Radiotherapy-Induced Astrocyte Senescence Promotes an Immunosuppressive Microenvironment in Glioblastoma to Facilitate Tumor Regrowth.

Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation-induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation-induced senescence in non-neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence-associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor-promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Identification of a RAD51B enhancer variant for susceptibility and progression to glioma.

BACKGROUND: RAD51B plays a significant role in homologous recombination-mediated repair of DNA double-strand breaks. Many enhancer variants are involved in cancer development and progression. However, the significance of enhancer variants of RAD51B in glioma susceptibility and progression remains unclear. METHODS: A case-control study consisting of 1056 individuals was conducted to evaluate the associations of enhancer variants of RAD51B with glioma susceptibility and progression. Sequenom MassARRAY technology was used for genotyping. The function of enhancer variants was explored by biochemical assays. RESULTS: A significantly decreased risk of glioma was associated with rs6573816 GC genotype compared with rs6573816 GG genotype (OR = 0.66, 95% CI 0.45-0.97; P = 0.034). Multivariable Cox regression revealed that rs6573816 was significantly associated with glioma progression in a sex-dependent manner. Worse PFS was found in the male patients with high grade glioma carrying rs6573816 GC or CC genotype (HR = 2.28, 95% CI 1.14-4.57; P = 0.020). The rs6573816 C allele repressed enhancer activity by affecting transcription factor POU2F1 binding, which resulted in lower expression of RAD51B. Remarkably attenuated expression of RAD51B was observed following POU2F1 knockdown. Consistently, positive correlation between the expression of POU2F1 and RAD51B was found in lymphoblastic cells and glioma tissues. CONCLUSIONS: These results indicate that an enhancer variant of RAD51B rs6573816 influences enhancer activity by changing a POU2F1 binding site and confers susceptibility and progression to glioma.

Induction chemotherapy reduces target volume drift in patients with locoregionally advanced nasopharyngeal carcinoma undergoing adaptive intensity-modulated radiotherapy: a retrospective cohort study.

Background: Adaptive radiotherapy (ART) provides real-time correction of the target and dose of radiation based on repeat computed tomography (CT) imaging and replanning during intensity-modulated radiation therapy (IMRT) and is important for locoregionally advanced nasopharyngeal carcinoma (NPC). However, repeat CT imaging and replanning are time-consuming and hinder the broader application of ART. The optimum dose and frequency of replanning time have been published in previous reports. The purpose of this study was to determine whether induction chemotherapy (IC) reduces target volume drift during IMRT, potentially reducing the replanning workload. Methods: From January 2012 to December 2017, 40 patients with locoregionally advanced, nonmetastatic stage III-IVa NPC treated in the Department of Radiation Oncology in the First Affiliated Hospital, College of Medicine, Zhejiang University, were enrolled into this study. Of the 40 patients, 20 received 2-3 cycles of IC before concurrent chemoradiotherapy (IC + CCRT), and the other 20 patients were treated with CCRT plus adjuvant chemotherapy (CCRT + AC). During CCRT, all patients underwent weekly simulated CT for 6 weeks. The gross tumor volume (GTV), clinical target volume (CTV), and body weight were measured weekly and compared between the 2 groups. Results: Compared with the baseline, the mean weight loss after 25 fractions was 7.0 kg (13.6%; range, 3.9-25.5%) in the CCRT + AC group and 5.7 kg (8.3%; range, 3.6-20%) in the IC + CCRT group. The mean GTV and CTV decreased by 16.55 mL (15.7%; range, 6.1-33.7%) and 61.25 mL (9.33%; range, 4.4-17.0%), respectively, in the IC + CCRT group, and by 39.86 mL (38.79%; range, 25.3-50.7%) and 87.72 mL (12.7%; range, 6.7-22.9%), respectively, in the CCRT + AC group. The degree of weekly reduction in the GTV of the IC + CCRT group was not significantly higher than that of the CCRT + AC group, with the following P values of each percentage reduction in comparison with the previous week over 5 weeks, respectively: P<0.001, P=0.015, P=0.01, P=0.01, and P<0.001. The weekly CTV reduction only significantly correlated with weight loss (P=0.005) in the IC + CCRT group. Conclusions: IC significantly decreased the degree of weight loss, GTV shrinkage, and CTV reduction during CCRT, consequently decreasing the anatomical and target dose drift during the adaptive replanning of IMRT. This may lead to a reduction in the recurrence of locoregionally advanced NPC, especially among patients with large metastatic cervical lymph nodes, potentially improving survival. This result provides favorable evidence that IC improves locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with locoregionally advanced NPC.

