ICBP90, an epigenetic regulator, induces DKK3 promoter methylation, promotes glioma progression, and reduces sensitivity to cis-platinum.

Glioma is the most common brain malignancy, characterized by high morbidity, high mortality, and treatment-resistance. Inverted CCAAT box Binding Protein of 90 kDa (ICBP90) has been reported to be involved in tumor progression and the maintenance of DNA methylation. Herein, we constructed ICBP90 over-expression and knockdown glioma cell lines, and found that ICBP90 knockdown inhibited glioma cell proliferation, migration, and invasion. ICBP90 silencing potentially enhanced cellular sensitivity to cis-platinum (DDP) and exacerbated DDP-induced pyroptosis, manifested by the elevated levels of gasdermin D-N-terminal and cleaved caspase 1; whereas, ICBP90 over-expression exhibited the opposite effects. Consistently, ICBP90 knockdown inhibited tumor growth in an in vivo mouse xenograft study using U251 cells stably expressing sh-ICBP90 and oe-ICBP90. Further experiments found that ICBP90 reduced the expression of Dickkopf 3 homolog (DKK3), a negative regulator of ß-catenin, by binding its promoter and inducing DNA methylation. ICBP90 knockdown prevented the nuclear translocation of ß-catenin and suppressed the expression of c-Myc and cyclin D1. Besides, DKK3 over-expression restored the effects of ICBP90 over-expression on cell proliferation, migration, invasion, and DDP sensitivity. Our findings suggest that ICBP90 inhibits the expression of DKK3 in glioma by maintaining DKK3 promoter methylation, thereby conducing to ICBP90-mediated carcinogenesis and drug insensitivity.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

The association of CASC16 variants with breast Cancer risk in a northwest Chinese female population.

PURPOSE: Genetic variants play a critical role in the development of breast cancer. This investigation aimed to explore the association between CASC16 polymorphisms and breast cancer susceptibility. METHODS: We conducted a case-control study of 681 patients and 680 healthy individuals to investigate the correlation of five SNPs with breast cancer in a Northwest Chinese female population. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association. RESULTS: Our study found that rs4784227 and rs12922061 were significantly related to an increased susceptibility to breast cancer (OR 1.22, p = 0.022; OR 1.21, p = 0.026). While rs3803662 was a protective role in breast cancer risk (OR 0.69, p = 0.042). Stratified analyses indicated that rs4784227 and rs12922061 would increase breast cancer susceptibility at age >  50 years. Rs3803662 was a reduced factor of breast cancer risk by age ≤ 50 years. Rs4784227 was significantly increased risk of breast cancer in stage III/IV. The rs45544231 and rs3112612 had a protective effect on breast cancer with tumor size > 2 cm. Rs4784227 and rs12922061 could enhance breast cancer risk in lymph node metastasis positive individuals. CASC16 rs12922061 and rs4784227 polymorphisms correlated with an increased risk of breast cancer in BMI >  24 kg/m2. Haplotype analyses revealed that Grs45544231 Trs12922061 Ars3112612 and Grs45544231 Crs12922061 Ars3112612 haplotypes decreased breast cancer risk. CONCLUSION: Our study revealed that CASC16 genetic variants were significantly related to breast cancer susceptibility, which might give scientific evidence for exploring the molecular mechanism of breast cancer.

A pooled analysis of the prognostic value of PD-L1 in melanoma: evidence from 1062 patients.

