Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis.

Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

FHOD1 is upregulated in glioma cells and attenuates ferroptosis of glioma cells by targeting HSPB1 signaling.

BACKGROUND: As a new type of regulatory cell death, ferroptosis has been proven to be involved in cancer pathogenesis and therapeutic response. However, the detailed roles of ferroptosis or ferroptosis-associated genes in glioma remain to be clarified. METHODS: Here, we performed the TMT/iTRAQ-Based Quantitative Proteomic Approach to identify the differentially expressed proteins between glioma specimens and adjacent tissues. Kaplan-Meier survival was used to estimate the survival values. We also explored the regulatory roles of abnormally expressed formin homology 2 domain-containing protein 1 (FHOD1) in glioma ferroptosis sensitivity. RESULTS: In our study, FHOD1 was identified to be the most significantly upregulated protein in glioma tissues. Multiple glioma datasets revealed that the glioma patients with low FHOD1 expression displayed favorable survival time. Functional analysis proved that the knockdown of FHOD1 inhibited cell growth and improved the cellular sensitivity to ferroptosis in glioma cells T98G and U251. Mechanically, we found the up-regulation and hypomethylation of HSPB1, a negative regulator of ferroptosis, in glioma tissues. FHOD1 knockdown could enhance the ferroptosis sensitivity of glioma cells via up-regulating the methylated heat-shock protein B (HSPB1). Overexpression of HSPB1 significantly reversed FHOD1 knockdown-mediated ferroptosis. CONCLUSIONS: In summary, this study demonstrated that the FHOD1-HSPB1 axis exerts marked regulatory effects on ferroptosis, and might affect the prognosis and therapeutic response in glioma.

Immunogenic cell death related risk model to delineate ferroptosis pathway and predict immunotherapy response of patients with GBM.

Immunogenic cell death (ICD) is a type of cell death that leads to the regulation and activation of the immune response, which is marked by the exposure and delivery of damage-associated molecular patterns (DAMPs) in the tumor microenvironment. Accumulating evidence has revealed the significance of ICD-related genes in tumor progression and therapeutic response. In this study, we obtained two ICD-related clusters for glioblastoma (GBM) by applying consensus clustering, and further constructed a risk signature on account of the prognostic ICD genes. Based on the risk signature, we found that higher risk scores were associated with worse patient prognosis. Besides, the results illustrated that ferroptosis regulators/markers were highly enriched the high-risk group, and ferroptosis were correlated with cytokine signaling pathway and other immune-related pathways. We also discovered that high-risk scores were correlated to specific immune infiltration patterns and good response to immune checkpoint blockade (ICB) treatment. In conclusion, our study highlights the significance of ICD-related genes as prognostic biomarkers and immune response indicators in GBM. And the risk signature integrating prognostic genes possessed significant potential value to predict the prognosis of patients and the efficacy of ICB treatment.

Molecular insight into pentraxin-3: Update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role.

Pentraxin-3 (PTX3) is the prototype of the long pentraxin subfamily, an acute-phase protein consisting of a C-terminal pentraxin domain and a unique N-terminal domain. PTX3 was initially isolated from human umbilical vein endothelial cells and human FS-4 fibroblasts. It was subsequently found to be also produced by synoviocytes, chondrocytes, osteoblasts, smooth muscle cells, myeloid dendritic cells, epithelial cells, and tumor cells. Various modulatory factors, such as miRNAs, cytokines, drugs, and hypoxic conditions, could regulate the expression level of PTX3. PTX3 is essential in regulating innate immunity, inflammation, angiogenesis, and tissue remodeling. Besides, PTX3 may play dual (pro-tumor and anti-tumor) roles in oncogenesis. PTX3 is involved in the occurrence and development of many non-cancerous diseases, including COVID-19, and might be a potential biomarker indicating the prognosis, activity,and severity of diseases. In this review, we summarize and discuss the potential roles of PTX3 in the oncogenesis and pathogenesis of non-cancerous diseases and potential targeted therapies based on PTX3.

Hyaluronic acids mediate the infiltration, migration, and M2 polarization of macrophages: evaluating metabolic molecular phenotypes in gliomas.

