Mitocytosis Mediated by an Enzyme-Activable Mitochondrion-Disturbing Polymer-Drug Conjugate Enhances Active Penetration in Glioblastoma Therapy.

The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, this work demonstrates a strategy of active transcellular transport of a mitochondrion-disturbing nanomedicine, pGBEMA22-b-pSSPPT9 (GBEPPT), in the GBM tissue through mitocytosis. GBEPPT is computer-aided designed and prepared by self-assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT is delivered to the tumor site, overexpressed γ-glutamyl transpeptidase (GGT) on the brain-blood endothelial cell, or the GBM cell triggered enzymatic hydrolysis of γ-glutamylamide on GBEPPT to reverse its negative charge to positive. Positively charged GBEPPT rapidly enter into the cell and target the mitochondria. These GBEPPT disturb the homeostasis of mitochondria, inducing mitocytosis-mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular-to-intercellular delivery cycle allows GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti-GBM effect. The process of mitocytosis mediated by the mitochondrion-disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors.

Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study.

BACKGROUND: Epigenetic clocks constructed from DNA methylation patterns have emerged as excellent predictors of aging and aging-related health outcomes. Iron, a crucial element, is meticulously regulated within organisms, a phenomenon referred as iron homeostasis. Previous researches have demonstrated the sophisticated connection between aging and iron homeostasis. However, their causal relationship remains relatively unexplored. RESULTS: Through two-sample Mendelian randomization (MR) utilizing the random effect inverse variance weighted (IVW) method, each standard deviation (SD) increase in serum iron was associated with increased GrimAge acceleration (GrimAA, BetaIVW = 0.27, P = 8.54E-03 in 2014 datasets; BetaIVW = 0.31, P = 1.25E-02 in 2021 datasets), HannumAge acceleration (HannumAA, BetaIVW = 0.32, P = 4.50E-03 in 2014 datasets; BetaIVW = 0.32, P = 8.03E-03 in 2021 datasets) and Intrinsic epigenetic age acceleration (IEAA, BetaIVW = 0.34, P = 5.33E-04 in 2014 datasets; BetaIVW = 0.49, P = 9.94E-04 in 2021 datasets). Similar results were also observed in transferrin saturation. While transferrin manifested a negative association with epigenetic age accelerations (EAAs) sensitivity analyses. Besides, lack of solid evidence to support a causal relationship from EAAs to iron-related biomarkers. CONCLUSIONS: The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.

Glutamine metabolism-related genes predict prognosis and reshape tumor microenvironment immune characteristics in diffuse gliomas.

Background: Diffuse gliomas possess a kind of malignant brain tumor with high mortality. Glutamine represents the most abundant and versatile amino acid in the body. Glutamine not only plays an important role in cell metabolism but also involves in cell survival and malignancies progression. Recent studies indicate that glutamine could also affect the metabolism of immune cells in the tumor microenvironment (TME). Materials and methods: The transcriptome data and clinicopathological information of patients with glioma were acquired from TCGA, CGGA, and West China Hospital (WCH). The glutamine metabolism-related genes (GMRGs) were retrieved from the Molecular Signature Database. Consensus clustering analysis was used to discover expression patterns of GMRGs, and glutamine metabolism risk scores (GMRSs) were established to model tumor aggressiveness-related GMRG expression signature. ESTIMATE and CIBERSORTx were applied to depict the TME immune landscape. The tumor immunological phenotype analysis and TIDE were utilized for predicting the therapeutic response of immunotherapy. Results: A total of 106 GMRGs were retrieved. Two distinct clusters were established by consensus clustering analysis, which showed a close association with the IDH mutational status of gliomas. In both IDH-mutant and IDH-wildtype gliomas, cluster 2 had significantly shorter overall survival compared with cluster 1, and the differentially expressed genes between the two clusters enriched in pathways related to malignant transformation as well as immunity. In silico TME analysis of the two IDH subtypes revealed not only significantly different immune cell infiltrations and immune phenotypes between the GMRG expression clusters but also different predicted responses to immunotherapy. After the screening, a total of 10 GMRGs were selected to build the GMRS. Survival analysis demonstrated the independent prognostic role of GMRS. Prognostic nomograms were established to predict 1-, 2-, and 3-year survival rates in the four cohorts. Conclusion: Different subtypes of glutamine metabolism could affect the aggressiveness and TME immune features of diffuse glioma, despite their IDH mutational status. The expression signature of GMRGs could not only predict the outcome of patients with glioma but also be combined into an accurate prognostic nomogram.

