Postoperative prognostic nomogram for adult grade II/III astrocytoma in the Chinese Han population.

Background: Prognostic models of glioma have been the focus of many studies. However, most of them are based on Western populations. Additionally, because of the complexity of healthcare data in China, it is important to select a suitable model based on existing clinical data. This study aimed to develop and independently validate a nomogram for predicting the overall survival (OS) with newly diagnosed grade II/III astrocytoma after surgery. Methods: Data of 472 patients with astrocytoma (grades II-III) were collected from Qilu Hospital as training cohort while data of 250 participants from Linyi People's Hospital were collected as validation cohort. Cox proportional hazards model was used to construct the nomogram and individually predicted 1-, 3-, and 5-year survival probabilities. Calibration ability, and discrimination ability were analyzed in both training and validation cohort. Results: Overall survival was negatively associated with histopathology, age, subtotal resection, multiple tumors, lower KPS and midline tumors. Internal validation and external validation showed good discrimination (The C-index for 1-, 3-, and 5-year survival were 0.791, 0.748, 0.733 in internal validation and 0.754, 0.735, 0.730 in external validation, respectively). The calibration curves showed good agreement between the predicted and actual 1-, 3-, and 5-year OS rates. Conclusion: This is the first nomogram study that integrates common clinicopathological factors to provide an individual probabilistic prognosis prediction for Chinese Han patients with astrocytoma (grades II-III). This model can serve as an easy-to-use tool to advise patients and establish optimized surveillance approaches after surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-023-00223-0.

Cyclin-dependent kinase subunit2 (CKS2) promotes malignant phenotypes and epithelial-mesenchymal transition-like process in glioma by activating TGFß/SMAD signaling.

BACKGROUND: Gliomas are a group of primary intracranial tumors with high morbidity and mortality. The previous researches indicated a crucial role of CKS2 (cyclin-dependent kinases regulatory subunit 2) in hepatocellular carcinoma and breast cancer; however, little is known about the molecular mechanism of CKS2 in the tumorigenesis and epithelial-mesenchymal transition-like (EMT) process in glioma. METHODS: Datasets for bioinformatics analysis were obtained from the GEO, TCGA and CGGA databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CKS2 among glioma and brain tissues. Glioma cells were transfected with small interfering RNA/overexpression plasmid against CKS2, then clone formation assay, CCK-8, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the apoptosis rate. Markers of cell invasion, apoptosis, EMT and TGFß/SMAD signaling were evaluated by WB and immunofluorescence (IF) assays. RESULTS: We found that CKS2 overexpression correlates with poor prognosis in human glioma and knockdown of CKS2 could inhibit cell proliferation, migration, invasion, and induced apoptosis in glioma cells. Besides, we also found that knockdown of CKS2 could reverse the EMT process via modulating EMT-related molecules. Glioma cells with overexpression of CKS2 were constructed to confirmed the fact that CKS2 induced nucleocytoplasmic translocation of SMAD2/3 and activated TGFß/SMAD pathway, then upregulated its downstream targets expression, while inhibition of TGFß/SMAD (by TGFß inhibitor LY2157299 or SMAD4 siRNA) could reverse the tumor-promoting effects and malignant phenotype caused by CKS2 overexpression. CONCLUSIONS: We identified CKS2 as a critical contributor to the gliomagenesis, which might provide a novel therapeutic target for inhibiting the spread and infiltration of glioma.

Corrigendum: RAB42 promotes glioma pathogenesis via the VEGF signaling pathway.

[This corrects the article DOI: 10.3389/fonc.2021.657029.].

Multiomics Analysis Reveals Aberrant Metabolism and Immunity Linked Gut Microbiota with Insomnia.

Studies have confirmed that insomnia is related to gut microbiota. Previous research suggests that immunity and metabolism are also associated with insomnia. However, to our knowledge, the integration of these factors has not been investigated in insomnia. Here, we explored the correlations across gut microbiota, serum metabolism, and inflammatory factors in insomnia. Our results showed that the composition and structure of gut microbiota and metabolism in insomnia patients were different from healthy controls. Compared to healthy controls, the relative abundances of Lactobacillus, Streptococcus, and Lactobacillus crispatus were significantly increased in insomniacs. There were five metabolic pathways in insomniacs (glycerophospholipid metabolism; glutathione metabolism; nitrogen metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis) significantly different between the two groups. Moreover, we found that IL-1ß levels were significantly higher in insomnia patients while TNF-α was significantly reduced. We further identified that the changes in the level of IL-1ß and TNF-α were associated with some specific bacteria and metabolites, such as Prevotella amnii, Prevotella buccalis, Prevotella timonensis, and Prevotella colorans. Mediation analysis further determined that the immune factors and metabolites could mediate the relationship between gut microbes and insomnia. IMPORTANCE Our study indicated that systematic inflammation and metabolites might be a pathway linking the gut microbiome with insomnia. These findings provide new insights and a better understanding of gut microbiota's role in insomnia as well as potential novel microbiome-related etiologies for insomnia.

