Curative effect analysis of robot-assisted drainage surgery in treatment of spontaneous hypertensive brainstem hemorrhage.

Objective: Spontaneous hypertensive brainstem hemorrhage (HBSH) is characterized by sudden onset, rapid progression and poor prognosis. There has been a growing tendency of surgical treatment for HBSH. This study aimed to investigate outcomes and potential factors associated with the prognosis of robot-assisted drainage surgery for HBSH treatment. Methods: Patients with HBSH from July 2016 to March 2023 at a single neurosurgery center were included and divided into conservative group and surgical groups. Baseline and clinical data, radiographic characteristics, complications, and outcome evaluations were recorded and analyzed. Results: A total of 125 patients, with 74 in the conservative group and 51 in the surgical group, were enrolled in the study. Mortality at 6 months was 59/74 (79.7%) in the conservative group and 9/51 (17.6%) in the surgical group. Twenty-four patients (47.1%) achieved favorable outcomes in the surgical group, whereas this rate in the conservative group was only 5.4% (4/74). There was a significant difference in NIHSS, GCS, and mRS at 6 months between surviving patients in the conservative and surgical groups. In prognostic analysis in the surgical subgroup, initial GCS score [5 (IQR 4-7) vs. 3 (IQR 3-4), p < 0.001], NIHSS [36 (IQR 32-38) vs. 40 (IQR 38-40), p < 0.001], smoking history [45.8% (11/24) vs. 74.1% (20/27), p = 0.039], hematoma volume [6.9 (IQR 6.2-7.6) vs. 9.6 (IQR 7.3-11.4), p = 0.001], and hemorrhage location (p = 0.001) were potential risk factors for poor 6-month prognosis after robot-assisted surgery for HBSH. Conclusion: Based on the results of this study, robot-assisted minimally invasive drainage of brain stem hematoma may significantly reduce mortality and improve prognosis. Surgery should be conducted for selected patients.

Budding uninhibited by benzimidazoles 1 promotes cell proliferation, invasion, and epithelial-mesenchymal transition via the Wnt/ß-catenin signaling in glioblastoma.

The pathogenesis and progression of GBM (glioblastoma), as one of the most frequently occurring malignancies of the central nervous system, are regulated by several genes. BUB1 (budding uninhibited by benzimidazoles 1) is a mitotic checkpoint that plays an important role in chromosome segregation as well as in various tumors. However, its role in glioma is unknown. The current study discovered prominently elevated BUB1 in glioma and a significant relationship between BUB1 expression, a high World Health Organization grade, and a poor prognosis in glioma patients. Moreover, BUB1 triggered EMT (epithelial-mesenchymal transition) apart from promoting glioma cell proliferation, migration, and infiltration. Besides, BUB1 promoted EMT by activating the Wnt/ß-catenin axis. As implied by our study, BUB1 probably has the potential as a target for GBM management.

An omicron-based vaccine booster elicits potent neutralizing antibodies against emerging SARS-CoV-2 variants in adults.

SARS-CoV-2 Omicron subvariants have become the predominantly strain in most countries. However, the neutralizing activity of the human serum after Omicron-based vaccine booster against different SARS-CoV-2 variants is poorly understood. Here, we developed an update Omicron vaccine (SCoK-Omicron), based on the RBD-Fc fusion protein vaccine (SCoK) and RBD domain of Omicron BA.1. To assess cross-variant neutralizing activity in adults, 25 volunteers that have received three doses of SCoK and 25 volunteers with two doses of CoronaVac (inactive vaccine) were further boosted with a dose updated vaccine (SCoK-Omicron). The results of pseudovirus neutralization assays demonstrated that the booster potently induced the high-level of neutralizing antibody against SARS-CoV-2 Wild type, Delta and Omicron subvariants in adults. Further assays of single point mutations showed that K444T, L452R, N460K, or F486V was key mutations to cause immune evasion. Together, these data suggest that SCOK-Omicron can be used as a booster vaccine candidate in adults receiving subunit protein or inactivated vaccine in response to the epidemic of COVID-19 Omicron subvariants, and the mutation K444T, L452R, N460K, or F486V needs to be considered in future vaccine design.

A randomized, double-blind, placebo-controlled phase 1 and phase 2 clinical trial to evaluate efficacy and safety of a SARS-CoV-2 vaccine SCoK in adults.

