fluorescence methods significantly outperformed those using chemiluminescence in sigma level. For AFP, the pseudo-median difference between these methods lies within a 95 % confidence interval of (−3.22, −1.93), while for uE3, it is at (−2.30, −1.40). Notably, the median sigma levels for all analytes reached the 4-sigma threshold, with free β-hCG even attaining the 6-sigma level. Conclusion: With current standards, China's second-trimester maternal serum screening is of relatively high analytical quality, and variations in sigma levels exist across different months and methods.

Abstract Layered group IV–VI compounds (i.e., SnSe, SnS, GeSe, and GeS) in the puckered structure resembling black‐phosphorene (BlackP) have attracted increasing interest because of their intriguing ferroic orders and outstanding thermoelectric properties. By invoking the guiding principles of isovalency and isomorphism for promoting van der Waals epitaxy, and based on comprehensive first‐principles calculations, here it is shown that the typically metastable BlackP‐like GeTe can be readily stabilized on the (001) surface of isostructural SnSe. Importantly, the ferroelectricity of such a BlackP‐like GeTe monolayer can be substantially enhanced compared to the freestanding state, due to the substrate enlarged in‐plane polar displacements. The GeTe/SnSe heterobilayer exhibits multiple ferroelectric/ferrielectric polarization states, which can be exploited for high‐density memory devices. These mutually switchable polarization states are also shown to be internally locked with the spin polarization of the valence/conduction bands with pronounced Rashba spin‐orbit splitting and Berry curvature dipole. These findings highlight the intuitive yet enabling power of van der Waals imprinting in growing novel 2D materials for enriched functionalities.

Abstract Background This study aimed to develop an integrated model for predicting the occurrence of postoperative seizures in patients with diffuse high-grade gliomas (DHGGs) using clinical and RNA-seq data. Methods Patients with DHGGs, who received prophylactic anti-epileptic drugs (AEDs) for three months following surgery, were enrolled into the study. The patients were assigned randomly into training (n = 166) and validation (n = 42) cohorts. Differentially expressed genes (DEGs) were identified based on preoperative glioma-related epilepsy (GRE) history. Least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to construct a predictive gene-signature for the occurrence of postoperative seizures. The final integrated prediction model was generated using the gene-signature and clinical data. Receiver operating characteristic analysis and calibration curve method were used to evaluate the accuracy of the gene-signature and prediction model using the training and validation cohorts. Results A seven-gene signature for predicting the occurrence of postoperative seizures was developed using LASSO logistic regression analysis of 623 DEGs. The gene-signature showed satisfactory predictive capacity in the training cohort [area under the curve (AUC) = 0.842] and validation cohort (AUC = 0.751). The final integrated prediction model included age, temporal lobe involvement, preoperative GRE history, and gene-signature-derived risk score. The AUCs of the integrated prediction model were 0.878 and 0.845 for the training and validation cohorts, respectively. Conclusion We developed an integrated prediction model for the occurrence of postoperative seizures in patients with DHGG using clinical and RNA-Seq data. The findings of this study may contribute to the development of personalized management strategies for patients with DHGGs and improve our understanding of the mechanisms underlying GRE in these patients.

Abstract Glioblastoma (GBM) is a highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, whether PFKP and VEGF are reciprocally regulated during GBM tumor growth remains unknown. Here, we show that PFKP can promote EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in both AKT/SP1-mediated transcriptional expression of HIF-1α and in the AKT-mediated β-catenin S552 phosphorylation, to fully enhance VEGF transcription, subsequently promoting blood vessel formation and brain tumor growth. Levels of PFKP Y64 phosphorylation in human GBM specimens are positively correlated with HIF-1α expression, β-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and also suggest that targeting the PFKP/VEGF regulatory loop might show therapeutic potential for treating GBM patients.

Abstract We aimed to develop a new biocompatible gastrin‐releasing peptide receptor (GRPR) targeted optical probe, IRDye800‐RM26, for fluorescence image‐guided surgery (FGS) of brain malignancies in near‐infrared window II (NIR‐II) imaging. We developed a novel GRPR targeting probe using a nine‐amino‐acid bombesin antagonist analog RM26 combined with IRDye800CW, and explored the fluorescent probe according to optical properties. Fluorescence imaging characterization in NIR‐I/II region was performed in vitro and in vivo. Following simulated NIR‐II image‐guided surgery, we obtained time‐fluorescent intensity curves and time‐signal and background ratio curves. Further, we used histological sections of brain from tumor‐beating mice model to compare imaging specificity between 5‐aminolevulinic acid (5‐ALA) and IRDye800‐RM26, and evaluated biodistribution and biocompatibility. IRDye800‐RM26 had broad emission ranging from 800 to 1200 nm, showing considerable fluorescent intensity in NIR‐II region. High‐resolution NIR‐II imaging of IRDye800‐RM26 can enhance the advantages of NIR‐I imaging. Dynamic and real time fluorescence imaging in NIR‐II region showed that the probe can be used to treat brain malignancies in mice between 12 and 24 h post injection. Its specificity in targeting glioblastoma was superior to 5‐ALA. Biodistribution analysis indicated IRDye800‐RM26 excretion in the kidney and liver. Histological and blood test analyses did not reveal acute severe toxicities in mice treated with effective dose (40 μg) of the probe for NIR‐II imaging. Because of the considerable fluorescent intensity in NIR‐II region and high spatial resolution, biocompatible and excretable IRDye800‐RM26 holds great potentials for FGS, and is essential for translation into human use.

