Efficacy of stereotactic radiosurgery as single or combined therapy for brain metastasis: A systematic review and meta-analysis.

To determine the efficacy of stereotactic radiosurgery (SRS) in treating patients with brain metastases (BMs), a network meta-analysis (NMA) of randomized controlled trials (RCTs) and a direct comparison of cohort studies were performed. Relevant literature regarding the effectiveness of SRS alone and in combination with whole-brain radiotherapy (WBRT) and surgery was retrieved using systematic database searches up to April 2019. The patterns of overall survival (OS), one-year OS, progression-free survival (PFS), one-year local brain control (LBC), one-year distant brain control (DBC), neurological death (ND), and complication rate were analyzed. A total of 18 RCTs and 37 cohorts were included in the meta-analysis. Our data revealed that SRS carried a better OS than SRS+WBRT (p = 0.048) and WBRT (p = 0.041). Also, SRS+WBRT demonstrated a significantly improved PFS, LBC, and DBC compared to WBRT alone and SRS alone. Finally, SRS achieved the same LBC as high as surgery, but intracranial relapse occurred considerably more frequently in the absence of WBRT. However, there were not any significant differences in ND and toxicities between SRS and other groups. Therefore, SRS alone may be a better alternative since increased patient survival may outweigh the increased risk of brain tumor recurrence associated with it.

SRS in Combination With Ipilimumab: A Promising New Dimension for Treating Melanoma Brain Metastases.

Dear Editor,I am writing to you in order to highlight some miscalculations in an article published in the journal of Technology in Cancer Research & Treatment, entitled; "SRS in Combination with Ipilimumab: A Promising New Dimension for Treating Melanoma Brain Metastases" by Khan, et al.1 These miscalculations changed the derived conclusion about median survival time, and adverse effects in the selected treatment groups. So, amending these miscalculations may help readers in future research decisions.

ATF4, DLX3, FRA1, MSX2, C/EBP-ζ, and C/EBP-α Shape the Molecular Basis of Therapeutic Effects of Zoledronic Acid in Bone Disorders.

OBJECTIVE: Zoledronic Acid (ZA) is one of the common treatment choices used in various boneassociated conditions. Also, many studies have investigated the effect of ZA on Osteoblastic-Differentiation (OSD) of Mesenchymal Stem Cells (MSCs), but its clear molecular mechanism(s) has remained to be understood. It seems that the methylation of the promoter region of key genes might be an important factor involved in the regulation of genes responsible for OSD. The present study aimed to evaluate the changes in the mRNA expression and promoter methylation of central Transcription Factors (TFs) during OSD of MSCs under treatment with ZA. MATERIALS AND METHODS: MSCs were induced to be differentiated into the osteoblastic cell lineage using routine protocols. MSCs received ZA during OSD and then the methylation and mRNA expression levels of target genes were measured by Methylation Specific-quantitative Polymerase Chain Reaction (MS-qPCR) and real-time PCR, respectively. The osteoblastic differentiation was confirmed by Alizarin Red Staining and the related markers to this stage. RESULTS: Gene expression and promoter methylation level for DLX3, FRA1, ATF4, MSX2, C/EBPζ, and C/EBPa were up or down-regulated in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21. ATF4, DLX3, and FRA1 genes were significantly up-regulated during the OSD processes, while the result for MSX2, C/EBPζ, and C/EBPa was reverse. On the other hand, ATF4 and DLX3 methylation levels gradually reduced in both ZA-treated and untreated cells during the osteodifferentiation process on days 0 to 21, while the pattern was increasing for MSX2 and C/EBPa. The methylation pattern of C/EBPζ was upward in untreated groups while it had a downward pattern in ZA-treated groups at the same scheduled time. The result for FRA1 was not significant in both groups at the same scheduled time (days 0-21). CONCLUSION: The results indicated that promoter-hypomethylation of ATF4, DLX3, and FRA1 genes might be one of the mechanism(s) controlling their gene expression. Moreover, we found that promoter-hypermethylation led to the down-regulation of MSX2, C/EBP-ζ and C/EBP-α. The results implicate that ATF4, DLX3 and FRA1 may act as inducers of OSD while MSX2, C/EBP-ζ and C/EBP-α could act as the inhibitor ones. We also determined that promoter-methylation is an important process in the regulation of OSD. However, yet there was no significant difference in the promoter-methylation level of selected TFs in ZA-treated and control cells, a methylation- independent pathway might be involved in the regulation of target genes during OSD of MSCs.

Bismuth-Based Nanomaterials: Recent Advances in Tumor Targeting and Synergistic Cancer Therapy Techniques.

