A Randomized, Controlled, Parallel-Group, Trial on the Long-term Effects of Melatonin on Fatigue Associated With Breast Cancer and Its Adjuvant Treatments.

OBJECTIVE: Cancer related fatigue is a distressing condition and correlated with decrease in quality of life of patients with malignant conditions. In continuation of our previous research, we assessed long term anti-fatigue effects of melatonin in patients with the breast cancer. MATERIAL AND METHODS: In this clinical trial, 92 breast cancer patients were randomly assigned to receive either melatonin (18 mg/day) or placebo from 1 week before the adjuvant treatments until 2 years after their completion. The levels of fatigue were assessed before and after intervention using Brief Fatigue Inventory (BFI) and were compared at a significance level of P ≤ .05. RESULTS: The BFI scores were similar between the 2 groups at the baseline (placebo group: 5.56 ± 1.59 and melatonin group: 5.72 ± 1.68, P = .67). After the intervention, not only the mean fatigue score was significantly lower in melatonin group (2.93 ± 1.04 vs 1.99 ± 1.02, P < .001, P ≤ .05), but also a greater reduction in fatigue score in intervention group was evident over time (P ≤ .001). CONCLUSION: Long-term usage of melatonin even after completion of adjuvant therapies in women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments. THE TRIAL REGISTRY NAME AND URL, AND REGISTRATION NUMBER: Iranian Registry of Clinical Trials, https://en.irct.ir/trial/62267, IRCT20180426039421N3.

Hypothyroidism Evaluation after Radiotherapy of Breast and Supraclavicular in Patients with Breast Cancer.

Background: This study aims to evaluate the risk of hypothyroidism (HT) after radiotherapy (RT) of breast and supraclavicular in patients with breast cancer (BC). Materials and Methods: In a historical cohort study, the records of all patients with BC who had been referred to the Mahdieh radiotherapy Center of Hamadan from 2017 to 2019 were reviewed. Demographic characteristics, clinical information, previous and current used treatment methods (surgery, radiotherapy, chemotherapy), number of RT sessions and doses, and HT (TSH >5 mIU/L) were extracted from the patient's documents. Data were analyzed using SPSS software version 16. Results: Out of 304 patients referred to the Center, 266 patients were investigated. The mean TSH was 6.3 ± 7.9 ml/L (1.5 to 65.4). Approximately half of the patients were in Stage 2 of the disease. 37 (16.4%) patients were diagnosed with HT, of which 8.8% were clinical, and 7.5% were subclinical. The mean total dose of HT patients (5621.62 ± 491.67) was significantly higher than other patients (5304.76 ± 937.98). 21 patients (56.8%) in Stage 3 and 4 and 16 (43.2%) patients in Stages 1 and 2 had HT (P = 0.006). Spearman correlation coefficient showed that there was a significant relationship between total dose and TSH hormone (r = 0.624), the number of RT sessions with TSH hormone (r = 0.237), and total dose with T4 hormone (r = -0.232). Conclusion: The findings of this study showed that the risk of HT increases significantly in patients with BC who undergo RT of breast and supraclavicular. Patients with higher stage, more radiation, and more RT sessions are at higher risk of HT.

Evaluating the Outcome of an Unnecessary Request for CT Scan in Be'sat Hospital of Hamadan.

Aim: This study aimed to investigate the frequency of unnecessary tests requested in Be'sat Hospital in Hamadan. Materials and Methods: This descriptive research was conducted in order to investigate the frequency of unnecessary requests for CT scan and radiography of patients referring to the imaging department of Be'sat Hospital in Hamadan in a 4- to 6-month period. Patient information, including gender, age, type of CT scan test, the reason for requesting the test, the expertise of the requesting physician, and the result of the radiologist's report on each test, was extracted and collected. Results: A total of 1000 CT scans were evaluated. The mean age of these patients was about 36 years and most of them were men. The highest and lowest percentages of unnecessary cases were related to CT scans of the brain (42.3%) and facial bones (2.3%), respectively. The most and the least unnecessary CT scans based on the reason given for the request were related to multiple physical trauma (30.7%) and chronic kidney disease (1.5%), respectively. Conclusion: In all tests, over 74% of the reports were unnecessary and less than 26% were necessary. Therefore, it is necessary to reduce unnecessary requests to reduce the radiation dose of patients. Also, the knowledge of doctors should be increased in the field of appropriate evaluation of CT scan tests based on clinical guidelines.