BACKGROUND: Programmed death-ligand 1 (PD-L1) was the first identified ligand of programmed death-1 (PD-1). PD-1/PD-L1 interactions inhibit T cell-mediated immune responses, limit cytokine production, and promote tumor immune escape. Recently, many studies have investigated the prognostic value of PD-L1 expression in patients with melanoma. However, the results of these analyses remain a subject of debate. We have therefore carried out a meta-analysis to identify the prognostic role of PD-L1 in melanoma. METHODS: A thorough medical literature search was performed in the databases PubMed, Web of Science, and Embase until October 2019. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to evaluate the correlation between PD-L1 overexpression and prognosis. Publication bias was evaluated using Begg's test and Egger's test. RESULTS: Thirteen articles with 1062 enrolled patients were included in this meta-analysis. High PD-L1 expression did not correlate with overall survival (OS) (HR = 0.93, 95% CI 0.57-1.52, P = 0.781) or progression-free survival (PFS) (HR = 0.82, 95% CI 0.43-1.54, P = 0.535). However, PD-L1 overexpression correlated with the absence of lymph node (LN) metastasis (OR = 0.46, 95% CI 0.22-0.95, P = 0.036). Further, there was no significant relationship between PD-L1 expression and sex (OR = 1.29, 95% CI 0.90-1.84, P = 0.159), age (OR = 0.90, 95% CI 0.51-1.57, P = 0.708), or Eastern Cooperative Oncology Group Performance Status (OR = 0.55, 95% CI 0.06-4.83, P = 0.592). CONCLUSIONS: This meta-analysis suggested that PD-L1 expression did not predict an inferior prognosis in patients with melanoma. However, high PD-L1 expression was associated with absence of LN metastasis in such patients.

Elevated PD-L1 expression predicts poor survival outcomes in patients with cervical cancer.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression has been shown to associate with poor prognosis in a variety of solid tumors. However, the prognostic value of PD-L1 expression in cervical cancer is still controversial. Therefore, we carried a meta-analysis to investigate the prognostic and clinicopathological impact of PD-L1 in cervical cancer. METHODS: A comprehensive literature search in was performed in PubMed, Embase, Web of Science, and Cochrane Library. The correlation between PD-L1 expression and overall survival (OS), progression-free survival (PFS), and clinicopathological features was analyzed by hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). RESULTS: Seven studies with 783 patients were included in this meta-analysis. The combined HR and 95% CI of OS was 2.52 (1.09-5.83), p = 0.031. The pooled results for PFS were HR = 2.07, 95% CI = 0.52-8.23, p = 0.302. The results of subgroup analysis showed that PD-L1 was a significant prognostic factor of poor OS in Asian patients (HR = 4.77, 95% CI = 3.02-7.54, p < 0.001) and of poor PFS in Asian patients (HR = 4.78, 95% CI = 1.77-12.91, p = 0.002). However, the pooled results suggested that PD-L1 was not significantly correlated with lymph node metastasis, tumor size, FIGO stage, depth of invasion, lymph-vascular invasion, or age. CONCLUSIONS: The results of this meta-analysis suggest that PD-L1 overexpression is related to poor OS in patients with cervical cancer and poor PFS in Asian patients with cervical cancer. This study also suggests that PD-L1 is a promising prognostic indicator for cervical cancer.

Efficacy, late complications, and cosmetic outcomes of targeted intraoperative radiotherapy in breast-conserving surgery for early-stage breast cancer: a single-centre study in China.

OBJECTIVE: The purpose of this study was to evaluate the efficacy, late complications, and cosmetic outcomes of targeted intraoperative radiotherapy for the treatment of Chinese patients with early-stage breast cancer. METHODS: Between September 2014 and May 2017, breast cancer patients undergoing targeted intraoperative radiotherapy at our facility were retrospectively recruited for this study. Intraoperative radiotherapy was performed with a 50-kV X-ray source in an Intrabeam system (Carl Zeiss Meditec, Oberkochen, Germany). The one-time prescribed irradiation dose to the tumour bed was 20 Gy. Recurrence, death, late complications, and cosmetic outcomes were recorded. Late radiotoxicity was assessed based on the grading criteria of the Radiation Therapy Oncology Group. RESULTS: A total of 77 patients who were treated with targeted intraoperative radiotherapy only were recruited. The cohort had a mean age of 58 years; patients with T1, N0, and invasive ductal carcinoma accounted for 75.3, 89.6, and 84.4%, respectively; the median follow-up duration was 40 months; there were 2 patients of recurrence and 2 patients of death. There were no patients of cardiac toxicity or skin or lung radiotoxicity of grade 2 or above. The main complications were breast oedema (18.2%), seroma (15.6%), chromatosis (9.1%), induration (7.8%), pain (5.2%), skin depression (2.6%), mild dry cough (2.6%), delayed wound healing (1.3%), and wound infection (1.3%). Seventy-three patients participated in the cosmetic outcome evaluation, which yielded an excellent or good rate of 95.9%. CONCLUSIONS: Due to its low recurrence rates, lack of high-grade late radiotoxicity, and excellent cosmetic outcomes, targeted intraoperative radiotherapy may be a suitable treatment for select early-stage breast cancer patients in China.

