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Background: Breast cancer is one of the most common types of malignancies in the world. Cancer resistance is an unavoidable consequence of therapy with radiation or other modalities. On-going research aims to improve cancer response to therapy. Aim: The aim of this study was to evaluate the possible sensitization effect of imperatorin (IMP) in combination with external radiotherapy (ERT) or HT. Method: After treatment of MCF-7 breast cancer cells with IMP, cells were exposed to 4 Gy X-rays or HT (42 °C for 1 hour). The viability of MCF-7 cells was measured using an MTT assay. Further-more, the expression of pro-apoptotic genes, including Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, was investigated using real-time PCR. The sensitizing effect of IMP in combination with ERT or HT was calculated and compared to ERT or HT alone. Results: Results showed an increase in the expression of pro-apoptotic genes and downregulation of anti-apoptotic Bcl-2 following ERT and HT. Furthermore, cell viability was reduced following these treatments. IMP was able to augment these effects of ERT and HT. Conclusion: IMP could increase the efficiency of HT and ERT. This effect of IMP may suggest it as an adjuvant for increasing the therapeutic efficiency of ERT.

The resistance to therapy of cancer cells is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation, as well as immunotherapy. Evidences show that apoptosis plays a key role in the response of cancer (stem) cells and their multi-drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase the efficiency of tumor response and amplify the therapeutic effects of radiotherapy, chemotherapy, targeted therapy, and also immunotherapy. To date, several agents, as adjuvant, have been proposed to overcome the resistance of cancer cells to apoptosis. Natural products are interesting because of the low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors, such as Fas Ligand (FasL). Resveratrol also triggers some pathways which induce the mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on antiapoptotic mediators, such as Nuclear Factor κ B (NF-κB), Cyclooxygenase-2 (COX-2), Phosphatidylinositol 3– Kinase (PI3K), and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.

Introduction Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics. Methods Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients. Results Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h–1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUCτ,SS) for 15 mg/kg/day (median [interquartile range]) was higher in Kenya and Sudan (172.7 µg·h/mL [145.9–214.3]) and Ethiopia (230.1 µg·h/mL [146.3–591.2]) compared with India (97.26 µg·h/mL [80.83–123.4]). Conclusion The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01036-8.

Modulation of the immune system is a critical part of anticancer therapies including immunotherapy, chemotherapy, and radiotherapy. The aim of immunomodulation in cancer therapy is boosting immune system cells including CD8+ T lymphocytes and natural killer (NK) cells, as well as suppression of immunosuppressive responses by macrophages and regulatory T cells (Tregs). Usually, using single or dual modality can induce immune system responses against cancer. However, immunosuppressive responses attenuate antitumor immunity following cancer therapy. Using some agents to boost immune system's function against cancer can increase therapeutic efficiency of anticancer therapy. Resveratrol, as a natural agent, has shown ability to modulate the immune system to potentiate antitumor immunity. Resveratrol has been shown to induce the release of anticancer cytokines such as IFN-γ and TNF-α and also inhibits the release of TGF-β. It also can stimulate the polarization of CD4+ T cells and macrophages toward anticancer cells and reduce infiltration and polarization of immunosuppressive cells. Furthermore, resveratrol can sensitize cancer cells to the released dead signals by anticancer immune cells. This review explains how resveratrol can boost the immune system against cancer via modulation of immune cell responses within tumor.

Background: Lung is one of the radiosensitive and late responding organs, and is an important target for ionizing radiation. Radiation-induced pneumonitis and fibrosis are major consequences of lung exposure to a high dose of radiation and pose threats to the lives of exposed people. Mitigation of lung injury following an accidental radiation event or for patients with lung cancer is one of the most interesting issues in radiobiology. In the current study, we aimed to determine whether celecoxib, the most common cyclooxygenase-2 (COX-2) inhibitor, is able to mitigate pneumonitis and fibrosis following lung irradiation or not. Materials and methods: 20 male mice were assigned to 4 groups: control, celecoxib treatment, radiation, and radiation plus celecoxib. Irradiation was performed with a dose of 18 Gy cobalt-60 (60Co) gamma rays. Celecoxib treatment (50 mg/kg) started 24 h after irradiation and continued four times per week for 4 weeks. Results: Irradiation of lung led to remarkable infiltration of macrophages, lymphocytes, mast cells and neutrophils. Also, a mild increase in fibrosis markers including accumulation of collagen, and alveolar and vascular thickening, was observed. Post-exposure treatment with celecoxib was able to mitigate fibrosis as well as alveolar and vascular changes, however, it was unable to mitigate pneumonitis markers. Conclusion: Celecoxib showed that it may have an anti-fibrosis effect following exposure of mice lung to radiation, although it was unable to prevent pneumonitis.

