Enhanced electron beam and X-ray beam therapy by applying nanoparticle heterojunctions: A Monte Carlo simulation.

Cancer has become one of the major diseases that seriously threaten human health. In order to improve the therapeutic gain ratio (TGF) of conventional X-ray and electron beams, we studied the dose enhancement effect and secondary electrons emission of Au-Fe nanoparticle heterostructures by Monte Carlo method. Under the irradiation of 6 MeV photon and 6 MeV electron beams, the Au-Fe mixture has a dose enhancement effect. For this reason, we explored the secondary electrons production that leads to dose enhancement. For 6 MeV electron beam irradiation, Au-Fe nanoparticle heterojunctions have an higher electrons emission than Au and Fe nanoparticles. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au-Fe nanoparticles is the highest, with a maximum value of 0.00024. For 6 MV X-ray beam irradiation, Au nanoparticle and Au-Fe nanoparticle heterojunction have similar electrons emission, while Fe nanoparticle has the lowest one. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au-Fe nanoparticles is the highest, with a maximum value of 0.000118. This study contributes to improve the tumor-killing effect of conventional X-ray radiotherapy treatment and has guiding significance for the research of new nanoparticles.

Epigenetic regulation in radiation-induced pulmonary fibrosis.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a common and serious adverse effect of radiotherapy for thoracic tumors, which occurs in the irreversible stage of radiation-induced lung injury (RILI) >6 months after irradiation. It is characterized by progressive and irreversible destruction of lung tissue and deterioration of lung function, which may impair quality of life and lead to respiratory failure and death. We hope this will draw attention to the involvement of epigenetics in the regulation of RIPF. CONCLUSIONS: This review summarizes research progress on the role and mechanism of DNA methylation, noncoding RNA and RNA methylation in RIPF or RILI, and the possible role and mechanism of histone modification in RIPF. We have noticed that in tissue fibrosis, the epigenetic regulation mechanisms inside and outside the nucleus can influence each other. We speculate that RIPF may be regulated by an epigenetic regulatory network during its development, and believe that TGF-ß, SNAIL, PTEN and EZH2 are four targets worthy of in-depth study.

Pink1/PARK2/mROS-Dependent Mitophagy Initiates the Sensitization of Cancer Cells to Radiation.

Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na+K+ ATPase, Ca2+Mg2+ ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.

Clinicopathologic Significance of Intestinal-type Molecules' Expression and Different EGFR Gene Status in Pulmonary Adenocarcinoma.

Variant pulmonary adenocarcinoma with intestinal-type molecules shares similar molecular expression with colorectal carcinoma. However, expression of such molecules and their association with survival time with clinicopathologic parameters, such as epidermal growth factor receptor (EGFR) gene status in other types of pulmonary adenocarcinoma, has been rarely demonstrated. Sixty patients with resected pulmonary adenocarcinoma were divided into the enteric differentiation group (I group, n=30) and the usual group (U group, n=30). Immunohistochemical staining was used to assess the expression of carcinoembryonic antigen (CEA), Villin, CK20, and caudal-related homeobox 2 (CDX2). EGFR gene status was examined by Fluorescence Quantitative polymerase chain reaction. Kaplan-Meier survival curve was drawn by GraphPad Prism 5.0 software. The results showed that there was a significant difference between the 2 groups (P<0.05) in the expression of Villin, CK20, and CDX2, whereas the expression of CEA showed no significant difference (P>0.05). Compared with the U group, patients in the I group were mainly female individuals and in clinical stages III to IV, prone to lymph node metastasis (P<0.05). The patients in the I group with CDX2CK20 phenotype (tumor size>5 cm) had a shorter survival time (P<0.05), and EGFR gene status was not associated with median survival time and the expression of CEA, Villin, CK20, and CDX2 (P>0.05). Thus, our research indicates that patients with enteric differentiation have unique clinical characteristics and different prognosis, which may play important roles in diagnosis and choosing therapeutic strategies for pulmonary adenocarcinoma patients in clinical practice.

MicroRNA­499 rs3746444 A/G polymorphism functions as a biomarker to predict recurrence following endoscopic submucosal dissection in primary early gastric cancer.