A Novel Semi-Soft Decision Scheme for Cooperative Spectrum Sensing in Cognitive Radio Networks.

Spectrum sensing (SS) is an essential part of cognitive radio (CR) technology, and cooperative spectrum sensing (CSS) could efficiently improve the detection performance in environments with fading and shadowing effects, solving hidden terminal problems. Hard and Soft decision detection are usually employed at the fusion center (FC) to detect the presence or absence of the primary user (PU). However, soft decision detection achieves better sensing performance than hard decision detection at the expense of the local transmission band. In this paper, we propose a tradeoff scheme between the sensing performance and band cost. The sensing strategy is designed based on three modules. Firstly, a local detection module is used to detect the PU signal by energy detection (ED) and send decision results in terms of 1-bit or 2-bit information. Secondly, and most importantly, the FC estimates the received decision data through a data reconstruction module based on the statistical distribution such that the extra thresholds are not needed. Finally, a global decision module is in charge of fusing the estimated data and making a final decision. The results from a simulation show that the detection performance of the proposed scheme outperforms that of other algorithms. Moreover, savings on the transmission band cost can be made compared with soft decision detection.

Genome-wide identification and analysis of epithelial-mesenchymal transition-related RNA-binding proteins and alternative splicing in a human breast cancer cell line.

Exploring the mechanism of breast cancer metastasis and searching for new drug therapeutic targets are still the focuses of current research. RNA-binding proteins (RBPs) may affect breast cancer metastasis by regulating alternative splicing (AS) during epithelial-mesenchymal transition (EMT). We hypothesised that during EMT development in breast cancer cells, the expression level of RBPs and the gene AS pattern in the cell were significantly changed on a genome-wide scale. Using GEO database, this study identified differentially expressed RBPs and differential AS events at different stages of EMT in breast cancer cells. By establishing the correlation network of differential RBPs and differential AS events, we found that RBM47, PCBP3, FRG1, SRP72, RBMS3 and other RBPs may regulate the AS of ITGA6, ADGRE5, TNC, COL6A3 and other cell adhesion genes. By further analysing above EMT-related RBPs and AS in breast cancer tissues in TCGA, it was found that the expression levels of ADAT2, C2orf15, SRP72, PAICS, RBMS3, APOBEC3G, NOA1, ACO1 and the AS of TNC and COL6A3 were significantly correlated with the prognosis of breast cancer patients. The expression levels of all 8 RBPs were significantly different in breast cancer tissues without metastasis compared with normal breast tissues. Conclusively, eight RBPs such as RBMS3 and AS of TNC and COL6A3 could be used as predictors of breast cancer prognosis. These findings need to be further explored as possible targets for breast cancer treatment.

Explore the Role of Frailty as a Contributor to the Association Between AT(N) Profiles and Cognition in Alzheimer's Disease.