BACKGROUND: To determine an appropriate dose of, and immunization schedule for, a vaccine SCoK against COVID-19 for an efficacy study; herein, we conducted randomized controlled trials to assess the immunogenicity and safety of this vaccine in adults. METHODS: These randomized, double-blind, placebo-controlled phase 1 and 2 trials of vaccine SCoK were conducted in Binhai District, Yan City, Jiangsu Province, China. Younger and older adult participants in phase 1 and 2 trials were sequentially recruited into different groups to be intramuscularly administered 20 or 40 µg vaccine SCoK or placebo. Participants were enrolled into our phase 1 and 2 studies to receive vaccine or placebo. RESULTS: No serious vaccine-related adverse events were observed in either trial. In both trials, local and systemic adverse reactions were absent or mild in most participants. In our phase 1 and 2 studies, the vaccine induced significantly increased neutralizing antibody responses to pseudovirus and live SARS-CoV-2. The vaccine induced significant neutralizing antibody responses to live SARS-CoV-2 on day 14 after the last immunization, with NT50s of 80.45 and 92.46 in participants receiving 20 and 40 µg doses, respectively; the seroconversion rates were 95.83% and 100%. The vaccine SCoK showed a similar safety and immunogenicity profiles in both younger participants and older participants. The vaccine showed better immunogenicity in phase 2 than in phase 1 clinical trial. Additionally, the incidence of adverse reactions decreased significantly in phase 2 clinical trial. The vaccine SCoK was well tolerated and immunogenic.

Development and validation of a prediction nomogram for a 6-month unfavorable prognosis in traumatic brain-injured patients undergoing primary decompressive craniectomy: An observational study.

Objective: This study was designed to develop and validate a risk-prediction nomogram to predict a 6-month unfavorable prognosis in patients with traumatic brain-injured (TBI) undergoing primary decompressive craniectomy (DC). Methods: The clinical data of 391 TBI patients with primary DC who were admitted from 2012 to 2020 were reviewed, from which 274 patients were enrolled in the training group, while 117 were enrolled in the internal validation group, randomly. The external data sets containing 80 patients were obtained from another hospital. Independent predictors of the 6-month unfavorable prognosis were analyzed using multivariate logistic regression. Furthermore, a nomogram prediction model was constructed using R software. After evaluation of the model, internal and external validations were performed to verify the efficiency of the model using the area under the receiver operating characteristic curves and the calibration plots. Results: In multivariate analysis, age(p = 0.001), Glasgow Score Scale (GCS) (p < 0.001), operative blood loss of >750 ml (p = 0.045), completely effaced basal cisterns (p < 0.001), intraoperative hypotension(p = 0.001), and activated partial thromboplastin time (APTT) of >36 (p = 0.012) were the early independent predictors for 6-month unfavorable prognosis in patients with TBI after primary DC. The AUC for the training, internal, and external validation cohorts was 0.93 (95%CI, 0.89-0.96, p < 0.0001), 0.89 (95%CI, 0.82-0.94, p < 0.0001), and 0.90 (95%CI, 0.84-0.97, p < 0.0001), respectively, which indicated that the prediction model had an excellent capability of discrimination. Calibration of the model was exhibited by the calibration plots, which showed an optimal concordance between the predicted 6-month unfavorable prognosis probability and actual probability in both training and validation cohorts. Conclusion: This prediction model for a 6-month unfavorable prognosis in patients with TBI undergoing primary DC can evaluate the prognosis accurately and enhance the early identification of high-risk patients.

Circular RNA VPS18 Promotes Glioblastoma Progression by Regulating miR-1229-3p/BCAT1 Axis.

Circular RNAs (circRNAs) have been verified to play important roles in malignant tumors, including glioblastoma. The aim of this study is to explore the biological roles and underlying mechanisms of circRNA vacuolar protein sorting 18 homolog (circVPS18) in glioblastoma. A quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expression of circVPS18, microRNA (miR)-1299-3p, and branched-chain amino acid transaminase 1 (BCAT1). In vitro experiments were conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays, respectively. Western blot was conducted to examine all protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to confirm the interaction between miR-1229-3p and circVPS18 or BCAT1. The murine xenograft model was established to conduct in vivo assay. CircVPS18 and BCAT1 were highly expressed while miR-1229-3p was lowly expressed in glioblastoma tissues and cells. CircVPS18 knockdown inhibited glioblastoma progression by inhibiting cell proliferation, migration, invasion, and angiogenesis, and promoting cell apoptosis. Moreover, miR-1229-3p could be targeted by circVPS18; inhibition of miR-1229-3p could invert the suppressive effect of circVPS18 knockdown on glioblastoma tumorigenesis. Furthermore, BCAT1 was a target of miR-1229-3p; functionally, BCAT1 overexpression could reverse the inhibitory effects of miR-1229-3p upregulation on glioblastoma cell malignant phenotypes. Moreover, we also verified that circVPS18A could regulate BCAT1 expression by sponging miR-1229-3p. Additionally, circVPS18 silencing also restrained tumor growth and metastasis in vivo. CircVPS18 accelerated glioblastoma progression by miR-1229-3p/BCAT1 axis, providing a potential therapeutic target for glioblastoma.