Objective: Lower grade gliomas (LGGs), classified as World Health Organization (WHO) grade II and grade III gliomas, comprise a heterogeneous group with a median survival time ranging from 4–13 years. Accurate prediction of the survival times of LGGs remains a major challenge in clinical practice. Methods: We reviewed the expression data of 865 LGG patients from 5 transcriptomics cohorts. The comparative profile of immune genes was analyzed for signature identification and validation. In-house RNAseq and microarray data from the Chinese Glioma Genome Atlas (CGGA) dataset were used as training and internal validation cohorts, respectively. The samples from The Cancer Genome Atlas (TCGA) and GSE16011 cohorts were used as external validation cohorts, and the real-time PCR of frozen LGG tissue samples (n = 36) were used for clinical validation. Results: A total of 2,214 immune genes were subjected to pairwise comparison to generate 2,449,791 immune-related gene pairs (IGPs). A total of 402 IGPs were identified with prognostic values for LGGs. The HOXA9-related and CRH-related scores facilitated identification of patients with different prognoses. An immune signature based on 10 IGPs was constructed to stratify patients into low and high risk groups, exhibiting different clinical outcomes. A nomogram, combining immune signature, 1p/19q status, and tumor grade, was able to predict the overall survival (OS) with c-indices of 0.85, 0.80, 0.80, 0.79, and 0.75 in the training, internal validation, external validation, and tissue sample cohorts, respectively. Conclusions: This study was the first to report a comparative profiling of immune genes in large LGG cohorts. A promising individualized immune signature was developed to estimate the survival time for LGG patients.

Abstract Background Adjuvant temozolomide (TMZ) chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma (HGG). However, the influence of long-term TMZ chemotherapy on serum ions concentration is unclear. Methods One hundred and thirty-eight patients with HGG were included. Their blood samples were collected for blood biochemistry and routine test. The alteration in serum ions concentration, total protein, albumin, globin, and blood cells counts were used to identify the impact of long-term TMZ chemotherapy. Results Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles, we identified that serum potassium concentration had a downward trend after TMZ administration (1st vs. 6th, p < 0.001; 1st vs. 12th, p < 0.001). Additionally, the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles (r = − 0.649, p = 0.023). The hematological adverse events mainly centered on grade 1 to 2. Conclusion Long-term administration of TMZ may lead to serum ions disturbance. Besides the myelosuppression, we should pay attention to the alteration in serum ions concentration, and give patients proper symptomatic treatment when necessary.

BackgroundMacrophages, the major immune cells in glioma microenvironment, are closely related to tumor prognosis. Further studies are needed to investigate macrophages, which will be helpful to fully understand the role of it and early achieve clinical translation.MethodsA total of 1334 glioma cases were enrolled in this study from 3 databases. In our works, the single cell cohorts from GSE89567, GSE84465, and the Chinese Glioma Genome Atlas (CGGA) datasets were used to analyze the key genes of macrophage. The bulk sequencing data from the Cancer Genome Atlas (TCGA) and CGGA datasets were respectively divided into the training set and validation set to test prognostic value of the key genes from single cell analysis.ResultsQuantitative and functional differences significantly emerge in macrophage clusters between LGG and GBM. Firstly, we used the Seurat R package to identify 281 genes differentially expressed genes in macrophage clusters between LGG and GBM. Furthermore, based on these genes, we developed a predictive risk model to predict prognosis and reflect the immune microenvironment in glioma. The risk score calculation formula was yielded as follows: Risk score = (0.11 × EXPMACC1) + (−0.31 × EXPOTUD1) + (−0.09 × EXPTCHH) + (0.26 × EXPADPRH) + (-0.40× EXPABCG2) + (0.21 × EXPPLBD1) + (0.12 × EXPANG) + (0.29 × EXPQPCT). The risk score was independently related to prognosis. Further, significant differences existed in immunological characteristics between the low- and high-risk score groups. What is more, mutation analysis found different genomic patterns associated with the risk score.ConclusionThis study further confirms that the proportion of macrophage infiltration is not only significantly different, but the function of them is also different. The signature, identified from the differentially expressed macrophage-related genes impacts poor prognosis and short overall survival and may act as therapeutic targets in the future.

Summary: Icaritin has shown antitumor activity in a variety of human solid tumors and myeloid leukemia cells. However, the direct target of icaritin and the underlying mechanisms remain unclear. In our study, CDK2 was found to be a direct target of icaritin in tumor cells. On one hand, icaritin interacted with CDK2 and interfered with CDK2/CyclinE complex formation, resulting in downregulation of CDK2 activity as illustrated with attenuated phosphorylation of FOXO1, Rb, and P27, and E2F/Rb dissociation. On the other hand, icaritin reduced the stability and translation efficiency of CDK2-mRNA by modulating microRNA-597 expression. To be of functional importance, icaritin inhibited proliferation and promoted apoptosis of tumor cells in vitro and in vivo, which was consistent with CDK2 inhibitors—k03861. Our data revealed CDK2 as the direct target of icaritin for its antitumor effects, which may suggest new therapeutics of icaritin or combinational therapeutics involving both icaritin and CDK2 inhibitors for cancers.