Background: The relationship between Alzheimer's disease (AD)-related pathology and cognition was not exactly consistent. Objective: To explore whether the association between AD pathology and cognition can be moderated by frailty. Methods: We included 1711 participants from the Alzheimer's Disease Neuroimaging Initiative database. Levels of cerebrospinal fluid amyloid-ß, p-tau, and t-tau were identified for AD-related pathology based on the amyloid-ß/tau/neurodegeneration (AT[N]) framework. Frailty was measured using a modified Frailty Index-11 (mFI-11). Regression and interaction models were utilized to assess the relationship among frailty, AT(N) profiles, and cognition. Moderation models analyzed the correlation between AT(N) profiles and cognition across three frailty levels. All analyses were corrected for age, sex, education, and APOEɛ4 status. Results: In this study, frailty (odds ratio [OR] = 1.71, p < 0.001) and AT(N) profiles (OR = 2.00, p < 0.001) were independently associated with cognitive status. The model fit was improved when frailty was added to the model examining the relationship between AT(N) profiles and cognition (p < 0.001). There was a significant interaction between frailty and AT(N) profiles in relation to cognitive status (OR = 1.12, pinteraction = 0.028). Comparable results were obtained when Mini-Mental State Examination scores were utilized as the measure of cognitive performance. The association between AT(N) profiles and cognition was stronger with the levels of frailty. Conclusions: Frailty may diminish patients' resilience to AD pathology and accelerate cognitive decline resulting from abnormal AD-related pathology. In summary, frailty contributes to elucidating the relationship between AD-related pathology and cognitive impairment.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Predictive Efficacy of Blood-Based Tumor Mutation Burden Assay for Immune Checkpoint Inhibitors Therapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: In non-small cell lung cancer (NSCLC) patients treated by immune checkpoint inhibitors (ICIs), tumor mutation burden (TMB) has been found to have predictive potential for survival. When compared to TMB detection in tissue (tTMB), detecting TMB in the blood (bTMB) has practical advantages; yet, the results of various studies are conflicting. The question of whether bTMB can be utilized as a predictive biomarker is becoming increasingly contentious. To confirm the predictive efficacy of bTMB, researchers did a systematic review and meta-analysis to look into the relationship between ICIs and bTMB. METHOD: From the inception to March 2021, Cochrane Library, PubMed, EMBASE and other databases were systematically searched. The predictive value of bTMB in ICIs, or the efficacy of ICIs against chemotherapy, was studied. The results were presented as pooled ratio rate (RR) and hazard ratio (HR) with 95% confidence intervals for the Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Subgroup analysis, heterogeneity analyses, and sensitivity analysis were also performed. RESULTS: A total of 2,610 NSCLC patients were studied in seven trials. There were no significant differences in OS (HR = 1.09; 95% CI: 0.62-1.91, P = 0.774) or PFS (HR = 0.73; 95% CI: 0.20-2.65, P = 0.629) between high and low bTMB groups in the ICIs cohort. When ICIs were compared to chemotherapy, ICIs were found to enhance OS (HR = 0.74; 95% CI: 0.59-0.92, P = 0.006), but the improvement in PFS and ORR was only a numerical trend (PFS: HR = 0.83; 95% CI: 0.63-1.09, P = 0.173; ORR: RR = 0.92, 95% CI: 0.77-1.10, P = 0.372). NSCLC patients treated with ICIs in the high bTMB group had better survival benefits than chemotherapy patients in terms of OS (HR = 0.63; 95% CI: 0.51-0.76, P <0.001), PFS (HR = 0.63; 95% CI: 0.52-0.76, P <0.001), and ORR (RR = 1.86; 95% CI: 1.32-2.62, P <0.001), while in the low TMB group, the results were no different or even reversed (OS: HR = 0.89; 95% CI: 0.64-1.24, P = 0.485; PFS: HR = 1.21, 95% CI: 0.93-1.58, P = 0.154; ORR: RR = 0.68, 95% CI: 0.54-0.85, P = 0.001). CONCLUSIONS: TMB could predict the enhanced survival benefit of NSCLC patients treated with ICIs; however the role of bTMB is limited at this stage. For NSCLC patients with high TMB, ICIc may be a better option than chemotherapy.

Intraoperative radiotherapy versus no radiotherapy for early stage low-risk breast cancer patients undergoing breast-conserving surgery: a propensity score matching study based on the SEER database.

PURPOSE: To compare the effect of intraoperative radiotherapy (IORT) and no radiotherapy in early stage low-risk breast cancer patients undergoing breast-conserving surgery. METHODS: According to the criteria recommended by ASTRO for patients eligible for IORT, we retrospectively selected women with early stage low-risk breast cancer who underwent breast-conserving surgery from 2010 to 2019 from the SEER database. Propensity score matching was used to balance the differences in baseline characteristics. The Kaplan-Meier method was used to calculate the overall survival (OS) and breast cancer-specific survival (BCSS) of patients, and the log-rank test was used to compare the differences. RESULTS: A total of 20,245 patients were included in the analysis, including 1738 in the IORT group and 18,507 in the no radiotherapy group, with a median follow-up of 41 months. Before matching, the 5-year OS rates of the IORT group and the no radiotherapy group were 95.5% and 85.7% (p < 0.001), respectively, and the 5-year BCSS rates of the two groups were 99.6% and 98.3% (p < 0.001), respectively. After matching, the 5-year OS rates were 95.6% and 90.3% (p < 0.001) in the IORT group and the no radiotherapy group, respectively, and the 5-year BCSS rates were 99.5% and 99.1% (p = 0.028), respectively. Cox multivariate analysis of the original data showed that radiotherapy was an independent prognostic factor for both OS and BCSS (p < 0.05). CONCLUSIONS: For patients aged 50 years or older with early stage low-risk breast cancer, IORT may be a better option, with improved BCSS compared to the elimination of radiotherapy. The study could not draw conclusions on OS, because underlying diseases may be unevenly distributed between the two groups.

