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Background: Immunochemotherapy has become the first‐line treatment for initial diagnosed metastatic nasopharyngeal carcinoma (mNPC). Loco‐regional radiotherapy combined with systemic chemotherapy significantly improves the survival. However, the safety and efficacy of loco‐regional radiotherapy combined with immunochemotherapy remained unknown. Methods: Patients with de novo mNPC who received immunochemotherapy followed by loco‐regional radiotherapy were included from two cancer centers. Toxicity and treatment response were assessed using CTCAE 5.0 and RECIST 1.1, respectively. Overall survival (OS) and progression‐free survival (PFS) were analyzed using the Kaplan–Meier method. Results: From 2019 to 2021, a total of 16 patients were retrospectively analyzed. The median follow‐up was 28 months (range 14–47 months). No one died. One‐year, 2‐year, and 3‐year PFS rate was 93.8%, 58.4% and 50.1%, respectively. Radiotherapy‐related acute severe (grade 3 or higher) toxicity was dermatitis (1/16, 6.3%) and mucositis (2/16, 12.5%). Conclusions: Loco‐regional radiotherapy provided a promising efficacy with modest toxicity for patients with mNPC who received immunochemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Exosomal miRNAs that play an important role in cell-cell communication have attracted major attention as potential diagnostic and prognostic biomarkers for various cancers. The aim of this study was to determine the diagnostic/prognostic significance of serum exosomal miR-301a in glioma patients. Methods: Quantitative real-time PCR was used to determine the serum exosomal expression levels of miR-301a. Kaplan-Meier survival analyses, Cox regression analyses and ROC working curve analyses were applied to assess the diagnostic and prognostic values of miR-301a in glioma patients. Also, several in vitro assays were used, including proliferation, invasion and cell signaling assays. Results: First, we established that serum exosomal miR-301a extracted from grade IV glioblastoma (GBM) patients was biologically active, i.e., promoted the proliferation and invasion of glioma-derived H4 cells. Subsequently, we found that serum exosomal miR-301a levels were significantly up-regulated in glioma patients compared to healthy controls. Additionally, we found that increased serum exosomal miR-301a levels were correlated with ascending pathological grades and lower Karnofsky performance status (KPS) scores. Importantly, we also found that the serum exosomal miR-301a levels were significantly reduced after surgical resection of primary tumors and increased again during GBM recurrence. Kaplan-Meier analysis of patients with an advanced pathological grade (III or IV) and an increased serum exosomal miR-301a level revealed a longer overall survival (OS) compared to those with a lower level ( p < 0.01). Both univariate and multivariate Cox regression analyses confirmed that serum exosomal miR-301a levels are independently associated with OS. Finally, we found that miR-301a may activate the AKT and FAK signaling pathways by down regulating PTEN. Conclusions: Our data indicate that serum exosomal miR-301a levels may reflect the cancer-bearing status and pathological changes in glioma patients. Serum exosomal miR-301a expression may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease. [ABSTRACT FROM AUTHOR]

Purpose: Circular RNAs (circRNAs) play an important role in tumorigenesis, and exosomal circRNAs have the potential to be novel biomarkers for cancer diagnosis. Here, we are committed to reveal serum exosomal circCCDC66 as a noninvasive biomarker to diagnose and predict recurrence in pituitary adenoma (PA)., Methods: A total of 90 PA patients and 50 healthy subjects were enrolled for clinical validation. Exosomes were extracted from the serum and validated by transmission electron microscopy, nanoparticle tracking analysis, and Western blot assay. The expression of circCCDC66 in serum exosomes was assessed using quantitative real-time PCR (qRT-PCR), and correlations between circCCDC66 expression and clinicopathological factors were analyzed. The reliability of serum exosomal circCCDC66 to diagnose PA was evaluated using receiver operating characteristic (ROC) analysis., Results: Initially, an obviously significantly increasing level of serum exosomal circCCDC66 was verified in the PA specimens compared with healthy controls. Importantly, serum exosomal circCCDC66, which was secreted and released by PA cells, could monitor tumor dynamics and serve as a potentially prognostic biomarker during treatment. Additionally, ROC curve analysis was performed and the corresponding area under the curve (AUC) values were used to confirm the ability of serum exosomal circCCDC66 as a potentially diagnostic and prognostic biomarker for PA patients. Importantly, the progression-free survival was much longer in the low serum exosomal circCCDC66 group than in the high serum exosomal circCCDC66 group., Conclusion: Serum exosomal circCCDC66 is abnormally elevated and may serve as a promising factor for the diagnosis of and predicting prognosis in PA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yue, Lan and Liu.)