Production from unconventional oil reservoirs has always been a critical issue for the oil industry. In this regard, we implemented a set of experimental scenarios containing CO2/N2 cyclic injection, the foams generated by nitrogen and carbon dioxide, cyclic carbon dioxide injection, and a combined effect of carbon dioxide and surfactant enhanced oil recovery methods. As water injection has reached a plateau around two pore volume injection, we continued the tests from two pore volume injection for different scenarios. It was observed that CO2/N2-foam has the highest oil recovery factor of 34.9%; however, CO2-foam, regarding more feasibility than N2, witnessed the highest oil recovery factor after CO2/N2-foam. On the other hand, the incremental oil recovery factor for surfactant flooding, carbonated water flooding, and carbonated water with surfactant flooding is measured at 4.9, 8.5, and 10.6%, respectively.

Human C-peptide is secreted in equimolar amounts with insulin by pancreatic beta-cells. Measurement of C-peptide plays an important role in the diagnosis and treatment of diabetes where it is used to evaluate the function of islet cells. However, C-peptide measurement results across different laboratories vary considerably and there is an urgent need to improve comparability between laboratories. As it is sensitive and specific, isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) has made a major contribution and will continue to play a significant role in the standardization of C-peptide measurement. Here, we reviewed the application of ID-LC-MS/MS in C-peptide measurement by discussing the biochemical properties of C-peptide, common sample preparation procedures, and the sensitivity problems often encountered with ID-LC-MS/MS C-peptide measurement. Collectively, these factors are crucial for the development of ID-LC-MS/MS methods for C-peptide measurement. We also discussed the advantages, disadvantages, and progress of implementing ID-LC-MS/MS as a routine measurement tool for C-peptide in clinical laboratories. Finally, we summarized the existing reference system and the status of C-peptide measurement in clinical laboratories to convey the necessity of improving the comparability of C-peptide measurement in clinical laboratories using ID-LC-MS/MS.

The Es4 source rock is the primary source of hydrocarbon in deep reservoirs in the Baxian Sag, Jizhong Depression of Bohai Bay Basin, China, and its quantitative description is useful for understanding hydrocarbon generation and accumulation in the deep basin. The Es4 source rock contains organofacies C, D/E and F, with organofacies C having a thin thickness of less than 40 m and organofacies D/E having a thickness of 50 m and 250 m. The drilled Es4 source rock has a maximum RO of 1.27%, indicating that it is in the late oil window. The kinetic parameters for three organofacies source rock have been obtained from the simulation of gold tube pyrolysis. The result showed that organofacies C, D/E and F source rock entered into the mature level in sequence, but that at 150 °C, the organofacies C will be transformed to around 90% of their original state. For organofacies D/E and F, the hydrocarbon generation potential is still high, with condensate and wet gas dominating.

In this paper, finite-time consensus control method is presented for a robot nonlinear multi-agent system. To achieve the goal of finite-time consensus control in the presence of input saturation as well as external disturbance, a new adaptive-terminal sliding mode control method has been proposed. The adaptive method is used to handle an external disturbance with unknown bound, while the terminal sliding mode makes it possible to achieve finite-time consensus and reduce settling and reaching times. In the proposed method, the resulting control signals are always below the saturation range, and of course the external disturbance is estimated in a limited time. The simulation results on nonlinear multi-agent robot system show the optimal performance of the proposed method.

Background: Methylmalonic acid (MMA) is an essential indicator of vitamin B12 (VB12) deficiency and inherited metabolic disorders (IMDs). The increasing number of requests for MMA testing call for higher requirements for convenient MMA testing methods. This study aims to develop a convenient quantification method for serum MMA. Methods: The method was established based on the stable isotope-dilution liquid chromatography–tandem mass spectroscopy (ID-LC-MS/MS) technique. The LC-MS/MS parameters and sample preparation were optimized. Specificity, sensitivity, robustness, accuracy, and clinical applicability were validated according to CLSI C62-A guidelines. MMA levels in VB12-sufficient subjects and VB12-deficient subjects were measured. Results: MMA and its intrinsic isomer, i.e., succinic acid (SA), were completely separated. The average slope, intercept, and correlation relationship (R) with 95% confidence intervals, during the two months, were 0.992 (0.926–1.059), −0.004 (−0.012–0.004), and 0.997 (0.995–0.999), respectively. The limit of detection and quantification were