Despite all of the efforts in the field of cancer therapy, the heterogeneous properties of tumor cells induce an insufficient therapeutic outcome when treated with conventional monotherapies, necessitating a shift in cancer treatment from monotherapy to combination therapy for complete cancer treatment. Multifunctional bismuth (Bi)-based nanomaterials (NMs) with therapeutic functions hold great promise for the fields of cancer diagnosis and therapy based on their low toxicity, X-ray sensitive capabilities, high atomic number, near-infrared driven semiconductor properties, and low cost. Herein, a comprehensive review of recent advances in various medicinal aspects of Bi-based NMs is presented including: evaluation of in-tumor site accumulation, tumor targeting, and therapeutic performance, as well as the characteristics, benefits, and shortcomings of Bi-based NM-mediated major monotherapies. In addition, the cooperative enhancement mechanisms between two or more of these monotherapies are described in detail to address common challenges in cancer therapy, such as multidrug resistance, hypoxia, and metastasis. Finally, this review opens new insights into the design of multimodal synergistic therapies for potential future clinical applications of Bi-based NMs.

Evidences from a Systematic Review and Meta-Analysis Unveil the Role of MiRNA Polymorphisms in the Predisposition to Female Neoplasms.

Breast (BCa) and gynecological (GCa) cancers constitute a group of female neoplasms that has a worldwide significant contribution to cancer morbidity and mortality. Evidence suggests that polymorphisms influencing miRNA function can provide useful information towards predicting the risk of female neoplasms. Inconsistent findings in the literature should be detected and resolved to facilitate the genetic screening of miRNA polymorphisms, even during childhood or adolescence, and their use as predictors of future malignancies. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and the risk of female neoplasms. Meta-analysis was performed by pooling odds-ratios (ORs) and generalized ORs while using a random-effects model for 15 miRNA polymorphisms. The results suggest that miR-146a rs2910164 is implicated in the susceptibility to GCa. Moreover, miR-196a2 rs11614913-T had a moderate protective effect against female neoplasms, especially GCa, in Asians but not in Caucasians. MiR-27a rs895819-G might pose a protective effect against BCa among Caucasians. MiR-499 rs3746444-C may slightly increase the risk of female neoplasms, especially BCa. MiR-124 rs531564-G may be associated with a lower risk of female neoplasms. The current evidences do not support the association of the remaining polymorphisms and the risk of female neoplasms.

A new insight on serum microRNA expression as novel biomarkers in breast cancer patients.

Breast cancer (BC) is one of the widespread lethal diseases affecting a large number of women worldwide. As such, employing and identifying significant markers for detecting BC in different stages can assist in better diagnosis and management of the disease. Several diverse markers have been introduced for diagnosis, but their limitations, including low specificity and sensitivity, reduce their application. microRNAs (miRNAs), as short noncoding RNAs, have been shown to significantly influence gene expression in different disease pathologies, especially BC. Clearly, among different samples used for detecting miRNA expressions, circulating miRNAs present as promising and useful biomarkers. Among different body fluid samples, serum serves as one of the most reliable samples, thanks to its high stability under various severe conditions and some unique features. Extensive research has suggested that BC-related miRNAs can remain stable in the serum. The objective of this review is to describe different samples used for detecting miRNAs in BC subjects with emphasis on serum miRNAs. So, this study highlights serum miRNAs with the potential of acting as biomarkers for different stages of BC. We reviewed the possible correlation between potential miRNAs and the risk of early breast cancer, metastatic breast cancer, response to chemotherapy, and relapse.

Association of mir-196a-2 rs11614913 and mir-149 rs2292832 Polymorphisms With Risk of Cancer: An Updated Meta-Analysis.

Background: Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences. This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies. Methods: PubMed, Embase, Scopus, and ScienceDirect databases were searched until 9 April 2018 to identify eligible studies. Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI). Studies that met the following criteria were excluded: review articles, meta-analysis, abstracts or conference papers; duplicate publications; studies on animals or cell-lines; studies without a case-control design; studies that did not report genotype frequencies. Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832. Stratified analysis according to quality scores, genotyping method, ethnicity, broad cancer category and cancer type was also performed. Results: Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population. The association was only significant in Asians but not Caucasians. In subgroup analysis, significant associations were found in high quality studies, gynecological cancers, ovarian, breast, and hepatocellular cancer. Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians. However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model. Conclusions: The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians. Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer. This study had some limitations such as significant heterogeneity in most contrasts, limited number of studies enrolling Africans or Caucasians ancestry and lack of adjustment for covariates and environmental interactions.