Gliomas cause high mortality around the world. The metabolic pattern of the tumor was previously suggested to be associated with the patient's survival outcome and immune activity. Yet, this relationship in glioma remains unknown. This study systematically evaluated the immune landscape in different phenotypes classified by metabolic-related pathways of 3068 glioma samples and 33 glioblastoma single-cell sequencing samples. Machine learning prediction analysis of microarray with R (pamr) was used for validating clustering results. A total of 5842 pan-cancer samples were used for external validation of the metabolic clusters. Cell Counting Kit-8 (CCK8) assay, cell clone assay, EdU assay, wound healing assay, Transwell assay, and co-culture assay were performed to verify the distinction in molecular characteristics among metabolic clusters. Metabolomics and RNA sequencing were performed on HS683 and U251 cells to annotate potential hyaluronic acid (HA)-mediated pathways. Three distinct metabolic phenotypes were identified. Metabolic cluster 1 correlated with a high number of immune infiltrating cells and poor survival of glioma patients. Metabolic clusters were proved with different levels of the macrophage markers CD68 and CD163 by multiplex immunofluorescence staining. Glioma cells from other metabolic clusters also expressed various levels of HA. HA was further found to mediate glioma proliferation, progression, and invasion. Moreover, HA potentially promoted macrophage recruitment and M2 polarization through the IL-1/CHI3L1 and TGF-b/CHI3L1 axes. HA also regulated the expression of PD-L1. This work revealed the significant connection between metabolic patterns, especially HA, and tumor immune infiltration in gliomas.

PTX3 mediates the infiltration, migration, and inflammation-resolving-polarization of macrophages in glioblastoma.

INTRODUCTION: Pentraxin 3 (PTX3) is an essential regulator of the immune system. However, the immune-modulatory role of PTX3 in the tumor microenvironment of glioma has not been elucidated. METHODS: The RNA seq samples were obtained from The Cancer Genome Atlas (TCGA) and the China Glioma Genome Atlas (CGGA) datasets. The single-cell sequencing data of glioblastoma (GBM) samples were obtained from the Single Cell Portal platform (http://singlecell.broadinstitute.org). Immunohistochemistry was used to assess PTX3 expression, HAVCR2, PD-1, PD-L1, and CD276 in glioma sections from the Xiangya cohort (n = 60). Multiplex immunofluorescence staining of PTX3, CD68, and CD163 was performed in several solid cancer types, including GBM. HMC3 was cocultured with U251 and U87, and transwell assay and flow cytometry assay were performed to explore the migration and polarization activity of HMC3. RESULTS: PTX3 expression is significantly increased in GBM. PTX3 expression predicts worse survival in the Xiangya cohort. PTX3 is closely related to the expression of PD-1, PD-L1, CD276, and HAVCR2 in the tumor microenvironment. Additionally, PTX3 is involved in tumorigenic and immunogenic processes, especially the activity of macrophages based on various signaling pathways in cellular communications and critical transcription factors. Specifically, PTX3 actively mediates macrophages' infiltration, migration, and inflammation-resolving-polarization. PTX3 could also predict immunotherapy response. CONCLUSION: PTX3 is critically involved in macrophage infiltration, migration, and inflammation-resolving-polarization and modulates an immunosuppressive microenvironment.

Prognostic Factors and Treatment Strategies for Elderly Patients with Malignant Meningioma: A SEER Population-Based Study.

Objective: Malignant meningioma (MM) is a relatively rare disease with poor survival. Few studies had focused on MM in the elderly population. This study aims to explore the prognostic factors and optimal therapeutic strategy in elderly patients with MM. Methods: We took advantage of the Surveillance, Epidemiology, and End Results (SEER) database to include 275 adult patients with histologically confirmed MM between 2011 and 2018. The Kaplan-Meier curves were plotted by different covariates to reveal the survival probability. Univariate and multivariable Cox proportional hazard regression analyses were applied to identify prognostic factors for cancer-specific survival (CSS). Results: The multivariable analysis in the elderly group revealed that when compared with patients receiving gross total resection (GTR), patients receiving biopsy had significantly worse CSS (HR = 3.72; 95% CI: 1.35-10.21; P = 0.011), whereas patients receiving subtotal resection (STR) had nearly the same CSS (HR = 0.83; 95% CI: 0.37-1.86; P = 0.653). Meanwhile, postoperative radiotherapy (PORT) showed no significant association with CSS in the elderly patient group (HR = 0.94; 95% CI: 0.42-2.12; P = 0.888). Conclusion: Surgical resection is recommended for elderly patients with MM in the absence of surgical contraindications, but GTR does not present survival benefit in the elderly patients compared with STR. Additional large-scale clinical studies are needed to explore the survival benefit of PORT applied in patients with MM.