Prognostic and Immunological Potential of Ribonucleotide Reductase Subunits in Liver Cancer.

Background: Ribonucleotide reductase (RR) consists of two subunits, the large subunit RRM1 and the small subunit (RRM2 or RRM2B), which is essential for DNA replication. Dysregulations of RR were implicated in multiple types of cancer. However, the abnormal expressions and biologic functions of RR subunits in liver cancer remain to be elucidated. Methods: TCGA, HCCDB, CCLE, HPA, cBioPortal, and GeneMANIA were utilized to perform bioinformatics analysis of RR subunits in the liver cancer. GO, KEGG, and GSEA were used for enrichment analysis. Results: The expressions of RRM1, RRM2, and RRM2B were remarkably upregulated among liver cancer tissue both in mRNA and protein levels. High expression of RRM1 and RRM2 was notably associated with high tumor grade, high stage, short overall survival, and disease-specific survival. Enrichment analyses indicated that RRM1 and RRM2 were related to DNA replication, cell cycle, regulation of nuclear division, DNA repair, and DNA recombination. Correlation analysis indicated that RRM1 and RRM2 were significantly associated with several subsets of immune cell, including Th2 cells, cytotoxic cells, and neutrophils. RRM2B expression was positively associated with immune score and stromal score. Chemosensitivity analysis revealed that sensitivity of nelarabine was positively associated with high expressions of RRM1 and RRM2. The sensitivity of rapamycin was positively associated with high expressions of RRM2B. Conclusion: Our findings demonstrated high expression profiles of RR subunits in liver cancer, which may provide novel insights for predicting the poor prognosis and increased chemosensitivity of liver cancer in clinic.

Prognostic Value of a CT Radiomics-Based Nomogram for the Overall Survival of Patients with Nonmetastatic BCLC Stage C Hepatocellular Carcinoma after Stereotactic Body Radiotherapy.

Purpose: This study aimed to investigatie the feasibility of pretherapeutic CT radiomics-based nomograms to predict the overall survival (OS) of patients with nondistant metastatic Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) undergoing stereotactic body radiotherapy (SBRT). Methods: A retrospective review of 137 patients with nondistant metastatic BCLC-C HCC who underwent SBRT was made. Radiomics features distilled from pretherapeutic CT images were selected by the method of LASSO regression for radiomics signature construction. Then, the clinical model was constructed based on clinical characteristics. A radiomics nomogram was constructed using the radiomics score (Rad-score) and clinical characteristics to predict post-SBRT OS in BCLC-C HCC patients. An analysis of discriminatory ability and calibration was performed to confirm the efficacy of the radiomics nomogram. Results: In order to construct the radiomic signature, seven significant features were selected. Patients were divided into low-risk (Rad-score < -0.03) and high-risk (Rad-score ≥ -0.03) groups based on the best Rad-score cutoff value. There were statistically significant differences in OS both in the training set (p < 0.0001) and the validation set (p=0.03) after stratification. The C-indexes of the radiomics nomogram were 0.77 (95% CI: 0.72-0.82) in the training set and 0.71 (95% CI: 0.61-0.81) in the validation set, which outperformed the clinical model and radiomics signature. An AUC of 0.76, 0.79, and 0.84 was reached for 6-, 12-, and 18-month survival predictions, respectively. Conclusions: The predictive nomogram that combines radiomic features with clinical characteristics has great prospects for application in the prediction of post-SBRT OS in nondistant metastatic BCLC-C HCC patients.