Background: Hypoxia-inducible factor 1α (HIF1A), the principal regulator of hypoxia, is involved in the suppression of antitumor immunity. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression.Methods: In this study, 692 patients, whose data were collected from the Chinese Glioma Genome Atlas (CGGA) database, and 669 patients, whose data were collected from The Cancer Genome Atlas database, were enrolled. We further screened the data of a cohort of paired primary and recurrent patients from the CGGA dataset (n = 50). The abundance of immune cells was calculated using the transcriptome data. The association between HIF1A and T-cell exhaustion-related genes and immune cells was investigated.Results: According to the median value of HIF1A expression, gliomas were classified into low-HIF1A-expression and high-HIF1A-expression groups. The expression levels of PDL1 (CD274), FOXO1, and PRDM1 in the high-HIF1A-expression group were significantly higher in both glioblastoma (GBM) and lower-grade glioma. The abundance of exhausted T cells and B cells was significantly higher in the high-HIF1A-expression group, while that of macrophage, monocyte, and natural killer cell was significantly higher in the low-HIF1A-expression group in both GBM and lower-grade glioma. After tumor recurrence, the expression of HIF1A significantly increased, and the correlation between HIF1A expression levels and exhausted T cells and induced regulatory T cells became stronger.Conclusion: In diffuse gliomas, the levels of T-cell exhaustion-associated genes and the abundance of immune cells were elevated under high HIF1A expression. Reversing hypoxia may improve the efficacy of immunotherapy.

Background: Glioma-related epilepsy (GRE) is the most common presenting sign of patients with diffuse glioma. According to clinical experience, new-onset postoperative seizures can be observed even in patients without preoperative GRE. The current study mainly aimed to explore the risk factors of new-onset postoperative seizures in those patients. In addition, the prognostic value of new-onset postoperative seizures was also discussed.Methods: Data of 313 patients without GRE were retrospectively reviewed. Chi-square test or Fisher's exact test were first performed to compare categorical variables between patients with new-onset postoperative seizures and those without. Subsequently, binary logistic regression analysis was conduct to further assess risk factors of new-onset postoperative seizures. Kaplan-Meier and Cox analysis were used to investigate the prognostic value of new-onset postoperative seizures for progression-free survival (PFS) and overall survival (OS).Results: Patients with low-grade tumors (p = 0.006), isocitrate dehydrogenase 1 (IDH1) mutation (p = 0.040) or low Ki-67 expression (p = 0.005) showed a higher incidence of new-onset postoperative seizures. IDH1 mutation was identified as the only independent predictor for new-onset postoperative seizures (OR, 2.075; 95% CI, 1.051–4.098; p = 0.035). Additionally, new-onset postoperative seizure occurrence was demonstrated as an independent predicter of prolonged OS (OR, 0.574; 95% CI, 0.335–0.983; p = 0.043), while younger age, gross total resection, low-grade and IDH1 mutation were independently correlated with prolonged OS and PFS.Conclusions: IDH1 mutation is an independent predictor for new-onset postoperative seizures in patients without preoperative GRE. Moreover, new-onset postoperative seizures can independently predict prolonged OS in those patients. The results of the current study can contribute to improving the individualized management of diffuse glioma.

MicroRNAs (miRNAs) are involved in human glioblastoma (GB). MiR-935 has been reported to have both tumor-inhibiting and tumorigenesis effects, but its role in GB remains unclear. Because of the high mortality and morbidity associated with the malignancy of GB, a deeper understanding of the molecular crosstalk that occurs in GB is needed to identify new potential targets for treatment. At present, the mechanism of GB at the molecular level is not fully understood. With the aid of bioinformatic analysis, miR-935 was significantly downregulated in GB, and it presented a poorer outcome. In the glioma cell line and in the nude mice model, the miR-935 inhibited cell proliferation by modulating cell circles in vitro and in vivo. Then, the target genes of miR-935 were analyzed by using the online database, and the direct binding was tested with a luciferase analysis. FZD6 was found to be the direct target of miR-935. The effect of miR-935 was recovered by the overexpression of FZD6 in vitro. In addition, the negative correlation of miR-935 and the expression of FZD6 were confirmed in our clinical samples, and the expression of FZD6 has a strong correlation with tumor malignancy and prognosis. This study showed that miR-935 directly inhibited the expression of FZD6 and inhibited the cell proliferation, thereby suppressing the development of GB, suggesting that miR-935 is a cancer suppressor miRNA and may become a prognostic biomarker or a promising potential therapeutic target for human GBs.

Glycolysis refers to one of the critical phenotypes of tumor cells, regulating tumor cell phenotypes and generating sufficient energy for glioma cells. A range of noticeable genes [such as isocitrate dehydrogenase (IDH), phosphatase, and tensin homolog (PTEN), or Ras] overall impact cell proliferation, invasion, cell cycle, and metastasis through glycolysis. Moreover, long non-coding RNAs (LncRNAs) are increasingly critical to disease progression. Accordingly, this study aimed to identify whether glycolysis-related LncRNAs have potential prognostic value for glioma patients. First, co-expression network between glycolysis-related protein-coding RNAs and LncRNAs was established according to Pearson correlation (Filter: |r| > 0.5 & P < 0.001). Furthermore, based on univariate Cox regression, the Least Absolute Shrinkage and Selection Operator (LASSO) analysis and multivariate Cox regression, a predictive model were built; vital glycolysis-related LncRNAs were identified; the risk score of every single patient was calculated. Moreover, receiver operating characteristic (ROC) curve analysis, gene set enrichment analysis (GSEA), GO and KEGG enrichment analysis were performed to assess the effect of risk score among glioma patients. 685 cases (including RNA sequences and clinical information) from two different cohorts of the Chinese Glioma Genome Atlas (CGGA) database were acquired. Based on the mentioned methods, the risk score calculation formula was yielded as follows: Risk score = (0.19 × EXPFOXD2-AS1) + (−0.27 × EXPAC062021.1) + (−0.16 × EXPAF131216.5) + (−0.05 × EXPLINC00844) + (0.11 × EXPCRNDE) + (0.35 × EXPLINC00665). The risk score was independently related to prognosis, and every single mentioned LncRNAs was significantly related to the overall survival of patients. Moreover, functional enrichment analysis indicated that the biologic process of the high-risk score was mainly involved in the cell cycle and DNA replication signaling pathway. This study confirmed that glycolysis-related LncRNAs significantly impact poor prognosis and short overall survival and may act as therapeutic targets in the future.