Outcomes of Traumatic Brain-Injured Patients With Glasgow Coma Scale < 5 and Bilateral Dilated Pupils Undergoing Decompressive Craniectomy.

Objective: Decompressive craniectomy (DC) plays an important role in the treatment of patients with severe traumatic brain injury (sTBI) with mass lesions and intractably elevated intracranial hypertension (ICP). However, whether DC should be performed in patients with bilateral dilated pupils and a low Glasgow Coma Scale (GCS) score is still controversial. This retrospective study explored the clinical outcomes and risk factors for an unfavorable prognosis in sTBI patients undergoing emergency DC with bilateral dilated pupils and a GCS score <5. Methods: The authors reviewed the data from patients who underwent emergency DC from January 2012 to March 2019 in a medical center in China. All data, such as patient demographics, radiological findings, clinical parameters, and preoperative laboratory variables, were extracted. Multivariate logistic regression analysis was performed to determine the factors associated with 30-day mortality and 6-month negative neurological outcome {defined as death or vegetative state [Glasgow Outcome Scale (GOS) score 1-2]}. Results: A total of 94 sTBI patients with bilateral dilated pupils and a GCS score lower than five who underwent emergency DC were enrolled. In total, 74 patients (78.7%) died within 30 days, and 84 (89.4%) had a poor 6-month outcome (GOS 1-2). In multivariate analysis, advanced age (OR: 7.741, CI: 2.288-26.189), prolonged preoperative activated partial thromboplastin time (aPTT) (OR: 7.263, CI: 1.323-39.890), and low GCS (OR: 6.162, CI: 1.478-25.684) were associated with a higher risk of 30-day mortality, while advanced age (OR: 8.812, CI: 1.817-42.729) was the only independent predictor of a poor 6-month prognosis in patients undergoing DC with preoperative bilateral dilated pupils and a GCS score <5. Conclusions: The mortality and disability rates are extremely high in severe TBI patients undergoing emergency DC with bilateral fixed pupils and a GCS score <5. DC is more valuable for younger patients.

MiR-181b suppress glioblastoma multiforme growth through inhibition of SP1-mediated glucose metabolism.

BACKGROUND: Glucose metabolic reprogramming is a significant hallmark of malignant tumors including GBM. Previous studies suggest that microRNAs play key roles in modulating this process in GBM cells. miR-181b acts as a tumor suppressor miRNA in influencing glioma tumorigenesis. Our previous results showed that miR-181b was down-regulated in glioma cells and tissues. METHODS: The extracellular acidification rate (ECAR), colony formation assay and levels of Glut1 and PKM2 were measured to assess the glucose metabolic and proliferation changes in GBM cells overexpressing miR-181b. Immunoblotting and luciferase reporter assay were performed to confirm the expression and role of SP1 as a direct target of miR-181b. ChIP assay was used to figure out the transcriptional regulation of SP1 on Glut1 and PKM2. In vivo study was examined for the role of miR-181b in GBM cells. RESULTS: MiR-181b overexpression significantly reduced the glucose metabolic and colony formation ability of GBM cells. And, SP1 was confirmed as a direct target of miR-181b while upregulation of SP1 could reverse the influence of overexpression of miR-181b. Furthermore, Glut1 and PKM2 could be regulated by SP1. Finally, miR-181b could inhibit the tumor growth in vivo. CONCLUSIONS: Our article demonstrated the inhibitory effect of miR-181b on glucose metabolism and proliferation in GBM by suppressing SP1 expression.

Fourteen-Day Mortality in Pediatric Patients with Traumatic Brain Injury After Early Decompressive Craniectomy: A Single-Center Retrospective Study.