Evaluation of the Mitigation Effect of Spirulina Against Lung Injury Induced by Radiation in Rats.

BACKGROUND: Some compounds have been investigated to mitigate the effect of radiation on the lung, such as pneumonitis and fibrosis. OBJECTIVE: This study aimed to examine the mitigation efficiency of Spirulina compared to the effect of Metformin. METHODS: 25 male Wistar rats were allotted in five groups: control, Spirulina, Radiation, Radiation plus Spirulina, and Radiation plus Metformin. Rat chest regions were irradiated by 15 Gray (Gy) xradiation using aLINAC. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. Eighty days after irradiation, all rats were sacrificed, and their lung tissues were removed for histopathological, and biochemical assays. RESULTS: The results demonstrated that irradiation increased MDA (Malondialdehyde) levels while suppressing the SOD (superoxide dismutase) and GPx(glutathione peroxidase) activity in the irradiated group. MDA levels in lung tissues were reduced with Metformin but not with Spirulina. Both Metformin and Spirulina increased the SOD and GPx activity in lung tissue. Moreover, histopathological evaluations showed extensive changes in the lung tissue including infiltration of lymph cells around the bronchioles and blood vessels, thickening of the alveolar wall, and the disruption of the alveolar structure, as well as accumulation of collagen fibers. Administration of Spirulina and Metformin significantly reduced pathological changes in lung tissue, although the effect of Metformin was greater than that of Spirulina. CONCLUSION: Spirulina could mitigate radiation-induced lung injury moderately, although Metformin is more effective than Spirulina as a mitigator agent.

Evaluating the Mitigation Effect of Spirulina Against Radiation-Induced Heart Injury.

BACKGROUND: During a radiological or nuclear disaster, exposure to a high dose of ionizing radiation usually results in cardiovascular diseases such as heart failure, attack, and ischemia. OBJECTIVE: The purpose of this study was to examine the mitigation effects of Spirulina in comparison to Metformin's. METHODS: 25 male Wistar rats were randomly assigned to five groups (5 rats in each): for the control group, rats did not receive any intervention. In group 2, spirulina was administered orally to rats. In group 3, rats were irradiated to the chest region with 15 Gray(Gy) x-radiation. In groups 4 and 5, rats were irradiated in the same way as group 3. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. All rats were sacrificed after ten weeks, and their heart tissues were removed for histopathological and biochemical assays. RESULTS: Results showed an elevation in Malondialdehyde (MDA) and decreasing superoxide dismutase (SOD) activity. Moreover, pathological changes of radiation were irregularities in the arrangement of myofibrils, proliferation, migration of mononuclear cells, vacuolation of the cytoplasm, and congestion. Administration of spirulina enhanced the SOD activity while did not affect MDA level and pathological change in heart tissue. Despite spirulina, metformin had a considerable effect on pathological lesions and decreased the level of MDA. CONCLUSION: Reactive oxygen species (ROS) may be involved in the late effects of radiationinduced heart injury, and scavenging these particles may contribute to reduced radiation side effects. Based on these results, Spirulina had no effect on radiation-induced cardiac damage, while metformin did. Higher Spirulina doses given over a longer period of time will likely have a greater heart-mitigate effect.

Human exposure to low dose ionizing radiation affects miR-21 and miR-625 expression levels.