Comparative and Combined Effects of Epigallocatechin-3-gallate and Caffeine in Reducing Lipid Accumulation in Caenorhabditis elegans.

Epigallocatechin-3-gallate (EGCG) and caffeine, two phytochemicals found in a wide range of natural dietary sources, have been reported to have protective effects against hyperlipidemia, a major risk factor for cardiovascular disease. However, their relative efficacy and synergy in lowering lipid level are unclear. This study intended to compare lipid-lowering activity of EGCG and caffeine and to elucidate their joint action using Caenorhabditis elegans (C. elegans) as a model organism. The worms were exposed to EGCG, caffeine or both agents, and lipid accumulation determined by levels of total lipids, triglycerides and cholesterol was monitored. A 3 × 3 factorial design combined with response surface methodology was used to characterize the nature of interactive effects. Total lipids, triglycerides and cholesterol in C. elegans were reduced by either EGCG or caffeine in a dose-dependent manner, with EGCG displaying a stronger lipid-lowering efficacy than caffeine. Overall, the EGCG/caffeine combination for lowering lipids was more effective than either substance alone. Factorial regression models revealed that the combination was antagonistic for total lipid reduction, perhaps due to a "ceiling" effect, and was synergistic for triglyceride-lowering and additive for cholesterol-lowering. Taken together, our work proposes the use of a combination of EGCG and caffeine as an alternative dietary intervention for the prevention of hyperlipidemia, and additionally highlights the suitability of C. elegans model for evaluating lipid-lowering capacity of natural products.

Different materials of cranioplasty for patients undergoing decompressive craniectomy: A protocol for systematic review and network meta-analysis.

BACKGROUND: Cranioplasty is widely applied on patients who has undergone decompress craniectomy (DC) due to intractable increased intracranial pressure and the cranioplasty materials have been on the bleeding edge of biomolecular and material science. This systematic review and network meta-analysis (NMA) will be conducted to comprehensively evaluate the safety and efficacy of different cranial implants for patients with cranial defects due to various reasons. METHODS AND ANALYSIS: This protocol has been reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. The following electronic databases will be searched from the date of database establishment to September 1, 2020: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, VIP, and Wanfang. Randomized controlled trials and non-randomized prospective studies focus on cranial implants will be included. Quality assessment will be conducted using Cochrane Collaboration's tool or risk of bias in nonrandomized studies of interventions based on their study designs. The primary outcome will be postoperative early mortality and implant failure while various complications for secondary outcomes. Pairwise and network meta-analysis will be conducted using STATA V.14 (StataCorp, College Station, Texas, USA). Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the results. ETHICS AND DISSEMINATION: This systematic review does not require an ethics approval or the need to obtain informed consent. The results will be published in a peer-reviewed scientific journal. PROTOCOL REGISTRATION NUMBER: INPLASY 202110001.

Prognostic Significance of Preoperative Albumin to Alkaline Phosphatase Ratio in Patients with Glioblastoma.

Objective: To explore the prognostic value of preoperative albumin to alkaline phosphatase ratio (AAPR) in patients with newly-diagnosed glioblastoma (GBM) and its association with clinical characteristics. Patients and methods: A retrospective analysis was carried out on patients with newly diagnosed GBM who had undergone operation at the Department of Neurosurgery at West China Hospital between June 1st 2016 to December 31st 2018. X-tile software was applied to determine the optimal cut-off values for AAPR, neutrophil to lymphocyte ratio (NLR), and albumin. Cox regression analyses were applied to evaluate the prognostic value of AAPR in GBM. PSM analysis was conducted to verify the results. Results: A total of 197 and 154 GBM patients were included in original cohort and PSM cohort respectively. The optimal cut-off value for AAPR, NLR, and albumin were 0.56, 4.55 and 42.2 g/L respectively. High AAPR was only significantly related to longer overall survival (OS) (p=0.010) in original cohort. In PSM cohort, no clinical variable was evidently related to the level of AAPR. AAPR was determined to be an independent prognostic indicator in both original cohort (HR=0.599, 95%CI 0.437-0.822, p=0.001) and PSM cohort (HR=0.649, 95%CI 0.459-0.918, p=0.015). Prognostic models including AAPR had better prognostic accuracy than that including albumin. Conclusion: Preoperative AAPR was determined to be an independent risk factor of prognosis in newly-diagnosed GBM patients, and its prognostic ability was stronger than albumin. And PSM analysis also validated the results.