OBJECTIVE: The purpose of this study was to analyze the risk factors for 14-day mortality in pediatric patients undergoing early decompressive craniectomy (DC) after traumatic brain injury (TBI). METHODS: This retrospective analysis included all pediatric patients (≤16 years of age) undergoing DC within 12 hours of TBI between August 2011 and July 2017 at the authors' institute. Demographic information, clinical characteristics, surgical information, and laboratory parameters were retrieved from medical records. Risk factors for 14-day mortality were analyzed using multivariate logistic regression models. First, potentially relevant variables were compared between those who died within 14 days versus those who did not. Variables with P < 0.10 were entered into the final multivariate regression analysis. RESULTS: A total of 36 patients (23 boys and 13 girls; median age, 7 years) were included in the analysis. Fall (n = 19, 52.8%) was the leading cause of injury. The 14-day mortality was 38.9% (14/36). At the time of admission, the median Glasgow Score Scale (GCS) was 6 (IQR 4-8), and the mean Injury Severity Score (ISS) (± standard deviation) was 29.03 ± 8.54. Preoperative hypoxia, defined as oxyhemoglobin arterial saturation <90% or apnea >20 seconds, was observed in 6 patients (16.7%). Coagulopathy was present in 14 patients (38.9%). Multivariate logistic regression analysis suggested an association between 14-day mortality and younger age (odds ratio [OR] = 0.708, 95% confidence interval [CI]: 0.513-0.978; P = 0.036) and higher ISS (OR = 1.399; 95% CI: 1.023-1.914; P = 0.035). CONCLUSIONS: In children undergoing early DC after TBI, risk factors for 14-day mortality include younger age and higher ISS.

The EZH2 inhibitor GSK343 suppresses cancer stem-like phenotypes and reverses mesenchymal transition in glioma cells.

Enhancer of zeste homolog 2 (EZH2) is the catalytic unit of polycomb repressive complex 2 (PRC2) which epigenetically silences many genes involved in tumor-suppressive mechanisms via the trimethylation of lysine 27 of histone H3 (H3K27me3). We recently found that overexpression of EZH2 was associated with poor outcome of glioblastoma (GBM). In this study, we examined the antitumor effects of the EZH2 inhibitor GSK343 on glioma cells in vitro and in vivo. The proliferation and cell cycle of glioma cells was measured. Wound healing assay and transwell invasion assay were performed to evaluate the capacity of migration and invasion of glioma cells. Western blot, qPCR, immunoprecipitation and fluorescent staining were used to test the levels of EZH2 and associated proteins. Spheroid formation assay and clonogenic assays were conducted to assess the stemness of glioma stem cells. Finally, the effect of GSK343 was measured through a nude mice model with intracranially xenotransplanted glioma. We found that GSK343 reduced proliferation, attenuated cell motility and reversed epithelial-mesenchymal transition in U87 and LN229 glioma cells. GSK343 also suppressed the stemness of cell lines and patient derived glioma stem cells. Further, GSK343 inhibited histone H3K27 methylation and upregulated the expression of EZH2 target genes thereby regulating the levels of markers involved in epithelial-mesenchymal transition and stemness. Taken together, our results indicate that GSK343 could be a potential drug against glioblastoma.

Identification of microRNAs associated with glioma diagnosis and prognosis.

The sensitivity and specificity of microRNAs (miRNAs) for diagnosing glioma are controversial. We therefore performed a meta-analysis to systematically identify glioma-associated miRNAs. We initially screened five miRNA microarray datasets to evaluate the differential expression of miRNAs between glioma and normal tissues. We next compared the expression of the miRNAs in different organs and tissues to assess the sensitivity and specificity of the differentially expressed miRNAs in the diagnosis of glioma. Finally, pathway analysis was performed using GeneGO. We identified 27 candidate miRNAs associated with glioma initiation, progression, and patient prognosis. Sensitivity and specificity analysis indicated miR-15a, miR-16, miR-21, miR-23a, and miR-9 were up-regulated, while miR-124 was down-regulated in glioma. Ten signaling pathways showed the strongest association with glioma development and progression: the p53 pathway feedback loops 2, Interleukin signaling pathway, Toll receptor signaling pathway, Parkinson's disease, Notch signaling pathway, Cadherin signaling pathway, Apoptosis signaling pathway, VEGF signaling pathway, Alzheimer disease-amyloid secretase pathway, and the FGF signaling pathway. Our results indicate that the integration of miRNA, gene, and protein expression data can yield valuable biomarkers for glioma diagnosis and treatment. Indeed, six of the miRNAs identified in this study may be useful diagnostic and prognostic biomarkers in glioma.