Pivotal interplays between fecal metabolome and gut microbiome reveal functional signatures in cerebral ischemic stroke.

BACKGROUND: Integrative analysis approaches of metagenomics and metabolomics have been widely developed to understand the association between disease and the gut microbiome. However, the different profiling patterns of different metabolic samples in the association analysis make it a matter of concern which type of sample is the most closely associated with gut microbes and disease. To address this lack of knowledge, we investigated the association between the gut microbiome and metabolomic profiles of stool, urine, and plasma samples from ischemic stroke patients and healthy subjects. METHODS: We performed metagenomic sequencing (feces) and untargeted metabolomics analysis (feces, plasma, and urine) from ischemic stroke patients and healthy volunteers. Differential analyses were conducted to find key differential microbiota and metabolites for ischemic stroke. Meanwhile, Spearman's rank correlation and linear regression analyses were used to study the association between microbiota and metabolites of different metabolic mixtures. RESULTS: Untargeted metabolomics analysis shows that feces had the most abundant features and identified metabolites, followed by urine and plasma. Feces had the highest number of differential metabolites between ischemic stroke patients and the healthy group. Based on the association analysis between metagenomics and metabolomics of fecal, urine, and plasma, fecal metabolome showed the strongest association with the gut microbiome. There are 1073, 191, and 81 statistically significant pairs (P < 0.05) in the correlation analysis for fecal, urine, and plasma metabolome. Fecal metabolites explained the variance of alpha-diversity of the gut microbiome up to 31.1%, while urine and plasma metabolites only explained the variance of alpha-diversity up to 13.5% and 10.6%. Meanwhile, there were more significant differential metabolites in feces than urine and plasma associated with the stroke marker bacteria. CONCLUSIONS: The systematic association analysis between gut microbiome and metabolomics reveals that fecal metabolites show the strongest association with the gut microbiome, followed by urine and plasma. The findings would promote the association study between the gut microbiome and fecal metabolome to explore key factors that are associated with diseases. We also provide a user-friendly web server and a R package to facilitate researchers to conduct the association analysis of gut microbiome and metabolomics.

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

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

G-protein Coupled Receptor 34 Promotes Gliomagenesis by Inducing Proliferation and Malignant Phenotype via TGF-Beta/Smad Signaling Pathway.

Background: G-protein coupled receptor 34 (GPR34) is involved in cell motility, differentiation, and mitosis. GPR34 was reported to be highly expressed and play an oncogenic role in several solid tumors. Here, we investigated the mechanisms underlying how GPR34 promotes glioma progression. Methods: Bioinformatic analysis was performed on RNA-seq and clinical data from the gene expression omnibus (GEO), cancer genome atlas (TCGA), and Genotype-Tissue Expression (GTEx) databases. TIMER database and single-sample GSEA (ssGAEA) method were used to investigate the association between the GPR34 expression and immune infiltration level in glioma. Cox regression analysis was employed to ascertain whether the risk signature was an independent prognostic indicator for glioma. The viability and migratory/invasive potential of glioma cells were assessed using Cell Counting Kit-8, colony formation, wound healing, and Transwell assays. Results: We found that GPR34 expression was positively correlated with immune infiltration level and that high GPR34 level may be associated with poor prognosis in glioma. We further found that GPR34 may serve as an independent prognostic marker and prediction factor for the clinicopathological features of glioma. We showed that knocking down GPR34 attenuated the viability and migratory/invasive capacity of glioma cells (U251 and LN229), while GPR34 overexpression exerted the opposite effects. Additionally, core enrichment in the GSEA analysis indicated that GPR34-mediated gliomagenesis was associated with the cell cycle arrest, epithelial-mesenchymal transition (EMT), and activation of the TGF-ß/Smad pathway; furthermore, inhibiting TGF-ß/Smad signaling using LY2157299, a TGF-ß inhibitor, reversed the oncogenic effects and malignant phenotype associated with GPR34 overexpression. Conclusion: GPR34 enhances the malignancy and carcinogenesis of glioma by promoting an EMT-like process, G1/S phase cell cycle transition, and TGF-ß/Smad signaling. Accordingly, GPR34 likely functions as an oncogene in glioma and may represent a potential therapeutic target for this cancer.