Outcome of Endoscopic Transsphenoidal Surgery for Recurrent or Residual Pituitary Adenomas and Comparison to Non-Recurrent or Residual Cohort by Propensity Score Analysis.

Objective: To evaluate the long-term outcomes and safety of endoscopic transsphenoidal surgery (ETS) in recurrent and residual pituitary adenomas (rrPAs), as well as the predictors of gross total resection (GTR) and intraoperative CSF leakage. Furthermore, to compare outcomes and complications with non-rrPAs cohort. Methods: Clinical and radiological characteristics of patients with rrPAs who underwent ETS were collected between 2017 and 2020. Data of patients with non-rrPAs were collected from 2019 to 2020. Logistic regression analyses were performed to investigate the factors influencing gross total resection (GTR) and intraoperative CSF leakage. Between-group comparisons of outcomes and complications were performed through propensity score analysis. Results: We enrolled 73 patients with rrPAs. GTR was achieved in 41 (56.1%) cases; further, GTR or near-total resection was achieved in 93.2% of patients. The mean tumor volumes for GTR and non-GTR cases were 6.2 ±7.2 cm3 and 11.1 ±9.1 cm3, respectively. Multivariate regression analysis of the GTR rate in patients with rrPAs revealed that Knosp grade was an independent factor (odds ratio [OR] = 0.324; p=0.005). Moreover, previous transcranial surgery and non-functional pituitary adenomas were risk factors for intraoperative CSF leakage in patients with rrPAs (OR=6.450, p=0.019 and OR=7.472, p=0.012, respectively). After propensity score matching, There was no significant difference in the GTR rate between patients with rrPAs and patients with non-rrPAs. Contrastingly, patients with rrPAs had a higher rate of intraoperative CSF leakage and longer postoperative hospital stay than patients with non-rrPAs. During the follow-up, vision improved in 9 (22.0%) and 24 (62.5%) patients with rrPAs and non-rrPAs, respectively. Although there was a trend that reoperation of rrPAs involved a lower hypopituitarism recovery rate and biochemical remission rate, as well as a higher hypopituitarism rate, there was no statistically significant between-group difference. Conclusions: Knosp grade was an independent factor for GTR in endoscopic transsphenoidal surgery in patients with rrPAs. Previous transcranial surgery and non-functional PAs were risk factors for intraoperative CSF leakage. Although associated with longer hospital stay, rrPAs did not associate with lower GTR rate or more frequent postoperative complications than non-rrPAs cohort.

Large-Scale Single-Cell and Bulk Sequencing Analyses Reveal the Prognostic Value and Immune Aspects of CD147 in Pan-Cancer.

CD147 plays an important role in promoting tumor proliferation and inhibiting cancer cell apoptosis in the tumor microenvironment. However, the mechanisms by which CD147 is involved in tumorigenesis remains unclear. This study systematically analyzed the prognostic value and immune characteristics of CD147 in 31 cancer types. The expression levels and mutant landscapes of CD147 in pan-cancer were explored. The Kaplan-Meier (KM) analysis was applied to analyze the prognostic value of CD147. The immune characteristics of CD147 in the tumor microenvironment were evaluated via TIMER 2.0 and R package (immunedeconv). We also explored the expression of CD147 on tumor cells and stromal cells through Gene Set Variation Analysis and single-cell sequencing analysis. The co-expression of CD147 and macrophage markers CD68 and CD163 in pan-cancer was detected using multiplex immunofluorescence staining on tissue microarrays. CD147 was found to be overexpressed in almost all cancer types, which was related to poor outcome. CD147 expression exhibited a strong association with immune infiltrates, immune checkpoint molecules, and neoantigen levels in the tumor microenvironment. In addition, CD147 was expressed on various cell types in the tumor microenvironment, including tumor cells, macrophages, T cells, monocytes, fibroblasts, etc. Furthermore, multiplex immunofluorescence revealed the co-expression pattern of CD147 and macrophage markers CD68 and CD163 in many tumor types. Finally, the immunotherapy response and sensitive small molecule drugs based on CD147 expression were predicted. In sum, CD147 has a significant relationship with the clinical outcome and immune infiltrates in multiple cancer types. Inhibiting the CD147-dependent signaling pathways might be a promising therapeutic strategy for tumor immunotherapy.