Oleuropein inhibits migration ability through suppression of epithelial-mesenchymal transition and synergistically enhances doxorubicin-mediated apoptosis in MCF-7 cells.

Distinct metastasis is one of the main causes of breast cancer (BC)-related mortality and epithelial-mesenchymal transition (EMT) is a primary step in metastasis dissemination. On the other hand, doxorubicin (DOX) is an effective chemotherapeutic agent against BC; unfortunately, its clinical use is limited by dose-dependent side effects. Therefore, extensive efforts have been dedicated to suppressing metastasis of BC and also to overcome DOX side effects together with keeping its antitumor efficacy. Studies supported the role of oleuropein (OLEU) in reducing DOX-induced side effects besides its antitumor actions. In this study, the antimigratory effect of OLEU was assessed and real-time PCR (RT-PCR) was used to detect OLEU effect on the expression level of EMT markers, in MCF-7 cells. The cytotoxic effect of OLEU and DOX was assessed by MTT assay, whereas the ratio of apoptosis was investigated by flow cytometry. The results showed that migration ability of MCF-7 cells remarkably decreased in OLEU treated group and RT-PCR results showed that OLEU may exert its antimigratory action by suppressing EMT through downregulation of sirtuin1 (SIRT1). Also, the results indicated that both OLEU and DOX were cytotoxic to MCF-7 cells, whereas DOX-OLEU cotreatment led to additive cytotoxicity and apoptosis rate. This study provides evidence regarding the suppressive role of OLEU on MCF-7 cells migration ability through suppression of EMT, and for the first time, it was proposed that SIRT1 downregulation can be involved in the OLEU antimigratory effect. Also, the findings demonstrated that OLEU can reduce DOX-induced side effects by reducing its effective dose.

HDACis (class I), cancer stem cell, and phytochemicals: Cancer therapy and prevention implications.

Epigenetics is independent of the sequence events that physically affect the condensing of chromatin and genes expression. The unique epigenetic memories of various cells trigger exclusive gene expression profiling. According to different studies, the aberrant epigenetic signatures and impaired gene expression profiles are master occurrences in cancer cells in which oncogene and tumor suppressor genes are affected. Owing to the facts that epigenetic modifications are performed earlier than expression and are reversible, the epigenetic reprogramming of cancer cells could be applied potentially for their prevention, control, and therapy. The disruption of the acetylation signature, as a master epigenetic change in cancers, is related to the expression and the activity of HDACs. In this context, class I HDACs play a significant role in the regulation of cell proliferation and cancer. More recently, cancer stem cell (CSC) has been introduced as a minority population of tumor that is responsible for invasiveness, drug resistance, and relapse of cancers. It is now believed that controlling CSC via epigenetic reprogramming such as targeting HDACs could be helpful in regulating the acetylation pattern of chromatin. Recently, a number of reports have introduced some phytochemicals as HDAC inhibitors. The use of phytochemicals with the HDAC inhibition property could be potentially efficient in overcoming the mentioned problems of CSCs. This review presents a perspective concerning HDAC-targeted phytochemicals to control CSC in tumors. Hopefully, this new route would have more advantages in therapeutic applications and prevention against cancer.

Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial-mesenchymal transition in cancer cells.

The epithelial-mesenchymal transition (EMT) is a highly networked cellular process which involves cell transition from the immotile epithelial to the motile mesenchymal phenotype, whereby cells lose their cell-cell adhesion and cell polarity. This important process is one of the underlying mechanisms for enabling invasion and metastasis of cancer cells which is considered as malignant phase of tumor progression. However, the molecular mechanisms of this process are not fully clarified. It is reported that Sirtuin1 (SIRT1), a NAD+ dependent class III histone deacetylase is associated with tumor metastasis through positive regulation of EMT in several types of cancers. Recent studies confirmed that up and down regulation of SIRT1 expression remarkably change the migration ability of different cancer cells in vitro and tumor metastasis in vivo. Also, according to this fact that carcinomas as the main human solid tumors, originate from different epithelial cell types, SIRT1 role in EMT has received a great attention due to its potential role in tumor development and metastasis. Therefore, SIRT1 has been proposed as a key regulator of cancer metastasis by promoting EMT, although little is known about the cleared effect of SIRT1 in this transition. Our aim in this review is to explain in more detail the role of SIRT1 in various signaling pathways related to carcinogenesis, with the focus on the promoting role of SIRT1 in EMT as a potential therapeutic target to control EMT and to prevent cancer progression.