RAB42 Promotes Glioma Pathogenesis via the VEGF Signaling Pathway.

Angiogenesis plays an important role in tumor initiation and progression of glioma. Seeking for biomarkers associated with angiogenesis is important in enhancing our understanding of glioma biologically and identifying its new drug targets. RNA-sequencing (RNA-seq) data and matched clinical data were downloaded from the CGGA database. A series of filtering analyses were performed to screen for reliable genes: survival, multivariate Cox, ROC curve filtration, and clinical correlation analyses. After immunohistochemical verification, RAB42 was identified as a reliable gene for further single gene analysis. Afterwards, we performed gene set enrichment analysis (GSEA) and co-expression analysis to establish the related molecular mechanisms and signal pathways in glioma. Finally, the gene functions and the mechanisms were investigated in vitro experiments. A total of 23270 mRNA expression and 1018 glioma samples were included in this study. After the three filtering analyses, we selected ten genes for immunohistochemical verification: KLHDC8A, IKIP, HIST1H2BK, HIST1H2BJ, GNG5, FAM114A1, TMEM71, RAB42, CCDC18, and GAS2L3. Immunostaining demonstrated that RAB42 was significantly expressed on the membrane of glioma tissues but not in normal tissues. These results were verified and validated in GEPIA datasets, and the association between RAB42 with clinical features was also evaluated. Analysis of gene functions indicated that RAB42 activated VEGF signaling pathways and the mechanism was associated with natural killer cell mediated cytotoxicity, JAK-STAT signaling pathway and apoptosis pathways by PI3K/AKT in gliomas. Experiments in vitro suggested that the proliferation and invasion of glioma cells might be inhibited after downregulating of RAB42. And the tumorigenesis promotion of RAB42 may relate to the activation of VEGF signaling pathway. Taken together, this study shows that the overexpression of RAB42 is an independent prognostic factor of adverse prognosis. Its pro-oncogenic mechanism may be associated with the activation of VEGF signaling pathways.

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

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

CUX1 Facilitates the Development of Oncogenic Properties Via Activating Wnt/ß-Catenin Signaling Pathway in Glioma.

Background: Homeobox cut like 1 (CUX1), which often presents aberrated expression in many cancer cells, exerts a crucial role in tumorigenesis. Evidence describing CUX1 in gliomagenesis is scarce, and the effects of CUX1 on the Wnt/ß-catenin pathway have not been reported. Our study aimed to explore the biological functions and molecular mechanisms involved in CUX1 activity in glioma. Methods: Datasets for bioinformatics analysis were obtained from the GEO, TCGA, CGGA, GTEX and CCLE databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CUX1 among glioma and brain tissues. CUX1 knockdown and overexpression vectors were transfected into glioma cell lines, the CCK-8, clone formation assay, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the cell cycle. WB and immunofluorescence (IF) assays were used to explore changes in cell cycle-related and Wnt/ß-catenin signaling protein levels. Results: Overexpression of CUX1 was identified in glioma tissues, and especially in glioblastoma (GBM), when compared to normal controls and correlated with poor prognosis. In comparison with untreated cells, TJ905 glioma cells overexpressing CUX1 showed higher proliferation and invasion abilities and S phase cell-cycle arrest, while the knockdown of CUX1 suppressed cell invasive ability and induced G1 phase arrest. Active Wnt/ß-catenin signaling was enriched and clustered in a CUX1-associated GSEA/GSVA analysis. IF and WB assays indicated that CUX1 regulated the distribution of Axin2/ß-catenin in glioma cells and regulated the expression of proteins downstream of the Wnt/ß-catenin signaling pathway, suggesting that CUX1 served as an upstream positive regulator of the Wnt/ß-catenin pathway. Finally, the knockdown of Axin2 or ß-catenin could reverse the tumor-promoting effects caused by CUX1 overexpression, suggesting that CUX1 induced gliomagenesis and malignant phenotype by activating the Wnt/ß-catenin signaling pathway. Conclusion: Our data suggested that the transcription factor CUX1 could be a novel therapeutic target for glioma with gene therapy.