Cancer or Tuberculosis: A Comprehensive Review of the Clinical and Imaging Features in Diagnosis of the Confusing Mass.

Confusing masses constitute a challenging clinical problem for differentiating between cancer and tuberculosis diagnoses. This review summarizes the major theories designed to identify factors associated with misdiagnosis, such as imaging features, laboratory tests, and clinical characteristics. Then, the clinical experiences regarding the misdiagnosis of cancer and tuberculosis are summarized. Finally, the main diagnostic points and differential diagnostic criteria are explored, and the characteristics of multimodal imaging and radiomics are summarized.

Polysaccharide-based nanomedicines for cancer immunotherapy: A review.

Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics. However, direct administration of "naked" immunotherapeutic agents (such as nucleic acids, cytokines, adjuvants or antigens without delivery vehicles) often results in: (1) an unsatisfactory efficacy due to suboptimal pharmacokinetics; (2) strong toxic and side effects due to low targeting (or off-target) efficiency. To overcome these shortcomings, a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, as they could interact with immune system to stimulate an enhanced immune response. Their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.

Clinical Significance of Preoperative Fibrinogen to Albumin Ratio in Patients with Glioblastoma: A Singe Center Experience.

OBJECTIVE: To explore the prognostic value of preoperative fibrinogen to albumin ratio (FAR) in patients with glioblastoma (GBM) and its association with clinical characteristics. PATIENTS AND METHODS: A retrospective analysis was carried out on patients with newly diagnosed GBM who had undergone operation at the Department of Neurosurgery at West China Hospital between June 1st 2015 to June 31st 2018. Receiver operating characteristic (ROC) curves were performed to determine the optimal cut-off values for fibrinogen, albumin, neutrophil to lymphocyte ratio (NLR), and FAR by calculating the maximum Youden index. Kaplan-Meier curves and Cox regression analyses were applied to evaluate the prognostic value of FAR in GBM. Harrell concordance index (C-index) and Akaike information criterion (AIC) were calculated to compare different prognostic models. RESULTS: A total of 206 GBM patients were included in this research. The optimal cut-off value for fibrinogen, albumin, NLR, and FAR were 2.57, 42.4, 2.28, and 0.068 respectively. High FAR was significantly related to older age, KPS≤80, IDH-1 wildtype, presence of preoperative seizures, higher NLR, and tumor location. In Cox regression analyses, high FAR was significantly associated with poor prognosis. Prognostic models including FAR had the largest C-index and lowest AIC. CONCLUSION: FAR was determined to be an independent risk factor of prognosis in patients with newly-diagnosed GBM. And the prognostic predictive ability of FAR is stronger than fibrinogen and albumin.

Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment.

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

Prognostic Significance and Gene Co-Expression Network of PLAU and PLAUR in Gliomas.

The urokinase-type plasminogen activator(PLAU) and its receptor PLAUR participate in a series of cell physiological activities on the extracellular surface. Abnormal expression of PLAU and PLAUR is associated with tumorigenesis. This study aims to evaluate the prognostic value of PLAU/PLAUR transcription expression in glioma and to explore how they affect the generation and progression of glioma. In this study, online databases are applied, such as Oncomine, GEPIA, CGGA, cBioPortal, and LinkedOmics. Overexpression of PLAU/PLAUR was found to be significantly associated with clinical variables including age, tumor type, WHO grade, histology, IDH-1 mutation, and 1p19q status. PLAU and PLAUR had a high correlation in transcriptional expression levels. High expression of PLAU and PLAUR predicted a poor prognosis in primary glioma and recurrent glioma patients, especially in lower grade gliomas. Cox regression analysis indicated that high expression of PLAU and PLAUR were independent prognostic factors for shorter overall survival in glioma patients. In gene co-expression network analysis PLAU and PLAUR and their co-expression genes were found to be involved in inflammatory activities and tumor-related signaling pathways. In conclusion, PLAU and PLAUR could be promising prognostic biomarkers and potential therapeutic targets of glioma patients.