Chlorogenic Acid, the Main Antioxidant in Coffee, Reduces Radiation-Induced Apoptosis and DNA Damage via NF-E2-Related Factor 2 (Nrf2) Activation in Hepatocellular Carcinoma.

Radiotherapy produces excessive reactive oxygen species (ROS), which can lead to DNA damage and apoptosis in tumor cells, thereby killing malignant cells. Chlorogenic acid (CGA) is a well-known antioxidant in coffee due to its strong ability to remove ROS. However, the effect of CGA on radiotherapeutic efficacy remains unclear. In this study, we showed that CGA could hinder the therapeutic effect of radiotherapy by inhibiting radiation-induced apoptosis and DNA damage via scavenging excessive ROS and activating the NF-E2-related factor 2 (Nrf2) antioxidant system in hepatocellular carcinoma (HCC) cells and a murine model. The knockdown of Nrf2 reversed CGA-mediated radiation resistance in HCC cells. In conclusion, CGA might be a potential tumor-protective compound upon irradiation and reduce the efficacy of radiotherapy via ROS scavenging and Nrf2 activation.

Analysis of deep inspiration breath-hold technique to improve dosimetric and clinical advantages in postoperative intensity-modulated radiation therapy for thymomas.

Background: Radiation therapy is one of the essential treatment modalities for invasive thymomas. Clinically, respiratory motion poses a challenge for the radiotherapy of thoracic tumors. One method to address this issue is to train patients to hold their breath at the end of deep inspiration. The purpose of this retrospective cohort study was to investigate the dosimetric and clinical advantages of the deep inspiration breath-hold (DIBH) technique in postoperative intensity-modulated radiation therapy (IMRT) for thymomas. Methods: Thymoma patients undergoing postoperative IMRT were included. Each patient underwent two computed tomography (CT) scans, one under free breath (FB) and the other under DIBH. Dosimetric parameters of organs at risk (OARs) were evaluated in three series plans. Dose analysis and volume comparisons were conducted during FB-3 mm (FB with 3 mm internal target volume margin), FB-10 mm (FB with 10 mm internal target volume margin), and DIBH and compared using a paired sample Student's t-test. Normal tissue complication probabilities (NTCP) for lungs and heart were calculated and compared. Results: The total lung volume significantly increased by 31% (4,216±198 vs. 2,884±166 mL) and the heart volume reduced by 12% (552±25 vs. 636±35 mL) between DIBH acquisitions compared to FB. A significant improvement was observed in all the dosimetric parameters (Dmean, V20, V5) of the lung on DIBH compared to FB-3 mm (54%±2.85% vs. 47%±2.90%, P<0.001; 15%±1.37% vs. 12%±1.32%, P=0.004; and 10.28±0.58 vs. 8.76±0.57 Gy, P<0.001, respectively), as well as in the Dmax and D2% of the esophagus and spine. The lung volume increment was related to a reduction in the mean dose of lungs, with a correlation coefficient of r=0.27, P=0.03. The NTCP values for pneumonitis significantly reduced with DIBH compared to the FB state (0.6% vs. 1.1%, P<0.001). Conclusions: The radiation dose to the OARs can be significantly reduced by using the DIBH technique in postoperative IMRT for thymomas. The increased volume of lungs using DIBH acquisitions can significantly reduce the incidence of pneumonitis.

Oncological outcomes of patients with salivary gland cancer treated with surgery and postoperative intensity-modulated radiotherapy: a retrospective cohort study.