Disruption of the EZH2/miRNA/ß-catenin signaling suppresses aerobic glycolysis in glioma.

EZH2 is up-regulated in various cancer types, implicating its role in tumorigenesis. Our recent data have shown that repression of EZH2 inhibited glioma growth by inhibition ß-catenin signaling. Here, we identified several miRNAs that were repressed by EZH2, which in turn regulate ß-catenin expression by its 3'UTR, such as miR-1224-3p, miR-328 and miR-214. Further, EZH2 silenced miR-328 expression by binding to miR-328 promoter and promoting methylation of miR-328 promoter. Finally, miR-328 largely abrogated EZH2 effects on ß-catenin expression and glucose metabolism in glioma cells. Taken together, we propose a model for a coordinated EZH2-ß-catenin oncoprotein axis, and epigenetic link between histone modification and DNA methylation, mediated by EZH2-scilenced miRNAs.

Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Viral vector-mediated expression of Ang-(1-7) dramatically suppressed NPC cell proliferation and migration in vitro. These effects were completely blocked by the specific Ang-(1-7) receptor antagonist A-779, suggesting that they are mediated by the Ang-(1-7) receptor Mas. In this study, Ang-(1-7) not only caused a significant reduction in the growth of human nasopharyngeal xenografts, but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. Mechanistic investigations revealed that Ang-(1-7) inhibited the expression of the proangiogenic factors VEGF and PlGF. Taken together, the data suggest that upregulation of MasR could be used as a diagnostic marker of NPC and Ang-(1-7) may be a novel therapeutic agent for nasopharyngeal cancer therapy because it exerts significant antiangiogenic activity.

NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells.

Aerobic glycolysis (production of lactate from glucose in the presence of oxygen) is a hallmark of cancer. Fenofibrate is a lipid-lowering drug and an agonist of the peroxisome proliferator-activated receptor alpha (PPARα). We found that FF inhibited glycolysis in a PPARα-dependent manner in glioblastoma cells. Fenofibrate inhibited the transcriptional activity of NF-κB/RelA and also disrupted its association with hypoxia inducible factor1 alpha (HIF1α), which is required for the binding of NF-κB/RelA to the PKM promoter and PKM2 expression. High ratios of PKM2/PKM1 promote glycolysis and inhibit oxidative phosphorylation, thus favoring aerobic glycolysis. Fenofibrate decreased the PKM2/PKM1 ratio and caused mitochondrial damage. Given that fenofibrate is a widely used non-toxic drug, we suggest its use in patients with glioblastoma multiforme (GBM).

Lentiviral Vectors Mediate Long-Term and High Efficiency Transgene Expression in HEK 293T cells.

OBJECTIVES: Lentiviral vectors have been used successfully to rapidly produce decigram quantities of active recombinant proteins in mammalian cell lines. To optimize the protein production platform, the roles of Ubiquitous Chromatin Opening Element (UCOE), an insulator, and selected promoters were evaluated based on efficiency and stability of foreign gene expression mediated by lentiviral vectors. METHODS: Five lentiviral vectors, pFIN-EF1α-GFP-2A-mCherH-WPRE containing EF1α promoter and HS4 insulator, p'HR.cppt.3'1.2kb-UCOE-SFFV-eGFP containing SFFV promoter and UCOE, pTYF-CMV(ß-globin intron)-eGFP containing CMV promoter and ß-globin intron, pTYF-CMV-eGFP containing CMV promoter, and pTYF-EF1α-eGFP with EF1α promoter were packaged, titered, and then transduced into 293T cells (1000 viral genomes per cell). The transduced cells were passaged once every three days at a ratio of 1:10. Expression level and stability of the foreign gene, green fluorescence protein (GFP), was evaluated using fluorescent microscopy and flow cytometry. Furthermore, we constructed a hepatitis C virus (HCV) E1 recombinant lentiviral vector, pLV-CMV-E1, driven by the CMV promoter. This vector was packaged and transduced into 293T cells, and the recombinant cell lines with stable expression of E1 protein were established by limiting dilution. RESULTS: GFP expression in 293T cells transduced with the five lentiviral vectors peaked between passages 3 and 5 and persisted for more than 5 weeks. The expression was prolonged in the cells transduced with TYF-CMV (ß-globin intron)-eGFP or TYF-CMV-eGFP, demonstrating less than a 50% decrease even at 9 weeks post transduction (p>0.05). The TYF-CMV-eGFP-transduced cells began with a higher level of GFP expression than other vectors did. The percentage of GFP positive cells for any of the five lentiviral vectors sustained over time. Moreover, the survival rates of all transfected cells exceeded 80% at both 5 and 9 weeks post transduction. Surprisingly, neither the HS4 insulator nor the UCOE sequence improved the GFP expression level or stability. Clonal cell lines with HCV E1 gene were generated from LV-CMV-E1 vector-infected 293T cells. A representative recombinant cell line maintained stable E1expression for at least 9 weeks without significant difference in morphology compared with untreated 293T cells. CONCLUSION: The results suggest that all five vectors can stably transduce 293T cells, producing long term transgene expression with different efficiencies. However, neither the insulator nor the UCOE improved the GFP expression. The vectors containing the promoter CMV or CMV (ß-globin intron) generated the highest gene expressions, manifesting as more favorable candidates for recombinant protein production in HEK293T cells.