The AlkB Family: Potential Prognostic Biomarkers and Therapeutic Targets in Glioblastoma.

The AlkB family of Fe (II) and α-ketoglutarate-dependent dioxygenases works by removing alkyl substituents from alkylation-damaged nucleic acid bases through oxidative dealkylation, subsequently affecting tumor progression and patient prognosis. However, the specific roles of the AlkB family in Glioblastoma remain to be elucidated. By taking advantage of the abundant bioinformatics databases, such as GEPIA2, cBioPortal and TIMER, we performed a comprehensive analysis of the AlkB family in GBM, and managed to identify the significant prognostic hallmarks and therapeutic targets within this family. We found that the expression levels of ALKBH2 and ALKBH8 were significantly up-regulated in GBM compared with normal tissues. Meanwhile, the patients with high levels of ALKBH2 and ALKBH8 possessed significant poor overall survival (OS). In addition, the results suggested that the biological function of the AlkB family was closely related to DNA damage repair, cell metabolism, cell proliferation and tumor immune infiltration in GBM. Furthermore, the high expression of ALKBH8 in GBM was verified by immunohistochemistry. Taken together, this study could provide meaningful information about the aberrant AlkB family associated with GBM initiation and progression, and help clinicians precisely predict patient survival and select alternative therapeutic drugs.

Retrospective Study on the Application of Enhanced Recovery After Surgery Measures to Promote Postoperative Rehabilitation in 50 Patients With Brain Tumor Undergoing Craniotomy.

OBJECTIVE: To investigate whether enhanced recovery after surgery (ERAS) can promote rehabilitation of patients after neurosurgical craniotomy. METHODS: The clinical data of 100 patients with brain tumor undergoing craniotomy in the Department of Neurosurgery, Xiangya Hospital, Central South University, from January 2018 to August 2020 were collected, including 50 patients in the ERAS group and 50 patients in the control group. t-Test, Wilcoxon's rank sum test, and chi-square analysis were used to compare the clinical characteristics, prognosis, and hospitalization time between the two groups. RESULTS: There was no significant difference in gender, age, and other general clinical data between the two groups (p > 0.05). The days of antiemetic drugs applied in the ERAS group were less than those in the control group (1.00 vs. 2.00 days, p = 0.003), and the proportion of patients requiring analgesics was lower than that of the control group (30% vs. 52%, OR = 0.41, 95% CI 0.18-0.93, p = 0.031). The time of urinary catheter removal and that of patients starting ambulation in the ERAS group were shorter than those in the control group (16.00 vs. 24.00 h, and 1.00 vs. 2.00 days, p < 0.001, respectively); and the hospital length of stay (LOS) in the ERAS group was shorter than that in the control group (Total LOS, 13.00 vs. 15.50 days; Postoperative LOS, 7.00 vs. 10.00 days, p < 0.001). By analyzing the prognosis of patients in the ERAS group and control group, we found that there was no significant difference in postoperative complications and Karnofsky Performance Status (KPS) score 1 month after operation between the two groups. CONCLUSION: The application of ERAS in craniotomy can accelerate the postoperative recovery of patients without increasing the perioperative risk, which is worthy of wide application. However, whether the ERAS measures can reduce the postoperative complications and improve the prognosis of patients still needs more large-scale case validation and multicenter collaborative study.

The molecular feature of macrophages in tumor immune microenvironment of glioma patients.