BackgroundThis study aimed to assess the comparability among assays using freshly frozen human sera and external quality assessment (EQA) data in China.MethodsTwenty-nine serum samples and two commercial EQA materials, obtained from the National Center for Clinical Laboratories (NCCL), were analyzed in triplicate using eight routine TSH assays. The commutability of commercial EQA materials (NCCL materials) was evaluated in accordance with the CLSI EP30-A and IFCC bias analysis. Median values obtained for the NCCL EQA materials were used to determine the systematic and commutability-related biases among immunoassays through back-calculation. The comparability of TSH measurements from a panel of clinical samples and NCCL EQA data was determined on the basis of Passing-Bablok regression. Furthermore, human serum pools were used to perform commutable EQA.ResultsNCCL EQA materials displayed commutability among three or five of seven assay combinations according CLSI or IFCC approach, respectively. The mean of systematic bias ranged from -13.78% to 9.85% for the eight routine TSH assays. After correcting for systematic bias, averaged commutability-related biases ranged between -42.26% and 12.19%. After correction for systematic and commutability -related biases, the slopes indicating interassay relatedness ranged from 0.801 to 1.299 using individual human sera, from 0.735 to 1.254 using NCCL EQA data, and from 0.729 to 1.115 using pooled human serum EQA(the commutable EQA).ConclusionsThe harmonization of TSH measurement is challenging; hence, systematic and commutability-related biases should be determined and corrected for accurate comparisons among assays when using human individual serum and the commercial EQA materials.

The prediction of permeability and the evaluation of tight oil reservoirs are very important to extract tight oil resources. Tight oil reservoirs contain enormous micro/nanopores, in which the fluid flow exhibits micro/nanoscale flow and has a slip length. Furthermore, the porous size distribution (PSD), stress sensitivity, irreducible water, and pore wall effect must also be taken into consideration when conducting the prediction and evaluation of tight oil permeability. Currently, few studies on the permeability model of tight oil reservoirs have simultaneously taken the above factors into consideration, resulting in low reliability of the published models. To fill this gap, a fractal permeability model of tight oil reservoirs based on fractal geometry theory, the Hagen–Poiseuille equation (H–P equation), and Darcy’s formula is proposed. Many factors, including the slip length, PSD, stress sensitivity, irreducible water, and pore wall effect, were coupled into the proposed model, which was verified through comparison with published experiments and models, and a sensitivity analysis is presented. From the work, it can be concluded that a decrease in the porous fractal dimension indicates an increase in the number of small pores, thus decreasing the permeability. Similarly, a large tortuous fractal dimension represents a complex flow channel, which results in a decrease in permeability. A decrease in irreducible water or an increase in slip length results in an increase in flow space, which increases permeability. The permeability decreases with an increase in effective stress; moreover, when the mechanical properties of rock (elastic modulus and Poisson’s ratio) increase, the decreasing rate of permeability with effective stress is reduced.

CMTM6, a previously uncharacterized protein, was identified as a critical regulator of PD-L1, which is reported as an immune checkpoint inhibitor, to modulate the T cell activities both in vitro and in vivo of other tumors. However, the role of CMTM6 has so far remained unclear in glioma. To investigate the role of CMTM6 in gliomas, we analyzed the transcriptome level, genomic profiles and its relationship with clinical practice. 1862 glioma samples with transcriptome data were enrolled in this study, including CGGA RNA-seq, TCGA RNA-seq, CGGA-microarray, GSE16011 and IVY GBM databases. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were also obtained. We found that CMTM6 expression was highly correlated with major clinical and molecular characteristics. Cases with high CMTM6 expression were more likely to be predicted as malignant entities and frequent with genomic aberrations of driver oncogenes. Moreover, gene ontology analysis based on significantly correlated genes of CMTM6 expression exhibited that CMTM6 was associated with immune responses and inflammatory activities. CMTM6 was synthetic with other immune checkpoint inhibitors. Additionally, CMTM6 was involved in immune functions via modulating T-lymphocyte-mediated anti-tumor immunity. Finally, high CMTM6 expression was associated with reduced survival time and may serve as a strong indicator of poor prognosis in gliomas. In brief, High level of CMTM6 expression is closely related to high malignant gliomas. Meanwhile, CMTM6 plays an important role in regulating T cell activation and antitumor responses. Therefore, CMTM6 is a promising target for developing immunotherapy of gliomas. Keywords: Glioma, CMTM6, Inflammatory activity, Immune response, Prognosis, Epigenetics

Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis. Here the authors show that PFK1 platelet isoform is upregulated in Glioblastoma and is required for tumor growth mechanistically, such upregulation is due to an increased stability induced by AKT activation via phosphorylation on residue S386.