The aim of the present study was to investigate the molecular mechanism, including the potential regulatory and signaling pathways, of platelet­derived growth factor receptor ß (PDGFRB), which underlies the recurrence of early gastric cancer (EGC) following endoscopic submucosal dissection (ESD). Online microRNA (miRNA) target prediction tools were used, which identified PDGFRB as the candidate target gene of miR­499a in gastric cancer cells, and PFGRBR was then confirmed as the direct gene using a luciferase reporter assay system. The Kaplan­Meier method was used to plot recurrence­free curves, which were compared between genotype groups. A negative regulatory association between miR­499a and PDGFRB was established by investigating the relative luciferase activity at different concentrations of miR­499a mimics. Furthermore, as the rs3746444 polymorphism has been previously reported to interfere with the expression of miR­499a, the present study investigated the expression levels of different genotypes, including TT (n=20), TC (n=9) and CC (n=3), the results of which supported the hypothesis that the presence of the minor allele (C) of the rs3746444 polymorphism compromised the expression of miR­499a. The present study also performed polymerase chain reaction and western blot analyses to examine the mRNA and protein expression levels of PFGRBR among different genotypes or cells treated with different concentrations of miR­499a mimics/inhibitors, which indicated the negative regulatory association between miR­499a and PDGFRB. The present study also investigated the relative viabilities of EGC cells transfected with miR­499a mimics (50 and 100 nM) and miR­499a inhibitors (100 nM), and confirmed that miR­499a negatively interfered with the viability of the EGC cells. The miR­499a rs3746444 polymorphism was also recognized as a biomarker to predict recurrence following ESD in patients with EGC via analyzing the recurrence­free rates among patients with EGC with different genotypes. The results showed that PDGFRB was validated as a target of miR­499a, and rs3746444 was identified as a potential biomarker to predict the recurrence of EGC following ESD.

Clinicopathological features for predicting central and lateral lymph node metastasis in papillary thyroid microcarcinoma: Analysis of 66 cases that underwent central and lateral lymph node dissection.

Currently the surgical approach for papillary thyroid microcarcinoma (PTMC), particularly the range of lymph node dissection, remains controversial. The present study aims to evaluate the risk factors for central and lateral lymph node metastasis (CLNM and LLNM) for appropriate clinical decision of neck lymph node dissection in PTMC. A total of 66 cases of PTMC that underwent unilateral or bilateral lobectomy plus prophylactic cervical lymph node dissection were collected for clinicopathological evaluation, including age, gender, tumor size, subtypes, extrathyroidal invasion, multifocality, calcifications, loss of cellular polarity/cohesiveness (LOP/C) in the invasive front, CLNM and LLNM, and retrospectively analysis. Univariate analysis revealed that LOP/C was significantly associated with CLNM (P=0.001) and LLNM (P<0.0001). The male gender was a risk factor of CLNM (P=0.04), while the age <45 years, tumor size >0.5 cm and multifocality were high-risk factors of LLNM (P=0.022, 0.044 and 0.005, respectively). Multivariable analysis revealed that LOP/C was significantly associated with CLNM [P=0.007, odds ratio (OR)=7.765, 95% confidence interval (CI)=1.773-33.996] and LLNM [P=0.029, OR=5.717, 95% CI=1.190-27.470]. Both multivariable analysis and χ2 test revealed that CLNM was another important high-risk factor of LLNM (P=0.021, OR=5.444, 95% CI=1.290-22.969, χ2=17.867, P<0.001). The present study revealed that prophylactic central lymph node dissection is essential for PTMC surgery and that prophylactic lateral lymph node dissection is recommend for patients with LOP/C and CLNM, which can be performed by intraoperative frozen section pathological examination. This must be considered discreetly in the case of patients with age <45 years, tumor size >0.5 cm and multifocal lesions.

Association between the expression levels of tumor necrosis factor-α-induced protein 8 and the prognosis of patients with gastric adenocarcinoma.