Temozolomide Drives Ferroptosis via a DMT1-Dependent Pathway in Glioblastoma Cells.

PURPOSE: Temozolomide is used in first-line treatment for glioblastoma. However, chemoresistance to temozolomide is common in glioma patients. In addition, mechanisms for the anti-tumor effects of temozolomide are largely unknown. Ferroptosis is a form of programmed cell death triggered by disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. The present study was performed to elucidate the involvement of ferroptosis in the anti-tumor mechanisms of temozolomide. MATERIALS AND METHODS: We utilized the CCK8 assay to evaluate cytotoxicity. Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), iron, and glutathione (GSH) were measured. Flow cytometry and fluorescence microscope were used to detect the production of reactive oxygen species (ROS). Western blotting, RT-PCR and siRNA transfection were used to investigate molecular mechanisms. RESULTS: Temozolomide increased the levels of LDH, MDA, and iron and reduced GSH levels in TG905 cells. Furthermore, we found that ROS levels and DMT1 expression were elevated in TG905 cells treated with temozolomide and were accompanied by a decrease in the expression of glutathione peroxidase 4, indicating an iron-dependent cell death, ferroptosis. Our results also showed that temozolomide-induced ferroptosis is associated with regulation of the Nrf2/HO-1 pathway. Conversely, DMT1 knockdown by siRNA evidently blocked temozolomide-induced ferroptosis in TG905 cells. CONCLUSION: Taken together, our findings indicate that temozolomide may suppress cell growth partly by inducing ferroptosis by targeting DMT1 expression in glioblastoma cells.

SRT1720 enhances maturity and quality of oocytes in aged mice.

This study aims to investigate the morphology and distribution of mitochondria, spindles, and chromosomes in oocytes of aged mice and examine the effects of SRT1720 on oocyte maturation. C57BL/6J mice were divided into young (4-8 weeks) and aged groups (48-52 weeks). In vitro maturation media contained (0.05, 0.1, and 1.0 µM) SRT1720 and 0.1-µM dimethyl sulfoxide (DMSO control). The rate of chromosome misalignment and spindle misorientation in oocytes of aged mice were significantly higher than that of young mice (P < 0.01). Fluorescence intensity of mitochondria from oocytes of aged mice was significantly lower than that of young mice (P < 0.01). SRT1720 at 0.1 µM significantly improved oocyte maturation, fertilization, and blastocyst formation in aged mice compared with young mice (P < 0.01). Additionally, immunofluorescence intensity of mitochondria, normal spindle morphology, and chromosome alignment were notably enhanced with SRT1720 when compared with the DSMO control group for metaphase II (MII)-stage oocytes matured in vitro (P < 0.01); 0.1-µM SRT1720 enhanced the expression level of SRIT1 in oocytes from aged mice. In summary, the aged mice oocytes showed increased nuclear and cytoplasmic defects, whereas SRT1720 enhanced oocyte maturation and quality. We concluded that 0.1-µM SRT1720 was an appropriate concentration for in vitro maturation media.

Prognostic Value of Eight-Gene Signature in Head and Neck Squamous Carcinoma.

Head and neck cancer (HNC) is the fifth most common cancer worldwide. In this study, we performed an integrative analysis of the discovery set and established an eight-gene signature for the prediction of prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Univariate Cox analysis was used to identify prognosis-related genes (with P < 0.05) in the GSE41613, GSE65858, and TCGA-HNSC RNA-Seq datasets after data collection. We performed LASSO Cox regression analysis and identified eight genes (CBX3, GNA12, P4HA1, PLAU, PPL, RAB25, EPHX3, and HLF) with non-zero regression coefficients in TCGA-HNSC datasets. Survival analysis revealed that the overall survival (OS) of GSE41613 and GSE65858 datasets and the progression-free survival(DFS)of GSE27020 and GSE42743 datasets in the low-risk group exhibited better survival outcomes compared with the high-risk group. To verify that the eight-mRNA prognostic model was independent of other clinical features, KM survival analysis of the specific subtypes with different clinical characteristics was performed. Univariate and multivariate Cox regression analyses were used to identify three independent prognostic factors to construct a prognostic nomogram. Finally, the GSVA algorithm identified six pathways that were activated in the intersection of the TCGA-HNSC, GSE65858, and GSE41613 datasets, including early estrogen response, cholesterol homeostasis, oxidative phosphorylation, fatty acid metabolism, bile acid metabolism, and Kras signaling. However, the epithelial-mesenchymal transition pathway was inhibited at the intersection of the three datasets. In conclusion, the eight-gene prognostic signature proved to be a useful tool in the prognostic evaluation and facilitate personalized treatment of HNSCC patients.