Aim: In this study, we aimed to determine possible mitigation of radiationinduced toxicities in the duodenum, jejunum and colon using post-exposure treatment with resveratrol and alpha-lipoic acid. Background: After the bone marrow, gastrointestinal system toxicity is the second critical cause of death following whole-body exposure to radiation. Its side effects reduce the quality of life of patients who have undergone radiotherapy. Resveratrol has an antioxidant effect and stimulates DNA damage responses (DDRs). Alpha-lipoic acid neutralizes free radicals via the recycling of ascorbic acid and alpha-tocopherol. Objective: This study is a pilot investigation of the mitigation of enteritis using resveratrol and alpha-lipoic acid following histopathological study. Methods: 60 male mice were randomly assigned to six groups; control, resveratrol treatment, alpha-lipoic acid treatment, whole-body irradiation, irradiation plus resveratrol, and irradiation plus alpha-lipoic acid. The mice were irradiated with a single dose of 7 Gy from a cobalt-60 gamma-ray source. Treatment with resveratrol or alpha-lipoic acid started 24 h after irradiation and continued for 4 weeks. All mice were sacrificed after 30 days for histopathological evaluation of radiation-induced toxicities in the duodenum, jejunum and colon. Results and Conclusion: Exposure to radiation caused mild to severe damages to vessels, goblet cells and villous. It also led to significant infiltration of macrophages and leukocytes, especially in the colon. Both resveratrol and alpha-lipoic acid were able to mitigate morphological changes. However, they could not mitigate vascular injury. Conclusion: Resveratrol and alpha-lipoic acid could mitigate radiation-induced injuries in the small and large intestine. A comparison between these agents showed that resveratrol may be a more effective mitigator compared to alpha-lipoic acid.

Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

Objective Side-effects to normal tissues reduce the therapeutic window of radiotherapy. During radiotherapy, the skin is inevitably exposed to doses of ionizing radiation, leading to varying degrees of skin damage. Natural antioxidants have been explored for their radioprotective potentials. Thus, the present study aimed to investigate the protective effect of curcumin against radiotherapy-induced oxidative damage to the skin. Methods Forty rats were divided into four groups as follows: vehicle control (without irradiation or drug treatment), treatment with 150 mg/kg curcumin, 10 Gy single dose irradiation only, and 150 mg/kg curcumin plus 10 Gy radiation (RC). In the treatment groups, each rat was treated orally with 150 mg/kg curcumin 1 day before irradiation to 3 consecutive days after irradiation. Weeks 1, 2, or 4 after irradiation, all rats were sacrificed and their skin tissues collected and frozen at -80°C for the determination of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity in skin tissues. Results Radiotherapy-induced oxidative injury to the skin was evidenced by elevated MDA levels as well as depleted CAT, SOD, and GSH-Px activities. However, the administration of curcumin before and after irradiation prevented radiotherapy-induced oxidative damage by significantly elevating the activities of antioxidant enzymes. Conclusion From the findings of the present study, curcumin showed potential for protection against radiotherapy-induced oxidative injury to the skin. However, future studies are required to evaluate its clinical efficacy.

Background: Radiotherapy is a commonly used cancer treatment modality. However, radiation-induced complications are major drawbacks, especially at high doses. Radiation-induced brachial plexopathy (RIBP) is mostly observed in breast and lung cancer patients some months to years after radiotherapy. RIBP symptoms have negative effects on patients’ quality of life. The aim of this study was to review RIBP according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Methods: Online databases (PubMed, Scopus, Web of Science and Embase) were searched to retrieve relevant studies on brachial plexopathy as a complication of radiotherapy. Results: Initial search results yielded a total of 657 articles. After careful screening of their titles and abstracts, according to the inclusion and exclusion criteria, 31 articles were finally included in this study. Findings from these 31 papers showed that a total of 9192 cancer patients had undergone radiotherapy for different regions including chest, axillary area, thoracic outlet, neck and breast. 26.4% of these patients had RIPB (associated with symptoms such as paresthesia, pain, weakness, and/or motor dysfunction, organ pathology/dysfunction etc.) with different follow up times, where 8.2% of patients had RIPB after a mean time of 1.2 years, 15.8% after 2.6 years, 51% after 5 years, 14% after 7.8 years, and 11% after 10.5 years. Conclusion: From our findings, we can conclude that the issue of radiation-induced brachial plexus complication in human is of great concern. Common symptoms associated with this complication include paresthesia, numbness, pain and weakness. We recommend the use of individual dose planning and computer-assisted image segmentation techniques that support rapid and reliable contouring of the brachial plexus. Also, the radiation dose to the brachial plexus should be limited as much as possible to reduce the risk of brachial plexopathy.