The present study aimed to investigate the expression levels of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in gastric adenocarcinoma. TNFAIP8 expression levels in gastric adenocarcinoma tissue samples (with and without lymph node metastasis), adjacent normal tissue samples and metastatic lymph node tissue samples were detected by immunohistochemistry. The correlation between TNFAIP8 expression levels and clinicopathological data and gastric adenocarcinoma prognosis was analyzed. The results demonstrated that TNFAIP8 expression in gastric adenocarcinoma tissue samples and metastatic lymph node tissue samples markedly increased at a rate of 47.2% (50/106) and 81.7% (49/60), respectively, as compared with the adjacent normal tissue samples in which no TNGFAIP8 expression was detected (0%). This increase in TNFAIP8 expression was statistically significant. TNFAIP8 expression rates in the primary tumors (60%, 36/60) of patients with lymph node metastasis were significantly higher compared with the primary tumors of patients without lymph node metastasis (30.4%, 14/46). TNFAIP8 expression was associated with an increase in the severity of TNM stage, tumor grade, vascular invasion, lymph node metastasis and serum CA72-4 levels. The overall survival rate of patients with gastric adenocarcinoma and high TNFAIP8 expression was poorer compared with patients with low TNFAIP8 expression, and TNFAIP8 expression was negatively correlated with patient prognosis. The results also demonstrated that TNFAIP8 was an independent prognostic marker in gastric adenocarcinoma (relative risk, 1.736; P=0.029). In conclusion, the results of the present study demonstrated that TNFAIP8 expression was associated with the occurrence, development and metastasis of gastric adenocarcinoma, and negatively correlated with the prognosis of patients with gastric adenocarcinoma. TNFAIP8 may therefore serve as a prognostic factor for gastric adenocarcinoma.

The clinical utility of RFA in esophageal and cardia cancer patients with severe malignant obstruction.

Malignant obstruction of esophageal and cardia cancer greatly affects the prognosis and life quality of patients. However, no better regimens have been reported up to now. In recent years, radiofrequency ablation (RFA) has been prospectively proven in the management of some tumors. So, we investigated the impact of RFA on the malignant obstruction of esophageal and cardia cancer. In this study, we evaluated the operation duration, ablation duration, immediate compilations, etc., and followed up for 12 months. Our findings showed that there existed no technical problems in all 22 patients with a mean operation duration of 58 min and mean ablation duration of 23 min. No complication was observed in addition to postoperative low pressure in one patient and retrostenal pain in another patient. Importantly, all 22 patients obtained complete remission with normal diet and felt no sense of obstruction. Mean hospitalization time was 3 days and then the 12-month follow-up continued. To our relief, re-obstruction was not observed in all patients for 2 months. In conclusion, the entire effect of RFA was satisfactory, and patients can obtain a better life quality, less pains, and complications. So RFA should be advocated and greatly investigated by more institutes and hospitals.

The Clinical Implications of Human Telomerase Reverse Transcriptase Expression in Grade and Prognosis of Gliomas: a Systematic Review and Meta-analysis.

Human telomerase reverse transcriptase (hTERT), a ribonucleoprotein, is reported as an important complex, which is required for stability of DNA molecular structure at the rear of the chromosome. Until now, hTERT has been linked to cell immortalization and tumorigenesis. A couple of articles have been published about the telomerase function in the gliomas; however, these results are conflicting in some degree. Thus, it is crucial to perform a meta-analysis to identify their real actions. We included eligible articles, and estimated odds ratios (ORs) with 95 % confidence intervals (95 % CIs). In our meta-analysis, all 15 eligible articles included 932 patients. Results from 10 studies on WHO grade showed that high hTERT gene or protein expression in glioma tissues was obviously related to high WHO grade (III + IV) (OR 2.45, 95 % CI 1.92-3.13; p = 0.000). What is more, hTERT expression was not associated with old age (OR 0.91, 95 % CI 0.72-1.16; p = 0.448) as well as gender (OR 1.06, 95 % CI 0.82-1.37; p = 0.664). Importantly, hTERT expression was significantly associated with 5-year overall survival (OS; n = 3; hazard ratio (HR) 2.25, 95 % CI 1.36-3.70; p = 0.002) of glioma patients. No heterogeneity was found in all studies. In conclusion, this meta-analysis suggests that hTERT is significantly associated with high glioma grade and poor 5-year overall survival, and pathological test of hTERT mRNA and protein in glioma tissues should be suggested as criteria of glioma grade in the clinical practice.

Co-expression and clinical utility of Snail and N-cadherin in papillary thyroid carcinoma.

