Revisiting of Properties and Modified Polyethylenimine-Based Cancer Gene Delivery Systems.

A new era of medical technology in cancer treatment is a directly specific modification of gene expression in tumor cells by nucleic acid delivery. Currently, the main challenge to achieving this goal is to find a non-toxic, safe, and effective strategy for gene transfer to cancer cells. Synthetic composites based on cationic polymers have historically been favored in bioengineering due to their ability to mimic bimolecular structures. Among them, polyethylenimines (PEIs) with superior properties such as a wide range of molecular weight and a flexible structure may propel the development of functional combinations in the biomedical and biomaterial fields. Here, in this review, we will focus on the recent progressions in the formulation optimization of PEI-based polyplex in gene delivery to treat cancer. Also, the effect of PEI's intrinsic characteristics such as structure, molecular weight, and positive charges which influence the gene delivery efficiency will be discussed.

The immunostimulant effects of the rice ragged stunt virus genome on the growth and metastasis of breast cancer in mouse model.

There are multiple treatment strategies that have been reported for breast cancer, while new and effective therapies against it are still necessary. Stimulating the immune system and its components against cancer cells is one of the unique treatment strategies of immunotherapy and long dsRNAs are immunostimulant in this regard. Based on bioinformatics approaches, a fragment of the Rice ragged stunt RNA virus genome was selected and synthesized according to its immunogenicity. Based on the in vitro transcription technique, dsRNA was synthesized and its binding ability to the PEI/PEI-Ac Polyethylenimine (PEI) or Acetylated polyethylenimine (PEI-Ac) was verified by the gel retardation assay. Then, the PEI-Ac was synthesized by adding acetyl groups to the PEI, and the results of the 1H NMR method indicated its successful synthesis. After cancer induction by 4 T1 cells in Balb/C mice, intraperitoneal (IP) and intratumoral (IT) treatment by the PEI/PEI-Ac-dsRNA were performed and the tumor growth inhibition was evaluated. Results demonstrated that PEI/PEI-Ac-dsRNA can lead to a decrease in tumor weight and volume in both the IP and IT routes. Also, by using macro-metastatic nodule counting and hematoxylin and eosin (H&E) staining we showed that PEI/PEI-Ac-dsRNA can prevent micro and macro-metastasis in the lung. Therefore, the PEI/PEI-Ac-dsRNA acts as an effective inhibitor of growth and metastasis of the breast cancer models. We showed that viral dsRNA can exert its antitumor properties by stimulating TNF-α and IFN-γ. In general, our results revealed that dsRNA derived from the plant virus genome stimulates the intrinsic immune system and can be a potential immune stimulant drug for cancer treatment.

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.

ADAMTS9-AS1 Long Non­coding RNA Sponges miR­128 and miR-150 to Regulate Ras/MAPK Signaling Pathway in Glioma.

Glioma is a malignancy of the central nervous system with a poor prognosis. Therefore, the elaboration of its molecular features creates therapeutic opportunities. Looking for the regulatory non-coding RNAs (lncRNAs and miRNAs) that are involved in glioma incidence/progression, RNA-seq analysis introduced upregulated ADAMTS9-AS1 as a bona fide candidate that sponges miR-128 and miR-150 and shows the negative correlation of expression with them. Then, RT-qPCR verified the upregulation of ADAMTS9-AS1 in glioma tissues and cell lines. Furthermore, dual-luciferase assay supported that cytoplasmic ADAMTS9-AS1 is capable of sponging miR-128 and miR-150, which are known as regulators of Ras/MAPK, PI3K, and Wnt pathways. Following the overexpression of ADAMTS9-AS1 in 1321N1 and U87 glioma cells, tyrosine kinase receptors (IGF1R and TrkC), as well as Wnt receptors (Lrp6 and Fzd) were upregulated, detected by RT-qPCR. Furthermore, downstream genes of both Ras/MAPK and Wnt pathways were upregulated. Finally following the ADAMTS9-AS1 overexpression, upregulation of Ras/MAPK and Wnt signaling pathways was verified through western blotting and Top/Fop flash assay, respectively. At the cellular level, ADAMTS9-AS1 overexpression brought about reduced sub-G1 cell population, increased proliferation rate, reduced apoptosis level, increased migration rate, shortened Bax/Bcl2 ratio, induced EMT, and stemness characteristics of transfected cells, detected by flow cytometry, MTT assay, scratch test, and RT-qPCR. Overall, these results introduced ADAMTS9-AS1 as an oncogene that upregulates Ras/MAPK and Wnt pathways through sponging of the miR-128 and miR-150 in glioma cells. The outcome of ADAMTS9-AS1 expression is more aggression of the glioma cells through increased EMT and stemness characteristics. These features candidate ADAMTS9-AS1 locus for glioma therapy. As a result, we discovered the oncogenic properties of ADAMTS9-AS1 in glioma cancer. It sponges miR-128 and miR-150 and subsequently overstimulates RAS/MAPK and Wnt signaling pathways, particularly at the receptors level. Thus, ADAMTS9-AS1 increases proliferation, migration, and stemness in glioma cell lines. A schematic representation showing the functional effect of ADAMTS9-AS1.