The role of radiotherapy in neuroendocrine cervical cancer: SEER-based study.

BACKGROUND: There are few randomised prospective data or guidelines for the treatment of neuroendocrine cervical cancer (NECC). In addition, the role of radiotherapy (RT) in NECC remains controversial. We used the Surveillance Epidemiology and End Results (SEER) database to investigate the role of RT for the treatment of NECC. Particular attention was paid to the different role of RT in patients with or without a metastasis (M1 or M0). METHODS: The SEER database was queried for studies on NECC. We limited the year of diagnosis to the years 2000 to 2015. A Pearson's two-sided Chi-squared test, the Kaplan-Meier method and Cox regression analysis models were used for statistical analyses. The overall survival (OS) was studied for the overall group and between-subgroup groups. RESULTS: NECC was an aggressive disease with a mean OS of only 46.3 months (range of 0-196 months, median of 23 months). No significant differences were shown between the surgery (S) and S + RT groups (p = 0.146) in the M0 (without metastasis) arm. However, there was a statistically significant difference in OS between the S and S + RT groups in the M1 (with metastasis) arm (median of 44.6 months for the S group and 80.9 months for the S + RT group), p = 0.004. The mean survival was significantly longer for M0 patients than for M1 patients when treated with S only (S arm), that is, 82.1 months versus 44.6 months, respectively (log-rank p = 0.000). We also noted that when patients received adjuvant RT (S + RT arm), there were no significant differences between the M0 and M1 groups (median of 90.6 and 81.0 months, p = 0.704, respectively). Age at diagnosis, chemotherapy, T stage and N stage were significant factors for OS in the M0 arm. Interestingly, radiotherapy was the only significant factor for OS with a multivariate HR for death of 0.502 (95% CI 0.206-0.750, p = 0.006) in the M1 arm. CONCLUSIONS: RT may be carefully used in patients who are negative for metastases. Using SEER data, we identified a significant survival advantage with the combination of radiotherapy and surgery in NECC with metastases. This suggests that active local treatment should be conducted and has a significant impact on OS, even if a distant metastasis has occurred.

Identification of low-dose radiation-induced exosomal circ-METRN and miR-4709-3p/GRB14/PDGFRα pathway as a key regulatory mechanism in Glioblastoma progression and radioresistance: Functional validation and clinical theranostic significance.

Glioblastoma is a central nervous malignancy with a very poor prognosis. This study attempted to explore the role of exosomes induced by low-dose radiation-induced (ldrEXOs) and ldrEXOs-derived circ-METRN in glioblastoma progression and radioresistance at the molecular, cellular, animal, and clinical levels. Results in the present study revealed that low-dose radiation stimulated the secretion of ldrEXOs which delivered high levels of circ-METRN. And circ-METRN-abundant ldrEXOs increased the expression of γ-H2AX, indicating an efficient DNA damage-repair process in glioblastoma cells. The ldrEXOs-derived circ-METRN enhanced the glioblastoma progression and radioresistance via miR-4709-3p/GRB14/PDGFRα pathway. Up-regulating PDGFRα can rescue the tumor-promoting function of ldrEXOs in groups previously treated with inhibition of GRB14. Additionally, in-vivo experiments revealed that treatments with ldrEXOs promoted the growth of xenografted tumors and shortened the survival period. Furthermore, clinical researches indicated that circ-METRN may be transported into the bloodstream by exosomes in the early stages of fractionated radiotherapy. It has important clinical values to detect the serum exosomal circ-METRN in the early stage of radiotherapy, which is not only conducive to predict radioresistance and prognosis but also to assist MRI diagnosis in detecting the very early recurrence of glioblastoma. In summary, this study reveals for the first time that low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14/PDGFRα pathway, providing mechanistic insights into the roles of circRNAs and a valuable marker for therapeutic targets in glioblastoma.