Background: Salivary gland cancer (SGC) is relatively rare and constitutes a variety of histological subtypes. Previously published studies of SGC patients suggest that postoperative radiation using conventional radiotherapy (RT) or 3-dimensional (3D) conformal radiotherapy may have led to suboptimal oncological outcomes. Methods: We identified 60 patients with major SGC treated with surgery followed by postoperative intensity-modulated radiotherapy (IMRT). Data for overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), prognostic factors, and treatment-related toxicities were analyzed. Survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Results: With a median follow-up of 55.5 months, based on Kaplan-Meier analyses, the OS and PFS rates for SGC patients at 3, 5, and 10 years were 90.7%, 85.1%, and 85.1% and 80.1%, 72.7%, and 63.1%, respectively. The LRRFS and DMFS rates at 3, 5, and 10 years were 87.4%, 82.1%, and 82.1% and 85.3%, 78.4%, and 66.1%, respectively. In multivariable analysis (MVA), the node stage (N stage) was an independent predictor of PFS [P=0.047; hazard ratio (HR) =0.089]. A positive margin was a significant prognostic factor for PFS (P=0.036; HR =4.086), LRRFS (P=0.026; HR =5.064), and DMFS (P=0.011; HR =6.367). Major nerve involvement was significantly correlated with PFS (P=0.034; HR =2.394) and DMFS (P=0.008; HR =2.115). The interval from surgery to radiotherapy predicted PFS (P=0.036; HR =3.934) and DMFS (P=0.012; HR =6.231). Adenoid cystic carcinoma (ACC) was the most common histology (n=21; 35%). For ACC, the 5-year OS, PFS, LRRFS, and DMFS were 100%, 67.7%, 76.2%, and 90.2%, respectively. The most common acute toxicities were mucositis and dermatitis, and xerostomia was the most common late adverse event. Lung metastasis was the most common pattern of distant failure. Conclusions: N stage, positive margin, major nerve involvement, and interval from surgery to radiotherapy were important factors associated with PFS, LRRFS, and DMFS. Postoperative IMRT leads to improved survival for SGC patients, with acceptable toxicities.

Superior survival for breast-conserving therapy over mastectomy in patients with breast cancer: A population-based SEER database analysis across 30 years.

Introduction: It has been believed that breast-conserving therapy (lumpectomy plus adjuvant radiation, Lum + RT) and mastectomy without radiation (Mast + NoRT) have equivalent survival outcomes. However, there is a need to re-evaluate the role of lumpectomy plus adjuvant radiation due to changed breast cancer management over time. This study aimed to conduct a population-based study that compare long-term oncologic survival outcomes after Lum + RT vs Mast + NoRT. Methods: The Surveillance, Epidemiology and End Results database was used to identify female breast cancer patients with a primary localized breast cancer diagnosis from 1988 to 2018. The standardized incidence/mortality ratio (SIR/SMR) for breast cancer recurrence (BCR) and breast cancer-specific death (BSD) was estimated by the SEER*Stat program. Cumulative incidences of BCR and BSD were assessed using Gray's method. We evaluated the effects of Lum + RT vs. Mast + NoRT on breast cancer recurrence-free survival (BRFS) and breast cancer-specific survival (BCSS). Fine-Gray competing risk model analyses, propensity score-adjusted Kaplan-Meier analyses and Cox proportional hazards model analyses were applied. Results: A total of 205,788 women were included in the study. Patients who underwent Lum + RT had higher SIR of BCR (4.14 [95% confidence interval, CI: 3.94-4.34] vs. 1.11 [95% CI: 1.07-1.14]) and lower SMR (9.89 [95% CI: 9.71-10.08] vs. 17.07 [95% CI: 16.82-17.33]) than patients who underwent Mast + NoRT. Lum + RT was associated with higher competing risk of BCR (adjusted hazard ratio [HR]: 1.996, 95% CI: 1.925-2.069, p < 0.001) and lower competing risk of BSD when compared to Mast + RT (adjusted HR: 0.584, 95% CI: 0.572-0.597, p < 0.001). Multivariate Cox regression analysis revealed similar results (adjusted HR after PSW for BRFS: 1.792, 95% CI 1.716-1.871, p < 0.001; adjusted HR after PSW for BCSS: 0.706, 95% CI 0.688-0.725, p < 0.001). These findings persisted in the sensitivity and subgroup analyses. Discussion: The present study further confirmed superior long-term survival with lumpectomy plus adjuvant radiation over mastectomy independent of patient characteristics including age, race, time period, historic subtype, tumor size, historic grade and stage, indicating that this benefit may result from the treatment itself.