BACKGROUND: Recently exposure to ionizing radiation driven by artificial radiation sources such as Medical X-rays and Nuclear medicine has increased hastily. Ionizing radiation-induced the DNA damage and activate the DNA damage response signaling pathways. The aim of this study was to evaluate the role of miR-21 and miR-625 in response to low-dose ionizing radiation. MATERIALS AND METHODS: In this study, the blood sample of 38 volunteer patients who underwent Cardiac scans before and after 99mTc-MIBI injection were used. The WBC of patients was used for RNA extraction and after cDNA synthesis by the poly-A method the expression level of miR-21 and miR-625 was evaluated by real-time PCR method. RESULTS: The results of this study indicated that miR-21 and miR- 625 were significantly upregulated under exposure to low-dose ionizing radiation. The expression level of these miRNAs was not significantly correlated with the age and BMI of patients. More ever the bioinformatics analysis indicated that SP1 was a common target of both miRNAs and had the highest degree between hub genes. CONCLUSION: In summary miR-21 and miR-625 can contribute to the response to acute low dose ionizing radiation by targeting the SP1. However further studies should be carried out on the molecular mechanism of effects of miR-21 and miR-625 in response to low dose ionizing radiation by targeting the SP1.

Gene expression and apoptosis response in hepatocellular carcinoma cells induced by biocompatible polymer/magnetic nanoparticles containing 5-fluorouracil

BACKGROUND: Super-paramagnetic iron oxide nanoparticles (SPION) contain a chemotherapeutic drug and are regarded as a promising technique for improving targeted delivery into cancer cells. RESULTS: In this study, the fabrication of 5-fluorouracil (5-FU) was investigated with loaded Dextran (DEXSPION) using the co-precipitation technique and conjugated by folate (FA). These nanoparticles (NPs) were employed as carriers and anticancer compounds against liver cancer cells in vitro. Structural, magnetic, morphological characterization, size, and drug loading activities of the obtained FA-DEX-5-FUSPION NPs were checked using FTIR, VSM, FESEM, TEM, DLS, and zeta potential techniques. The cellular toxicity effect of FA-DEX-5-FU-SPION NPs was evaluated using the MTT test on liver cancer (SNU-423) and healthy cells (LO2). Furthermore, the apoptosis measurement and the expression levels of NF-1, Her-2/neu, c-Raf-1, and Wnt-1 genes were evaluated post-treatment using flow cytometry and RT-PCR, respectively. The obtained NPs were spherical with a suitable dispersity without noticeable aggregation. The size of the NPs, polydispersity, and zeta were 74 ± 13 nm, 0.080 and 45 mV, respectively. The results of the encapsulation efficiency of the nano-compound showed highly colloidal stability and proper drug maintenance. The results indicated that FA-DEX-5-FU-SPION demonstrated a sustained release profile of 5-FU in both phosphate and citrate buffer solutions separately, with higher cytotoxicity against SNU-423 cells than against other cells types. These findings suggest that FA-DEX-SPION NPs exert synergistic effects for targeting intracellular delivery of 5-FU, apoptosis induction, and gene expression stimulation. CONCLUSIONS: The findings proved that FA-DEX-5-FU-SPION presented remarkable antitumor properties; no adverse subsequences were revealed against normal cells.

Cross-Resistance of Acquired Radioresistant Colorectal Cancer Cell Line to gefitinib and regorafenib.

BACKGROUND: Usually, chemoradiotherapy can be used for the treatment of locally advanced colorectal cancer (CRC) before surgery. On the other hand, some studies have shown that fractional radiation of tumor cells leads to chemoresistance. The aim of this study was to evaluate the chemoresistance of radioresistant sub-line (RR sub-line). METHODS: This study was done in Hamadan University of Medical Sciences in 2017-2018. MTT assay and sub-G1 fraction analysis by flow cytometry were used to evaluate cross-resistance of RR sub-line to gefitinib and regorafenib. Real-time PCR was used to investigate the role of four miRNAs and their target genes in the cross-resistance of RR sub-line. The t test and repeated measures test were used for the assessment of statistical significance between groups. RESULTS: The IC50 of gefitinib and regorafenib for RR sub-line were significantly higher than those of the parental cell line. On the other hand, the resistance index of RR sub-line for gefitinib and regorafenib were 1.92 and 1.44, respectively. The sub-G1 fraction of RR sub-line following treatment with gefitinib and regorafenib was significantly lower than that of the parental cell line (P=0.012 and P=0.038, respectively). The expression of miR-9, Let-7e, and Let-7b in RRsub-line was significantly lower than that of the parental cell line. However, NRAS, IGF1R, NFKB1, and CCND1 found to be upregulated in RR sub-line in comparison with the parental cell line. CONCLUSION: We can conclude that the acquired RR sub-line was cross-resistance to gefitinib and regorafenib. Furthermore, miR-9/NFKB1, let-7b/CCND1, let-7e/NRAS, and IGF1R played essential roles in the chemoradioresistance of CRC.