Stereotactic radiosurgery with immune checkpoint inhibitors for brain metastases: a meta-analysis study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an emerging tool in the treatment of brain metastases (BMs), Stereotactic radiosurgery (SRS), traditionally used for BMs, elicits an immune brain response and can act synergistically with ICIs. We aim to investigate the efficacy of ICI administered with SRS and determine the impact of timing on BM response. METHODS: A systematical search was performed to identify potential studies concerning BMs managed with SRS alone or with SRS + ICI with relative timing administration (ICI concurrent with SRS, ICI nonconcurrent with SRS, SRS before ICI, SRS after ICI). The overall survival (OS), 12-month OS, local progression-free survival (LPFS), 12-month local brain control (LBC), distant progression-free survival (DPFS), 12-month distant brain control (DBC), and adverse events (intracranial hemorrhage, radionecrosis) were analyzed using the random-effects model. RESULTS: A total of 16 retrospective studies with 1356 BM patients were included. Compared to nonconcurrent therapy, concurrent therapy revealed a significantly longer OS (HR= 1.43; p = 0.008) and 12-months LBC (HR = 1.91; p = 0.04), a similar 12-months DBC (HR = 1.12; p = 0.547) and higher complication rate (R = 0.77; p = 0.346). Concurrent therapy leads to a significantly higher OS compared to ICI before SRS (HR = 2.55; p = 0.0003). CONCLUSION: The combination of SRS with ICI improves patients' clinical and radiological outcomes. The effectiveness of the combination is subject to the identification of an optimal therapeutic window.

LINC02381-ceRNA exerts its oncogenic effect through regulation of IGF1R signaling pathway in glioma.

PURPOSE: LncRNAs play essential roles in the cellular and molecular biology of glioma. Some LncRNAs exert their role through sponging miRNAs and regulating multiple signaling pathways. LINC02381 is involved in several cancer types as either oncogene or tumor suppressor. Here, we intended to find the molecular mechanisms of the LINC02381 effect during the glioma progression in related cell lines. METHODS AND RESULTS: RNA-seq data analysis indicated the oncogenic characteristics of LINC02381, and RT-qPCR results confirmed its upregulation compared to normal tissues. Besides its expression was relatively stronger in invasive glioma cell lines. Furthermore, in silico analysis revealed LINC02381 is concentrated in the cytoplasm and predicted its sponging effect against miR-128 and miR-150, which was verified through dual luciferase assay. When LINC02381 was overexpressed in 1321N1, U87, and A172 cell lines, IGF1R and TrkC receptors as well as their downstream pathways (PI3K and RAS/MAPK), were upregulated, detected by RT-qPCR, and verified by western analysis. Consistently, LINC02381 overexpression was followed by an increased proliferation rate of transfected glioma cell lines, detected by flow cytometry and MTT assay, and RT-qPCR. It also resulted in elevated EMT and stemness markers expression level, increased migration rate, and reduced apoptosis rate, detected by RT-qPCR, western analysis, scratch test, and Annexin/PI flow cytometry analysis, respectively. CONCLUSION: The overall results indicated that LINC02381 exerts its oncogenic effect in glioma cells through sponging miR-128 and miR-150 to upregulate the IGF1R signaling pathway. Our results introduce LINC02381 and miR-128, and miR-150 as potential prognosis and therapy targets for the treatment of glioma.

Molecular and cellular evidence for hsa-miR-1254 suppressor effect against HER2 signaling in breast cancer.