MiR-218 Inhibited Growth and Metabolism of Human Glioblastoma Cells by Directly Targeting E2F2.

In recent years, microRNA has become a hotspot in research on diseases, especially in the initiation and progression of different types of cancer. In this study, we found that miR-218 could inhibit growth and metabolism in gliomas by directly targeting E2F2. First, we obtained data from the Chinese Glioma Genome Atlas (CGGA) database to analyze miR-218 expression in different grades of gliomas. The effects of miR-218 on cell cycle progression and cell proliferation in U87 and U251 cell lines were investigated by flow cytometry, specifically CCK8 assay and tablet cloning, respectively. Glucose consumption and lactate production of glioma cell lines were measured by correlative test kits. Furthermore, we used Western blot analysis and luciferase reporter assay to identify the direct and functional target of miR-218. Data from the CGGA database and real-time quantitative reverse transcription-PCR demonstrated that miR-218 was obviously reduced in human glioblastoma tissues, as well as in the cell lines. When miR-218 level was elevated in vitro, cell cycle progression was arrested in the G1 phase, and cell proliferation was dramatically inhibited. Both glucose consumption and lactate production of glioma cells were significantly reduced. Western blot analysis and luciferase reporter assay revealed that E2F2 was a direct target of miR-218 in glioma cells. This investigation demonstrated that elevated E2F2 expression could partly weaken the effect of miR-218 in vitro. This study also showed that miR-218 may be a repressor in glioma by directly targeting E2F2, as well as a potential therapeutic target in gliomas.

PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop.

Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/ hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention.

Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in 2 to 70 year old healthy people in China: A phase III double blind, randomized clinical trial.

To evaluate the safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23), a randomized, double-blind and parallel controlled clinical trial was conducted in Yancheng, Jiangsu Province of China. There were 1200 subjects randomized into 2 groups with a 1:1 allocation. Subjects received 0.5 mL of tested PPV23 or control PPV23 by intramuscular injection in the deltoid, respectively. Results showed that seroconversion rates of all 23 types except type 3 were not significantly different between the 2 groups. The seroconversion rate of the Group T for type 3 (P = 0.0009) was significantly higher than the Group C. The post-vaccination GMCs of the Group T for types 1 (P = 0.0340), 3 (P = 0.0003), 9V (P = 0.0016), 11A (P = 0.0222) and 33F (P = 0.0344) were significantly higher than the Group C. The frequencies of local and general reactions were not significantly different and acceptable in both groups. In conclusion, The PPV23 showed a good immunogenicity and tolerability in 2 to 70 y old healthy people.

Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27 kip pathway in human glioblastoma cells.

Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcriptional activity has been reported to exhibit anticancer effects, the underlying mechanisms are poorly understood. In this study, we investigated the mechanisms behind the antiproliferative effects of fenofibrate in U87MG cells (human glioma cell line) using the WST-8 Cell Proliferation Assay Kit. Furthermore, we examined genome-wide gene expression profiles and molecular networks using the DAVID online software. Fenofibrate reduced the expression of 405 genes and increased the expression of 2280 genes. DAVID analysis suggested that fenofibrate significantly affected cell cycle progression and pathways involved in cancer, including the mTOR signaling pathway and insulin signaling pathway. Results of flow cytometry analysis indicated that fenofibrate induced cell cycle G0/G1 arrest in U87MG cells. Furthermore, we identified the FoxO1-p27(kip) signaling axis to be involved in fenofibrate-induced cell cycle arrest. Our findings suggest that in addition to its known lipid-lowering effects, fenofibrate may be used as an antitumor agent in glioma therapy.