TROAP regulates cell cycle and promotes tumor progression through Wnt/ß-Catenin signaling pathway in glioma cells.

AIMS: Experimental evidence demonstrated a crucial role of TROAP (Trophinin-associated protein) in regulating the cell proliferation of multiple tumors, while TROAP expression and function were largely unknown in glioma. We aimed to investigate the oncogenic role of TROAP and its potential mechanisms in gliomagenesis. METHODS: Four gene expression databases (GEO, TCGA, GTEx and CCLE) were enrolled in our study and used for TROAP expression and survival analysis. TROAP expression was quantified by qRT-PCR, western blot and immunohistochemistry assays in glioma tissues and cell lines. TROAP knockdown and overexpression vector were constructed and transfected into glioma cells. CCK-8, colony formation, transwell, and wound healing assays were used to evaluate cell viability, migration and invasion, flow cytometry to determine cell cycle arrest. Gene set enrichment analysis (GSEA) was conducted to screen the pathway involved in TROAP-high phenotype. The expression of cell cycle and Wnt/ß-Catenin signaling proteins were analyzed by immunofluorescence and western blot. RESULTS: Based on the bioinformatic analysis and a series of functional assays, we found the TROAP was enriched in glioma tissues and cell lines, its overexpression was correlated with the clinicopathologic characteristics and poor prognosis. TROAP knockdown inhibited cell proliferation, migration, invasion, and G1/S cell cycle arrest compared with control group in glioma. Mechanism analysis revealed that TROAP activated Wnt/ß-Catenin pathway and upregulated its downstream targets expression, while silencing ß-Catenin or Axin2 could reverse the tumor-promoting effects caused by TROAP, confirming that TROAP-induced malignant phenotype and tumorigenesis via Wnt/ß-Catenin signaling pathway. CONCLUSION: The present study found that TROAP accelerated the progression of gliomagenesis through Wnt/ß-Catenin pathway, and TROAP might be considered as a novel target for glioma therapy.

An MRI-based radiomics signature as a pretreatment noninvasive predictor of overall survival and chemotherapeutic benefits in lower-grade gliomas.

OBJECTIVES: The aim of this study was to develop and validate a radiomics signature for predicting survival and chemotherapeutic benefits of patients with lower-grade gliomas (LGG). METHODS: Radiomics features were extracted from precontrast axial fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced axial T-1 weighted (CE-T1-w) sequence. Lasso Cox regression model was used for feature selection and radiomics signature building. The radiomics signature was developed in a primary cohort that consisted of 149 LGG patients and was then validated on an entirely new validation cohort that contained 66 LGG patients. A radiomics nomogram for the prediction of OS was established by adding the radiomics to clinicopathologic nomogram which developed with clinical data. RESULTS: A radiomics signature derived from joint CE-T1-w and FLAIR images showed better prognostic performance (C-index, 0.798) than signatures derived from CE-T1-w (C-index, 0.744) or FLAIR (C-index, 0.736) sequences alone. Multivariable Cox regression revealed that the radiomics signature was an independent prognostic factor. One radiomics nomogram integrated the radiomics signature from joint CE-T1-w and FLAIR sequences with the clinicopathologic nomogram outperformed the clinicopathologic nomogram based on clinicopathologic data alone in predicting OS of LGG (C-index, 0.821 vs. 0.692; p < 0.001). Further analysis revealed that patients with higher radiomics signature were prone to benefit from chemotherapy. CONCLUSIONS: The radiomics signature was independent with clinicopathologic data and was a noninvasive pretreatment predictor for LGG patients' survival. Moreover, it could predict which patients with LGG benefit from chemotherapy. KEY POINTS: • A radiomics signature derived from joint CE-T1-w and FLAIR sequences showed better prognostic performance than signatures derived from either single imaging modality. • The radiomics signature is an independent prognostic factor and outperformed clinicopathologic features in predicting overall survival of LGG patients. • The radiomics signature could help preoperatively identify LGG patients who may benefit from chemotherapy.