HER2 signaling upregulation is a hallmark of breast cancer which is the second cause of cancer-related death in women. Here, we were looking for the candidate microRNAs which is capable of regulating the HER2 receptor and the genes of its downstream. To this aim, preliminary bioinformatics analysis introduced hsa-miR-1254 (miR-1254) as a potential common regulator of HER2, HER3, PIK3R2, and AKT1 genes. Then, reverse-transcription quantitative polymerase chain reaction (RT-qPCR) analysis indicated a lower expression level of miR-1254 in breast cancer specimens, compared to their normal pairs. Furthermore, overexpression of miR-1254 resulted in HER2, HER3, PIK3R2, and AKT1 genes downregulation, detected by RT-qPCR and confirmed by western blot analysis and enzyme-linked immunosorbent assay test against AKT1, BAX, FADD, and HER2 protein levels in SKBR3 cells. Dual-luciferase assay also supported direct interaction of miR-1254 with MREs within 3' untranslated region sequences of HER2, HER3, PIK3R2, and AKT1 target genes. Overexpression of miR-1254 in SKBR3 cells was followed by increased BAX/BCL2 expression ratio, detected by RT-qPCR, and increased proportion of G1 cell population, detected by flow cytometry. Corroborated by cell cycle analysis, MTT, Annexin V-FITC, and Live-Dead cell staining assays, overexpression of miR-1254 in MDA-MB-231 cells showed opposing results following the overexpression of miR-1254. Taken together, results indicated that miR-1254 acts as cell-type-specific tumor suppressor that targets HER2, HER3, PIK3R2, and AKT1 transcripts. These results suggest miR-1254 as a potential therapeutic candidate for breast cancer subtypes.

Transition in Smoking Stages and Its Relationship with Family Psychological Function and Perceived Social Support in Adolescents of Tabriz, Iran.

BACKGROUND: There is limited information on the relationship between family psychological functions and perceived social support with progress in cigarette smoking stages in adolescents. This study was aimed to determine the relationship between family psychological function and perceived social support through a transition in different stages of cigarette smoking in adolescents of Tabriz, Iran. METHODS: In this study, 4,216 students (14-19 years old) from high schools were selected by multistage cluster sampling method. Initially, we used valid and reliable questionnaires for demographic characteristics, risk factors, Iranian family psychological function, and perceived social support. The smoking status questionnaire was administered twice, with an interval of 6 months. Data were analyzed using univariate and multivariate logistic regression analysis. RESULTS: Overall, 3,968 students with the mean (standard deviation) age of 15.96 (0.75) years completed the questionnaire in the first phase of the study. The results showed that lower levels of family psychosocial function (P < 0.001) and perceived social support (P < 0.001) in the univariate state were significantly associated with progress in cigarette smoking stages. By controlling the potential confounding factors, the weak and moderate family psychological function compared to the strong function increased the chance of progress in the cigarette smoking stages by almost 11 and 4 times, respectively (P < 0.001). The low and moderate level of perceived social support compared to the high level increased the chance of progress in cigarette smoking stages by almost 7 and 2 times, respectively (P < 0.001). CONCLUSIONS: It is suggested to perform an organized, precise, and operational planning for strengthening the family psychological functions and providing an appropriate social support condition among adolescents to prevent the tendency toward cigarette smoking and its more advanced phases.

Epidemiology and Determinants of Self-Injury Among High School Students in Iran: a Longitudinal Study.

Non-suicidal self-injury (NSSI) among adolescents is a major health concern globally. The epidemiology and determinant of NSSI have not been studied extensively in Iran. Thus, this longitudinal study sought to investigate the prevalence, incidence and contributing factors of NSSI among adolescents in Iran. This study was conducted at high school students aged 14-18 years old in the metropolitan city of Tabriz, located in north western Iran. Data were collected from 6229 10th-grade students at two time-points, with 12 months interval in October and November 2017 and 2018. A self-administered questionnaire was used to collect information on demographic, NSSI and cigarette and hookah smoking from the study participants. The results showed that lifetime prevalence of NSSI among students was 6.2% (95% confidence interval [CI]: 5.7 to 6.9) at the first assessment. Scratching and hair pulling were the most and least common methods of self-injury, respectively. Over the one year, 206 students (3.6% CI 95%: 3.1-4.1) reported the onset of NSSI. Tobacco smoking and previous year average grade were related to the incidence of NSSI. Although gender was significantly associated with the prevalence of NSSI, the relationship between gender and incidence of NSSI was not significant. Although the prevalence of NSSI was low among adolescents, the incidence rate was considerable. Further studies are required to understand the risk factors of NSSI in Iran.