Abstract Necrosis is a hallmark feature of glioblastoma (GBM). This study investigated the prognostic role of necrotic patterns in GBM using fractal dimension (FD) and lacunarity analyses of magnetic resonance imaging (MRI) data and evaluated the role of lacunarity in the biological processes leading to necrosis. We retrospectively reviewed clinical and MRI data of 95 patients with GBM. FD and lacunarity of the necrosis on MRI were calculated by fractal analysis and subjected to survival analysis. We also performed gene ontology analysis in 32 patients with available RNA-seq data. Univariate analysis revealed that FD 0.46 significantly correlated with poor progression-free survival (p = 0.006 and p = 0.012, respectively) and overall survival (p = 0.008 and p = 0.005, respectively). Multivariate analysis revealed that both parameters were independent factors for unfavorable progression-free survival (p = 0.001 and p = 0.015, respectively) and overall survival (p = 0.002 and p = 0.007, respectively). Gene ontology analysis revealed that genes positively correlated with lacunarity were involved in the suppression of apoptosis and necrosis-associated biological processes. We demonstrate that the fractal parameters of necrosis in GBM can predict patient survival and are associated with the biological processes of tumor necrosis.

Recent evidence has confirmed that a mutation of the isocitrate dehydrogenase (IDH) gene occurs early in gliomagenesis and contributes to suppressed immunity. The present study aimed to determine the candidate genes associated with IDH mutation status that could serve as biomarkers of immune suppression for improved prognosis prediction. Clinical information and RNA-seq gene expression data were collected for 932 glioma samples from the CGGA and TCGA databases, and differentially expressed genes in both lower-grade glioma (LGG) and glioblastoma (GBM) samples were identified according to IDH mutation status. Only one gene, interferon-stimulated exonuclease gene 20 (ISG20), with reduced expression in IDH mutant tumors, demonstrated significant prognostic value. ISG20 expression level significantly increased with increasing tumor grade, and its high expression was associated with a poor clinical outcome. Moreover, increased ISG20 expression was associated with increased infiltration of monocyte-derived macrophages and neutrophils, and suppressed adaptive immune response. ISG20 expression was also positively correlated with PD-1, PD-L1, and CTLA4 expression, along with the levels of several chemokines. We conclude that ISG20 is a useful biomarker to identify IDH-mediated immune processes in glioma and may serve as a potential therapeutic target.

GBM tissues are comprised of not only tumor cells but also tumor-associated nontumor cells, such as stromal cells and immune cells, which dilute the purity of glioma cells and function in glioma biology. However, the roles of miRNAs in modulating glioma purity are not clarified. In total, 838 glioma samples with transcriptome data, including 537 RNAseq data from TCGA project and 301 microarray data from Chinese Glioma Genome Atlas (CGGA project), were recruited into our investigation. Tumor purity, molecular subtypes and IDH status were also available. R language was employed as the main tool for statistical analysis and graphical work. Screening miRNA profiling and paired TCGA samples’ transcriptome data demonstrates that miR-17-5p expression harbors the most significant positive correlation with glioma purity among all miRNAs. CXCL14 shows robust negative correlation with miR-17-5p expression in TCGA and CGGA dataset. miR-17-5p directly targets CXCL14 and functions as a tumor-suppressor of GBM. CXCL14 showed lower expression in proneural subtype and may contribute as a potential marker for proneural subtype in glioma. Genes markedly correlated with CXCL14 are involved in essential functions associated with anti-tumor immune process. CXCL14 has a strong correlation with immune(T cells, Monocytic lineage and Neutrophils) and Fibroblasts within glioma environment. miR-17-5p and CXCL14 exhibited predictive values for high-grade glioma(HGG) patients: Higher miR-17-5p indicated significantly longer survival while lower CXCL14 indicated longer survival. Our results highlight the importance of the miR-17-5p-CXCL14 axis in regulating key steps of anti-tumor immune process and may serve as potential targets of immune treatments for gliomas.

Background: Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs).Method and patients: A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation.Results: We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-κB pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints.Conclusion: Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.