Targeted Intraoperative Radiotherapy Is Non-inferior to Conventional External Beam Radiotherapy in Chinese Patients With Breast Cancer: A Propensity Score Matching Study.

Purpose: To investigate the efficacy of targeted intraoperative radiotherapy (TARGIT) vs. conventional external beam radiotherapy (EBRT) in Chinese patients with breast cancer. Methods: We retrospectively analyzed breast cancer patients who underwent breast-conserving surgery (BCS) at our hospital between April 2009 and October 2017. Patients were divided into TARGIT group and EBRT group according to different radiotherapy methods. TARGIT was performed with low-energy X-rays emitted by the Intrabeam system to deliver a single dose of 20 Gy to the applicator surface. Propensity score matching was performed at 1:1. The Kaplan-Meier method was used to calculate the locoregional recurrence (LR), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of the two groups, and the log-rank test was run to analyse between-group difference before and after matching. Results: A total of 281 patients were included, with a median follow-up of 43 months. Of them, 82 were included in the TARGIT group and 199 in the EBRT group. Using the risk-adapted approach, 6.1% of patients received supplemental EBRT in the TARGIT group. The 5-year LR rate was 3.2% in the TARGIT group and 3.1% in the EBRT group (P = 0.694), the 5-year DMFS rates were 100 and 96.7%, respectively (P = 0.157); the 5-year DFS rates were 96.8 and 94.2% (P = 0.604); and the 5-year OS rates were 97.6 and 97.8% (P = 0.862). After matching which eliminated interference from imbalanced baseline factors, 128 matched patients were analyzed by the Kaplan-Meier method. The 5-year LR rate was 2.3% in the TARGIT group and 1.6% in the EBRT group; the 5-year DMFS rates were 100 and 98.4%, respectively; the 5-year DFS rates were 97.7 and 98.4%; and the 5-year OS rates were 98.4 and 98.4% (P = 0.659, 0.313, 0.659, 0.987). There was no significant difference in efficacy between TARGIT group and EBRT group. Conclusion: TARGIT and EBRT have similar 5-year outcomes in selected Chinese breast cancer patients undergoing BCS, and it can be used as an effective alternative to standard therapy, with substantial benefits to patients. The results need to be further confirmed by extending the follow-up time.

Prognostic and clinicopathological significance of systemic immune-inflammation index in colorectal cancer: a meta-analysis.

BACKGROUND: Previous studies on the systemic immune-inflammation index (SII), which is based on platelet, neutrophil and lymphocyte counts, as a prognostic marker in patients with colorectal cancer (CRC) yielded inconsistent results. The aim of this study was to evaluate the prognostic and clinicopathological role of SII in CRC via meta-analysis. METHODS: A comprehensive literature survey was performed on PubMed, Web of Science, Embase and the Cochrane Library databases to include studies published up to 6 April 2020. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed to estimate the prognostic and clinicopathological value of SII in CRC. RESULTS: A total of 12 studies published between 2016 and 2019 were included in our meta-analysis. The combined analysis showed that high SII levels were significantly associated with worse overall survival (OS; HR = 1.61, 95% CI = 1.21-2.13, p = 0.001) and progression-free survival (HR = 1.74, 95% CI = 1.26-2.39, p = 0.001) in CRC. Moreover, elevated SII was also correlated with poor tumor differentiation (OR = 1.60, 95% CI = 1.27-2.02, p < 0.001), presence of distant metastasis (OR = 2.27, 95% CI = 1.10-4.67, p = 0.026), ECOG PS of 1-2 (OR = 1.98, 95% CI = 1.39-2.84, p < 0.001) and tumor size ⩾5 cm (OR = 1.49, 95% CI = 1.18-1.88, p = 0.001). However, high SII was not significantly associated with sex, tumor location, lymph node metastasis, or age in patients with CRC. CONCLUSION: Our meta-analysis indicated that high SII levels predicted poor prognosis in CRC. In addition, an elevated SII was also associated with clinical factors, implying higher malignancy of the disease.