Modified nodal stage of esophageal cancer based on the evaluation of the hazard rate of the negative and positive lymph node.

BACKGROUND: The study aimed to propose a modified N stage of esophageal cancer (EC) on the basis of the number of positive lymph node (PLN) and the number of negative lymph node (NLN) simultaneously. METHOD: Data from 13,491 patients with EC registered in the SEER database were reviewed. The parameters related to prognosis were investigated using a Cox proportional hazards regression model. A modified N stage was proposed based on the cut-off number of the re-adjusted ratio of the number of PLN (numberPLN) to the number of NLN (numberNLN), which were derived from the comparison of the hazard rate (HR) of numberPLN and numberNLN. The modified N stage was confirmed using the cross-validation method with the training and validation cohort, and it was also compared to the N stage from the American Joint Committee on Cancer (AJCC) staging system (7th edition) using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: The numberPLN on prognosis was 1.042, while numberNLN was 0.968. The modified N stage was defined as follows: N1 stage: the ratio range was from 0 to 0.21; N2 stage: more than 0.21, but no more than 0.48; N3 stage: more than 0.48. The log-rank test indicated that significant survival differences were confirmed among the N1, N2 and N3 sub-groups of patients in the training population. The difference of all the patients using the modified N stage method were more significant than AJCC N stage. The result of ROC analysis indicated that the modified N stage could represent the N stage of EC more accurately. CONCLUSION: The modified N stage based on the re-adjusted ratio of numberPLN to numberNLN can evaluate tumor stage more accurately than the traditional N stage.

Characterization of the Vaginal Microbiome in Women with Infertility and Its Potential Correlation with Hormone Stimulation during In Vitro Fertilization Surgery.

Perturbation of vaginal microbiome of reproductive-age women influences all the phases of a woman's reproductive life. Although studies have shown that dynamic changes in vaginal microbiome can affect pregnancy, its role in secondary infertility (i.e., inability to become pregnant or to carry a pregnancy successfully after previous success in delivering a child) and in vitro fertilization (IVF) remains to be unraveled. To determine the vaginal microbiome in women undergoing in vitro fertilization and embryo transfer (IVF-ET) and investigate its potential correlations with hormone stimulation, we recruited 30 patients with secondary infertility and receiving IVF and 92 matched healthy women and analyzed their vaginal microbiome composition using 16S rRNA gene sequencing. Our results show that women suffering from infertility (infertile women) exhibit a significant decrease in microbiome diversity and richness compared with healthy women during the nonovulation period (follicular phase) (P < 0.01), whereas vaginal microbiome of healthy women reveals dramatic fluctuations during ovulation (P < 0.05). Interestingly, infertility patients show no change of the vaginal microbiome under conditions of gonadotropin-releasing hormone (GnRH) agonist and recombinant human chorionic gonadotropin (r-hCG) induction (P > 0.05). Moreover, our results indicate that infertile women show characteristic variations in vaginal microbiome, such as increased abundance of Atopobium, Aerococcus, and Bifidobacterium and decreased abundance of Lactobacillus and Leuconostoc IMPORTANCE The microbiome had been hypothesized to be involved in the physiology and pathophysiology of assisted reproduction before the first success in IVF, while the data supporting or refuting this hypothesis were less than conclusive. Thanks to sequencing data from the 16S rRNA subunit, we characterized the microbiome in the reproductive tract of infertile women, and we found that changes in the vaginal microbiome are related to female infertility. We also found that the characteristic microbiome bacteria are mainly members of several genera and that the vaginal microbiome of infertile women is not sensitive to hormonal changes during IVF. In conclusion, our report provides data that can be used for discovering the role of the vaginal microbiome in patients suffering from secondary infertility.

Blood Loss Leads to Increase in Relative Abundance of Opportunistic Pathogens in the Gut Microbiome of Rabbits.