Effect of Extremely Low Frequency Electromagnetic Fields on Expression of T-bet and GATA-3 Genes and Serum Interferon-γ and Interleukin-4.

This study investigated the effect of various magnetic flux densities of extremely low frequency electromagnetic fields (ELF-EMF) on expression of T-box transcription factor (T-bet) and GATA binding protein-3 (GATA-3) genes in the spleen and thymus of rats injected with human serum albumin (HSA). Moreover, serum levels of interferon (IFN)-γ and interleukin (IL)-4 were evaluated at two phases, that is, prestimulation and poststimulation with HSA. Eighty rats were separated into five groups, and four groups were exposed daily to 50 Hz EMF of 1, 100, 500, and 2000 µT magnetic flux densities for 60 days. To activate the immune system, 100 µg HSA was intraperitoneally injected into each rat on days 31, 44, and 58 of the regimen. Splenic and thymic T-bet and GATA-3 messenger RNA (mRNA) expression on day 61 was evaluated by reverse transcription quantitative PCR. Serum IFN-γ and IL-4 (in blood on day 31 before HSA and again on day 61) levels were evaluated by enzyme-linked immunosorbent assay. Expression of T-bet and GATA-3 mRNA was decreased in the spleen in hosts exposed to densities of 1 and 100 µT. Serum IFN-γ and IL-4 levels were also significantly decreased in 100 µT-exposed rats, but only at the prestimulation phase. From these findings, it appears that (30 and 60 days) ELF-EMF exposure could suppress the expression of some key genes associated with T helper (Th) cells and on some of their associated functions, that is, the ability to generate (in some cases, spontaneously) select cytokines. Whether this is attributable to effects on Th1/Th2 levels in the hosts and/or due to potential effects of the EMF on cellular functions remains to be determined.

MiR-185 enhances radiosensitivity of colorectal cancer cells by targeting IGF1R and IGF2.

OBJECTIVE: Radioresistance is a significant obstacle for effective treatment of colorectal cancer (CRC). Recent studies have indicated that miR-185 inhibits proliferation, survival, and invasion of CRC; however, the role of this miRNA in radioresistance of CRC has not been identified yet. The aim of this study is to investigate the role of miR-185 in radiosensitivity of CRC. METHODS: After transfecting the cells with mimic miR-185, expressions of IGF1R and IGF2 were evaluated by real-time PCR and western blot. The radiation response of transfected cells was also examined by colony forming assay. Sub-G1 fraction analysis through flow cytometry and caspase 3 activity was used to evaluate apoptosis. RESULTS: The results of real-time PCR and western blot indicated that IGF1R and IGF2 are downregulated in the transfected cells. Colony forming assay revealed that transfected cells were more radiosensitive than other cells. On the other hand,following irradiation the rate of apoptosis was significantly higher in the transfected cells than in the other cells. CONCLUSION: In summary, our study is the first to show that upregulation of miR-185 enhances the sensitivity of CRC cells to ionizing radiation. miR-185 may act as a novel biomarker of radioresistance and may clinically enhance the radiation response of CRC.

Water liquid-vapor interface subjected to various electric fields: A molecular dynamics study.

Investigation of the effects of E-fields on the liquid-vapor interface is essential for the study of floating water bridge and wetting phenomena. The present study employs the molecular dynamics method to investigate the effects of parallel and perpendicular E-fields on the water liquid-vapor interface. For this purpose, density distribution, number of hydrogen bonds, molecular orientation, and surface tension are examined to gain a better understanding of the interface structure. Results indicate enhancements in parallel E-field decrease the interface width and number of hydrogen bonds, while the opposite holds true in the case of perpendicular E-fields. Moreover, perpendicular fields disturb the water structure at the interface. Given that water molecules tend to be parallel to the interface plane, it is observed that perpendicular E-fields fail to realign water molecules in the field direction while the parallel ones easily do so. It is also shown that surface tension rises with increasing strength of parallel E-fields, while it reduces in the case of perpendicular E-fields. Enhancement of surface tension in the parallel field direction demonstrates how the floating water bridge forms between the beakers. Finally, it is found that application of external E-fields to the liquid-vapor interface does not lead to uniform changes in surface tension and that the liquid-vapor interfacial tension term in Young's equation should be calculated near the triple-line of the droplet. This is attributed to the multi-directional nature of the droplet surface, indicating that no constant value can be assigned to a droplet's surface tension in the presence of large electric fields.