BACKGROUND: Gliomas are one of the most common types of primary tumors in central nervous system. Previous studies have found that macrophages actively participate in tumor growth. METHODS: Weighted gene co-expression network analysis was used to identify meaningful macrophage-related gene genes for clustering. Pamr, SVM, and neural network were applied for validating clustering results. Somatic mutation and methylation were used for defining the features of identified clusters. Differentially expressed genes (DEGs) between the stratified groups after performing elastic regression and principal component analyses were used for the construction of MScores. The expression of macrophage-specific genes were evaluated in tumor microenvironment based on single cell sequencing analysis. A total of 2365 samples from 15 glioma datasets and 5842 pan-cancer samples were used for external validation of MScore. RESULTS: Macrophages were identified to be negatively associated with the survival of glioma patients. Twenty-six macrophage-specific DEGs obtained by elastic regression and PCA were highly expressed in macrophages at single-cell level. The prognostic value of MScores in glioma was validated by the active proinflammatory and metabolic profile of infiltrating microenvironment and response to immunotherapies of samples with this signature. MScores managed to stratify patient survival probabilities in 15 external glioma datasets and pan-cancer datasets, which predicted worse survival outcome. Sequencing data and immunohistochemistry of Xiangya glioma cohort confirmed the prognostic value of MScores. A prognostic model based on MScores demonstrated high accuracy rate. CONCLUSION: Our findings strongly support a modulatory role of macrophages, especially M2 macrophages in glioma progression and warrants further experimental studies.

Suppression of DLBCL Progression by the E3 Ligase Trim35 Is Mediated by CLOCK Degradation and NK Cell Infiltration.

The majority of diffuse large B-cell lymphoma (DLBCL) patients develop relapsed or refractory disease after standard ruxolitinib, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, which is partly related to a dysregulated tumor immune microenvironment. However, how the infiltration of immune cells is appropriately regulated is poorly understood. Herein, we show that the E3 ubiquitin ligase Trim35 is expressed at low levels in human DLBCL tissues. We also show that overexpression of Trim35 suppresses DLBCL cell proliferation and correlates with inferior survival in DLBCL patients. Our mechanistic study shows that Trim35 functions as an E3 ligase to mediate the ubiquitination and degradation of CLOCK, a key regulator of circadian rhythmicity. High expression of Trim35 correlates with NK cell infiltration in DLBCL, partly due to the degradation of CLOCK. Consistently, patients with high expression of CLOCK show poor overall survival. Overall, these findings suggest that Trim35 suppresses the progression of DLBCL by modulating the tumor immune microenvironment, indicating that it may be a promising diagnostic and prognostic biomarker in DLBCL.

Competing risk model to determine the prognostic factors and treatment strategies for elderly patients with glioblastoma.

The prognostic factors and optimal treatment for the elderly patient with glioblastoma (GBM) were poorly understood. This study extracted 4975 elderly patients (≥ 65 years old) with histologically confirmed GBM from Surveillance, Epidemiology and End Results (SEER) database. Firstly, Cumulative incidence function and cox proportional model were utilized to illustrate the interference of non-GBM related mortality in our cohort. Then, the Fine-Gray competing risk model was applied to determine the prognostic factors for GBM related mortality. Age ≥ 75 years old, white race, size > 5.4 cm, frontal lobe tumor, and overlapping lesion were independently associated with more GBM related death, while Gross total resection (GTR) (HR 0.87, 95%CI 0.80-0.94, P = 0.010), radiotherapy (HR 0.64, 95%CI 0.55-0.74, P < 0.001), chemotherapy (HR 0.72, 95%CI 0.59-0.90, P = 0.003), and chemoRT (HR 0.43, 95%CI 0.38-0.48, P < 0.001) were identified as independently protective factors of GBM related death. Based on this, a corresponding nomogram was conducted to predict 3-, 6- and 12-month GBM related mortality, the C-index of which were 0.763, 0.718, and 0.694 respectively. The calibration curve showed that there was a good consistency between the predicted and the actual mortality probability. Concerning treatment options, GTR followed by chemoRT is suggested as optimal treatment. Radiotherapy and chemotherapy alone also provide moderate clinical benefits.

The Survival Benefits of Surgical Resection and Adjuvant Therapy for Patients With Brainstem Glioma.