Background: Lung is a radiosensitive organ. Studies have shown that exposure of the lung to acute and high doses of radiation following inhalation of radioactive agents or an accidental radiological event may lead to pneumonitis and fibrosis, which are associated with a risk of death. So far, some agents have been studied for mitigation of pneumonitis and fibrosis following exposure of murine lung tissues to ionizing radiation. In this study, we aimed to detect the possible mitigatory effect of alpha-lipoic acid, resveratrol and their combination on mice pneumonitis and fibrosis markers following irradiation. Methods: 25 mice were divided into 5 groups: control, radiation; radiation plus alpha-lipoic acid; radiation plus resveratrol; and radiation plus both resveratrol and alpha-lipoic acid. Mice chest regions were irradiated with 18 Gy using a cobalt-60 gamma rays source. Treatments started 24 h after irradiation and continued for two weeks. After 100 days, all mice were sacrificed and their lung tissues removed for histopathological evaluation. Results: Pathological study showed that exposure to radiation led to severe pneumonitis and moderate fibrosis after 100 days. Both resveratrol and alpha-lipoic acid, as well as their combination could mitigate pneumonitis and fibrosis markers. Although, resveratrol could not mitigate infiltration of most inflammatory cells as well as inflammation and vascular damage, alpha-lipoic acid and its combination were able to mitigate most damaged markers. Conclusion: Alpha-lipoic acid and its combination with resveratrol were able to mitigate fibrosis and pneumonitis markers in mice lung tissues following lung irradiation. Although resveratrol has a protective effect on some markers, it has a weaker effect on lung injury. In conclusion, our results suggest that the combination of resveratrol and alpha-lipoic acid has a potent mitigatory effect compared to the single forms of these agents.

Background: Radiation-induced enteritis and proctitis are common side effects of abdominopelvic cancers among patients that undergo radiotherapy for prostate, colorectal or urinary cancers. Exposure of these tissues to high doses of radiation leads to damage to villous, inflammation, pain, ulcer and bleeding, which may cause malabsorption and gastrointestinal disorders. To date, several procedures such as pharmaceutical treatment have been proposed for protection and mitigation of gastrointestinal toxicity following radiotherapy. Aims: In the current study, we aimed to investigate the possible radioprotection of ileum and colon in rats using a combination of melatonin and metformin. Methods: In this experimental study, 30 male Wistar rats were randomly assigned to six groups: control, melatonin (100 mg/kg) treatment, melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment, radiation (10 Gy to whole body) group, radiation + melatonin (100 mg/kg) treatment, and radiation + melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment. After 3.5 days, rats were sacrificed and their ileum and colon tissues carefully removed. Histopathological evaluations were conducted on these tissue samples. Results: Histological evaluations reported moderate to severe damages to ileum and colon following whole body irradiation. Melatonin administration was able to protect the ileum remarkably, while the combination of melatonin and metformin was less effective. Interestingly, for the colon, melatonin was less effective while its combination with metformin was able to protect against radiation toxicity completely. Conclusion: For the ileum, melatonin was a more effective radioprotector compared to its combination with metformin. However, the combination of melatonin and metformin can be proposed as an ideal radioprotector for the colon.

Background: ejunum is one of the most radiosensitive parts of the gastrointestinal system. This is the main issue, leading to several side effects to patients with abdominal cancers, in addition to affecting their quality of life. Epithelial layer and clonogenic cells in the jejunum are the most sensitive parts of the intestine, while damage to vascular may lead to chronic inflammation and bleeding. Both melatonin and metformin have shown abilities to attenuate radiation toxicities through the modulation of DNA damage responses, neutralization of free radicals and alleviation of inflammation. In this study, we aimed to evaluate the possible radioprotective effects of melatonin and metformin when administered either alone or as a combination, in rat’s jejunum against a high dose of radiation. Methods: 40 male rats were divided into 8 groups as G1: control; G2: metformin; G3: melatonin; G4: melatonin + metformin; G5: radiation; G6: radiation + melatonin; G7: radiation + metformin; G8: metformin + melatonin + radiation. Rats were irradiated with 10 Gy gamma rays, while treatments were administered at 100 mg/kg. The ratio for melatonin and metformin was 1:1. 3.5 days after irradiation, all rats were sacrificed, followed by histopathological evaluation of the jejunum. Results: This study showed that whole body irradiation of rats led to severe injuries to the epithelial and vascular of jejunum. A single administration of either melatonin or metformin was unable to mitigate radiation toxicity. However, administering the combination of melatonin and metformin could mildly mitigate radiation-induced jejunum injury. Conclusion: From the results of this study, we suggest that the combination of melatonin and metformin has superior radioprotective effect for jejunum compared with the single administration of these drugs.