Massive blood loss, a common pathological complication in the clinic, is often accompanied by altered gut integrity and intestinal wall damage. Little is known to what extent the gut microbiome could be correlated with this process. The gut microbiome plays a crucial role in human health, especially in immune and inflammatory responses. This study aims to determine whether acute blood loss affects the gut microbiome and the dynamic variation of the gut microbiome following the loss of blood. We used New Zealand rabbits to mimic the blood loss complication and designed a five-time-point fecal sampling strategy including 24-h pre-blood loss procedure, 24 h, 36 h, 48 h, and 1-week post-blood loss procedure. Gut microbiome composition and diversity were analyzed using 16S rRNA gene sequencing and downstream α-diversity, ß-diversity, and taxonomy analysis. The gut microbiome changed dramatically after blood loss procedure. There was a significant increase in diversity and richness of the gut microbiome at 24-h post-procedure (P = 0.038). Based on an analysis of similarities, the composition of gut microbiome in the samples collected at 24-h post-procedure was significantly different from that of pre-procedure samples (r = 0.79, P = 0.004 weighted unifrac distance; r = 0.99, P = 0.002, unweighted unifrac distance). The relative abundance of Lactobacillus was significantly decreased in the post-procedure samples (P = 0.0006), while the relative abundance of Clostridiales (P = 0.018) and Bacteroidales (P = 0.015) was significantly increased after procedure. We also found the relative abundance of Bacilli, Lactobacillus, Myroides, and Prevotella decreased gradually at different time points after blood loss. The relative abundance of the Clostridia, Alphaproteobacteria, and Sporosarcina increased at 24-h post-procedure and decreased thereafter. This preliminary study discovered potential connections between blood loss and dysbiosis of gut microbiome. The diversity and abundance of the gut microbiome was affected to various extents after acute blood loss and unable to be restored to the original microbiome profile even after one week. The increase in relative abundance of opportunistic pathogens after blood loss could be an important indication to reconsider immune and inflammatory responses after acute blood loss from the perspective of gut microbiome.

The dual roles of autophagy in gliomagenesis and clinical therapy strategies based on autophagic regulation mechanisms.

Autophagy, a self-digestion intracellular catabolic process, plays a crucial role in cellular homeostasis under conditions of starvation, oxidative stress and genotoxic stress. The capability of maintaining homeostasis contributes to preventing malignant behavior in normal cells. Many studies have provided compelling evidence that autophagy is involved in brain tumor recurrence and chemotherapy and radiotherapy resistance. Gliomas, as the primary central nervous system (CNS) tumors, are characterized by rapid, aggressive growth and recurrence and have a poor prognosis and bleak outlook even with modern multimodality strategies involving maximal surgical resection, radiotherapy and alkylating agent-based chemotherapy. Autophagy-associated signaling pathways, such as the extracellular signal-regulated kinase1/2 (ERK1/2) pathway, class I phosphatidylinositol 3-phosphate kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and nuclear factor kappa-B (NF-κB) pathway, act as tumor suppressors or protect tumor cells against chemotherapy/radiotherapy-induced cytotoxicity in gliomagenesis. Through these pathways, both lethal autophagy and protective autophagy play crucial roles in tumor initiation, chemoresistance and glioma stem cell differentiation. Moreover, lethal autophagy and protective autophagy have been identified as novel therapeutic targets in glioma according to the mechanisms described above. Here, we discuss the multiple impacts of the autophagic response on distinct phases of gliomagenesis and the advanced progress of therapies based on this concept.

Upregulated Expression of CUX1 Correlates with Poor Prognosis in Glioma Patients: a Bioinformatic Analysis.

Cut-like homeobox-1 (CUX1) is expressed in the upper layer of the cortex and participates in DNA replication, cell cycle control, and DNA repair. It has been shown to be involved in the proliferation of various types of solid tumors. The aims of this study were to explore the relationship between CUX1 expression and the prognosis of glioma by performing a series of functional experiments and bioinformatic analyses. Firstly, we found that CUX1 expression levels differed among patients with different grades of gliomas, and they were significantly correlated with the prognosis of glioma patients according to an analysis of data from a public database. qRT-PCR, western blotting, and immunohistochemical analysis of CUX1 were performed to demonstrate that the expression of CUX1 was positively correlated with the glioma WHO grade (P < 0.05) and several malignant clinical pathological parameters, including Ki67 and P53mut. In addition, the multivariate Cox regression and Kaplan-Meier curves showed that CUX1 expression exerted predictive value for overall survival. Finally, to further investigate the functions of CUX1, we identified CUX1-associated genes and, though GO/KEGG analysis, their associated biological functions and signaling pathways; the results suggested that the activity of CUX1 might be exerted via the JAK-STAT pathway or other key regulators of the cell cycle to promote proliferation, inflammation, and chemotherapy resistance in glioma. Taken together, these results indicate that CUX1 is a potential biomarker of malignancy and prognosis and may serve as a potential therapeutic target for glioma patients.