A novel hydrogel orthotopic injection model in moderately hypofractionated radiation therapy for prostate cancer: Adaptive degradation and durable imaging.

Purpose: Moderately hypofractionated radiotherapy (MHRT) holds an important position in prostate cancer management. Existing hydrogel spacers can protect the rectum from radiation damage, but need improvement. We explored the application of a novel hydrogel in MHRT with adaptive degradation and durable imaging functions. Methods and materials: The hydrogels were irradiated with 6MV x-ray to detect the radio-resistance property. Male SD rats (n=45) underwent hydrogel injection between the prostate and rectum. CT was used for investigating the novel spacer's degradation and imaging functions over three months. The hydrogel's radiation-attenuation properties and biocompatibility were further assessed. Results: Hydrogel weight and volume remained stable for six weeks post-injection. After MHRT ended, the hydrogel showed accelerated degradation characteristics and remained in the body for at most three months. CT values of hydrogels exceeded 300 Hounsfield units (HU) throughout treatment, significantly higher than in surrounding normal tissues. A significant dose drop behind the hydrogel was observed post-implantation. Biocompatibility tests of hydrogel found it safe enough for living organisms. Conclusions: The novel hydrogel application was fully adaptable to prostate cancer MHRT modalities, largely stable during treatment, rapidly degraded after radiotherapy ended, and consistently maintained superior imaging performance and biocompatibility. This novel spacer will be an effective tool in the era of hypofractionated radiotherapy.

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated. METHODS: The associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case-control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown. RESULTS: We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39-0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40-0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27-0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35-0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21-0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population. CONCLUSIONS: The study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.

The methylation modification of m6A regulators contributes to the prognosis of head and neck squamous cell carcinoma.

BACKGROUND: N6-methyladenosine (m6A) regulation is a common type of messenger ribonucleic acid (mRNA) modification, and has been proven to contribute to the malignant behavior of tumors. However, the expression pattern and the prognostic role of m6A RNA methylation regulators in head and neck squamous cell carcinoma (HNSCC) remains unclear. METHODS: We downloaded the data of 422 patients from The Cancer Genome Atlas (TCGA) database. The relationship between the expression level of m6A RNA methylation regulators and clinicopathological variables in HNSCC was analyzed by R language. RESULTS: The m6A gene alteration was significantly correlated with tumor grade and tumor stage. Next, a least absolute shrinkage and selection operator (LASSO) Cox regression model was used to identify three m6A RNA methylation regulators [i.e., methyltransferase-like 14 (METTL14), methyltransferase-like 3 (METTL3), and heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC)] to construct a risk signature. Based on the risk signature, the patients were classified into high- and low-risk groups. The overall survival (OS) rate of the low-risk group was significantly higher than that of the high-risk group. Additionally, the risk panel was an independent prognostic marker in HNSCC patients. CONCLUSIONS: The m6A RNA methylation regulators are involved in HNSCC cancer progression. Further and more importantly, the risk signature comprising the three selected m6A RNA methylation regulators could serve as a potential marker to predict HNSCC patient outcomes.

Identification of IFN-Induced Transmembrane Protein 1 With Prognostic Value in Pancreatic Cancer Using Network Module-Based Analysis.

Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer.

Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer.

PURPOSE: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC. METHODS AND MATERIALS: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and ß-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo. RESULTS: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs. CONCLUSIONS: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.

Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant.