PURPOSE: The role of surgical resection in the treatment of brainstem glioma (BSG) is poorly understood. For pediatric low-grade (LGBSG) group, several monocentric small-scale retrospective studies reported contradictory conclusions. And there was no clinical study focused on surgical resection for adult or pediatric high-grade (HG) patient groups. This study aims to illustrate whether surgical resection and adjuvant therapy provide survival benefits for patients with histologically confirmed BSG. PATIENTS AND METHODS: This retrospective cohort study included 529 patients with histologically confirmed BSG in Surveillance Epidemiology and End Results (SEER) database from 2006-2015. Patients were divided into four groups by age and World Health Organization (WHO) grade. Kaplan-Meier curves of CSS were plotted by different treatment options to compare the survival probability. Univariate and multivariable analyses were then conducted to determine the prognosis effects of surgical resection and adjuvant therapy on cancer specific survival (CSS). All analyses were done in four different groups separately. RESULTS: The final sample included 529 patients. The entire study population was divided into groups of pediatric LG (n=236, 44.6%), pediatric HG (n=37, 7.0%), adult LG (n=204, 38.6%) and adult HG (n=52, 9.8%). 52.7% (n=144) of pediatric patients had pilocytic astrocytoma and 45.3% (n=116) of adult patients had ependymoma. Pediatric LGBSG group had the highest gross total resection (GTR) rate (61.4%) and 5-year CSS rate (88.6%). Kaplan-Meier curves of pediatric LGBSG group revealed that patients treated with GTR had significantly better survival probability (P=0.033). Multivariable analysis identified GTR as independently significant predictor for prolonged CSS in pediatric LGBSG group (HR0.29, 95%CI 0.11-0.78, P=0.015); Surgical resection showed no relation to CSS in other patient groups. Kaplan-Meier curves of adult HGBSG group showed that patients treated with both RT and CT in adult HGBSG group had the best survival probability (P=0.02). However, multivariable analysis showed the combination of radiotherapy (RT) and chemotherapy (CT) was not significantly related to better CSS in adult HGBSG group (HR0.35, 95%CI 0.11-1.09, P=0.070). Adjuvant therapy didn't associate with better CSS in other patient groups. CONCLUSION: Pediatric LGBSG group had the highest GTR rate and the most favorable clinical outcome. GTR can provide significant survival benefits for pediatric LGBSG group.

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas.

Gliomas are the most common and lethal primary malignant tumor of the brain. Routine treatment including surgical resection, chemotherapy, and radiotherapy produced limited therapeutic effect, while immunotherapy targeting the glioma microenvironment has offered a novel therapeutic option. PDIA5 protein is the member of PDI family, which is highly expressed in glioma and participates in glioma progression. Based on large-scale bioinformatics analysis, we discovered that PDIA5 expression level is upregulated in aggressive gliomas, with high PDIA5 expression predicting poor clinical outcomes. We also observed positive correlation between PDIA5 and immune infiltrating cells, immune related pathways, inflammatory activities, and other immune checkpoint members. Patients with high PDIA5 high-expression benefited from immunotherapies. Additionally, immunohistochemistry revealed that PDIA5 and macrophage biomarker CD68 were upregulated in high-grade gliomas, and patients with low PDIA5 level experienced favorable outcomes among 33 glioma patients. Single cell RNA sequencing exhibited that PDIA5 was in high level presenting in neoplastic cells and macrophages. Cell transfection and co-culture of glioma cells and macrophages revealed that PDIA5 in tumor cells mediated macrophages exhausting. Altogether, our findings indicate that PDIA5 overexpression is associated with immune infiltration in gliomas, and may be a promising therapeutic target for glioma immunotherapy.

The ALDH Family Contributes to Immunocyte Infiltration, Proliferation and Epithelial-Mesenchymal Transformation in Glioma.

Gliomas are malignant tumors that originate from the central nervous system. The aldehyde dehydrogenase family has been documented to affect cancer progression; however, its role in gliomas remains largely unexplored. Bulk RNA-seq analysis and single-cell RNA-Seq analysis were performed to explore the role of the aldehyde dehydrogenases family in gliomas. Training cohort contained The Cancer Genome Atlas data, while data from Chinese Glioma Genome Atlas and Gene Expression Omnibus were set as validation cohorts. Our scoring system based on the aldehyde dehydrogenases family suggested that high-scoring samples were associated with worse survival outcomes. The enrichment score of pathways were calculated by AUCell to substantiate the biofunction prediction results that the aldehyde dehydrogenases family affected glioma progression by modulating tumor cell proliferation, migration, and immune landscape. Tumor immune landscape was mapped from high-scoring samples. Moreover, ALDH3B1 and ALDH16A1, two main contributors of the scoring system, could affect glioblastoma cell proliferation and migration by inducing cell-cycle arrest and the epithelial-mesenchymal transition. Taken together, the aldehyde dehydrogenases family could play a significant role in the tumor immune landscape and could be used to predict patient prognosis. ALDH3B1 and ALDH16A1 could influence tumor cell proliferation and migration.