Papillary thyroid carcinoma is one of the most common subtypes of thyroid cancer and portends a good prognosis. N-cadherin (neural cadherin) is a member of the classical cadherin family and is often overexpressed in many types of cancers. Snail, a kind of zinc finger protein, is a transcriptional repressor which has been intensively studied in mammals. We investigate the immunohistochemical expression of Snail and N-cadherin in papillary thyroid carcinoma tissues and cells and then discuss the clinical value of Snail and N-cadherin expression. Immunohistochemical technique was performed to detect Snail and N-cadherin in 60 cases of papillary thyroid carcinoma and analyzed the relationship between the expression of Snail, N-cadherin, and clinicopathological indicators. Western blot was used to investigate the constitutive and inducible expression of Snail and N-cadherin. In our study, the expression rate of Snail and N-cadherin was 85.0 % (51/60) and 78.3 % (47/60), respectively, in papillary thyroid carcinoma. The expression rate of Snail and N-cadherin in thyroid papillary carcinoma with metastatic lymph nodes was 93.3 and 86.7 %, respectively, while in papillary thyroid carcinoma tissue without lymph node metastasis, the expression rate was 60.0 and 53.3 %, respectively. The positive correlation of Snail and N-cadherin was observed (r = 0.721, p < 0.01). In addition, Western blot further identified the constitutive and inducible expression of Snail and N-cadherin in papillary thyroid carcinoma tissues and cell lines. In conclusion, Snail and N-cadherin are constitutively and inducibly expressed in papillary thyroid carcinoma and may play important roles in the development and metastasis of papillary thyroid carcinoma. Snail and N-cadherin may be used as an effective indicator.

SDF-1/CXCR4 Axis Regulates Cell Cycle Progression and Epithelial-Mesenchymal Transition via Up-regulation of Survivin in Glioblastoma.

Stromal cell-derived factor 1 (SDF-1)/CXCR4 ligand-receptor axis is widely recommended as an attractive target for cancer therapy. Meanwhile, epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. As one of inhibitors of apoptosis proteins, survivin is implicated in the onset and development of cancer. In the present study, we tried to determine the cause-effect associations between SDF-1/CXCR4 axis and survivin expression in glioblastoma U-251 cell line. Survivin activation and inhibition were induced with exogenous SDF-1 and survivin small interfering RNA (survivin siRNA), respectively. Western blot was used to detect relevant proteins in SDF-1/CXCR4 axis. Western blot analysis revealed that survivin expression in U-251 increased in a dose- and time-dependent manner in response to SDF-1 treatment. However, the interference with MEK/ERK and PI3K/AKT pathway prohibited SDF-1-induced survivin up-regulation. Importantly, survivin knockdown abrogated cell cycle progression and the expression of snail and N-cadherin, compared with non-transfectants. In conclusion, the present study shows that SDF-1 up-regulates survivin via MEK/ERK and PI3K/AKT pathway, leading to cell cycle progression and EMT occurrence dependent on survivin. The blockade of survivin will allow for the treatment of glioblastoma.

Outcomes for jejunal interposition reconstruction compared with Roux-en-Y anastomosis: A meta-analysis.

AIM: To compare the clinical outcomes between jejunal interposition reconstruction and Roux-en-Y anastomosis after total gastrostomy in patients with gastric cancer. METHODS: A systematic literature search was conducted by two independent researchers on PubMed, EMBASE, the Cochrane Library, Google Scholar, and other English literature databases, as well as the Chinese Academic Journal, Chinese Biomedical Literature Database, and other Chinese literature databases using "Gastrostomy", "Roux-en-Y", and "Interposition" as keywords. Data extraction and verification were performed on the literature included in this study. RevMan 5.2 software was used for data processing. A fixed-effects model was applied in the absence of heterogeneity between studies. A random effects model was applied in the presence of heterogeneity between studies. RESULTS: Ten studies with a total of 762 gastric cancer patients who underwent total gastrostomy were included in this study. Among them, 357 received jejunal interposition reconstruction after total gastrostomy, and 405 received Roux-en-Y anastomosis. Compared with Roux-en-Y anastomosis, jejunal interposition reconstruction significantly decreased the incidence of dumping syndrome (OR = 0.18, 95%CI: 0.10-0.31; P < 0.001), increased the prognostic nutritional index [weighted mean difference (WMD) = 6.02, 95%CI: 1.82-10.22; P < 0.001], and improved the degree of postoperative weight loss [WMD = 2.47, 95%CI: -3.19-(-1.75); P < 0.001]. However, there is no statistically significant difference in operative time, hospital stay, or incidence of reflux esophagitis. CONCLUSION: Compared with Roux-en-Y anastomosis, patients who underwent jejunal interposition reconstruction after total gastrostomy had a lower risk of postoperative long-term complications and improved life quality.

Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas.