Mitogen-activated protein kinase-associated protein 1 (MAPKAP1) is a unique component of the mechanistic target of rapamycin (MTOR) pathway which plays a pivotal role in carcinogenesis. The role of enhancer variant in carcinogenesis receives increased attentions. However, the significance of enhancer variants of MAPKAP1 in glioma has not yet been investigated. The associations of enhancer variants of MAPKAP1 with glioma susceptibility were evaluated in a cohort of 400 glioma patients and 651 controls. The function of glioma susceptibility locus was examined by a set of biochemical assays. We found that an enhancer variant of MAPKAP1 rs473426 was associated with a significantly increased risk of glioma in a dominant manner (OR 1.53, 95% CI 1.13-2.06; P = 0.006). The association for rs1339499 located in the same enhancer approached the borderline of significance after multiple testing correction (OR 0.74, 95% CI 0.56-0.98; P = 0.037). Furthermore, cumulative associations of rs473426 and rs1339499 with glioma risk were observed (P = 0.011). Functional analyses showed that the risk allele rs473426 C downregulated the regulatory activity of enhancer by reducing the binding affinity of a transcriptional activator NFΙC, which resulted in lower gene expression both in vitro and in vivo. These results demonstrate for the first time that enhancer variant of MAPKAP1 confers susceptibility to glioma by downregulation of MAPKAP1 expression, and provide further evidence highlighting MAPKAP1 as a cancer suppressor in glioma carcinogenesis.

The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma.

Several studies have investigated strategies to improve the clinical efficacy of radiotherapy (RT) against hepatocellular carcinoma (HCC), yet the prognosis remains poor. Human adipose tissue-derived mesenchymal stem cells (AT-MSCs), easily accessible and abundant in quantity, have represented as an attractive therapeutic tool for the stem cell-based treatment for cancer diseases. Through direct co-culture and indirect separate culture experiments, we showed that AT-MSCs could enhance inhibitory effect of RT on reducing HCC cell growth, migration and invasion in both in vitro and in vivo experiments. RNA-sequencing analysis revealed a noticeable interferon-induced transmembrane 1 (IFITM1)-induced tumor gene signature. Gain and loss of mechanistic studies indicated that mechanism was attributed to downregulated expression of signal transducer and activator of transcription 3 (STAT3) and matrix metallopeptidases (MMPs) and upregulated expression of P53 and caspases. Collectively, our findings suggest that AT-MSCs might enhance the therapeutic effects of RT on HCC, providing a rationale for AT-MSCs and RT combination therapy as a new remedy for HCC.

Prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The efficacy of prophylactic cranial irradiation (PCI) in treating patients with small cell lung cancer (SCLC) has not been clear, and recent randomized studies have demonstrated conflicting results from previously published findings. The purpose of this study was to reevaluate the efficacy of PCI in patients with SCLC and to assess factors associated with its efficacy. METHODS: We conducted a quantitative meta-analysis to explore the efficacy of PCI in patients with SCLC. A literature search was performed using EMBASE, MEDLINE, Cochrane and ClinicalTrials.gov databases. We pooled the data and compared overall survival (OS) and brain metastasis (BM) between patients treated with PCI (PCI group) and patients without PCI treatment (observation group). RESULTS: Of the 1074 studies identified in our analysis, we selected seven studies including 2114 patients for the current meta-analysis. Our results showed that the PCI group showed decreased BM (HR = 0.45, 95% CI: 0.38-0.55, P < 0.001) and prolonged OS (HR = 0.81, 95% CI: 0.67-0.99, P < 0.001). However, in terms of OS, the pooled analysis showed a high heterogeneity (I2 = 74.1%, P = 0.001). In subgroup analyses of OS, we found that the heterogeneity mainly came from patients with brain imaging after initial chemoradiotherapy (HR = 0.94, 95% CI: 0.74-1.18, P = 0.59). CONCLUSIONS: The results of this study showed that PCI has a significant effect on decreasing BM but little benefit in prolonging OS when brain imaging was introduced to confirm lack of BM after initial chemoradiotherapy and before irradiation.

An intronic genetic variation of MGMT affects enhancer activity and is associated with glioma susceptibility.