Background Nowadays, breast cancer is the second cause of death after cardiovascular diseases. In general, about one out of eight women (about 12%) suffer from this disease during their life in the USA and European countries. If breast cancer is detected at an early stage, its survival rate will be very high. Several methods have been introduced to diagnose breast cancer with their clinical advantages and disadvantages. Main text In this review, various methods of breast imaging have been introduced. Furthermore, the sensitivity and specificity of each of these methods have been investigated. For each of the imaging methods, articles that were relevant to the past 10 years were selected through electronic search engines, and then the most relevant papers were selected. Finally, about 40 articles were studied and their results were categorized and presented in the form of a report as follows. Various breast cancer imaging techniques were extracted as follows: mammography, contrast-enhanced mammography, digital tomosynthesis, sonography, sonoelastography, magnetic resonance imaging, magnetic elastography, diffusion-weighted imaging, magnetic spectroscopy, nuclear medicine, optical imaging, and microwave imaging. Conclusion The choice of these methods depends on the patient’s state and stage, the age of the individual and the density of the breast tissue. Hybrid imaging techniques appear to be an acceptable way to improve detection of breast cancer. This review article can be useful in choosing the right method for imaging in people suspected of breast cancer.

Background: In Sudan, neither mumps nor rubella vaccines are currently used and comprehensive data on the seroepidemiology of measles, mumps, and rubella (M.M.R), as well as information about circulating mumps virus genotypes, are lacking. Methods: In 2015/2016, dried blood spot samples were collected from 294 children, 153 adults from the general population, and 241 healthcare workers (HCWs) from Khartoum. The samples were investigated for M.M.R IgG antibodies using ELISA. Oral fluid samples from 16 clinical mumps cases collected in 2017 were characterized by RT-PCR and sequencing. Results: The seroprevalence of M.M.R antibodies among children was 93.5%, 63.6%, and 55.8%, while it was 93.5%, 90.8%, and 94.1% among adult volunteers and 99.2%, 97.1%, and 97.9% among HCWs. A high measles seroprevalence was observed among all children age groups, suggesting an effective control programme, while the mumps and rubella seroprevalence increased significantly with age (p

Background: Radiotherapy is a treatment method for cancer mostly utilized for about 60% of cancer patients. Peripheral neuropathy is one of the severe complications of radiotherapy. Two stages of neuropathy will occur following irradiation; electrophysiological and biochemical variations as the first stage, while the second stage involves fibrosis of soft tissues surrounding the exposed nerve. This novel study aimed to investigate the radioprotective effects of melatonin against ionizing radiation-induced sciatic nerve damage. Methods: 60 rats were randomly assigned to four groups; C (Control), M (Melatonin), R (Radiation), MR (Radiation + Melatonin). Their right legs were exposed to 30 Gy single dose gamma rays. Melatonin (100 mg/kg) was administered 30 min before irradiation and once daily (5 mg/kg) till the day of rats’ sacrifice. Their exposed nerve tissues were evaluated for biochemical changes in addition to Electromyography (EMG) and Nerve Conduction Study (NCS). Results: 4, 12 and 20 weeks post-irradiation, EMG and NCS examinations in R group showed reduced Compound Muscle Action Potential (CMAP) representing axonal degeneration when compared with C and M groups. Prolonged latency and a decrease in Conduction Velocity (CV) gave an indication of demyelinating neuropathy at 12 and 20 weeks. EMG and NCS results of R group showed partial nerve lesion. Biochemical assessments showed that irradiation of sciatic nerve led to increased MDA level, as well as decreased CAT and SOD activities. However, in all cases, treatment with melatonin can reverse these effects. Conclusion: We conclude that melatonin can improve electrophysiological, oxidative stress and antioxidant defense features of irradiated rats’ sciatic nerves. We would also recommend the use of melatonin in an optimal and safe dose. It should be administered over a long period of time for effective protection of the peripheral nerve tissues, as well as improving the therapeutic ratio of radiotherapy.

Background To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes. Methods Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at 6 months. Results The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within 6 months of follow-up at a cutoff of 20 parasites/mL (area under the curve 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ = 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a > 80% power to detect a difference in cure rate between treatment regimens if this difference was high (> 50%) and when minimally 30 patients were included per regimen. Conclusions Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities., Blood Leishmania parasite load, determined by qPCR, is a promising early biomarker to predict relapse in visceral leishmaniasis patients and might particularly be useful in the context of dose finding studies of new chemical entities.