Significance of transmission electron microscopy in subtyping of monocytic leukemia.

The objective of this paper is to produce an ultrastructural classification of acute monocytic leukemia (AML-M5) in relation to clinical behaviors. The ultrastructural characteristics of blasts of the monocytic series were analyzed in 72 M5 patients by transmission electron microscopy (TEM), in terms of their content of typical monoblasts, atypical monoblasts, atypical promonocytes, and typical promonocytes in bone-marrow aspirates. Four kinds of monocytic blasts were identified by cell size and shape, nuclear profile, nucleocytoplasmic ratio, heterochromatin content, nucleolus, granules, vesicles, and Golgi apparatus. Their characteristics of remission rate, cytochemistry, immunophenotype, and cytogenetics were also investigated. The data obtained permitted M5 patients to be divided into monoblast and promonocyte types. Monoblast-type patients expressed weaker monocytic enzymograms and specific antigen staining for CD14 and CD64, compared with promonocyte-type patients. Monoblast patients had higher CR than promonocyte patients. Therefore, TEM subclassification of patients differs from and improves upon the light microscopical criteria for distinguishing monoblasts and promonocytes and has clinical significance.

Circular METRN RNA hsa_circ_0037251 Promotes Glioma Progression by Sponging miR-1229-3p and Regulating mTOR Expression.

Circular RNAs (circRNAs) are a newly identifed non-coding RNA in many cellular processes and tumours. This study aimed to investigate the role of hsa_circ_0037251, one circRNA generated from several exons of the gene termed METRN, in glioma progression. Through in vitro experiments, we discovered that high expression of hsa_circ_0037251 was related to low expression of the microRNA miR-1229-3p and high expression of mTOR. The over-expressed hsa_circ_0037251 promoted cell proliferation, invasion and migration in glioma, while knockdown of hsa_circ_00037251 promoted cell apoptosis and induced G1 phase arrest. Then, hsa_circ_0037251 was observed to directly sponge miR-1229-3p, and mTOR was identified as a direct target of miR-1229-3p. In addition, knockdown of hsa_circ_0037251 up-regulated the expression of miR-1229-3p and inhibited the expression of mTOR. And overexpression of miR-1229-3p or low-expressed mTOR inhibited the glioma cell progression. Furthermore, transfection with mTOR overexpression vectors can restore the abilities of glioma cell progression even if hsa_circ_00037251 was knocked down using siRNAs. In vivo experiments revealed that hsa_circ_00037251 promoted the growth of xenografted tumours and shortened the survival period. These results indicated that hsa_circ_0037251 may act as a tumour promoter by a hsa_circ_0037251/miR-1229-3p/mTOR axis, and these potential biomarkers may be therapeutic targets for glioma.

FOXC1 silencing inhibits the epithelial­to­mesenchymal transition of glioma cells: Involvement of ß­catenin signaling.

Glioma is a type of malignant brain tumor. Forkhead box C1 (FOXC1) is a conserved transcription factor that is involved in tumorigenesis; however, the function of FOXC1 in glioma remains unclear. The present study aimed to investigate the effects of FOXC1 silencing on the epithelial­to­mesenchymal transition (EMT) of glioma cells. FOXC1­specific small interfering RNAs were employed to downregulate the expression levels of FOXC1 in glioma cells. The proliferation, migration and invasion of glioma cells were assessed by MTT assay, wound healing assay and Transwell assay. Western blot analysis was performed to reveal the effects of FOXC1 on EMT­associated proteins and ß­catenin signaling. The results revealed that, following FOXC1 silencing, the proliferation, migration and invasion of glioma cells were decreased. The expression levels of EMT­associated proteins were also affected. Further examination demonstrated that ß­catenin signaling was involved in the effects of FOXC1 on glioma cells. Previous results suggested that overexpression of ß­catenin reversed the effects of FOXC1 silencing on glioma cells. The present study demonstrated that FOXC1 may regulate the EMT of glioma cells, potentially via ß­catenin signaling. Therefore, FOXC1 may be a potential therapeutic target for the treatment of glioma.