PURPOSE: O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in repairing damaged DNA caused by alkylating agents. A number of cancer susceptibility loci have been recognized as enhancer variants. This study aimed to explore the significance of enhancer variants of MGMT in glioma susceptibility. PATIENTS AND METHODS: A retrospective case-control study consisting of 150 glioma patients and 327 controls was conducted to test whether enhancer variants of MGMT are associated with glioma susceptibility. Genotypes were determined by Sequenom MassARRAY technology. Associations were estimated by logistic regression. Biochemical assays were used to examine the function of glioma susceptibility locus. RESULTS: We found that the A allele of rs10764901, an intronic variant of MGMT, was associated with a significantly decreased risk of glioma. The rs10764901 AA genotype carriers had an OR of 0.49 (95% CI, 0.24-0.98; P=0.045) compared with the rs10764901 GG genotype. When the rs10764901 AG and AA genotypes were pooled for analysis, a significantly decreased risk of glioma was also found (OR, 0.63; 95% CI, 0.43-0.93; P=0.021). Functional analyses showed that the rs10764901 A allele drove a lower luciferase expression and had higher transcription factor binding affinity than the G allele. CONCLUSION: An enhancer variant of MGMT rs10764901 affects the regulatory activity of enhancer by altering the binding affinity of transcription factors and is associated with glioma susceptibility.

Topics related to neoadjuvant chemotherapy for resectable liver metastases from colorectal cancer.

Metastases to the liver from colorectal cancer (CRC) are common, and only a minority of patients are candidates for upfront surgery at the initial diagnosis. Carefully selected patients can achieve long-term survival from surgery with curative intent. Unfortunately, the risk of recurrence remains substantial after liver resection. In order to reduce the risk of relapse and improve the outcomes, the role of neoadjuvant chemotherapy has been assessed for resectable colorectal liver metastases (CRLM) with an improvement in progression-free survival (PFS). In particular, this approach seems to be more beneficial for resectable patients with risk factors associated with unfavorable prognosis. However, controversies still remain as to whether neoadjuvant chemotherapy would bring long-term survival benefit for patients with resectable CRLM, along with the main challenge in identifying those who can benefit greatly from this approach due to lack of well documented selection criteria for patient stratification. In addition, no evidence directly addresses whether targeted agents such as cetuximab and bevacizumab should be offered with chemotherapy in the preoperative setting of resectable patients, despite that these aggressive strategies could result in high response rates. To offer the reader an insight into these complex and unresolved issues we will give an overview of three hot topics related to neoadjuvant chemotherapy for initially resectable CRLM.

Identification of expression quantitative trait loci of MTOR associated with the progression of glioma.

Mechanistic target of rapamycin (MTOR) encodes a key modulator of cell growth, proliferation, and apoptosis. Previous studies have demonstrated that the dysregulation of MTOR is involved in the development and progression of several types of cancer, including glioma. In the present study, a comprehensive analysis was conducted to examine whether the expression quantitative trait loci (eQTLs) of MTOR are associated with the progression of glioma. Candidate eQTLs of MTOR were obtained from the Genotype-Tissue Expression eQTL Browser. The Kaplan-Meier method and multivariate Cox model were used to analyze the progression-free survival time of glioma patients. Based on the analysis of 138 glioma patients, one eQTL of MTOR, rs4845964, was demonstrated to be significantly associated with the progression of glioma in a dominant manner. The adjusted hazard ratios (HRs) for patients with the AG or AA genotype at rs4845964 were 2.82 [95% confidence interval (CI), 1.27-6.27; P=0.0111] and 2.79 (95% CI, 1.10-7.07; P=0.0312), respectively, compared with those with the GG genotype. When the rs4845964 AG and AA genotypes were combined for analysis, the HR was 2.70 (95% CI, 1.25-5.82; P=0.0114) vs. the GG genotype. Stratified analyses revealed similar associations between the rs4845964 genotypes and the progression of glioma in all subgroups (following stratification by age, sex and tumor grade). These results demonstrate for the first time that the MTOR eQTL rs4845964 is associated with the progression of glioma.