Post–kala-azar dermal leishmaniasis may occur after successful treatment of visceral leishmaniasis and is characterized by macules, papules, or nodules in the skin, with varying size. The response to antileishmanial therapy remains difficult to assess because there are presently no reliable biomarkers. To date, skin lesions are clinically assessed for decrease in size or change in color, which is invariably subjective. Novel 3-dimensional optical scanning devices offer safe and field-adapted methods to objectively assess skin lesions for changes over time in size and color that can be quantified with great accuracy.

Background: In this study, we aimed to detect the changes in the level of interleukin (IL)-4 and IL-13 cytokines and their downstream genes including interleukin-13 receptor subunit alpha-2 (IL13Ra2), interleukin-4 receptor subunit alpha-1 (IL4Ra1), dual oxidase 1 (DUOX1) and dual oxidase 2 (DUOX2). The protective effects of Selenium-L-methionine on radiation-induced histopathological damages and changes in the level of these cytokines and genes were detected. Methods: Four groups of 20 rats (5 rats in each) namely, control; Selenium-L-methionine, radiation and radiation plus Selenium-L-methionine were used in this study. 4 mg/kg of Selenium-Lmethionine was administered 1 day before irradiation and five consecutive days after irradiation. Irradiation was done using a dose of 15 Gy 60Co gamma rays at 109 cGy/min. All rats were sacrificed 10 weeks after irradiation for detecting changes in IL-4 and IL-13 cytokines, the expressions of IL13Ra2, IL4Ra1, Duox1 and Duox2 and histopathological changes. Results: The level of IL-4 but not IL-13 increased after irradiation. This was associated with increased expression of IL4Ra1, Duox1 and Duox2, in addition to changes in morphological properties. Selenium-L-methionine could attenuate all injury markers following lung irradiation. Conclusion: Selenium-L-methionine can protect lung tissues against toxic effects of ionizing radiation. It is possible that the modulation of immune responses and redox interactions are involved in the radioprotective effect of this agent.

Background:Radiotherapy (RT) is a treatment method for cancer using ionizing radiation (IR). The interaction between IR with tissues produces free radicals that cause biological damages.As the largest organ in the human body, the skeletal muscles may be affected by detrimental effects of ionizing radiation. To eliminate these side effects, we used melatonin, a major product secreted by the pineal gland in mammals, as a radioprotective agent.Materials and Methods:For this study, a total of sixty male Wistar rats were used. They were allotted to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). Rats’ right hind legs were irradiated with 30 Gy single dose of gamma radiation, while 100 mg/kg of melatonin was given to them 30 minutes before irradiation and 5 mg/ kg once daily afternoon for 30 days. Five rats in each group were sacrificed 4, 12 and 20 weeks after irradiation for histological and biochemical examinations.Results:Our results showed radiation-induced biochemical, histological and electrophysiological changes in normal rats’ gastrocnemius muscle tissues. Biochemical analysis showed that malondialdehyde (MDA) levels significantly elevated in R group (PConclusion:Melatonin can improve biochemical, electrophysiological and morphological features of irradiated gastrocnemius muscle tissues.Our recommendation is that melatonin should be administered in optimal dose. For effective protection of muscle tissues, and increased therapeutic ratio of radiation therapy, this should be done within a long period of time.

Radiotherapy is a treatment method for cancers using ionizing radiation (IR). Radiotherapy-induced complications to normal tissues have been major drawbacks. One of the strategies for preventing or reducing these side effects is the use of natural radioprotectors such as melatonin. Melatonin is largely secreted in the pineal glands of mammals. Studies have evaluated its radioprotective effect mostly using animal models. However, in this review, we discuss the findings of various clinical studies that utilized melatonin in radiotherapy. Online databases (PubMed, Scopus, Embase, and Google Scholar) and ClinicalTrials.gov were searched to retrieve relevant clinical studies which utilized melatonin alongside radiotherapy. The literature reviewed showed that melatonin administration prevented radiation-induced dermatitis, delayed the onset of oral mucositis, and improved treatment outcomes as well as patients’ quality of life after radiotherapy. These studies reported minimal toxicities from melatonin administration. However, their results were not in agreement in terms of patient survival. The application of melatonin in radiotherapy showed potentials for improving treatment outcomes as well as preventing or ameliorating radiotherapy-induced side effects. We recommend further clinical trials for more insights especially in areas such as optimal melatonin dose and patient survival.