Recent studies have suggested that Crk-like adapter protein (CrkL) and epithelial-to-mesenchymal transition (EMT) induced by CCL19/CCR7 play an important role in ovarian epithelial carcinogenesis. However, the regulatory mechanisms of CrkL on the CCL19/CCR7 signaling pathways in epithelial ovarian carcinomas (EOC) are not well characterized. Here, CCR7 and CrkL proteins were tested in 30 EOC tissues and cell lines. In vitro, the roles of CrkL in CCL19-stimulated SKOV-3 cell invasion and migration were investigated. In this work, CCR7 and CrkL over-expressed in EOC tissues and cell lines and correlated with FIGO stage and lymph node metastasis. Moreover, CCR7 and CrkL serve as an independent prognostic factor. In SKOV-3 cells, CrkL knockdown markedly suppressed the CCL19-stimulated expression of p-ERK and EMT biomarkers (N-cadherin, Snail and MMP9), compared with control. In contrast, p-AKT expression level did not change. On the other hand, functional analysis revealed CrkL knockdown could significantly decrease SKOV-3 cell invasion number of transwell invasion assay, and wound closure area of wound healing assay, compared to control. In conclusion, CrkL regulates CCL19/CCR7-induced EMT via ERK signaling pathway in EOC patients, which further suggested CrkL could be suggested as an efficient target in ovarian cancer treatment.

The Clinical Utility of Matrix Metalloproteinase 9 in Evaluating Pathological Grade and Prognosis of Glioma Patients: A Meta-Analysis.

In the recent years, matrix metalloproteinase 9 (MMP-9) has been focused on as an indicator of glioma grade and prognosis, especially in China. However, all results resulted in many conflicts. So, it is necessary to conduct a meta-analysis to secure a convincing correlation between MMP-9 and grade and prognosis. Eligible studies were included via multiple searches, and then odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated. Funnel plots were available for evaluation of publication bias. In addition, heterogeneity and sensitivity were also analyzed. In the present meta-analysis, 23 articles were allowed for inclusion with total 1,635 patients. Coincidentally, all studies were conducted in Chinese populations. High MMP-9 expression in gliomas was closely associated with high WHO grade (III+IV) (n = 22, OR = 5.25, 95% CI = 4.09-6.73; p = 0.000), while MMP-9 expression did not correlate to age (n = 4, OR = 1.02, 95 % CI = 0.67-1.54; p = 0.929) and gender (n = 5, OR = 0.91, 95% CI = 0.63-1.33; p = 0.632). Besides, overall survival analysis from two articles revealed MMP-9 expression significantly predicted 5-year-OS (HR = 6.44, 95% CI = 3.88-10.70; p = 0.000) in glioma patients. No heterogeneity and publication bias were observed across all studies. To conclude, this meta-analysis suggests MMP-9 is potently associated with high grade and poor 5 years prognosis, and MMP-9 test of glioma tissues should be established in department of pathology as a routine in clinical practice.

Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via AKT and ERK signaling pathways in gastric cancer.

Although deregulation of bone morphogenetic protein 2 (BMP2) signaling has been linked to various types of cancers, the relationships between abnormal activation of these signaling pathways and tumorigenesis are not clear in gastric cancer. We hypothesized that BMP2 might be involved in epithelial-mesenchymal transition (EMT) process of gastric cancer. Here, BMPR-II activation and inhibition in gastric cancer cell line AGS were induced with exogenous BMP2 and with BMPR-II small interfering RNA (siRNA), respectively. BMPR-II downstream signal molecules AKT, ERK phosphorylation, and EMT biomarkers (vimentin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. In the present study, our results showed that BMP2 can induce AKT and ERK phosphorylation in a dose-dependent method, and endogenous BMPR-II can be inhibited completely by BMPR-II siRNA in AGS. Notably BMP2 alone treatment can induce the up-regulation of vimentin, snail, and N-cadherin in AGS cells, besides, the down-regulation of E-cadherin also occurred. On the contrary, BMPR-II siRNA significantly prohibited BMP2-induced AKT and ERK phosphorylation, at the same time, EMT biomarkers changes were not observed. On the other hand, BMPR-II knockdown could significantly affect AGS wound closure and the migration ability (p < 0.001) compared to control siRNA and BMP2 alone. In conclusion, this study suggested that EMT process can be triggered by the BMP2/BMPR axis in gastric cancer and then involved in the tumor cell migration, invasion, and metastasis via the activation of PI3K/AKT and MEK/ERK pathways. Our study lays a new foundation for the treatment of gastric cancer through antagonizing BMP2 system.