Background: PD-1 plays a critical part in control of immune response to malignancy. Anti-PD-1 treatment is a hopeful strategy to improve the dismal prognosis of gliomas. To characterize the role of PD-1 in diffuse gliomas, we investigated its related biological process at transcriptome level and its clinical prognostic value. Method and patients: Through Chinese Glioma Genome Atlas and TCGA datasets, we systematically reviewed a total of 994 cases with RNA-seq data and analyzed the functional annotation of PD-1 by Gene ontology (GO) analysis. Univariate and multivariate survival analysis were performed in 907 patients with survival data. Results: We found PD-1 was significantly upregulated in glioblastoma and isocitrate dehydrogenase wild type tumors. According to TCGA transcriptional classification scheme, PD-1 expression was higher in tumors of mesenchymal subtype than other subtypes, and shown good predictive value to mesenchymal subtype. GO analysis revealed that genes significantly correlated with PD-1 were involved in essential functions associated with anti-tumor immune process. Through screening transcriptomic data, we found a strong correlation between PD-1 and immune cell populations especially for T cells. In addition, we investigated the association between PD-1 and genes related to its function, and found that PD-1 was significantly correlated with genes including TGFB1, IDO1, CD40, ICOS and SATB1, and other immune checkpoint molecules including CTLA4, LAG3, TIM3 and CD276. Survival analysis suggested that higher PD-1 expression was independently associated with worse prognosis of patients with diffuse gliomas. Conclusion: Our results indicated that PD-1 was involved in key steps of anti-tumor immune process and independently predicted worse prognosis in diffuse gliomas. These findings may expend our understanding of potential anti-PD-1 treatments.

Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma. Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas. R language was used as the main tool for statistical analysis and graphical work. Results: TIM-3 was enriched in glioblastoma (the most malignant glioma) and IDH-wildtype glioma. TIM-3 can act as a potential marker for mesenchymal molecular subtype according to TCGA transcriptional classification scheme in glioma. TIM-3 was closely related to immune functions in glioma, especially T cell mediated immune response to tumor cell and T cell mediated cytotoxicity directed against tumor cell target. Moreover, TIM-3 and PD-L1 played almost exactly the same inflammatory activation functions in glioma. Clinically, high expression of TIM-3 was an independent indicator of poor prognosis. Conclusion: The expression of TIM-3 is closely related to the pathology and molecular pathology of glioma. Meanwhile, in glioma TIM-3 plays a specific role in T cell tumor immune response. Therefore, TIM-3 is a promising target for immunotherapeutic strategies, providing an alternative treatment when glioma gains resistance to antibodies of PD-1/PD-L1.

Glioblastomas (GBM) are comprised of a heterogeneous population of tumor cells, immune cells, and extracellular matrix. Interactions among these different cell types and pro-/anti-inflammatory cytokines may promote tumor development and progression.The objective of this study was to develop a cytokine-related gene signature to improve outcome prediction for patients with primary GBM.Here, we used Cox regression and risk-score analysis to develop a cytokine-related gene signature in primary GBMs from the whole transcriptome sequencing profile of the Chinese Glioma Genome Atlas (CGGA) database (n=105). We also examined differences in immune cell phenotype and immune factor expression between the high-risk and low-risk groups.Cytokine-related genes were ranked based on their ability to predict survival in the CGGA database. The six genes showing the strongest predictive value were CXCL10, IL17R, CCR2, IL17B, IL10RB, and CCL2. Patients with a high-risk score had poor overall survival and progression-free survival. Additionally, the high-risk group was characterized by increased mRNA expression of M2 microglia/macrophage markers and elevated levels of IL10 and TGFβ1.The six cytokine-related gene signature is sufficient to predict survival and to identify a subgroup of primary GBM exhibiting the M2 cell phenotype.

The measurement of cardiac troponin is crucial in the diagnosis of myocardial infarction. The performance of troponin measurement is most conveniently monitored by external quality assessment (EQA) programs. The commutability of EQA samples is often unknown and the effectiveness of EQA programs is limited.Commutability of possible EQA materials was evaluated. Commercial control materials used in an EQA program, human serum pools prepared from patient samples, purified analyte preparations, swine sera from model animals and a set of patient samples were measured for cTnI with 4 assays including Abbott Architect, Beckman Access, Ortho Vitros and Siemens Centaur. The measurement results were logarithm-transformed, and the transformed data for patient samples were pairwise analyzed with Deming regression and 95% prediction intervals were calculated for each pair of assays. The commutability of the materials was evaluated by comparing the logarithmic results of the materials with the limits of the intervals. Matrix-related biases were estimated for noncommutable materials. The impact of matrix-related bias on EQA was analyzed and a possible correction for the bias was proposed.Human serum pools were commutable for all assays; purified analyte preparations were commutable for 2 of the 6 assay pairs; commercial control materials and swine sera were all noncommutable; swine sera showed no reactivity to Vitros assay. The matrix-related biases for noncommutable materials ranged from -83% to 944%. Matrix-related biases of the EQA materials caused major abnormal between-assay variations in the EQA program and correction of the biases normalized the variations.Commutability of materials has major impact on the effectiveness of EQA programs for cTnI measurement. Human serum pools prepared from patient samples are commutable and other materials are mostly noncommutable. EQA programs should include at least one human serum pool to allow proper interpretation of EQA results.