Effects of radiofrequency radiation in the presence of gold nanoparticles for the treatment of renal cell carcinoma.

Introduction: The most common type of kidney cancer is renal cell carcinoma (RCC), which accounts for more than 80% of all kidney cancers. Objectives: The aim of this study was to evaluate the effects of radiofrequency (RF) radiation in the presence of gold nanoparticles (GNPs) for the treatment of RCC. Materials and Methods: Human embryonic kidney (HEK) cancer cells were divided into 6 groups. Various tests were performed on HEK cells in the presence of RF and GNPs. In order to investigate the radiation effects on the cells' survival, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-iphenyltetrazolium bromide] assay was performed at different days during and post-irradiation period. The repeated measure analysis of variance (ANOVA) method was used for statistical analysis of the cells' survival using SPSS version 16.0. A significant level of 0.05 was considered to the tests. Results: Using the ANOVA test, a significant decrease in cell's survival was seen in the RF exposed group 3 compared to the control group (P=0.035). While, differences were not significant between RF exposed group 2 and the control group (P>0.05). A significant decrease in cell's survival in the RF exposed groups 5 (P=0.025) and 6 (P=0.018) at the presence of GNP compared to the control group was seen. Conclusion: Results of this study showed that, this method can be efficiently used for RCC treatment as an alternative to nephrectomy. More follow up in vivo studies on mammalians are needed to investigate the potential of the presented method for clinical applications.

The application of the linear quadratic model to compensate the effects of prolonged fraction delivery time on a Balb/C breast adenocarcinoma tumor: An in vivo study.

Purpose To investigate the effect of increasing the overall treatment time as well as delivering the compensating doses on the Balb/c breast adenocarcinoma (4T1) tumor. Materials and methods A total of 72 mice were divided into two aliquots (classes A and B) based on the initial size of their induced tumor. Each class was divided into a control and several treatment groups. Among the treatment groups, group 1 was continuously exposed to 2 Gy irradiation, and groups 2 and 3 received two subfractions of 1 Gy over the total treatment times of 30 and 60 min, respectively. To investigate the effect of compensating doses, calculated based on the developed linear quadratic model (LQ) model, the remaining two groups (groups 4 and 5) received two subfractions of 1.16 and 1.24 Gy over the total treatment times of 30 and 60 min, respectively. The growing curves, Tumor Growth Time (TGT), Tumor Growth Delay Time (TGDT) and the survival of the animals were studied. Results For class A (tumor size ≤ 30 mm(3)), the average tumor size in the irradiated groups 1-5 was considerably different compared to the control group as one unit (day) change in time, by amount of -160.8, -158.9, +39.4 and +44.0, respectively. While these amounts were +22.0, +17.9, -21.7 and -0.1 for class B (tumor size ≥ 400 mm(3)). For the class A of animals, the TGT and TGDT parameters were significantly lower (0 ≤ 0.05) for the groups 2 and 3, compared to group 1. There was no significant difference (p > 0.05) between groups 1, 4 and 5 in this class. There was no significant difference (p > 0.05) between all the treated groups in class B. Conclusions Increasing total treatment time affects the radiobiological efficiency of treatment especially in small-sized tumor. The compensating doses derived from the LQ model can be used to compensate the effects of prolonged treatment times at in vivo condition.

Estimation of cell response in fractionation radiotherapy using different methods derived from linear quadratic model.