Introduction: Redox interactions play a key role in radiation injury including heart diseases. In present study, we aimed to detect the possible protective role of selenium-L-methionine on infiltration of immune cells and Duox1&2 upregulation in rat’s heart tissues. Methods: In this study, 20 rats were divided into 4 groups (5 rats in each) namely: irradiation; irradiation plus Selenium-L-methionine; control; and Selenium-L-methionine treatment. Irradiation (15 Gy to chest) was performed using a cobalt-60 gamma ray source while 4 mg/kg of selenium-L-methionine was administered intraperitoneally. Ten weeks after irradiation, rats were sacrificed for detection of IL-4 and IL-13 cytokines, infiltration of macrophages and lymphocytes as well as the expressions of IL4Ra1, Duox1, IL13Ra2 and Duox2. Results: Results showed an increase in the level of IL-4 as well as the expressions of IL4Ra1, Duox1 and Duox2. Similarly, there was an increase in the infiltration of lymphocytes and macrophages. There was significant attenuation of all these changes following treatment with selenium-L-methionine. Conclusion: Selenium-L-methionine has the potential to protect heart tissues against radiation injury. Downregulation of pro-oxidant genes and modulation of some cytokines such as IL-4 are involved in the radioprotective effect of selenium-L-methionine on heart tissues.

Background:Radiotherapy is one of the treatment methods for cancers using ionizing radiations. About 70% of cancer patients undergo radiotherapy. Radiation effect on the skin is one of the main complications of radiotherapy and dose limiting factor. To ameliorate this complication, we used melatonin as a radioprotective agent due to its antioxidant and anti-inflammatory effects, free radical scavenging, improving overall survival after irradiation as well as minimizing the degree of DNA damage and frequency of chromosomal abrasions.Methods:Sixty male Wistar rats were randomly assigned to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). A single dose of 30 Gy gamma radiation was exposed to the right hind legs of the rats while 40 mg/ml of melatonin was administered 30 minutes before irradiation and 2 mg/ml once daily in the afternoon for one month till the date of rat’s sacrifice. Five rats from each group were sacrificed 4, 12 and 20 weeks after irradiation. Afterwards, their exposed skin tissues were examined histologically and biochemically.Results:In biochemical analysis, we found that malondialdehyde (MDA) levels significantly increased in R group and decreased significantly in M and MR groups after 4, 12, and 20 weeks, whereas catalase (CAT) and superoxide dismutase (SOD) activities decreased in the R group and increased in M and MR groups during the same time periods compared with the C group (p0.05) at 4 and 20 weeks except for inflammation and hair follicle atrophy, while there were significant effects at 12 weeks (pConclusion:Melatonin can be successfully used for the prevention and treatment of radiation-induced skin injury. We recommend the use of melatonin in optimal and safe doses. These doses should be administered over a long period of time for effective radioprotection and amelioration of skin damages as well as improving the therapeutic ratio of radiotherapy.

Background: Heart injury is one of the most important concerns after exposure to a high dose of radiation in chest cancer radiotherapy or whole body exposure to a radiation disaster. Studies have proposed that increased level of inflammatory and pro-fibrotic cytokines following radiotherapy or radiation events play a key role in the development of several side effects such as cardiovascular disorders. In the current study, we aimed to evaluate the expression of IL-4 and IL-13 cytokines as well as signaling pathways such as IL4Ra1, IL13Ra2, Duox1 and Duox2. In addition, we detected the possible protective effect of curcumin on the expression of these factors and infiltration of inflammatory cells. Materials and Methods: Twenty rats were divided into 4 groups including control; curcumin treated; radiation; and radiation plus curcumin. After 10 weeks, rats were sacrificed for evaluation of mentioned parameters. Results: Results showed an increase in the level of IL-4 and all evaluated genes, as well as increased infiltration of lymphocytes and macrophages. Treatment with curcumin could attenuate these changes. Conclusion: Curcumin could reduce radiation-induced heart injury markers in rats.

Background:Melatonin is a natural body product that has shown potent antioxidant property against various toxic agents. For more than two decades, the abilities of melatonin as a potent radioprotector against toxic effects of ionizing radiation (IR) have been proved. However, in the recent years, several studies have been conducted to illustrate how melatonin protects normal cells against IR. Studies proposed that melatonin is able to directly neutralize free radicals produced by IR, leading to the production of some low toxic products.Discussion:Moreover, melatonin affects several signaling pathways, such as inflammatory responses, antioxidant defense, DNA repair response enzymes, pro-oxidant enzymes etc. Animal studies have confirmed that melatonin is able to alleviate radiation-induced cell death via inhibiting pro-apoptosis and upregulation of anti-apoptosis genes. These properties are very interesting for clinical radiotherapy applications, as well as mitigation of radiation injury in a possible radiation disaster. An interesting property of melatonin is mitochondrial ROS targeting that has been proposed as a strategy for mitigating effects in radiosensitive organs, such as bone marrow, gastrointestinal system and lungs. However, there is a need to prove the mitigatory effects of melatonin in experimental studies.Conclusion:In this review, we aim to clarify the molecular mechanisms of radioprotective effects of melatonin, as well as possible applications as a radiation countermeasure in accidental exposure or nuclear/radiological disasters.