Objective: Although glucose metabolism reengineering is a typical feature of various tumors, including glioma, key regulators of glycolytic reprogramming are still poorly understood. The authors sought to investigate whether glycolysis inhibition by microRNA (miR)-448 increases radiosensitivity in glioma cells., Methods: The authors used glioma tissue samples from glioma patients, cells from glioblastoma (GBM) cell lines and normal human astrocyte cells, and subcutaneous tumor-bearing U87 cells in mice to examine the effects of signaling regulation by miR-448 in the response of glioma tissues and cells to radiation treatment. Techniques used for investigation included bioinformatics analyses, biochemical assays, luciferase reporter assays, and establishment of subcutaneous tumors in a mouse model. Glucose consumption, LDH activity, and cellular ATP were measured to determine the ability of glioma cells to perform glycolysis. Expression of HIF-1α was measured as a potential target gene of miR-448 in glycolysis., Results: miR-448 was detected and determined to be significantly downregulated in both glioma tissues from glioma patients and GBM cell lines. Furthermore, miR-448 acted as a tumor-inhibiting factor and suppressed glycolysis in glioma by negatively regulating the activity of HIF-1α signaling and then interfering with its downstream regulators relative to glycolysis, HK1, HK2, and LDHA. Interestingly, overexpression of miR-448 increased the x-radiation sensitivity of glioma cells. Finally, in in vivo experiments, subcutaneous tumor-bearing U87 cells in a mouse model verified that high expression of miR-448 also enhanced glioma radiosensitivity via inhibiting glycolytic factors., Conclusions: miR-448 can promote radiosensitivity by inhibiting HIF-1α signaling and then negatively controlling the glycolysis process in glioma. A newly identified miR-448-HIF-1α axis acts as a potentially valuable therapeutic target that may be useful in overcoming radioresistance in glioma treatment.

The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

Objective: Toll-like receptors (TLRs) are highly or lowly expressed in a wide variety of tumors and exhibit either pro-tumor or anti-tumor activities. In the present study, we investigate whether there are relationships between the expressions of TLRs and the occurrence of radiation pneumonia in advanced NSCLC patients treated with radiotherapy., Materials and Methods: 76 patients diagnosed with NSCLC and 50 healthy controls were recruited from Oct 2012 to Jan 2014. The expressions of serum TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9 were detected by ELISA techniques. Fisher exact test, χ(2) test, ROC working curve and Cox regression model were applied to analyze all data., Results: serum TLR1, TLR2, TLR4, and TLR9 exhibited a relative high expression level in NSCLC patients compared with healthy controls. Importantly, pre-neutrophil granulocyte ratio was associated with the expression of TLR1, TLR2, and TLR4. Moreover, the patients with high ratio of neutrophil granulocyte significantly increased the occurrence of fever in comparison to normal neutrophil ratio in NSCLC patients during the course of radiotherapy. We further evaluated the containing of TLRs when patients had temperatures and found serum TLR1, TLR2 and TLR4 were over-expressed. Finally, 26 of 76 patients were diagnosed with different stages of radiation induced pneumonia; as a result, the contents of TLR1 and TLR4 before radiotherapy were identified as independent significances with pneumonia occurrence., Conclusions: The pretreatment levels of TLR1 and TLR4 have the predictive value to be clinically potential biomarkers of pneumonia risk in locally advanced NSCLC.

Transcription factor 7 like 2 (TCF7L2, also known as TCF4) is a Wnt signaling pathway transcription factor involved in regulation of numerous Wnt targeted genes. Recently, thousands of high-confidence TCF4 binding sites were reported in LS174T colon carcinoma cells, however, potential TCF4 target miRNAs remain largely unknown. Here, we utilized a bioinformatics approach to discover 26 miRNA transcription start sites (TSSs) within close proximity to TCF4 chromatin occupancy sites, and validated these sites as bona fide TCF4 targets in LS174T colon carcinoma cells, MCF-7 breast cancer cells and U87 glioma cells by ChIP-PCR. We then selected miR-21 to demonstrate for the first time direct TCF4 transcriptional activation of a miRNA via binding to the promoter region. Tissue array analysis supported this finding, revealing a positive correlation between activation of the β-catenin pathway and in situ expression of miR-21. Finally, based upon the well known but poorly understood preventive effect of aspirin on colorectal cancer incidence and mortality, we report downregulation of miR-21 upon administration of aspirin. In sum, our findings identify direct transcriptional regulation of miR-21 by TCF4 and suggest a role for miR-21 in cancer cell proliferation and invasion upon activation of β-catenin/TCF4 signaling.