BACKGROUND: The aim of this study was to use various theoretical methods derived from the Linear Quadratic (LQ) model to calculate the effects of number of subfractions, time intervals between subfractions, dose per subfraction, and overall fraction time on the cells' survival. Comparison of the results with experimental outcomes of melanoma and breast adenocarcinoma cells was also performed. Finally, the best matched method with experimental outcomes is introduced as the most accurate method in predicting the cell response. MATERIALS AND METHODS: The most widely used theoretical methods in the literature, presented by Keall et al., Brenner, and Mu et al., were used to calculate the cells' survival following radiotherapy with different treatment schemes. The overall treatment times were ranged from 15 to 240 minutes. To investigate the effects of number of subfractions and dose per subfraction, the cells' survival after different treatment delivery scenarios were calculated through fixed overall treatment times of 30, 60 and 240 minutes. The experimental tests were done for dose of 4 Gy. The results were compared with those of the theoretical outcomes. RESULTS: The most affective parameter on the cells' survival was the overall treatment time. However, the number of subfractions per fractions was another effecting parameter in the theoretical models. This parameter showed no significant effect on the cells' survival in experimental schemes. The variations in number of subfractions per each fraction showed different results on the cells' survival, calculated by Keall et al. and Brenner methods (P<0.05). CONCLUSIONS: Mu et al. method can predict the cells' survival following fractionation radiotherapy more accurately than the other models. Using Mu et al. method, as an accurate and simple method to predict the cell response after fractionation radiotherapy, is suggested for clinical applications.

Curcumin-loaded guanidine functionalized PEGylated I3ad mesoporous silica nanoparticles KIT-6: practical strategy for the breast cancer therapy.

In this research, we have synthesized guanidine functionalized PEGylated mesoporous silica nanoparticles as a novel and efficient drug delivery system (DDS). For this purpose, guanidine functionalized PEGylated I3ad mesoporous silica nanoparticle KIT-6 [Gu@PEGylated KIT-6] was utilized as a promising system for the effective delivery of curcumin into the breast cancer cells. The modified mesoporous silica nanoparticles (MSNs) was fully characterized by different techniques such as transmission and scanning electron microscopy (TEM & SEM), N2 adsorption-desorption measurement, thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD), and dynamic light scattering (DLS). The average particle size of [Gu@PEGylated KIT-6] and curcumin loaded [Gu@PEGylated KIT-6] nanoparticles were about 60 and 70 nm, respectively. This new system exhibited high drug loading capacity, sustained drug release profile, and high and long term anticancer efficacy in human cancer cell lines. It showed pH-responsive controlled characteristics and highly programmed release of curcumin leading to the satisfactory results in in vitro breast cancer therapy. Our results depicted that the pure nanoparticles have no cytotoxicity against human breast adenocarcinoma cells (MCF-7), mouse breast cancer cells (4T1), and human mammary epithelial cells (MCF10A).

The Cell Survival of F10B16 Melanoma and 4T1 Breast Adenocarcinoma Irradiated to Gamma Radiation Using the MTT Assay Based on Two Different Calculation Methods.

BACKGROUND: various MTT assay methods are proposed to obtain the cell survival parameters. OBJECTIVE: determining the survival curve characteristics of two cancerous cells of interest based on a common and a novel MTT assay method after exposing them to ionizing radiation. METHODS: a common and a novel MTT assay method were used and compared for obtaining the F10B16 melanoma and 4T1 breast adenocarcinoma survivals after exposing them to ionizing radiation from a Co-60 machine. To obtain the survival parameters of the cells based on the common method, the cells were inoculated in 96-well plates. After irradiating the plates, the MTT assay was performed over the following days for a period of 8 days. Thereafter, the survival fraction was calculated from a simple equation for every day from which the best day was selected. To acquire the cells' survival parameters based on the novel method, extensive experiments were performed on a large number of samples. Then, the MTT assay was done in every day following various experimental treatments to acquire the exponential growth. Finally, the cells' survivals were determined by measuring the space between relevant growing curves. RESULTS: at low doses (<4Gy) the two MTT assay methods indicated the same results. However, at higher doses there were significant differences among the findings. CONCLUSION: both of the MTT methods indicated that the cells' responses are dependent on the dose levels used. Although the implementation of the common MTT assay method is simpler, the novel method seems to show more precise and reliable results at all levels of radiation doses.