Rab27a belongs to the Rab small GTPase superfamily. The protein is membrane-bound and may be involved in protein transport and small GTPase-mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. However, the prognostic and molecular features of gliomas with Rab27a expression are still unclear.We used a whole-genome mRNA expression microarray dataset of 220 glioma samples from the Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn) as a discovery set. In this set, 220 gliomas, consisting of 97 WHO Grade II gliomas, 34 WHO Grade III gliomas, and 89 WHO Grade IV gliomas, were analyzed using the Kaplan-Meier method. To validate the protein expression of Rab27a, we assayed another 162 glioma samples by immunohistochemistry. Three additional datasets were obtained as validation sets. Gene ontology (GO) analysis and gene set variation analysis (GSVA) were used for the functional annotation of Rab27a in 89 WHO Grade IV gliomas.Rab27a was significantly associated with grade progression and high mortality in all grades of glioma in the discovery set. Rab27a also showed a mesenchymal subtype, G3 subtype and isocitrate dehydrogenase 1 (IDH1) wild-type preference and association with migration. The 3 validation datasets revealed similar findings. Rab27a was more highly expressed in gliomas than in normal brain tissues, and its expression increased with glioma grade progression.Rab27a expression was significantly associated with grade progression and worse prognosis in all grades of gliomas, suggesting Rab27a as a novel biomarker with potentially important therapeutic implications.

BACKGROUND: Recent studies have determined that branched-chain (BCAAs) and aromatic (AAAs) amino acids are strongly correlated with obesity and atherogenic dyslipidemia and are strong predictors of diabetes. However, it is not clear if these amino acids are capable of identifying subjects with coronary artery disease (CAD), particularly with subclinical atherosclerosis who are at risk of developing CAD. METHODS: Four hundred and seventy two Chinese subjects (272 males and 200 females, 42-97 y of age) undergoing physical exams were recruited at random for participation in the cross-sectional study. Serum BCAAs and AAAs were measured using our previously reported isotope dilution liquid chromatography tandem mass spectrometry method. Bilateral B-mode carotid artery images for carotid intima-media thickness (cIMT) were acquired at end diastole and cIMT values more than 0.9 mm were categorized as increased. Correlations of BCAAs with cIMT and other CAD risk factors were analyzed. RESULTS: BCAAs and AAAs were significantly and positively associated with risk factors of CAD, e.g., cIMT, BMI, waist circumference, blood pressure, fasting blood glucose, TG, apoB, apoB/apoAI ratio, apoCII, apoCIII and hsCRP, and were significantly and negatively associated with HDL-C and apoAI. Stepwise multiple linear regression analysis revealed that age (β = 0.175, P

BACKGROUND: Reference intervals of Liver function tests are very important for the screening, diagnosis, treatment, and monitoring of liver diseases. We aim to establish common reference intervals of liver function tests specifically for the Chinese adult population. METHODS: A total of 3210 individuals (20-79 years) were enrolled in six representative geographical regions in China. Analytes of ALT, AST, GGT, ALP, total protein, albumin and total bilirubin were measured using three analytical systems mainly used in China. The newly established reference intervals were based on the results of traceability or multiple systems, and then validated in 21 large hospitals located nationwide qualified by the National External Quality Assessment (EQA) of China. RESULTS: We had been established reference intervals of the seven liver function tests for the Chinese adult population and found there were apparent variances of reference values for the variables for partitioning analysis such as gender(ALT, GGT, total bilirubin), age(ALP, albumin) and region(total protein). More than 86% of the 21 laboratories passed the validation in all subgroup of reference intervals and overall about 95.3% to 98.8% of the 1220 validation results fell within the range of the new reference interval for all liver function tests. In comparison with the currently recommended reference intervals in China, the single side observed proportions of out of range of reference values from our study for most of the tests deviated significantly from the nominal 2.5% such as total bilirubin (15.2%), ALP (0.2%), albumin (0.0%). Most of reference intervals in our study were obviously different from that of other races. CONCLUSION: These used reference intervals are no longer applicable for the current Chinese population. We have established common reference intervals of liver function tests that are defined specifically for Chinese population and can be universally used among EQA-approved laboratories located all over China.

Background: Clinical chemistry tests are most widely used in clinical laboratories, and diverse measurement systems for these analyses are available in China. We evaluated the imprecision of clinical chemistry measurement systems based on internal QC (IQC) data. Methods: IQC data for 27 general chemistry analytes were collected in February each year from 2013 to 2022. Four performance specifications were used to calculate pass rates for CVs of IQC data in 2022. Boxplots were drawn to analyze trends of CVs, and differences in CVs among different groups were assessed using the Mann-Whitney U-test or Kruskal-Wallis test. Results: The number of participating laboratories increased significantly from 1,777 in 2013 to 5,425 in 2022. CVs significantly decreased for all 27 analytes, except creatine kinase and lipase. Triglycerides, total bilirubin, direct bilirubin, iron, and γ-glutamyl transferase achieved pass rates >80% for all goals. Nine analytes with pass rates <80% based on 1/3 allowable total error were further analyzed; the results indicated that closed systems exhibited lower CVs than open systems for all analytes, except total protein. For all nine analytes, differences were significant between tertiary hospitals and non-tertiary hospitals and between accredited and non-accredited laboratories. Conclusions: The CVs of IQC data for clinical chemistry have seen a continuous overall improvement in China. However, there is ample room for imprecision improvement for several analytes, with stricter performance specifications. [ABSTRACT FROM AUTHOR]