Prognostic and clinicopathological significance of long non-coding RNA in glioma.

Growing evidence from recent studies have revealed that long non-coding RNA (lncRNA) might be a useful prognostic biomarker for glioma; we therefore conducted the current meta-analysis to evaluate prognostic and clinicopathological predictive value of lncRNA expression for glioma patients. Eligible studies were identified through multiple research strategies in PubMed, EMBASE, Web of Science, and Cochrane Library up to May 2017. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were utilized to calculate patient's survival. Fourteen eligible studies with 1415 patients were ultimately included in this meta-analysis. Our meta-analysis showed a significant association between high lncRNA expression level and OS in glioma patients (HR 2.09, 95% CI 1.68-2.58, P < 0.001). Subgroup analysis was conducted to explore the potential heterogeneity. As for clinicopathological parameters, lncRNA expression was significantly associated with tumor diameter (< 3 vs ≥ 3 cm, OR 0.39, 95% CI 0.27-0.56, P < 0.001; < 5 vs ≥ 5 cm, OR 0.56, 95% CI 0.34-0.92, P = 0.02), tumor grade (OR 0.21, 95% CI 0.13-0.34, P < 0.001), and Karnofsky Performance Status Scale (OR 2.52, 95% CI 1.54-4.11, P < 0.001). LncRNA may serve as a biomarker for prognosis and clinicopathological features in glioma patients.

Prognostic Value of Ki-67/MIB-1 Expression in Meningioma Patients: A Meta-Analysis.

Ki-67/MIB-1 is the most widely used immumohistochemical marker to measure cell proliferation in recent years, and its high expression is significantly related to high malignancy and short survival cycle. This meta-analysis was conducted to confirm the prognostic value of Ki-67/MIB-1 in meningioma patients. A comprehensive search was carried out of mainstream electronic databases including Pubmed, EMBASE, Google Scholar, Web of Science, and Cochrane Library, and finally 10 studies containing 1,414 meningioma patients were included in the meta-analysis. The combined hazard ratio (HR) and its 95% confident intervals (CIs) were used to evaluate the association between Ki-67/MIB-1 expression and survival. High expression of Ki-67/MIB-1 was found to be significantly associated with low RFS (HR 3.31, 95% CI 1.62-6.78, P = 0.001, random effect) and PFS(HR 3.14, 95% CI 1.64-6.00, P = 0.001, fixed effect). Subgroup analysis was conducted to explore the potential heterogeneity. Results of the meta-analysis indicated that high expression of Ki-67/MIB-1 may serve as a useful biomarker for poor prognosis in meningioma patients.

Prognostic significance of epidermal growth factor receptor expression in glioma patients.

PURPOSE: There is a great controversy regarding the prognostic significance of epidermal growth factor receptor (EGFR) in glioma patients. The current meta-analysis was conducted to evaluate the effect of abnormal EGFR expression on overall survival in glioma patients. MATERIALS AND METHODS: A comprehensive literature search of PubMed, EMBASE, Google Scholar, Web of Science, and Cochrane Library was conducted. The combined hazard ratio (HR) and its 95% confidence intervals (CIs) were used to evaluate the association between EGFR expression and survival in glioma. RESULTS: A total of 476 articles were screened, and 17 articles containing 1,458 patients were selected. The quality assessment of the included studies was performed by the Newcastle-Ottawa Scale. Overexpression of EGFR was found to be an indicator of poor prognosis in overall survival in glioma patients (HR =1.72, 95% CI 1.32-2.25, P=0.000, random effect) and glioblastoma multiforme patients (HR =1.57, 95% CI 1.15-2.14, P=0.004, random effect). Subgroup analysis was conducted to explore the source of high heterogeneity. CONCLUSION: This meta-analysis indicated that high expression of EGFR may serve as a biomarker for poor prognosis in glioma patients.