The Basic Characteristics of the Pentraxin Family and Their Functions in Tumor Progression.

The pentraxin is a superfamily of proteins with the same domain known as the pentraxin domain at C-terminal. This family has two subgroups, namely; short pentraxins (C-reactive protein and serum amyloid P component) and long pentraxins (neuronal pentraxin 1, neuronal pentraxin 2, neuronal pentraxin receptor, pentraxin 3 and pentraxin 4). Each group shares a similar structure with the pentameric complexes arranged in a discoid shape. Previous studies revealed the functions of different pentraxin family members. Most of them are associated with human innate immunity. Inflammation has commonly been associated with tumor progression, implying that the pentraxin family might also participate in tumor progression. Therefore, we reviewed the basic characteristics and functions of the pentraxin family and their role in tumor progression.

Pentraxin 3 Promotes Glioblastoma Progression by Negative Regulating Cells Autophagy.

Glioblastoma is the most malignancy tumor generated from the central nervous system along with median survival time less than 14.6 months. Pentraxin 3 has been proved its association with patients' poor survival outcome in various tumor. Recently, several studies revealed its association with glioblastoma progression but the mechanism is remained unknown. Autophagy is a programmed cells death and acts critical role in tumor progression. In this study, pentraxin 3 is recognized as prognostic prediction biomarker of glioblastoma and can promote glioblastoma progression through negative modulating tumor cells autophagy. Transcription factor JUN is assumed to participate in cells autophagy modulation by regulating pentraxin 3 expression. This work reveals novel mechanism of pentraxin 3 mediated glioblastoma progression. Furthermore, JUN is identified as potential transcription factor involves in pentraxin 3 mediated tumor cells autophagy.

The Epidemiological Characteristics and Prognostic Factors of Low-Grade Brainstem Glioma: A Real-World Study of Pediatric and Adult Patients.

Purpose: Our current understanding of low-grade brainstem glioma (LGBSG) is still limited. This study aimed to conduct a large-scale population-based real-world study to understand the epidemiological characteristics of LGBSG and determine the predictive factors of cancer-specific survival (CSS) and overall survival (OS) of LGBSG patients. Patients and Methods: We used Surveillance Epidemiology and End Results database to conduct this study of patients with histologically confirmed LGBSG. Patient demographics, tumor characteristics, and treatment options were compared between pediatric and adult patients. Univariate and multivariate analyses were employed to determine prognostic factors of CSS and OS. Kaplan-Meier curve and decision tree were used to confirm the prognostic factors. All variables were further identified by L1-penalized (Lasso) regression and then a nomogram was established to predict the 5- and 8-year CSS and OS rate. The precision of the nomogram was evaluated by calibration plots, Harrell's concordance index, and time-dependent receiver operating characteristic curve. The clinical use of nomogram was estimated by decision curve analysis. Results: A cohort of 305 patients with LGBSG, including 165 pediatric and 140 adult patients, was analyzed. Adult and pediatric patients showed different patterns concerning tumor size, tumor extension, adjuvant therapy, and survival rate. Univariate analysis revealed that pediatric group, gross total resection (GTR), World Health Organization grade II, radiotherapy, extension to ventricular system, and diffuse astrocytic and oligodendroglial tumor (DAOT) were significantly associated with CSS. Multivariate analysis showed that pediatric group, metastasis, ventricular system involvement, and DAOT were independently associated with CSS. The prognostic factors were further confirmed by Kaplan-Meier curve and decision tree. Kaplan-Meier curve also showed that adjuvant therapy added no benefits in patients with GTR and non-GTR. In addition, the nomogram was developed and the C-index of internal validation for CSS was 0.87 (95% CI, 0.78-0.96). Conclusion: This study shows that pediatric and adult patients have different tumor characteristics, treatment options, and survival rate. Pediatric group, DAOT, ventricular system involvement, and metastasis were identified as independent prognostic factors for CSS by multivariate analysis. Adjuvant therapy showed no benefits on CSS in patients with GTR and non-GTR. The nomogram was discriminative and clinically useful.