Background:Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy.Discussion:So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation.Conclusion:In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs.

Background: Epidemiological studies have shown an increased incidence of heart diseases among survivors of Chernobyl disaster as well as Hiroshima and Nagasaki atomic bomb explosion. Similar results were observed for lung and left breast cancer patients. Experimental studies have proposed the chronic upregulation of some pro-inflammatory and pro-fibrotic cytokines. Recent studies have shown that upregulation of pro-oxidant enzymes play a key role in the development of late effects of ionizing radiation such as fibrosis. Interleukin-4 (IL-4) and Interleukin-13 (IL-13) are two important cytokines that have shown ability to induce production of free radicals through dual oxidases (Duox) i.e. Duox1 and Duox2. In this study, we aimed to detect the expression of IL-4 receptor-a1 (IL-4Ra1), IL-13 receptor-a2 (IL-13Ra2), Duox1 and Duox2 genes following irradiation of rat’s heart. In addition, we evaluated the possible role of the combination of curcumin and selenium-L-methionine on the regulation of these genes. Methods: Twenty rats were divided into 4 groups as follows; G1: control; G2: treatment with the combination of curcumin and selenium-L-methionine; G3: radiation; G4: radiation plus treatment with the combination of curcumin and selenium-L-methionine. Rats were sacrificed 10 weeks after irradiation for detecting the expression of IL-4Ra1, IL-13Ra2, Duox1 and Duox2. Results: Results showed that exposure to ionizing radiation caused upregulation of IL-4Ra1 by more than 4-fold as well as Duox1 and Duox2 by more than 5-fold. However, results showed no detectable expression for IL-13Ra2. Treatment with the combination of curcumin and selenium-L-methionine could attenuate the upregulation of all genes. Conclusion: This study has shown that exposing rat’s heart tissues to radiation leads to chronic upregulation of IL-4Ra1, Duox1 and Duox2 as well as pro-oxidant enzymes. Treatment with the combination of curcumin and selenium-L-methionine showed ability to attenuate the upregulation of these genes.

Abstract: Cancer is a chronic disorder that involves several elements of both the tumor and the host stromal cells. At present, the complex relationship between the various factors presents in the tumor microenvironment (TME) and tumor cells, as well as immune cells located within the TME, is still poorly known. Within the TME, the crosstalk of these factors and immune cells essentially determines how a tumor reacts to the treatment and how the tumor can ultimately be destroyed, remain dormant, or develop and metastasize. Also, in TME, reciprocal crosstalk between cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), hypoxia-inducible factor (HIF) intensifies the proliferation capacity of cancer stem cells (CSCs). CSCs are a subpopulation of cells that reside within the tumor bulk and have the capacity to self-renew, differentiate, and repair DNA damage. These characteristics make CSCs develop resistance to a variety of treatments, such as radiotherapy (RT). RT is a frequent and often curative treatment for local cancer which mediates tumor elimination by cytotoxic actions. Also, cytokines and growth factors that are released into TME have been involved in the activation of tumor radioresistance and the induction of different immune cells, altering local immune responses. In this review, we discuss the pivotal role of TME in the resistance of CSCs to RT.

This paper defines a model for University of Khartoum course timetabling problem and explores selection optimization methods. A combination of three selection methods (Random Permutation, Simple Random and Greedy) and three move acceptance methods (Great Deluge, Simulated Annealing and Only Improving Moves) is measured to generate an optimal solution. Greedy-Simulated Annealing combination is found to show the best performance according to the metrics of minimum, maximum and average evaluation function within a short running time.

Background: It has been proposed that increased levels of pro-inflammatory and pro-fibrotic cytokines play a key role in radiation-induced lung injury. Interleukin-4 (IL-4) and IL-13 are two pro-fibrotic cytokines that promote the production of free radicals through stimulation of Duox1 and Duox2. In this experimental study, we aimed to evaluate the expression of IL4Ra1, Duox1, IL13Ra2, and Duox2 genes following rat’s lung irradiation. Objectives: Also, we detected the modulatory effect of a combination of curcumin and L-selenomethionine on the expression of these genes. Methods: Twenty male rats were divided into four groups as G1: control (no treatment or radiation); G2: treatment with a combination of curcumin and L-selenomethionine; G3: radiation; G4: radiation plus a combination of curcumin and L-selenomethionine. sixty-seven days after irradiation, rats were killed for detecting the expression of IL4Ra1, IL13Ra2, Duox1, and Duox2. Results: The results showed no detectable expression for IL13Ra2, while the expression of IL4Ra1, Duox1, and Duox2 was increased. Treatment with a combination of curcumin and L-selenomethionine could attenuate the expression of these genes. Conclusions: This study proposes that upregulation of Duox1 and Duox2 may be involved in radiation-induced lung injury. Treatment with a combination of curcumin and L-selenomethionine may be useful for the mitigation of lung injury through modulation of these genes.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway., Graphical abstract, Post-kala-azar dermal leishmaniasis (PKDL) is a chronic parasitic disease with limited treatment options. Here, Musa and colleagues report on a phase IIa therapeutic trial of the adenoviral-vectored leishmaniasis vaccine ChAd63-KH. Single-dose vaccination with ChAd63-KH was safe and induced innate and T cell responses in Sudanese patients with PKDL.

Background: The spermatogenesis system includes highly radiosensitive cells. Hence, this system is a potential target for toxic effects of ionizing radiation during radiotherapy of abdomen and pelvis cancers, as well as after accidental radiation events. Accordingly, metformin and melatonin are two important radioprotectors that have shown an ability to prevent cell death through neutralization of free radicals and stimulating DNA damage responses. Objective: To evaluate the radioprotective effects of melatonin and metformin on mice spermatogenesis when administered alone or as a combination. Materials and Methods: In this histological Study, 40 (6-8 wk, 30 gr) NMRI mice were divided into 8 groups (n = 5/each) as control, metformin, melatonin, melatonin + metformin, radiation, radiation + melatonin, radiation + metformin, and radiation + melatonin + metformin. 37 days after the irradiation, the testicular tissues were collected for histological evaluation. Results: Single administration of melatonin could ameliorate effectively radiation toxicity in mice testis. Metformin showed radioprotective effects on some parameters such as the numbers of spermatogonia and mature sperms. Interestingly, the melatonin and metformin combination reversed the reduced number of sperms rather than single drug administration. Conclusion: The combination of melatonin with metformin can protect mice spermatogenesis against ionizing radiation more effectively compared to the single forms of these drugs. Key words: Radiation, Testis, Leydig cells, Melatonin, Metformin, Spermatogenesis.

Post kala azar dermal leishmaniasis (PKDL) is a chronic, stigmatising skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a Phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (NCT02894008) was an open label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration 30 months; range 6 -180 months). Patients received a single intramuscular vaccination of 1×1010 viral particles (v.p.; adults only) or 7.5×1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow up. AmBisome® was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole blood transcriptomics and ELISpot. 7 patients (30.4%) monitored to study completion showed >90% clinical improvement and 6 (25%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomised controlled trial to determine whether these clinical responses were vaccine related and whether ChAd63-KH vaccine has clinical utility is underway.

BackgroundStandard protocols for Pulsed-field gel electrophoresis (PFGE) were adopted and being used in a global scale for surveillance of many bacterial food-borne diseases. Matched PFGE bands are considered regardless of co-migration of different DNA fragments. Molecular epidemiology is turning toward whole genome sequencing (WGS). Although, WGS results can be digested In-silico, PFGE and WGS data are being compared separately. We describe a new image analysis algorithm that enables identification of how many DNA fragments co-migrate during PFGE. We built a database that compare described PFGE results to in-silico obtained digestion models (from WGS). Reliability of the method was assessed in-silico using novel computer simulation approach. From WGS, 1,816 digestion model (DMs) were obtained as recommended by PulseNet international. Simulation codes were designed to predict PFGE profiles when DMs are separated at 5% PFGE resolution in addition to expected co-migration levels.ResultsPFGE simulation has shown that about 35% of DNA fragments co-migrate at 5% PFGE resolution. Similar result was obtained when wet-lab PFGE profiles were analyzed using image analysis algorithm mentioned earlier. When image analysis results were compared to DMs, results returned by geltowgs.uofk.edu database revealed reasonable relatedness to DMs. In terms of number of PFGE typable DNA fragments, 45,517 were typable (representing 46.54% out of 97,801). Previously mentioned typable fragments (in terms of typable sizes) comprised 91.24% of the sum of nucleotides of all chromosomes tested (7.24 billion bp). However, significant variations were shown within and between different digestion protocols.ConclusionsIdentification of co-migration levels will reveal the third dimension of PFGE profiles. This will provide a better way for evaluating isolate relationships. Linking old PFGE results to WGS by means of simulation demonstrated here will provide a chance to link millions of PFGE epidemiological data accumulated during the last 24 years to the new WGS era. Evaluation of population dynamics of pathogenic bacteria will be deeper through space and time. Selection of restriction enzymes for PFGE typing will have a powerful in-silico evaluation tool.